Effect of Cyclooxygenase Inhibition on Peripheral Venous Distension Reflex in Healthy Humans.

BACKGROUND: Peripheral venous distension evokes a pressor reflex (venous distension reflex). Afferent group III and IV nerves innervating veins are suggested as the afferent arm of the venous distension reflex. Prostaglandins stimulate/sensitize group III/IV nerves. We hypothesized that inhibition of prostaglandin synthesis by local cyclooxygenase blockade would attenuate the muscle sympathetic nerve activity (MSNA) and blood pressure responses to venous distension. METHODS: Nineteen healthy volunteers (age, 27±5 years) participated in the study with 2 visits. To induce venous distension, a volume of solution (saline alone or 9 mg ketorolac tromethamine in saline) was infused into the vein in the antecubital fossa of an arterially occluded forearm. During the procedure, beat-by-beat heart rate, blood pressure and MSNA were recorded simultaneously. The vein size was measured with ultrasound. RESULTS: In both visits, the venous distension procedure significantly increased blood pressure, heart rate, and MSNA (all, P<0.05). The increase in mean arterial pressure and MSNA in the ketorolac visit was significantly lower than in the control visit (∆ mean arterial pressure, 7.0±6.2 versus 13.8±7.7 mm Hg; ∆MSNA, 6.0±7.1 versus 14.8±7.7 bursts/min; both, P<0.05). The increase in vein size induced by the infusion was not different between visits. CONCLUSIONS: The presented data show that cyclooxygenase blockade attenuates the responses in MSNA and blood pressure to peripheral venous distension reflex. The results suggest that cyclooxygenase products play a key role in evoking afferent activation responsible for the venous distension reflex.

Stoma-less IPAA Is Not Associated With Increased Anastomotic Leak Rate or Long-term Pouch Failure in Patients With Ulcerative Colitis.

BACKGROUND: There is debate regarding the utility of diverting loop ileostomy with IPAA construction in patients requiring colectomy for ulcerative colitis. OBJECTIVE: This study aimed to determine whether the omission of diverting loop ileostomy at the time of IPAA construction increases the risk of complications. DESIGN: This was a retrospective study. SETTINGS: The study was conducted in a high-volume, quaternary referral center with an IBD program. PATIENTS: The patients, who underwent IPAA with or without ileostomy, were diagnosed for ulcerative colitis. MAIN OUTCOME MEASURES: Anastomotic leak rate and pouch failure rates were determined between patients who either had a diverting ileostomy at the time of IPAA creation or had stoma-less IPAA. RESULTS: Of the 414 patients included in this study, 91 had stoma-less IPAA. When compared to IPAA with diverting loop ileostomy, patients with stoma-less IPAA were less likely to be taking prednisone and had decreased blood loss. Short- and long-term outcomes were similar when comparing stoma-less IPAA and IPAA with diverting loop ileostomy, with no significant difference in anastomotic leak rate and long-term pouch failure rates. Diverting loop ileostomy was associated with a 14.6% risk of complication at the time of stoma reversal. LIMITATIONS: The study is limited by its retrospective nature. CONCLUSIONS: The results of this study suggest that the omission of a diverting ileostomy is feasible in select patients undergoing IPAA. Stoma-less IPAA does not have a statistically significant higher risk of anastomotic leak or pouch failure when compared to IPAA with diverting loop ileostomy in properly selected patients. Diverting loop ileostomies have their own risks, which partially offset their perceived safety. See Video Abstract at http://links.lww.com/DCR/B891 .LA ANASTOMÓSIS DE RESERVORIO ILEAL AL ANO SIN ESTOMA NO ESTÁ ASOCIADO CON UN AUMENTO EN LA TASA DE FUGA ANASTOMÓTICA O DISFUNCIÓN DE LA BOLSA A LARGO PLAZO EN PACIENTES CON COLITIS ULCERATIVA. ANTECEDENTES: Existe debate en lo que respecta a la utilidad de efectuar una ileostomía en asa en la construcción de una anastomosis de reservorio ileal al ano en pacientes que requieren colectomía para colitis ulcerativa. OBJETIVO: Determinar si el evitar una ileostomía de derivación en el momento de efectuar una anstomósis de reservorio ileal al ano aumenta el riesgo de complicaciones. DISEO: Estudio retrospectivo. REFERENCIA: Centro de referencia de cuarto nivel de grandes volúmenes con programa de enfermedad inflamatoria intestinal. PACIENTES: Con diagnóstico de colitis ulcerativa sometidos a anastomosis de reservorio ileal al ano con o sin ileostomía derivative. PRINCIPALES MEDIDAS DE RESULTADOS: Tasa de fuga anastomótica y disfunción del reservorio en pacientes sometidos a anastomosis de reservorio ileal al ano con ileostomía derivativa en el mismo evento y aquellos sin derivación de protección. RESULTADOS: De los 414 pacientes incluídos en el estudio, 91 no contaban con ileostomía de protección de la anastomosis del reservorio ileal al ano. Al comprarse con aquellos con ileostomía derivativa, aquellos sin estoma requirieron menor dosis de prednisona y presentaron menor pérdida sanguínea. Los resultados a corto y largo plazo fueron similares al comprar ambos grupos sin haber evidencia significativa de fuga anastomótica o falla del reservorio a largo plazo. La derivación con ileostomía en asa se asoció en un 14.6% de riesgo de complicaciones al efectuar el cierre de la misma. LIMITACIONES: Es una revision retrospectiva. CONCLUSIONES: : Los resultados de este estudio sugieren que la omisión de una ileostomía de protección es posible en pacientes seleccionados sometidos a una anastomosis de reservorio ileoanal. La anastomosis sin derivación de protección no confiere un riesgo estadísticamente significativo de fuga anastomótica o disfunción de la misma al compararse con el procedimiento con estoma derivativo en pacientes seleccionados. Las ileostomías de derivación en asa tienen su propia morbilidad que cuestiona la perfección de su seguridad. Consulte Video Resumen at http://links.lww.com/DCR/B891 . (Traducción- Dr. Miguel Esquivel-Herrera ).

A Comparison of Anticoagulation Strategies in Veno-venous Extracorporeal Membrane Oxygenation.

Bleeding remains a major source of morbidity associated with veno-venous extracorporeal membrane oxygenation (VV-ECMO). Moreover, there remains significant controversy, and a paucity of data regarding the ideal anticoagulation strategy for VV-ECMO patients. All patients undergoing isolated, peripheral VV-ECMO between January 2009 and December 2014 at our institution were retrospectively reviewed. Patients (n = 123) were stratified into one of three sequential eras of anticoagulation strategies: activated clotting time (ACT: 160-180 seconds, n = 53), high-partial thromboplastin time (H-PTT: 60-80 seconds, n = 25), and low-PTT (L-PTT: 45-55 seconds, n = 25) with high-flow (>4 L/min). Pre-ECMO APACHE II scores, SOFA scores, and Murray scores were not significantly different between the groups. Patients in the L-PTT group required less red blood cell units on ECMO than the ACT or H-PTT group (2.1 vs. 1.3 vs. 0.9; p < 0.001) and patients in the H-PTT and L-PTT group required less fresh frozen plasma than the ACT group (0.33 vs. 0 vs. 0; p = 0.006). Overall, major bleeding events were significantly lower in the L-PTT group than in the ACT and H-PTT groups. There was no difference in thrombotic events. In this single-institution experience, a L-PTT, high-flow strategy on VV-ECMO was associated with fewer bleeding and no difference in thrombotic events than an ACT or H-PTT strategy.

Carotid artery duplex velocity criteria might be equivocal after left ventricular assist device implantation.

BACKGROUND: Although conventional angiography remains the reference standard for the grading of carotid stenosis, carotid duplex ultrasound (CDUS) is the most commonly used modality for determining the degree of carotid stenosis. The validity of CDUS findings for patients after left ventricular assist device (LVAD) implantation is questionable, because the velocities are often altered secondary to the continuous flow nature of the devices. METHODS: A retrospective review was performed of all patients who had undergone LVAD implantation from January 2007 to December 2019. All patients who had undergone CDUS before and after LVAD implantation were included. Patients receiving extracorporeal membrane oxygenation, those with unusable carotid imaging studies, and those with internal carotid artery (ICA) occlusion were excluded. The peak systolic velocity (PSV) and end-diastolic velocity (EDV) in the ICA and common carotid artery (CCA) and the ICA/CCA ratios were compared before and after LVAD implantation. RESULTS: A total of 36 patients (mean age 59 years; 30 men; 6 women) had undergone CDUS both before and after LVAD implantation (mean, 647 days between imaging studies). A total of 61 ICAs had met the criteria for inclusion. Before LVAD, 7 carotid arteries (13%) had had >50% carotid stenosis and 53 (87%) had had 0% to 50% stenosis. The mean changes in the velocities after LVAD were as follows. The ICA PSV had decreased by 6.12 ± 4.34 cm/s, and the ICA EDV had increased by 13.44 ± 4.23 cm/s. The CCA PSV had decreased by 17.22 ± 4.95 cm/s, and the CCA EDV had increased by 10.83 ± 2.59 cm/s. The mean ICA/CCA ratio had increased by 0.18 ± 0.05. All the mean changes in velocity were significant (P < .01), except for the ICA PSV (P = .167). Among four patients with known stenosis of 60% to 69%, the degree of increase in the ICA and CCA EDVs (75.8 and 13.3 cm/s, respectively) was significantly greater than that for patients with <50% or no stenosis. Carotid artery laterality did not significantly affect the differences in mean velocity. Centrifugal LVADs resulted in a significantly larger increase in the ICA EDV compared with axial LVADs (26.0 vs 6.3 cm/s; P < .01). CONCLUSIONS: LVADs were associated with significant changes in CCA PSV, ICA and CCA EDV, and ICA/CCA ratios. However, the magnitude of these changes in patients with <50% stenosis was minimal and might not be clinically significant. The LVAD type might only have an effect on EDV measurements in the CCA, and the left and right carotid arteries did not appear to have different degrees of change in velocity. The currently used criteria for determining carotid stenosis might result in an under- or overestimation of carotid stenosis in patients with an LVAD.

Lymphatic malformations: a 20-year single institution experience.

PURPOSE: Lymphatic malformations (LMs) are congenital abnormalities which result from disturbances in the embryologic development of the lymphatic system. We sought to determine the characteristics and treatment patterns for LMs in a rural setting, and the effect of a specialized vascular malformations clinic on triage and follow-up. METHODS: This is a retrospective cohort study at a single tertiary care institution. Sixty-two patients were identified; chart review was completed to obtain demographic, surgery/sclerotherapy session and follow-up information. RESULTS: The head/neck region was the most predominant LM location (N = 26, 41.9%), followed by trunk (N = 16, 25.8%), extremity (N = 11, 17.7%), and intraabdominal/retroperitoneal (N = 7, 11.3%). Twenty-eight patients were managed non-surgically, while 21, 7 and 6 patients required surgery, sclerotherapy, or both. Head/neck LMs were the most likely to recur (73%, p = 0.028). Patients seen in specialty clinic had similar duration of follow-up and time to intervention, but were more often below 1 year of age (p = 0.030). Average LM volume among patients with available imaging was much larger in those referred to specialty clinic (73.2 cm3 versus 14.8 cm3, p = 0.022). CONCLUSION: Our experience reiterates not only the wide variety of clinical presentations of lymphatic malformations, but also demonstrates the necessity of multiple subspecialties and their collaboration to achieve prompt and efficacious treatment.

Immediate postoperative hyperglycemia after peripheral arterial bypass is associated with short-term and long-term poor outcomes.

OBJECTIVE: Although the impact of poorly controlled diabetes on surgical outcomes of patients undergoing lower extremity revascularization is well-known, it is not clear if immediate postoperative hyperglycemia (IPH) itself can be used as a surrogate for poor outcomes after peripheral arterial bypass. We sought to examine the effect of IPH in this patient population with its impact on short-term and long-term outcomes. METHODS: Retrospective review was completed for 505 patients who underwent either suprainguinal bypass surgery or infrainguinal bypass surgery between July 2002 and April 2018 for the treatment of peripheral arterial disease. All patients were undergoing first-time open bypass grafting. Patients were stratified into those who were normoglycemic or hyperglycemic (glucose ≥ 140 mg/dL) within 24 hours after surgery. A comparative analysis was performed on comorbidities and outcomes. RESULTS: Of 505 patients who underwent bypass grafting, 255 patients (50.5%) were hyperglycemic. The mean age of patients was 63.5 ± 14.1 years. The median follow-up was 5.2 years (range, 0.0-15.2 years). The distribution of procedures was as follows: femoral to popliteal bypasses (29%), femoral to femoral bypasses (17%), femoral to tibial bypasses (12%), aortobifemoral bypasses (10%), iliofemoral bypasses (9%), and axillofemoral bypasses (7%). At 30 days, hyperglycemic patients had an increased incidence of limb loss (8.3% vs 4.0%) and myocardial infarction (4.8% vs 0.8%) and incurred higher costs of hospital stay ($27,701 vs $22,990) (all P < .05). At 10 years, these patients had a higher incidence of needing major amputations (15.4% vs 9.4%; P = .025). Hyperglycemia after infrainguinal bypass was associated with nearly twice the risk of limb loss at 5 years (hazard ratio, 1.91; P = .034). Among the cohort of patients who required major amputations, the time duration between index revascularization and amputation was significantly shorter as compared with normoglycemic patients (P = .003). CONCLUSIONS: In this single-institution study with long-term follow-up, IPH was associated with increased rates of 30-day amputation and myocardial infarction, as well as an increased cost of hospital stay. In the long term, postoperative hyperglycemia was associated with greater major limb loss. Among the cohort of patients who required major amputations, the time period between revascularization and amputation was shorter for those patients who had IPH. IPH is an independent marker for poor outcomes after lower extremity revascularization procedures.

Dexmedetomidine Is an Equal Cost Alternative to Propofol in Transcatheter Aortic Valve Replacement, With Equivalent In-Hospital and 30-Day Outcomes.

OBJECTIVE: Transcatheter aortic valve replacement (TAVR) with monitored anesthesia care (MAC) is well-tolerated and is growing in popularity. Differences in outcomes based on anesthetic agent choice with MAC has received less attention. The authors sought to determine whether differences in outcomes and cost exist based on whether patients receive dexmedetomidine or propofol when undergoing TAVR with MAC. DESIGN: Retrospective cohort study. SETTING: The Penn State Milton S. Hershey Medical Center, Hershey, Pennsylvania. PARTICIPANTS: The study comprised 161 patients who underwent TAVR with MAC between May 2014 and March 2019. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A propofol-only (n = 58) group and dexmedetomidine-only (n = 103) group were identified. No differences in in-hospital mortality or complication rate were identified when evaluating for stroke, transfusion, new arrhythmia, cardiac arrest, or bleeding and vascular complications (p > 0.05, all). Thirty-day outcomes were also equivalent, with no differences in mortality, stroke, vascular complication, new arrhythmia, or myocardial infarction (p > 0.05, all). The average amount of epinephrine, norepinephrine, or phenylephrine used intraoperatively was not significantly different. Overall median hospitalization costs were equivalent ($57,554.31 with dexmedetomidine v $58,538.08 with propofol, p = 0.97). CONCLUSIONS: There were no significant differences in in-hospital outcomes, 30-day outcomes, or total cost of the patient's hospitalization, based on the use of dexmedetomidine versus propofol in patients undergoing TAVR.

Late Cardiac Tamponade 4 Years After Total Artificial Heart Implantation.

Cardiac tamponade after ventricular assist device or total artificial heart implantation can typically occur within days or weeks after surgery. This report describes the case of a woman who presented over 4 years after SynCardia 70cc total artificial heart implantation, with physiology consistent with right ventricular outflow tract obstruction. The cause was initially attributed to device membrane failure based on the device console waveform; however, during operative exploration, a large amount of proteinaceous exudate was surrounding the device and causing the obstruction. This report illustrates how tamponade can result years after device implantation, secondary to porosity of the outflow grafts.

Triage and optimization: A new paradigm in the treatment of massive pulmonary embolism.

BACKGROUND: Massive pulmonary embolism (PE) remains a highly fatal condition. Although venoarterial extracorporeal membrane oxygenation (VA-ECMO) and surgical pulmonary embolectomy in the management of massive PE have been reported previously, the outcomes remain less than ideal. We hypothesized that the institution of a protocolized approach of triage and optimization using VA-ECMO would result in improved outcomes compared with historical surgical management. METHODS: All patients with a massive PE referred to the cardiac surgery service between 2010 and 2017 were retrospectively reviewed. Patients were stratified by treatment strategy: historical control versus the protocolized approach. In the historical control group, the primary intervention was surgical pulmonary embolectomy. In the protocol approach group, patients were treated based on an algorithmic approach using VA-ECMO. The primary outcome was 1-year survival. RESULTS: A total of 56 patients (control, n = 27; protocol, n = 29) were identified. All 27 patients in the historical control group underwent surgical pulmonary embolectomy, whereas 2 of 29 patients in the protocol approach group were deemed appropriate for direct surgical pulmonary embolectomy. The remaining 27 patients were placed on VA-ECMO. In the protocol approach group, 15 of 29 patients were treated with anticoagulation alone and 14 patients ultimately required surgical pulmonary embolectomy. One-year survival was significantly lower in the historical control group compared with the protocol approach group (73% vs 96%; P = .02), with no deaths occurring after surgical pulmonary embolectomy in the protocol approach group. CONCLUSIONS: A protocolized strategy involving the aggressive institution of VA-ECMO appears to be an effective method to triage and optimize patients with massive PE to recovery or intervention. Implementation of this strategy rather than an aggressive surgical approach may reduce the mortality associated with massive PE.

Outcomes after surgical pulmonary embolectomy for acute submassive and massive pulmonary embolism: A single-center experience.

OBJECTIVES: Ideal treatment strategies for submassive and massive pulmonary embolism remain unclear. Recent reports of surgical pulmonary embolectomy have demonstrated improved outcomes, but surgical technique and postoperative outcomes continue to be refined. The aim of this study is to describe in-hospital survival and right ventricular function after surgical pulmonary embolectomy for submassive and massive pulmonary embolism with excessive predicted mortality (≥5%). METHODS: All patients undergoing surgical pulmonary embolectomy (2011-2015) were retrospectively reviewed. Patients with pulmonary embolism were stratified as submassive, massive without arrest, and massive with arrest. Submassive was defined as normotensive with right ventricular dysfunction. Massive was defined as prolonged hypotension due to the pulmonary embolism. Preoperative demographics, intraoperative variables, and postoperative outcomes were compared. RESULTS: A total of 55 patients were identified: 28 as submassive, 18 as massive without arrest, and 9 as massive with arrest. All patients had a right ventricle/left ventricle ratio greater than 1.0. Right ventricular dysfunction decreased from moderate preoperatively to none before discharge (P < .001). In-hospital and 1-year survival were 93% and 91%, respectively, with 100% survival in the submassive group. No patients developed renal failure requiring hemodialysis at discharge or had a postoperative stroke. CONCLUSIONS: In this single institution experience, surgical pulmonary embolectomy is a safe and effective therapy to treat patients with a submassive or massive pulmonary embolism. Although survival in this study is higher than previously reported for patients treated with medical therapy alone, a prospective trial comparing surgical therapy with medical therapy is necessary to further elucidate the role of surgical pulmonary embolectomy in the treatment of pulmonary embolism.

Selective CD28 Inhibition Modulates Alloimmunity and Cardiac Allograft Vasculopathy in Anti-CD154-Treated Monkeys.

BACKGROUND: Selective CD28 inhibition is actively pursued as an alternative to B7 blockade using cytotoxic T lymphocyte antigen 4 Ig based on the hypothesis that the checkpoint immune regulators cytotoxic T lymphocyte antigen 4 and programmed death ligand 1 will induce tolerogenic immune signals. We previously showed that blocking CD28 using a monovalent nonactivating reagent (single-chain anti-CD28 Fv fragment linked to alpha-1 antitrypsin [sc28AT]) synergizes with calcineurin inhibitors in nonhuman primate (NHP) kidney and heart transplantation. Here, we explored the efficacy of combining a 3-week "induction" sc28AT treatment with prolonged CD154 blockade. METHODS: Cynomolgus monkey heterotopic cardiac allograft recipients received sc28AT (10 mg/kg, d0-20, n = 3), hu5C8 (10-30 mg/kg, d0-84, n = 4), or combination (n = 6). Graft survival was monitored by telemetry. Protocol biopsies and graft explants were analyzed for International Society of Heart and Lung Transplantation acute rejection grade and cardiac allograft vasculopathy score. Alloantibody, T-cell phenotype and regulatory T cells were analyzed by flow cytometry. Immunochemistry and gene expression (NanoString) characterized intra-graft cellular infiltration. RESULTS: Relative to modest prolongation of median graft survival time with sc28AT alone (34 days), hu5C8 (133 days), and sc28AT + hu5C8 (141 days) prolonged survival to a similar extent. CD28 blockade at induction, added to hu5C8, significantly attenuated the severity of acute rejection and cardiac allograft vasculopathy during the first 3 months after transplantation relative to hu5C8 alone. These findings were associated with decreased proportions of circulating CD8 and CD3CD28 T cells, and modulation of inflammatory gene expression within allografts. CONCLUSIONS: Induction with sc28AT promotes early cardiac allograft protection in hu5C8-treated NHPs. These results support further investigation of prolonged selective CD28 inhibition with CD40/CD154 blockade in NHP transplants.

Utilization of Veno-Arterial Extracorporeal Membrane Oxygenation for Massive Pulmonary Embolism.

BACKGROUND: The management of massive pulmonary embolism remains challenging, with a considerable mortality rate. Although veno-arterial extracorporeal membrane oxygenation (VA-ECMO) for massive pulmonary embolism has been reported, its use as salvage therapy has been associated with poor outcomes. We reviewed our experience utilizing an aggressive, protocolized approach of VA-ECMO to triage, optimize, and treat these patients. METHODS: All patients with a massive pulmonary embolism who were placed on VA-ECMO, as an initial intervention determined by protocol, were retrospectively reviewed. ECMO support was continued until organ optimization was achieved or neurologic status was determined. At that time, if the thrombus burden resolved, decannulation was performed. If substantial clot burden was still present with evidence of right ventricular (RV) strain, operative therapy was undertaken. RESULTS: Twenty patients were identified. Before cannulation, all patients had an RV-to-left ventricular ratio greater than 1.0 and severe RV dysfunction. The median duration of ECMO support was 5.1 days, with significant improvement in end-organ function. Ultimately, 40% received anticoagulation alone, 5% underwent catheter-directed therapy, and 55% underwent surgical pulmonary embolectomy. Care was withdrawn in 1 patient with a prolonged pre-cannulation cardiac arrest after confirmation of neurologic death. In-hospital and 90-day survival was 95%. At discharge, 18 of 19 patients had normal RV function, and 1 patient, who received catheter-directed therapy, had mild dysfunction. CONCLUSIONS: VA-ECMO appears to be an effective tool to optimize end-organ function as a bridge to recovery or intervention, with excellent outcomes. This approach may allow clinicians to better triage patients with massive pulmonary embolism to the appropriate therapy on the basis of recovery of RV function, residual thrombus burden, operative risk, and neurologic status.

Comparative Evaluation of αCD40 (2C10R4) and αCD154 (5C8H1 and IDEC-131) in a Nonhuman Primate Cardiac Allotransplant Model.

BACKGROUND: Specific blockade of T cell costimulation pathway is a promising immunomodulatory approach being developed to replace our current clinical immunosuppression therapies. The goal of this study is to compare results associated with 3 monoclonal antibodies directed against the CD40/CD154 T cell costimulation pathway. METHODS: Cynomolgus monkey heterotopic cardiac allograft recipients were treated with either IDEC-131 (humanized αCD154, n = 9), 5C8H1 (mouse-human chimeric αCD154, n = 5), or 2C10R4 (mouse-rhesus chimeric αCD40, n = 6) monotherapy using a consistent, comparable dosing regimen for 3 months after transplant. RESULTS: Relative to the previously reported IDEC-131-treated allografts, median survival time (35 ± 31 days) was significantly prolonged in both 5C8H1-treated (142 ± 26, P < 0.002) and 2C10R4-treated (124 ± 37, P < 0.020) allografts. IDEC-131-treated grafts had higher cardiac allograft vasculopathy severity scores during treatment relative to either 5C8H1 (P = 0.008) or 2C10R4 (P = 0.0002). Both 5C8H1 (5 of 5 animals, P = 0.02) and 2C10R4 (6/6, P = 0.007), but not IDEC-131 (2/9), completely attenuated IgM antidonor alloantibody (alloAb) production during treatment; 5C8H1 (5/5) more consistently attenuated IgG alloAb production compared to 2C10R4 (4/6) and IDEC-131 (0/9). All evaluable explanted grafts experienced antibody-mediated rejection. Only 2C10R4-treated animals exhibited a modest, transient drop in CD20 lymphocytes from baseline at day 14 after transplant (-457 ± 152 cells/µL) compared with 5C8H1-treated animals (16 ± 25, P = 0.037), and the resurgent B cells were primarily of a naive phenotype. CONCLUSIONS: In this model, CD154/CD40 axis blockade using IDEC-131 is an inferior immunomodulatory treatment than 5C8H1 or 2C10R4, which have similar efficacy to prolong graft survival and to delay cardiac allograft vasculopathy development and antidonor alloAb production during treatment.

Veno-Venous Extracorporeal Membrane Oxygenation Use in the Treatment of Bleomycin Pulmonary Toxicity.

Pulmonary toxicity is a devastating complication of bleomycin chemotherapy. This insult is likely exacerbated by the free radical injury induced by high inspired oxygen content, which is required to support these patients. Traditional treatment consists of high-dose corticosteroids. We report the case of a 45-year-old man who developed bleomycin pulmonary toxicity, which failed to respond to treatment with high-dose corticosteroids. We used protective mechanical ventilatory settings while supported on veno-venous extracorporeal membrane oxygenation using a bicaval dual-lumen, single cannula system to allow for lung recovery. This case demonstrates the feasibility of using veno-venous extracorporeal membrane oxygenation to treat bleomycin pulmonary toxicity in a patient who has failed traditional therapy.

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: αCD154 (IDEC-131)-treated cynomolgus monkey heart allograft recipients were given peritransplant rituximab (αCD20) alone or with rabbit antihuman thymocyte globulin. RESULTS: Relative to previously reported reference groups, αCD20 significantly prolonged survival, delayed Ab detection, and attenuated CAV within 3 months in αCD154-treated recipients (αCD154 + αCD20 graft median survival time > 90 days, n = 7, vs 28 days for αCD154 alone (IDEC-131), n = 21; P = 0.05). Addition of rabbit antihuman thymocyte globulin to αCD154 (n = 6) or αCD154 + αCD20 (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 αCD20-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 αCD154 trough levels (below 100 µg/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.

Thrombosis of the Right Internal Jugular Vein is Not a Contraindication to Ambulatory Veno-Venous Extracorporeal Membrane Oxygenation with a Bicaval Dual-Lumen, Single Cannula System.

BACKGROUND: Veno-venous extracorporeal membrane oxygenation (VV-ECMO) is an ever-emerging method of managing respiratory failure in patients who are refractory to conventional mechanical ventilatory support. An increasingly common method of cannulation involves placement of a bicaval dual-lumen, single cannula via the right internal jugular (IJ) vein. Thrombus in this vein has been considered a contraindication for cannula placement. CASE REPORT: A 45-year-old Hispanic male presented with bleomycin-induced respiratory failure resulting in acute respiratory distress syndrome (ARDS). Ambulatory VV-ECMO support was initiated, and during surgical cannula placement an occlusive thrombus was noted in the right IJ vein. A tract was dilated and the cannula was placed without any thromboembolic complications. CONCLUSION: This case demonstrates that cannulation for ambulatory VV-ECMO in the setting of an occlusive IJ thrombus can be safe and feasible.

Serum-based tracking of de novo initiated liver cancer progression reveals early immunoregulation and response to therapy.

BACKGROUND & AIMS: Liver inflammatory diseases associated with cancer promoting somatic oncogene mutations are increasing in frequency. Preclinical cancer models that allow for the study of early tumor progression are often protracted, which limits the experimental study parameters due to time and expense. Here we report a robust inexpensive approach using Sleeping Beauty transposition (SBT) delivery of oncogenes along with Gaussia Luciferase expression vector GLuc, to assess de novo liver tumor progression, as well as the detection of innate immune responses or responses induced by therapeutic intervention. METHODS: Tracking de novo liver tumor progression with GLuc was demonstrated in models of hepatocellular carcinoma (HCC) or adenoma (HCA) initiated by hydrodynamic delivery of SBT oncogenes. RESULTS: Rising serum luciferase levels correlated directly with increasing liver tumor burden and eventual morbidity. Early detection of hepatocyte apoptosis from mice with MET+CAT transfected hepatocytes was associated with a transient delay in HCC growth mediated by a CD8(+) T-cell response against transformed hepatocytes. Furthermore, mice that lack B cells or macrophages had an increase in TUNEL(+) hepatocytes following liver MET transfection demonstrating that these cells provide protection from MET-induced hepatocyte apoptosis. Treatment with IL-18+IL-12 of mice displaying established HCC decreased tumor burden which was associated with decreased levels of serum luciferase. CONCLUSIONS: Hydrodynamic delivery of the SBT vector GLuc to hepatocytes serves as a simple blood-based approach for real-time tracking of pathologically distinct types of liver cancer. This revealed tumor-induced immunologic responses and was beneficial in monitoring the efficacy of therapeutic interventions.