Shahrooz S. Kelishadi

Preemptive CD20+ B cell depletion attenuates cardiac allograft vasculopathy in cyclosporine-treated monkeys

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 (alphaCD20) rituximab depleted CD20+ B cells in peripheral blood, secondary lymphoid organs, and the graft in cynomolgus monkey recipients of heterotopic cardiac allografts. Furthermore, CD20+ B cell depletion therapy combined with the calcineurin inhibitor cyclosporine A (CsA) prolonged median primary graft survival relative to treatment with alphaCD20 or CsA alone. In animals treated with both alphaCD20 and CsA that achieved efficient B cell depletion, alloantibody production was substantially inhibited and the CAV severity score was markedly reduced. We conclude therefore that efficient preemptive depletion of CD20+ B cells is effective in a preclinical model to modulate pathogenic alloimmunity and to attenuate chronic rejection when used in conjunction with a conventional clinical immunosuppressant. This study suggests that use of this treatment combination may improve the efficacy of transplantation in the clinic.

Alloimmunity in Primate Heart Recipients with Cd154 Blockade: Evidence for Alternative Costimulation Mechanisms

Background. CD154 mediates key facets of humoral and cellular immunity to alloantigens, and is tolerogenic to influenza antigens in primates. Barriers to CD154-based tolerance induction for primate cardiac allografts have not previously been defined. Methods. Heterotopic cardiac allograft outcomes in cynomolgus monkeys treated with a CD154 inhibitor, IDEC-131 (n=27), were compared to no treatment (n=4) or cyclosporine A (n=6). Results. CD154 blockade significantly prolonged median allograft survival, from 6.2 (range 6, 7, n=4) days in untreated controls, to 39 (8,112, n=16) days with intensive monotherapy and 93 (>25, 386; n=3) days with added antithymocyte globulin (ATG), but did not yield tolerance. Alloantibody production was delayed but not prevented by IDEC-131 alone or with ATG, and was exacerbated by infusion of donor bone marrow (n=8). Expression of ICOS was prominent in graft infiltrating lymphocytes, and preceded elaboration of antidonor antibody and vasculopathy. Conclusion. CD154 monotherapy modulates primate cardiac alloimmunity, but does not readily induce tolerance. Targeting alternative costimulation pathways, including ICOS, may facilitate tolerance induction based on CD154 blockade.

Significant predictors of complications after sternal wound reconstruction: a 21-year experience.

BackgroundWe sought to identify patient comorbidities that predict complications after tissue flap sternal reconstruction. MethodsA retrospective study, December 1989 to December 2010, analyzed numerous comorbidities, including diabetes mellitus (DM), hypertension (HTN), coronary artery disease, congestive heart failure (CHF), and renal insufficiency, as independent risk factors for postoperative complications. Pearson &khgr;2 test, Fisher exact test, 2-sample t test, and median-unbiased estimation were used for data analysis. Significance was P ⩽ 0.05. ResultsIn all, 106 patients received 161 sternal tissue flap repairs. Nineteen patients (18%) required reoperation because of complications, including recurrent wound infection, tissue necrosis, wound dehiscence, mediastinitis, and hematoma formation. Our analysis found DM, HTN, and CHF as significant predictors of complications after sternal reconstruction (P = 0.014, 0.012, and 0.006). ConclusionsResults suggest DM, HTN, and CHF may contribute to complications after tissue flap repair of sternal wounds, possibly through impaired perfusion and healing of repairs.

Pectoralis major turnover versus advancement technique for sternal wound reconstruction.

BackgroundWe compared the efficacy of pectoralis turnover versus advancement technique for sternal wound reconstruction. MethodsA retrospective chart review was performed, December 1989 to December 2010, to compare postoperative complication rates between pectoralis major turnover versus pectoralis major advancement reconstruction techniques. Complications included hematomas, wound infections, tissue necrosis, dehiscence, and need for reoperation. Pearson &khgr;2 and logistic regression were used and significance was P < 0.05. ResultsSixty-seven patients received 91 tissue flaps. Eleven patients (16%) required reoperation due to complications, including recurrent wound infection, tissue necrosis, wound dehiscence, mediastinitis, and hematoma formation. Four patients (6%) were treated conservatively for minor complications. Overall, complication rates were significantly higher after pectoralis major advancement reconstruction (32.5% vs. 3.7%, P = 0.004). ConclusionsWhen feasible, pectoralis major turnover flap offers a superior reconstructive technique for complex sternal wounds, with diminished complications compared with the pectoralis advancement flap.

Preemptive CD20+ B cell Depletion Attenuates Cardiac Allograft Vasculopathy in CD154-Treated Monkeys.

Background Anti-CD154 monotherapy is associated with antidonor allo-antibody (Ab) elaboration, cardiac allograft vasculopathy (CAV), and allograft failure in preclinical primate cell and organ transplant models. In the context of calcineurin inhibitors (CNI), these pathogenic phenomena are delayed by preemptive “induction” B cell depletion. Methods &agr;CD154 (IDEC-131)–treated cynomolgus monkey heart allograft recipients were given peritransplant rituximab (&agr;CD20) alone or with rabbit antihuman thymocyte globulin. Results Relative to previously reported reference groups, &agr;CD20 significantly prolonged survival, delayed Ab detection, and attenuated CAV within 3 months in &agr;CD154-treated recipients (&agr;CD154 + &agr;CD20 graft median survival time > 90 days, n = 7, vs 28 days for &agr;CD154 alone (IDEC-131), n = 21; P = 0.05). Addition of rabbit antihuman thymocyte globulin to &agr;CD154 (n = 6) or &agr;CD154 + &agr;CD20 (n = 10) improved graft protection from graft rejection and failure during treatment but was associated with significant morbidity in 8 of 16 recipients (6 infections, 2 drug-related complications). In &agr;CD20-treated animals, detection of antidonor Ab and relatively severe CAV were anticipated by appearance of CD20+ cells (>1% of lymphocytes) in peripheral blood and were associated with low &agr;CD154 trough levels (below 100 &mgr;g/mL). Conclusions These observations support the hypothesis that efficient preemptive “induction” CD20 B cell depletion consistently modulates pathogenic alloimmunity and attenuates CAV in this translational model, extending our prior findings with calcineurin inhibitors to the context of CD154 blockade.

Facial Fracture Patterns Associated with Traumatic Optic Neuropathy

Traumatic optic neuropathy (TON) is rare. The heterogeneity of injury patterns and patient condition on presentation makes diagnosis difficult. Fracture patterns associated with TON have never been evaluated. Retrospective review of 42 patients diagnosed with TON at the R. Adams Cowley Shock Trauma Center from May 1998 to August 2010 was performed. Thirty-three patients met criteria for study inclusion of fracture patterns. Additional variables measured included patient demographics and mechanism. Cluster analysis was used to form homogenous groups of patients based on different fracture patterns. Fracture frequency was analyzed by group and study population. Visual depiction of fracture patterns was created for each group. Cluster analysis of fracture patterns yielded five common “groups” or fracture patterns among the study population. Group 1 (n = 3, 9%) revealed contralateral lateral orbital wall (100%), zygoma (67%), and nasal bone (67%) fractures. Group 2 (n = 7, 21%) demonstrated fractures of the frontal bone (86%), nasal bones (71%), and ipsilateral orbital roof (57%). Group 3 (n = 14, 43%) involved fractures of the ipsilateral zygoma (100%), lateral orbital wall (29%), as well as frontal and nasal bones (21% each). Group 4 (n = 5, 15%) consisted of mid- and upper-face fractures; 100% fractured the ipsilateral orbital floor, medial and lateral walls, maxilla, and zygoma; 80% fractured the orbital roof and bilateral zygoma. Group 5 (n = 4, 12%) was characterized by fractures of the ipsilateral orbital floor, medial and lateral orbital walls (75% each), and orbital roof (50%). A notably high 15 of 33 patients (45%) sustained penetrating trauma. Our study demonstrates five fracture pattern groups associated with TON. Zygomatic, frontal, nasal, and orbital fractures were the most common. Fractures with a combination of frontal, nasal, and orbital fractures are particularly concerning and warrant close attention to the eye.

Pectoralis Major Turnover Versus Advancement Flap for Sternal Wound Reconstruction: A 21-Year Experience

concluSIon: DIEP flaps appear to be as profitable as pTRAM flaps with lower morbidity. The transition from pTRAM to perforator flaps can be done successfully with well-trained microsurgeons, an already established breast reconstruction practice, and support from leadership and hospital staff. We believe that the development of a perforator flap practice represents an opportunity cost in optimizing patient care, and should be an option available to patients seeking autologous breast reconstruction. Pectoralis Major Turnover Versus Advancement Flap for Sternal Wound reconstruction: A 21-year Experience