Origin, phenotype and autoimmune potential of T cells in human immune system mice receiving neonatal human thymus tissue.

Robust human immune system (HIS) mice are created using human fetal thymus tissue and hematopoietic stem cells (HSCs). A HIS mouse model using neonatal human thymus tissue and umbilical cord blood (CB) HSCs (NeoHu) was recently described. We improved the model by removing the native murine thymus, which can also generate human T cells, and demonstrated definitively the capacity of human T cells to develop in a grafted neonatal human thymus. Human T cells derived from the neonatal thymus tissue appeared in peripheral blood early post-transplantation and CB-derived T cells appeared later. Naïve T cells were demonstrated in peripheral blood but effector memory and T peripheral helper phenotypes predominated later, in association with development of autoimmunity in some animals. Treatment of thymus grafts with 2-deoxyglucose (2-DG) increased the proportion of stem cells derived from injected HSCs, delayed onset of autoimmune disease, reduced early T cell reconstitution, and reduced effector/memory T cell conversion. Younger neonatal human thymus tissue was associated with improved T cell reconstitution. While the NeoHu model bypasses the need for fetal tissue, it has yet to demonstrate equivalent reconstitution to fetal tissue, though 2-DG can improve results by removing native thymocytes prior to transplantation.

Readmission After Pancreas Transplantation: Timing of Surgery Matters.

OBJECTIVES: Pancreas transplantation is associated with good long-term outcomes, but readmissions are frequent. In this study, our objective was to understand the effects of operation start time on postoperative outcomes. MATERIALS AND METHODS: We conducted a retrospective review of all patients who underwent deceased donor pancreas transplant in a single center from January 2017 to December 2018. We compared postoperative outcomes of patients in relation to operation start time, which included morning (6 AM to 3 PM), afternoon (3 PM to 7 PM), and evening (7 PM to 6 AM). RESULTS: Eighty-three patients were included in the study. The median age was 45 years old, 54.2% were males, and 79.5% had diabetes mellitus type 1. With regard to surgery start time, 50 patients (60.2%) had a start time in the morning, 25 patients (30.1%) in the afternoon, and 8 (9.6%) in the evening. Patients in the morning group had a significantly lower readmission rate compared with the afternoon and evening groups, respectively (50% vs 84% vs 87.5%; P = .04).There were no significant differences in reoperation rate (26% vs 32% vs 12.5%; P = .57), percutaneous drain placement (20% vs 12% vs 12.5%; P = .75), or graft failure (8% vs 4% vs 12.5%; P = .55) among the 3 groups. CONCLUSIONS: Morning operative start times were associated with lower readmission after pancreas transplant.

Ischemia-reperfusion Injury in the Transplanted Lung: A Literature Review.

Lung ischemia-reperfusion injury (LIRI) and primary graft dysfunction are leading causes of morbidity and mortality among lung transplant recipients. Although extensive research endeavors have been undertaken, few preventative and therapeutic treatments have emerged for clinical use. Novel strategies are still needed to improve outcomes after lung transplantation. In this review, we discuss the underlying mechanisms of transplanted LIRI, potential modifiable targets, current practices, and areas of ongoing investigation to reduce LIRI and primary graft dysfunction in lung transplant recipients.

Successful Implementation of Unmanned Aircraft Use for Delivery of a Human Organ for Transplantation.

OBJECTIVE: To understand and overcome the challenges associated with moving life-urgent payloads using unmanned aircraft. BACKGROUND DATA: Organ transportation has not been substantially innovated in the last 60 years. Unmanned aircraft systems (UAS; ie, drones) have the potential to reduce system inefficiencies and improve access to transplantation. We sought to determine if UASs could successfully be integrated into the current system of organ delivery. METHODS: A multi-disciplinary team was convened to design and build an unmanned aircraft to autonomously carry a human organ. A kidney transplant recipient was enrolled to receive a drone-shipped kidney. RESULTS: A uniquely designed organ drone was built. The aircraft was flown 44 times (total of 7.38 hours). Three experimental missions were then flown in Baltimore City over 2.8 miles. For mission #1, no payload was carried. In mission #2, a payload of ice, saline, and blood tubes (3.8 kg, 8.4 lbs) was flown. In mission #3, a human kidney for transplant (4.4 kg, 9.7 lbs) was successfully flown by a UAS. The organ was transplanted into a 44-year-old female with a history of hypertensive nephrosclerosis and anuria on dialysis for 8 years. Between postoperative days (POD) 1 and 4, urine increased from 1.0 L to 3.6 L. Creatinine decreased starting on POD 3, to an inpatient nadir of 6.9 mg/dL. The patient was discharged on POD 4. CONCLUSIONS: Here, we completed the first successful delivery of a human organ using unmanned aircraft. This study brought together multidisciplinary resources to develop, build, and test the first organ drone system, through which we performed the first transplant of a drone transported kidney. These innovations could inform not just transplantation, but other areas of medicine requiring life-saving payload delivery as well.

Ex Vivo Lung Perfusion: Current Achievements and Future Directions.

There is a severe shortage in the availability of donor organs for lung transplantation. Novel strategies are needed to optimize usage of available organs to address the growing global needs. Ex vivo lung perfusion has emerged as a powerful tool for the assessment, rehabilitation, and optimization of donor lungs before transplantation. In this review, we discuss the history of ex vivo lung perfusion, current evidence on its use for standard and extended criteria donors, and consider the exciting future opportunities that this technology provides for lung transplantation.

Surgical Scarring after Arterial Bypass, an Etiology of Venous Hypertension.

Venous ulcers can be a chronic debilitating condition with a high rate of recurrence. Herein, we describe a case of a patient who successfully underwent an arterial bypass for rest pain but returned with lower extremity swelling and venous ulcers. Venography demonstrated a focal common femoral vein stenosis due to scarring from the surgical exposure. This was treated with endovenous stenting and resulted in resolution of the swelling and ulceration.

Endovascular Thrombectomy of Septic Thrombophlebitis of the Inferior Vena Cava: Case Report and Review of the Literature.

We describe the cases of 2 patients who had septic thrombophlebitis and were successfully managed with endovascular thrombectomy. Patient A developed septic thrombophlebitis of the inferior vena cava after several retroperitoneal resections for metastatic renal cell carcinoma. The thrombus was successfully removed via endovascular mechanical balloon thrombectomy. Patient B was a patient with pancreatic adenocarcinoma involving the portal vein who developed a septic inferior vena cava thrombus extending from the level and beyond the renal veins, for which she underwent endovascular thrombectomy. We argue that this approach is safe and feasible. It should be considered as a supplemental treatment modality for select decompensating patients who require lifesaving interventions and have contraindications to traditional management of surgical thrombectomy or excision of the involved venous segment.

Laser Fenestration for Treatment of a Complicated Chronic Type B Aortic Dissection.

We report a case of a complex chronic type B aortic dissection treated by thoracic endovascular aortic repair and laser fenestration of the false septum to preserve flow to branch vessels originating from both the true and false lumen. Dissections complicated by thoracoabdominal aneurysmal degeneration with critical organs being perfused by branches arising from both true and false lumens are rare and leave limited options for repair. Despite advancements in endovascular techniques, fenestration remains one of the only means of preserving flow to both the true and false lumens and thus was necessary in the management of our patient. This novel procedure allows complex aortic dissections to be addressed endovascularly, which increases the flexibility and management of this challenging problem that previously required an open repair with significant morbidity.

Risk of complication during surgical abortion in obese women.

BACKGROUND: Surgical abortion is a generally safe procedure. Obesity is a known risk factor for complications in other surgical procedures, but insufficient information exists to determine the effects of increasing body mass index on the risk of surgical abortions. OBJECTIVE: The purpose of this study was to determine whether obesity is a risk factor for major complications in surgical abortions. METHODS: A quality control database from a single outpatient center was analyzed to determine rates of major complications during surgical abortions in relation to obesity class. Complications included hemorrhage, need for repeat evacuation, uterine perforation, cervical laceration, medication reaction, unexpected surgery, or unplanned admission to the hospital. Chi-squared and analysis of variance were used for analysis. RESULTS: We included 2468 procedures: 1475 procedures (59.8%) in the first trimester and 993 procedures (40.2%) in the second trimester. The overall complications rate was 2.2%. Second-trimester procedures were more likely than those in the first trimester to have complications (3.1% vs 1.6%; P=.009). Overall, 39.6% of the women were obese, and 9.6% of them met criteria for class 3 obesity (body mass index, >40 kg/m2). Women who underwent second-trimester abortions with class 3 obesity had a rate of complication of 8.7%, which was significantly more than normal weight women (odds ratio, 5.90; 95% confidence interval, 1.93-8.07; P<.001). COMMENT: Surgical abortions are overall safe procedures, but class 3 obesity increases the rate of complication in second-trimester procedures.

Site-specific targeting of platelet-rich plasma via superparamagnetic nanoparticles.

BACKGROUND: Muscle strains are one of the most common injuries treated by physicians. Standard conservative therapy for acute muscle strains usually involves short-term rest, ice, and non-steroidal anti-inflammatory medications, but there is no clear consensus regarding treatments to accelerate recovery. Recently, clinical use of platelet-rich plasma (PRP) has gained momentum as an option for therapy and is appealing for many reasons, most notably because it provides growth factors in physiological proportions and it is autologous, safe, easily accessible, and potentially beneficial. Local delivery of patients' PRP to injured muscles can hasten recovery of function. However, specific targeting of PRP to sites of tissue damage in vivo is a major challenge that can limit its efficacy. HYPOTHESIS: Location of PRP delivery can be monitored and controlled in vivo with non-invasive tools. STUDY DESIGN: Controlled laboratory study using rats. METHODS: Superparamagnetic iron oxide nanoparticles (SPIONs) can be visualized by both MRI (in vivo) and fluorescence microscopy (after tissue harvesting). We labeled PRP with SPIONs and administered intramuscular injections of SPION-containing platelets. MRI was used to monitor the ability to manipulate and retain the location of PRP in vivo by placement of an external magnet. Platelets were isolated from whole blood and incubated with SPIONs. Following SPION incubation with PRP, a magnetic field was used to manipulate platelet location in culture dishes. In vivo, the tibialis anterior muscles (TAs) of anesthetized Sprague-Dawley rats were injected with SPION-containing platelets and MRI was used to track platelet position with and without a magnet worn over the TAs for 4 days. RESULTS: The method used to isolate PRP yielded a high concentration (almost 4-fold increase) of platelets. In vitro experiments show that the platelets successfully took up SPIONs and then rapidly responded to an applied magnetic field. Platelets without SPIONs did not respond to the magnetic field. In vivo experiments show that the SPION-containing platelets can be non-invasively maintained at a specific site with the application of a magnetic field. CONCLUSION: PRP may be a useful product in clinical treatment of muscle injuries, but one problem with using PRP as a therapeutic tool, is retaining PRP at the site of injury. We propose a potential solution with our findings that support this method at the cell, whole muscle, and in vivo levels. Controlling the location of PRP will allow the clustering of PRP to enrich the target area with growth factors and will prevent loss of the platelets over time at the site of injury.

Soluble CD27-pool in humans may contribute to T cell activation and tumor immunity.

The interaction between CD27 and its ligand, CD70, has been implicated in regulating cellular immune responses to cancer. In this article, we report on the role of soluble CD27 (sCD27) in T cell activation and its elevation in the serum of cancer patients after immunotherapy. In vitro, sCD27 is preferentially derived from activated CD4(+) T cells. Adding sCD27 to stimulated PBMCs increases T cell activation and proliferation, and is associated with the immunologic synapse-related proteins myosin IIA, high mobility group box 1, and the TCR Vß-chain. The pool of serum sCD27 is shown to be greater in healthy donors than in cancer patients. However, metastatic cancer patients treated with immunotherapy showed a significant increase in the serum sCD27-pool posttherapy (p < 0.0005); there was also an increased trend toward an association between enhanced sCD27-pool posttherapy and overall survival (p = 0.022). The identification of sCD27 as an immune modulator associated with enhanced human T cell activation in vitro and in vivo provides a rationale for developing new immunotherapeutic strategies aimed at enhancing sCD27 for treating cancer and potentially other diseases.

Elevated serum soluble CD40 ligand in cancer patients may play an immunosuppressive role.

Tumor cells can induce certain cytokines and soluble receptors that have a suppressive effect on the immune system. In this study, we showed that an extracellular portion of a membrane-bound ligand of CD40 (soluble CD40 ligand; sCD40L) was significantly elevated in the serum of cancer patients compared with healthy donors. In addition, PBMCs from cancer patients had a relatively larger population of myeloid-derived suppressor cells (MDSCs), defined as CD33(+)HLA-DR(-) cells, and these cells expressed higher levels of CD40. T-cell proliferation and IFN-γ production decreased when stimulated T cells were cocultured with an increased amount of autologous MDSCs. The addition of recombinant monomeric sCD40L enriched MDSCs and had an additive inhibitory effect on T-cell proliferation. PBMCs cultured in vitro with sCD40L also showed an expansion of regulatory T cells (CD4(+)CD25(high)Foxp3(+)), as well as induction of cytokines, such as IL-10 and IL-6. Moreover, sCD40L-induced enrichment of programmed death-1-expressing T cells was greater in cancer patients than in healthy donors. Preexisting sCD40L also inhibited IL-12 production from monocytes on activation. These data suggest that the higher levels of sCD40L seen in cancer patients may have an immunosuppressive effect.