Papers by Tiffany Stoddard
Background and Objectives: Symptomatic hydrocephalus is a surprisingly common clinical condition.... more Background and Objectives: Symptomatic hydrocephalus is a surprisingly common clinical condition. Neurosurgeons are expert at ventriculostomy, but minimally invasive peritoneal access is outside the realm of their current training. We have adopted a multidisciplinary approach, with general surgeons positioning the distal shunt. Our objective was to review this recent experience. Methods: All distal shunts were placed by a single surgeon with resident assistance. After ventriculostomy, the shunt tubing was tunneled onto the anterior abdominal wall. A Veress needle was placed through the tunnel incision and the abdomen insufflated. A 5-mm optical access trocar and camera were introduced via a separate stab incision. The shunt tubing was then directed into the
Transplantation Journal, 2010
American Journal of Transplantation
Xenotransplantation, Jan 14, 2015
We describe the incidence of early graft failure (EGF, defined as loss of function from any cause... more We describe the incidence of early graft failure (EGF, defined as loss of function from any cause within 3 days after transplant) in a large cohort of GalTKO pig organs transplanted into baboons in three centers, and the effect of additional expression of a human complement pathway-regulatory protein, CD46 or CD55 (GalTKO.hCPRP). Baboon recipients of life-supporting GalTKO kidney (n = 7) or heterotopic heart (n = 14) grafts received either no immunosuppression (n = 4), or one of several partial or full immunosuppressive regimens (n = 17). Fourteen additional baboons received a GalTKO.hCPRP kidney (n = 5) or heart (n = 9) and similar treatment regimens. Immunologic, pathologic, and coagulation parameters were measured at frequent intervals. EGF of GalTKO organs occurred in 9/21 baboons (43%). hCPRP expression reduced the GalTKO EGF incidence to 7% (1/14; P < 0.01 vs. GalTKO alone). At 30 mins, complement deposits were more intense in organs in which EGF developed (P < 0.005). T...
Xenotransplantation, 2010
IntroductionHyperacute (HAR) and delayed xenograft (DXR) rejection are well defined barriers foll... more IntroductionHyperacute (HAR) and delayed xenograft (DXR) rejection are well defined barriers following discordant transplantation of porcine organs into primate recipients. Significant progress has been made in recent years to overcome these immunological barriers, based on the development of pigs genetically modified to reduce immunogenicity: [1,2] A major step has been the generation of pigs lacking expression of Gala1,3Gal (GalTKO), the principal carbohydrate target of human anti-pig antibody. [3,4] However, both in vitro and in vivo studies demonstrated that non-gal antibodies have the ability to activate endothelial cells, and thus, amplify procoagulant molecular incompatibilities between pig and primate.[5,6] Based on our prior work with pigs expressing the Gal epitope, we tested the hypothesis that over-expression of human complement regulatory proteins (hCRP) and/or blockade of the CD154/CD40 costimulation pathway will result in reduced graft injury, anti-pig responses and coagulation dysregulation. Briefly, twenty two organs (13 hearts, 9 kidneys) from GalT-KO pigs (9 expressing hCRP) were transplanted into baboons that received no immunosuppressive therapy, or a therapeutic regimen based on costimulation blockade. The incidence of HAR was decreased in GalTKO organs expressing hCRP as compared to GalTKO. Pre-transplant anti-non-Gal antibody titers were inconsistently associated with early GalT-KO xenograft failure. In contrast, coagulation cascade activation and platelet activation correlated closely with incidence of HAR of GalTKO organs. Strong elicited anti-non-gal antibody responses were detected after transplantation of a GalTKO organ. Delayed xenograft rejection was associated with coagulation dysregulation and elicited anti-non-gal antibody production. Future work in xenotransplantation should place emphasis on further targeting of anti-non gal humoral immune responses and inhibiting coagulation activation. References 1. Pierson RN III. JAMA 2009; Current status of xenotransplantation. 30: 967–969. 2. Cooper DK, Dorling A, Pierson RN III, et al. Alpha1,3-galactosyltransferase gene-knockout pigs for xenotransplantation: where do we go from here? Transplantation 2007; 84: 1–7. 3. Yamada K, Yazawa K, Shimizu A, et al. Marked prolongation of porcine renal xenograft survival in baboons through the use of alpha1,3-galactosyltransferase gene-knockout donors and the cotransplantation of vascularized thymic tissue. Nat Med 2005; 11: 32–34. 4. Kuwaki K, Tseng YL, Dor FJ, et al. Heart transplantation in baboons using alpha1,3-galactosyltransferase gene-knockout pigs as donors: initial experience. Nat Med 2005; 11: 29–31. 5 Saethre M, Baumann BC, Fung M, Seebach JD, Mollnes TE. Characterization of natural human anti-non-gal antibodies and their effect on activation of porcine gal-deficient endothelial cells. Transplantation. 2007; 84: 244–250. 6. Hisashi Y, Yamada K, Kuwaki K, et al. Rejection of cardiac xenografts transplanted from alpha1,3-galactosyltransferase gene-knockout (GalT-KO) pigs to baboons. Am J Transplant. 2008; 8: 2516–2526.
Transplantation, 2008
Over 50% of clinical cardiac allograft recipients develop cardiac allograft vasculopathy (CAV). P... more Over 50% of clinical cardiac allograft recipients develop cardiac allograft vasculopathy (CAV). Peri-transplant depletion of B-cells might inhibit chronic rejection by reducing the precursor pool for anti-donor antibodyproducing plasma cells or by blunting antigen presentation to donor-specifi c T-helper cells. Methods: Thirteen cynomologus monkeys received MLR-mismatched heterotopic cardiac allografts and "therapeutic" cyclosporine (CsA: target trough >500ng/ml); fi ve also received anti-CD20 therapy (á-CD20: 20mg/kg IV on days 0, 7, 14, and 21). Anti-donor alloantibody was quantifi ed by fl ow cytometry. Surviving grafts were censored at 90 days. Results: Three animals (2 with CsA alone and one with CsA+áCD20) were excluded from analysis with beating grafts due to non-immune related complications. Primary graft survival with CsA+áCD20 (median >90d) and proportion of grafts surviving to 90 days (4/4) was increased relative to CsA alone (median 71d, 3/6 >90d; p=0. 035). CsA+áCD20 inhibited CAV (median CAV score 0. 2; range 0. 1-0. 34) relative to CsA alone (median 2. 1; range 1. 5-2. 4; p=0. 0013). Anti-donor alloantibody was detected in a minority of animals in either treatment group. Conclusions: When used with a dose of conventional CsA immunosuppression that is "therapeutic" in this species, depletion of CD20+ B cells at the time of engraftment attenuates chronic rejection (as CAV) and signifi cantly decreases the incidence of graft loss. Interestingly, attenuation of CAV occurred independent of a measurable effect on anti-donor antibody incidence or titer. This approach to attenuate CAV could be readily evaluated in the clinic. Whether synergy exists (effi cacy with reduced CsA exposure/toxicity) and durability of the effect as B-cells recover over longer follow-up remain to be determined.
Transplantation, 2008
MONDAY levels of baboon TF mRNA. Conclusions: Irrespective of the presence or absence of the adap... more MONDAY levels of baboon TF mRNA. Conclusions: Irrespective of the presence or absence of the adaptive immune response, the development of AHXR is associated with the expression of TF on recipient monocytes and platelets. TF expression by innate immune cells of the recipient may be a major procoagulant factor that contributes to the development of TM. Pigs transgenic for tissue factor pathway inhibitor (TFPI) should have advantages in preventing AHXR.
Journal of the American College of Surgeons, 2008
Journal of Surgical Research, 2008
our inclusion criteria. 707 pts. were bridged to OHTx with a MCS device. Short-and long-term surv... more our inclusion criteria. 707 pts. were bridged to OHTx with a MCS device. Short-and long-term survival was significantly better in the OHTx group than in the HHTx group (PϽ0.001). 1-, 5-, 10-year survival was 88%, 77%, 67% and 82%, 58%, 42%, respectively. Pre-HTx transpulmonary gradient was significantly higher (Pϭ0.001) in the HHTx than in the OHTx group (12.2 Ϯ 7.0 vs. 9.6 Ϯ 6.3). Pre-HTx cardiac output was significantly higher (PϽ0.001) in the HHTx than in the OHTx group (4.3 Ϯ 1.4 vs. 4.1 Ϯ 1.4). There was no significant difference in age, BMI, creatinine or post-Tx hospital days stay between the groups. Conclusions: HHTx is rarely used with overall survival rates that are inferior to OHTx. However, it remains a viable option in patients who do not qualify for OHTx, due to size mismatch or an increased transpulmonary gradient. With a 1-year survival rate of 82%, it still exceeds the results achieved with left ventricular assist devices as destination treatment (REMATCH-trial/1-year survival of 52%). Hence, after 3 decades of experience with HHTx, it remains part of our armentarium to treat a specific and highly selected patient population with end-stage heart failure.
Journal of Surgical Research, 2008
JSLS : Journal of the Society of Laparoendoscopic Surgeons, 2011
Background and Objectives: Symptomatic hydrocephalus is a surprisingly common clinical condition.... more Background and Objectives: Symptomatic hydrocephalus is a surprisingly common clinical condition. Neurosurgeons are expert at ventriculostomy, but minimally invasive peritoneal access is outside the realm of their current training. We have adopted a multidisciplinary approach, with general surgeons positioning the distal shunt. Our objective was to review this recent experience. Methods: All distal shunts were placed by a single surgeon with resident assistance. After ventriculostomy, the shunt tubing was tunneled onto the anterior abdominal wall. A Veress needle was placed through the tunnel incision and the abdomen insufflated. A 5-mm optical access trocar and camera were introduced via a separate stab incision. The shunt tubing was then directed into the abdominal cavity using a Hickman introducer kit, with flow confirmed visually. Results: Study patients who had between 0 and 10 previous abdominal operations received 111 consecutive shunts. There was one intraoperative complication, a colon injury during trocar placement. In this case, the colotomy was repaired and the shunt placed in the pleural space. There were no conversions to the open abdominal approach. Postoperatively, there were no wound infections, no cases of shunt malpositioning, and there were no deaths. Conclusions: Laparoscopic placement of ventriculoperitoneal shunts is feasible, safe, and carries a low rate of complications. The value to resident education in the practice of this procedure has not been previously emphasized. In the era of increased awareness of patient safety, laparoscopic VP shunting serves as a model for accomplishing both goals of improved outcomes and quality surgical education.
The Journal of Heart and Lung Transplantation, 2008
Purpose: Chronic illness and traumatic medical and surgical treatment may result in elevated leve... more Purpose: Chronic illness and traumatic medical and surgical treatment may result in elevated levels of distress and stress in parents but to date little research has been carried out into the stress experienced by parents of paediatric heart transplant (Tx) recipients. Methods and Materials: Parents of 81 recipients (70 heart, 6 bilateral lung, 5 heart-lung) aged 6 months to 18 years completed measures of psychological distress and illness-related parenting stress 3 months to 15 years (median 3 years) after Tx, at either a routine clinic visit or annual review. Results: One third of mothers and 25% of fathers obtained scores indicative of significant psychological distress. Mothers of children with a pre-Tx diagnosis of cardiomyopathy (CM) had higher levels of distress (33%) than mothers of children with congenital heart disease (CHD) (15%), although the groups did not differ in terms of time since
The Journal of Heart and Lung Transplantation, 2008
Purpose: Mycophenolate mofetil (MMF), through its active metabolite mycophenolic acid (MPA), inhi... more Purpose: Mycophenolate mofetil (MMF), through its active metabolite mycophenolic acid (MPA), inhibits purine biosynthesis and is an effective immunosuppressent but has frequent adverse events (AE). Genetic polymorphisms (GP) may contribute to variability in efficacy and AE. We hypothesized that multidrug resistance protein 2 (MRP2) and inosine 5'-monophosphate dehydrogenase 1 and 2 (IMPDH1, IMPDH2) GPs may influence AE. Methods and Materials: 61 pediatric heart recipients who received MMF were included. 56/61 received tacrolimus with MMF. AE data was obtained by Tx database and chart review. GI intolerance was defined as diarrhea, vomiting, nausea or abdominal pain requiring dose holding for Ͼ48 hours or MMF discontinuation. Bone marrow toxicity (BMT) was assessed using Common Terminology Criteria for Adverse Events. DNA was obtained from whole blood and genotypes were assessed by Taqman analysis of the following: MRP2 C-24T, IMPDH2 rs11706052 (Intron 7), and IMPDH1 rs2278294 (Intron 7), rs2228075 (Exon 15), and rs2288553 (Intron 1). Statistical analyses were performed using Fisher exact test. Results: GI AE occurred in 36% of patients, and 36% experienced BMT: 3 with grade 3-4 leucopenia, 19 with grade 3-4 neutropenia, 8 requiring dose holding and 4 requiring MMF discontinuation. The MRP2 C-24T SNP was associated with significantly greater GI intolerance leading to drug discontinuation (pϭ0.0001). The IMPDH1 rs228075 T variant was also associated with significantly greater GI AE (pϭ0.0013). The IMPDH2 rs11706052 G variant was associated with more frequent neutropenia requiring dose holding (pϭ0.0410). Conclusions: MRP2 and IMPDH GP may be associated with MMF GI intolerance and BMT. MRP2 is important in enterohepatic recirculation of MPA(G), so its association with GI AE is logical, as is the association of an IMPDH2 GP with neutropenia. The influence of GP on MMF pharmacokinetics, efficacy and AE is being explored further within a large multi-center study.
Journal of Clinical Investigation, 2010
Chronic rejection currently limits the long-term efficacy of clinical transplantation. Although B... more Chronic rejection currently limits the long-term efficacy of clinical transplantation. Although B cells have recently been shown to play a pivotal role in the induction of alloimmunity and are being targeted in other transplant contexts, the efficacy of preemptive B cell depletion to modulate alloimmunity or attenuate cardiac allograft vasculopathy (CAV) (classic chronic rejection lesions found in transplanted hearts) in a translational model has not previously been described. We report here that the CD20-specific antibody (aCD20) rituximab depleted CD20 + B cells in peripheral blood, secondary lymphoid organs, and the graft in
American Journal of Transplantation, 2014
Evaluation of lungs from GalTKO.hCD46 pigs, genetically modified to lack the galactose-a(1,3)-gal... more Evaluation of lungs from GalTKO.hCD46 pigs, genetically modified to lack the galactose-a(1,3)-galactose epitope (GalTKO) and to express human CD46, a complement regulatory protein, has not previously been described. Physiologic, hematologic and biochemical parameters during perfusion with heparinized fresh human blood were measured for 33 GalTKO. hCD46, GalTKO (n ¼ 16), and WT pig lungs (n ¼ 16), and 12 pig lungs perfused with autologous pig blood. Median GalTKO.hCD46 lung survival was 171 min compared to 120 for GalTKO (p ¼ 0.27) and 10 for WT lungs (p < 0.001). Complement activation, platelet activation and histamine elaboration were significantly reduced during the first 2 h of perfusion in GalTKO. hCD46 lungs compared to GalTKO (DC3a at 120 0 812 AE 230 vs. 1412 AE 1047, p ¼ 0.02; DCD62P at 120 0 9.8 AE 7.2 vs. 25.4 AE 18.2, p < 0.01; Dhistamine at 60 0 97 AE 62 vs. 189 AE 194, p ¼ 0.03). We conclude that, in addition to significant down-modulation of complement activation, hCD46 expression in GalTKO lungs diminished platelet and coagulation cascade activation, neutrophil sequestration and histamine release. Because GalTKO.hCD46 lung failure kinetics correlated directly with platelet and neutrophil sequestration, coagulation cascade activation and a rise in histamine levels within the first hour of perfusion, further progress will likely depend upon improved control of these pathways, by rationally targeted additional modifications to pigs and pharmacologic interventions.
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Papers by Tiffany Stoddard