Primary Graft Research Articles

Ten-Year Follow-Up After Descemet Membrane Endothelial Keratoplasty.

To examine clinical results up to 10 years after Descemet Membrane Endothelial Keratoplasty (DMEK) and Triple-DMEK. Prospective study including 201 eyes, of which 54 eyes [38 DMEKs and 16 Triple-DMEKs; Fuchs endothelial dystrophy (n = 45), pseudophakic bullous keratopathy (n = 9)] reached the minimum follow-up of 5 years and were followed up for up to 10 years. We evaluated best-corrected visual acuity (BCVA, logarithm of the minimum angle of resolution [logMAR]), endothelial cell density (ECD, cells/mm2), minimal central corneal thickness (CCT, μm), central retinal thickness (μm), rebubbling, graft survival and re-DMEK rate, chamber angle alterations, and incidence of glaucoma. Fifty-four eyes had a 5-year and 37 eyes an 8- to 10-year follow-up. Mean follow-up was 94.4 ± 12.1 months. Best-corrected visual acuity increased from 0.6 ± 0.3 logMAR to 0.1 ± 0.2 logMAR at 6 months (P ≤ 0.001) and was 539 ± 54 μm at long term. Endothelial cell density decreased from 2488 ± 320.9 (donor) to 980.1 ± 437 cells/mm2 with an average ECD loss/year of 4% and did not correlate with BCVA. Central corneal thickness decreased from 596.9 ± 82.2 μm to 498.6 ± 24.3 μm at 12 months (P ≤ 0.001) and remained stable (P = 1.000). Mean rebubbling rate was 0.3 ± 0.5/eye and did not correlate with BCVA. Eight eyes (14.8%) received at least 1 rebubbling. Primary graft failure/rejection rate was 1.5%/0% within the first postoperative year, and secondary graft failure rate was 12.4% at 7 years. Eight eyes (preoperative n = 3, de novo n = 5) had open-angle glaucoma without chamber angle changes (14.8%, P ≤ 0.001). Although ECD decreases continuously in the long-term follow-up, excellent visual acuity can be preserved 10 years after DMEK and Triple-DMEK. The final outcome can be estimated 6 months after surgery.

End-to-end anastomosis as a superior repair type to prevent recurrence of arteriovenous fistula aneurysms and improve patency outcomes.

Arteriovenous fistulae (AVF) complicated by aneurysms are repaired through several mechanisms. Little is known about risk factors for aneurysm recurrence or the efficacy of subsequent repair of recurring aneurysms. About 291 patients underwent AVF aneurysm repair between 2009 and 2019 at a large urban medical center. Patients who underwent staged repair, had a primary graft with pseudoaneurysm, were status-post kidney transplant, or using other dialysis access at the time of repair were excluded. One hundred sixty-two patients were included in the study, of which 52 developed a secondary aneurysm. Chi-square and t-test analyses were used to compare demographics. Multivariate logistic regression was used to examine independent risk factors for aneurysm recurrence. Of the 52 patients with recurrent aneurysms, 41 were repaired again. Patency was examined for each group 1 year postoperatively. Patients without secondary aneurysms were more likely to have a Charlson Comorbidity Index score ⩾5 (p = 0.045). Males were 2.8 times more likely to develop a secondary aneurysm compared to females (p = 0.023). Patients who underwent elective compared to emergent or urgent surgery for primary aneurysms were significantly less likely to recur (OR = 0.222; p = 0.016). Primary aneurysms repaired by end-to-end anastomosis, compared to aneurysmorrhaphy or graft, were significantly less likely to recur (OR = 0.239; p = 0.041). Among patients with secondary aneurysms, those repaired via end-to-end anastomosis had a significantly higher primary patency rate 1 year postoperatively (p = 0.024). Secondary aneurysm repairs exhibited 1-year primary and secondary patency rates of 51.2% and 82.9%, respectively. End-to-end anastomosis reduces risk of recurrence and demonstrates superior patency rates when repairing recurrent aneurysms. It remains unclear why some patients are prone to aneurysm recurrence, however continued attempts to repair existing vascular access are proven to be successful.

Infusion of Non-HLA-Matched Off-the-Shelf Ex Vivo Expanded Cord Blood Progenitors in Patients Undergoing Cord Blood Transplantation: Result of a Phase II Clinical Trial.

Recipients of myeloablative cord blood transplants (CBT) are known to experience delayed hematopoietic recovery and an increased risk of transplant related mortality (TRM). We developed methods for ex vivo expansion and cryopreservation of CB stem and progenitor cells. 15 patients with hematologic malignancies were enrolled in this single center phase II trial between September 2010 and August 2012 to assess the safety of infusing a non-HLA-matched expanded CB product to bolster a conventional CBT. On the day of transplant, an infusion of the expanded CB product followed the primary graft (1 or 2 unmanipulated CB units). All patients engrafted. Median time to neutrophil and platelet recovery was 19 and 35 days, respectively. Early myelomonocytic recovery was almost entirely due to cells arising from the non-HLA-matched expansion product and were no longer detected at day 14 in all but 2 patients. The probability of 3-years disease free survival was 86%. No TRM was observed throughout the study period, and only 2 patients relapsed. All patients presented with grade II acute graft-versus-host disease (aGVHD) at a median time of 32 days, with no grade III-IV aGVHD observed. At 2 years only 2 patients remain on immunosuppressive therapy for mild chronic GVHD. This phase II safety study demonstrate that infusion of an off-the-shelf non-HLA-matched expanded CB product in addition to a conventional CB graft was safe and led to sustained myeloid recovery. Based on these encouraging results, a prospective multicenter randomized trial utilizing this product has been conducted and results will be soon released. ClinicalTrials.gov Identifier: NCT01175785.

The Practice of Retransplantation for Recurrent Alcohol-associated Liver Disease in the United States Is Uncommon With Acceptable Outcomes.

Background.Alcohol-associated liver disease (ALD) is the leading indication for liver transplantation (LT) in the United States. Alcohol use disorder relapse can lead to graft failure and the need for liver retransplantation (re-LT). Despite the rising incidence of LT for ALD, the practice of re-LT for recurrent ALD is not well understood. We aimed to define the practice of re-LT for recurrent ALD during the last 20 y.Methods.Using the US national transplant registry, adults who underwent re-LT for recurrent ALD were compared with LT recipients who died from recurrent ALD and propensity score–matched re-LT recipients with non-ALD indications. All groups had at least 1-y survival of their primary graft. Kaplan-Meier analysis was used to calculate 1- and 5-y survivals.Results.Between 2000 and 2020, 74 re-LTs were performed for recurrent ALD (1.0% of all re-LTs). There was an increase in recurrent ALD re-LT practice from 2017 to 2020 versus 2014 to 2016 (20 versus 2). At the time of re-LT, patients with recurrent ALD had a significant decrease in body mass index (median 25.1 versus 28.8 kg/m2; P < 0.001) versus the index LT. Patient and graft survivals were similar between patients who underwent re-LT for ALD and non-ALD (56.4% versus 56.9% 5-y graft survival, P = 0.96; 62.8% versus 59.0% 5-y patient survival, P = 0.58).Conclusions.The practice of re-LT for recurrent ALD is uncommon in the United States. Graft and patient survivals seem to be acceptable and support the occasional practice of re-LT for recurrent ALD should the patient be deemed an appropriate candidate.

Hemodialysis Reliable Outflow (HeRO) graft creation in upper extremities abandoned due to stent obstruction via recanalization and HeRO outflow component insertion across stent interstices.

The purpose of this study was to assess the feasibility and outcomes of recanalization and subsequent HeRO graft outflow component insertion across stent interstices in patients with an otherwise abandoned upper extremity. Over a 10-year period, 15 patients underwent central venous recanalization by interventional radiology across the interstices of one or more occluded stents for the purpose of subsequent HeRO graft creation. A tunneled central venous catheter was left across the stent and occlusions with tip in right atrium. On a later date, the catheter was used for rapid guidewire access for HeRO graft implantation in the OR by vascular surgery. Procedural and clinical outcomes were determined by retrospective review. Primary and secondary HeRO graft patency rates were estimated with the Kaplan-Meier technique. The technical success rates of recanalization across stent interstices was 100% (15/15). Between one and four overlapping stent walls were traversed. The technical success of the patients who underwent attempted HeRO graft implantation with outflow component traversing across stent interstices was 91% (11/12). No major complications were encountered with either recanalization or HeRO graft implantation. The primary and secondary HeRO patency rates at 12 months were 64% and 80%, respectively. HeRO graft insertion across stent interstices is feasible and can provide effective permanent AV access; thus, the presence of stents across the subclavian and brachiocephalic veins should not be considered a contraindication.

Outcomes and toxicity of allogeneic hematopoietic cell transplantation in chronic myeloid leukemia patients previously treated with second-generation tyrosine kinase inhibitors: a prospective non-interventional study from the Chronic Malignancy Working Party of the EBMT

Allogeneic hematopoietic cell transplantation (allo-HCT) remains a treatment option for patients with chronic myeloid leukemia (CML) who fail to respond to tyrosine kinase inhibitors (TKIs). While imatinib seems to have no adverse impact on outcomes after transplant, little is known on the effects of prior use of second-generation TKI (2GTKI). We present the results of a prospective non-interventional study performed by the EBMT on 383 consecutive CML patients previously treated with dasatinib or nilotinib undergoing allo-HCT from 2009 to 2013. The median age was 45 years (18–68). Disease status at transplant was CP1 in 139 patients (38%), AP or >CP1 in 163 (45%), and BC in 59 (16%). The choice of 2GTKI was: 40% dasatinib, 17% nilotinib, and 43% a sequential treatment of dasatinib and nilotinib with or without bosutinib/ponatinib. With a median follow-up of 37 months (1–77), 8% of patients developed either primary or secondary graft failure, 34% acute and 60% chronic GvHD. There were no differences in post-transplant complications between the three different 2GTKI subgroups. Non-relapse mortality was 18% and 24% at 12 months and at 5 years, respectively. Relapse incidence was 36%, overall survival 56% and relapse-free survival 40% at 5 years. No differences in post-transplant outcomes were found between the three different 2GTKI subgroups. This prospective study demonstrates the feasibility of allo-HCT in patients previously treated with 2GTKI with a post-transplant complications rate comparable to that of TKI-naive or imatinib-treated patients.

Evaluation of the Extent of Primary Buccal Mucosal Graft Contracture in Augmentation Urethroplasty for Stricture Urethra: A Prospective Observational Study at a Tertiary Healthcare Centre.

Introduction Buccal mucosal graft (BMG) urethroplasty is considered as gold standard in the treatment of urethral stricture disease. The successful outcome after BMG urethroplasty varies between 66 and 99%. One of the possible causes for failure is BMG contracture. Primary BMG contracture rate is poorly understood and unreported. The present study aimed to evaluate the extent of contracture of buccal mucosa immediately after harvesting. Materials and Methods This was a prospective observational study conducted in the Department of Urology at our institute between January 2016 and December 2019. All patients with urethral stricture disease undergoing BMG urethroplasty for the first time were enrolled in the study after obtaining informed consent. Demographic and patient clinical profile was noted. Based on the intraoperative urethral stricture size, the preharvest graft was marked on the buccal mucosa and the size was calculated. Postharvest unstretched size of the graft was measured immediately after graft removal from the oral cavity. Alteration in BMG size was analysed using paired t-test. Results Forty-four patients were included in the study. Mean age of the patient was 53.6 years. Mean stricture length was 7.45 cm (range 4–12 cm). Mean pre- and postharvest BMG size was 8.3 × 1.5 cm and 7.6 × 1.3 cm, respectively. There was a 8.4% decrease in length and 9.5% decrease in width of the buccal mucosal graft. Conclusion Primary buccal mucosal graft contracture is around 8.4% in length and 9.5% in width. It would be better to mark wider than necessary while harvesting buccal mucosa so that tension-free anastomosis is performed.

Salvage HLA-haploidentical hematopoietic stem cell transplantation with post-transplant cyclophosphamide for graft failure in non-malignant disorders

Graft failure requires urgent salvage HSCT, but there is no universally accepted approach for this situation. We investigated T-cell replete haploidentical HSCT with post-transplantation cyclophosphamide following serotherapy-based, radiation-free, reduced intensity conditioning in children with non-malignant disorders who had rejected their primary graft. Twelve patients with primary or secondary graft failure received T-cell replete bone marrow grafts from haploidentical donors and post-transplantation cyclophosphamide. The recommended conditioning regimen comprised rituximab 375 mg/m2, alemtuzumab 0.4 mg/kg, fludarabine 150 mg/m2, treosulfan 20–24 g/m2 and cyclophosphamide 29 mg/kg. After a median follow-up of 26 months (7–95), eleven of twelve patients (92%) are alive and well with complete donor chimerism in ten. Neutrophil and platelet engraftment were observed in all patients after a median of 18 days (15–61) and 39 days (15–191), respectively. Acute GVHD grade I was observed in 1/12 patients (8%) and mild chronic GVHD in 1/12 patients (8%). Viral reactivations and disease were frequent complications at 75% and 42%, respectively, but no death from infectious causes occurred. In summary, this retrospective analysis demonstrates that a post-transplantation cyclophosphamide-based HLA-haploidentical salvage HSCT after irradiation-free conditioning results in excellent engraftment and overall survival in children with non-malignant diseases.

Evaluation of Donor Ankle Function after Harvesting Peroneus Longus Tendon Graft for Anterior Cruciate Ligament Reconstruction- A Prospective Cohort Study

Introduction: Primary full thickness Peroneus Longus Tendon Graft (PLTG) for Anterior Cruciate Ligament Reconstruction (ACLR) has been used with good clinical outcome. Recently, it is designated as a promising graft option for ACLR. The effect of harvesting PLTG on donor ankle function is still not completely understood. Peroneus Longus Tendon (PLT) is thought to play a major role in proprioceptive regulation of the ankle joint. All the studies till date did cross-sectional assessments of ankle and foot function at or after 6 months that might have overlooked the timely detection of donor site morbidities. Aim: To evaluate the ankle function and compare the affected and sound limb function in subjects with an ACLR with autologous PLTG starting at an early postoperative visit upto six months. Materials and Methods: A prospective cohort study was conducted at a tertiary rehabilitation centre from March 2019 to March 2021 including the follow-up evaluation. As per the inclusion criteria, 63 participants after ACLR with PLTG were considered for assessment using the American Orthopaedic Foot and Ankle Society (AOFAS) ankle and hind foot scale and Foot and Ankle Ability Measure (FAAM) scale at 6 weeks, 3 months and 6 months post-ACLR follow-up. Comparison between sound and affected limbs was done during all follow-ups. The statistical analysis was done using Statistical Package for the Social Sciences (SPSS) version 18.0. Both FAAM and AOFAS ankle and foot scores were analysed with non parametric tests. Results: Mean age of 63 participants were 29.25 years. Median of AOFAS and FAAM score at 6 week, 3 month, and 6 month post- ACLR follow-ups were (88, 98 and 100) and (97.22, 98.80 and 100), respectively. Statistically significant increase in AOFAS and FAAM scores were observed at 3 month and 6 month as compared to 6 week follow-ups with p=0.001 and p-value=0.001 respectively. The group comparison between the affected and sound side functional scores at different study visits showed statistically significant greater values for the sound ankle than the affected ankle (FAAM: 6 week: p-value=0.001; 3 month: p-value=0.001; 6 month: p-value=0.001 and AOFAS p-value=0.001; p-value=0.001; p-value=0.001, respectively). Conclusion: The evaluation of functional outcomes showed gradual and linear improvement at subsequent postoperative visits and restores fully to 100% at 6 month indicating a near- normal to normal donor ankle function following ACLR with PLTG by 6 months. The group comparison showed only marginal but significant difference between affected and sound ankle function.

Outcome of primary tendon grafts for open Zone 3 extensor tendon injuries

Open injuries of the extensor mechanism in Zone 3 (dorsum of the proximal interphalangeal joint) have poor outcomes. We retrospectively analysed the outcomes of treating 19 Zone 3 extensor tendon injuries in 17 patients. The treatment comprised wound excision and debridement, primary tendon graft to reconstruct the damaged/missing extensor tendon, skeletal fixation when required, local flaps to vascularize the zone of injury and immediate short arc motion therapy. Using the criteria defined by Geldmacher etal., the outcome was predicted to be poor in nine, satisfactory in seven and good in three cases. In this study the outcomes were excellent in 10, good in six and satisfactory in three cases. Mean range of motion was 75° (range 25°-115°) at the proximal interphalangeal joint. We conclude that using the protocol described there should no longer be the perception of a dismal outcome for these complex Zone 3 extensor tendon injuries.Level of evidence: IV.

Hematopoietic stem cell transplantation with TCRαβ+/CD19+ - graft depletion for hemophagocytic lymphohistiocytosis

The study was approved by the Independent Ethics Committee and the Scientific Council of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology, and Immunology. We present the outcomes of allogeneic hematopoietic stem cell transplantation (HSCT) with TCRab+/CD19+ graft depletion in patients with genetic hemophagocytic lymphohistiocytosis (HLH) at the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology, and Immunology from 2012 to 2019. Thirty-six patients with various HLH: familial HLH (n = 20), X-linked lymphoproliferative disease (XLP) type 1 (n = 4), XLP type 2 (n = 9), Griscelli syndrome (n = 1), Chediak–Higashi syndrome (n = 2) received HSCT. Conditioning regimens were based on treosulfan in 9 patients, or on two alkylating agents: treosulfan with either melphalan, or thiotepa in 27 patients; all 36 patients received fludarabine and serotherapy. Thirty-two patients received rituximab 100 mg/m2 the day before stem cell infusion. Post- HSCT “graft versus host” disease (GvHD) prophylaxis was used in 29 patients. As a graft source peripheral blood stem cells from matched unrelated (n = 23), matched related (n = 3) and haploidentical family (n = 10) donors after TCRαβ+/CD19+ graft depletion were used. The cumulative incidence of primary and secondary graft failure in all patients was 0.11 (95% CI 0.04–0.29). The incidence of acute GvHD was limited to stage I-II. Overall survival was 0.91 (95% CI 0.82–1) without any significant differences in various donor groups (p = 0.33) as well as different conditioning regimens (p = 0.75). Allogeneic HSCT with TCRαβ+/CD19+ graft depletion after treosulfan-based conditioning is effective and safe technology for patients with genetic HLH.

The use of aerosolized - Adrenergic agonist therapy after lung transplantation in pediatric age

It is my opinion the use of aeresolized –adrenergic agonist such as salbutamol may be helpfull not only to reduced the early mortality but also the chronic allograft dysfunction after lung transplantation in children The reduction of pulmonary edema could be prevent the induction of Obstructive Bronchiolites Syndrome (less pneumonia and viral infections etc) such as the primary graft dysfunction.As we know by international literature Lung transplantation continues to suffer from less-than-ideal long-term outcomes, even in pediatric patients.

P1707SIMULTANEOUS HEART-KIDNEY TRANSPLANT: OUR 10 YEARS' EXPERIENCE

Abstract Background and Aims The number of patients listed and receiving simultaneous heart-kidney transplantation (SHKT) has significantly increased in the last decade. This is likely due to the increased knowledge that SHKT is associated with a significant survival benefit in patients with heart failure with chronic kidney disease (CKD), compared to isolated heart transplant and sequential heart and kidney transplantation. Recent analysis of large data bases has shown a survival benefit in SHKT even in older patients and beyond dialysis dependent patients. However, this benefit is only proven for irreversible CKD which is often difficult to prove in patients with severe heart failure. Our center has the largest experience in SHKT in Portugal, and our aim is to report our experience with a total of 8 recipients and their outcomes after 10 years of follow up. Method We performed a retrospective analysis of all the patients submitted to SHKT in Coimbra University Hospital Center from 1 January 2009 to 31 December 2019. Data was collected using the clinical and laboratorial registries from our database. Follow up at December 2019 varied between 6 months to 10 years (median 5,5 years). Results A total of 8 patients received SHKT between 1 January 2009 and 31 December 2019. Only one patient was female and the mean age at transplant was 58.88 ± 9.7 years. The etiology of heart failure was dilated cardiomyopathy (N=4, 50%), severe valvular disease (N=2, 25%), ischemic cardiomyopathy (N=1, 12,5%) and one patient had familiar amyloidosis (N=1, 12,5%). Regarding CKD, the majority of the patients had type 2 cardiorenal syndrome (N=5, 62,5%), one patient had calcineurin toxicity due to previous liver transplantation, one patient had autosomal dominant polycystic disease, and in one patient the etiology remained unknown. Half of the patients were on chronic hemodialysis program for more than 3 months, and the remaining were preemptive. Regarding post-transplant results, average hospitalization was 19 days. Seven patients (87,5%) had immediate cardiac graft function (mean LVEF 70 ± 5.8% and mean PSAP 22.25 ± 5.6 mmHg). One patient had acute cardiac and subsequent renal graft dysfunction and died during hospitalization. Regarding renal graft outcomes, besides the patient that died, another patient had primary renal graft dysfunction due to renal artery thrombosis and one patient presented late graft function. The remaining five patients had immediate graft function and presented normal kidney graft function at follow up. Regarding complications, neoplasia was reported in two patients (one with sarcoma and the other with prostatic cancer), and there were twenty-five episodes of infection, present in all patients. Mortality at follow up was 37% (N=3). One of these, described above, died during hospitalization twenty-two days after transplant, and the other two died 4 and 5 years later due to a cardiovascular event and sarcoma, respectively. At follow up in 2019 five patients present stable kidney graft, good cardiac function and no recent complications. Conclusion In selected patients with co-existing heart and kidney failure, combined heart and kidney transplantation might be the best approach and appears to be associated with better graft and patient survival. Despite having a small number of cases, our center has the biggest experience in SHKT in Portugal and our results are very satisfying. A multidisciplinary approach between Nephrology, Cardiology and Cardiothoracic Surgery is fundamental and in the next decades it is expected an increase in SHKT number.

Comparing 4- and 6-week post-flap protocols in patients with spinal cord injury

Objective: For patients with spinal cord injury (SCI) who undergo flap surgery to treat pressure injuries (PIs), the optimal duration of post-operative bedrest to promote healing and successful remobilization to sitting is unknown. At the study center, the minimum duration of post-operative bedrest was changed from 4 to 6 weeks. The purpose of this study is to compare outcomes of patients who underwent flap surgery using bedrest protocols of different duration. Design: This was a retrospective review of all flap procedures completed at VA Puget Sound Health Care System from 1997 to 2016 to treat PIs in patients with SCI. Surgeries were excluded if they were not a flap (i.e. primary skin closure or graft), involved a non-pelvic region, or were a same-hospitalization revision of a prior surgery. The primary outcome of this investigation was the number of days between surgery and the first time the patient mobilized to sitting out of bed for 2 h with an intact surgical incision. Methods: 190 patients received a total of 286 flap surgeries from 1994 to 2016. A chart review of each case was completed to determine the planned duration of bedrest (4- vs 6-weeks), first date of successful mobilization out of bed for 2 h, length of stay post-surgery, and occurrence of complications such as dehiscence or need for operative revisions. Results: Among 286 primary surgeries, 171 surgeries used the 4-week protocol and 115 used the 6-week protocol. When compared to the 4-week protocol, patients treated with the 6-week protocol were slightly older, more likely to have a diagnosis of diabetes, and less likely to be current smokers. Healing was never achieved after 4 surgeries in the 4-week group and 2 surgeries in the 6-week group. With the analysis restricted to a single surgery per subject who achieved healing (109 treated with 4-week protocol and 75 with 6-week protocol), there was a significant difference in days until 2-h sitting: median 54 days for the 4-week protocol compared to 60 days for the 6-week protocol (p = 0.041). Up to about 60 days post-operatively, the 4-week protocol produced a greater proportion remobilized to sitting, and thereafter the proportion of patients successfully remobilized did not differ between protocols. Conclusions: The 6-week protocol was not associated with improved remobilization outcomes (reduced rates of dehiscence or surgical revisions), and the 4-week protocol resulted in a significantly shorter time to remobilization to sitting for 2 h as well as a shorter length of stay. We did not identify any subgroup of patients that benefited from the longer protocol.

Case report - coronary vasospasm in transplanted heart: a puzzling phenomenon

BackgroundCoronary artery spasm (CAS) is an underdiagnosed disease especially in heart transplant patients, and in those patients the etiology and pathophysiology remain largely unknown, although it has been associated with cardiac allograft vasculopathy or graft rejection.Case presentationWe report the case of a heart-transplant patient whose cardiac graft experienced two coronary vasospasms: the first before transplantation, and the other at one-month of a postoperative course complicated by primary graft failure.ConclusionOur case illustrates that a transplanted heart predisposed with coronary vasospasm may suffer from early relapse in the recipient despite of complete post-surgical autonomic denervation. Exacerbated endothelial dysfunction of the donor heart after transplant, with the addition of systemic factors in the recipient may be involved in the genesis of this puzzling phenomenon.

Risk factors influencing survival of acellular porcine corneal stroma in infectious keratitis: a prospective clinical study

BackgroundA worldwide lack of donor corneas demands the bioengineered corneas be developed as an alternative. The primary objective of the current study was to evaluate the efficacy of acellular porcine corneal stroma (APCS) transplantation in various types of infectious keratitis and identify risk factors that may increase APCS graft failure.MethodsIn this prospective interventional study, 39 patients with progressive infectious keratitis underwent therapeutic lamellar keratoplasty using APCS and were followed up for 12 months. Data collected for analysis included preoperative characteristics, visual acuity, graft survival and complications. Graft survival was evaluated by the Kaplan–Meier method and compared with the log-rank test.ResultsThe percentage of eyes that had a visual acuity of 20/40 or better increased from 10.3% preoperatively to 51.2% at 12 months postoperatively. Twelve patients (30.8%) experienced graft failure within the follow-up period. The primary reasons given for graft failure was noninfectious graft melting (n = 5), and the other causes included recurrence of primary infection (n = 4) and extensive graft neovascularization (n = 3). No graft rejection was observed during the follow-up period. A higher relative risk (RR) of graft failure was associated with herpetic keratitis (RR = 8.0, P = 0.046) and graft size larger than 8 mm (RR = 6.5, P < 0.001).ConclusionsAPCS transplantation is an alternative treatment option for eyes with medically unresponsive infectious keratitis. Despite the efficacy of therapeutic lamellar keratoplasty with APCS, to achieve a good prognosis, restriction of surgical indications, careful selection of patients and postoperative management must be emphasized.Trial registration Prospective Study of Deep Anterior Lamellar Keratoplasty Using Acellular Porcine Cornea, NCT03105466. Registered 31 August 2016, ClinicalTrails.gov

Incorporation of Thiotepa in a Reduced Intensity Conditioning Regimen Leads to Improved Engraftment after Stem Cell Transplant for Patients with Hemophagocytic Lymphohistiocytosis

Introduction: Hematopoietic stem cell transplantation (HSCT) for patients with hemophagocytic lymphohistiocytosis (HLH) following myeloablative conditioning regimens (MAC) is associated with high rates of non-relapse mortality. A previously reported prospective, phase 2 multi-center trial (RICHI) using using RIC strategy of fludarabine, melphalan and alemtuzumab (day -14) for HLH and primary immune deficiency syndromes (PIDS) demonstrated improved mortality rates but fewer than half the patients with HLH (41%) successfully engrafted without secondary graft failure, need for donor lymphocyte infusion (DLI) or second transplant. Incorporation of thiotepa during conditioning has been to shown to be safe and improve engraftment. We report the results of a retrospective analysis of nine consecutive patient treated with the inclusion of thiotepa into the RICHI backbone (RICHI+TT). Methods: Patients received a single additional dose of thiotepa 10mg/kg on day -3 added to the fludarabine/melphalan/alemtuzumab backbone (RICHI+TT) with the same graft-versus-host disease prophylaxis of methyprednisolone through day +28 and cyclosporine through day 180. To determine sustained engraftment, we used the same parameters the RICHI study defined as &gt; 5 % donor chimerism without any intervention and alive at 1 year post-transplant. Results: Our cohort consisted of 8 males and 1 female with a median age of 7 years (range 1-18 years). Seven patients had HLH with proven pathogenic genetic mutations (biallelic PRF1 - 2, UNC13D - 2, STXBP1- 1, RAB27A-1, STAT3 gain of function-1), while the other 2 patients had HLH without identified pathogenic mutations (1- chronic active EBV, 1- juvenile idiopathic arthritis with refractory macrophage activation syndrome).The majority of patients received a bone marrow product (n = 8), one patient received a peripheral blood stem cell product; 6 patients received a graft from a matched related donor , two from a mismatched unrelated donor, and one from a matched unrelated donor. All patients engrafted at a median of 15 days post-transplant (8 patients at 100% donor chimera; 1 patient at 99% donor chimera at initial engraftment). Six of the 9 patients were evaluable to assess donor chimerism at 1 year as per study definitions with a median follow up of 875 days (range: 366 -1000 days). All 6 patients had &gt; 5% donor chimerism and were alive at 1 year. Five of the 6 evaluable patients met criteria for sustained donor engraftment without need for intervention and all maintained 100% donor chimerism at last follow-up (Table 1). Only one of the six patients had evidence of falling donor chimerism; this stabilized at 40% donor chimerism after DLI. No patients had primary or secondary graft failure. Three patients were not evaluable for long-term assessment due to death prior to 1 year. Six of the 9 patients described here are alive and disease-free with stable long-term engraftment. The incorporation of Thiotepa to the RICHI backbone improved on previously reported sustained donor engraftment (Table 2). Conclusions: The RICHI+TT approach had better long-term donor engraftment with a decreased need for DLI or second transplant without increased rates of non-relapse mortality. Prospective studies are needed to determine the optimal treatment strategies for patients with HLH who require HSCT for cure. Disclosures Heslop: Cell Medica: Research Funding; Tessa Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Marker Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Kiadis: Membership on an entity's Board of Directors or advisory committees; Allovir: Equity Ownership; Gilead Biosciences: Membership on an entity's Board of Directors or advisory committees.

Rituximab for Desensitization during HLA-Mismatched Stem Cell Transplantation in Patients with a Positive Donor Specific Anti-HLA Antibody: A Prospective Study

A prospective, clinical trial in non-manipulated haploidentical allografts was initiated to define the efficacy of a single dose of 375 mg/m2 rituximab as a desensitization regimen for donor-specific anti-HLA antibody (DSA)-positive patients with 2,000 ≤ mean fluorescence intensity (MFI) &lt; 10,000. In the clinical cohort, compared to pretransplantation [median, 4791, n=28], the median MFI levels at day 7 [0], 14 [0], 21 [0], 30 [0], and 45 [0] following transplantation were significantly decreased (P&lt;0.0001 for all). The incidence of primary poor graft function (PGF) in the clinical cohort (n=55) was comparable to that in the matched-pair cohort (n=110) negative for the DSA (5% vs. 1%, P=0.076), both of which were significantly lower than that in the historical cohort (n=22) with 2,000 ≤ MFI&lt;10,000 without receiving any treatment to cope with DSA (27%, P&lt;0.001, for all). Rituximab desensitization was associated with a reduced incidence of primary PGF (HR 0.200, P=0.023). The 3-year non-relapse mortality of patients in the clinical cohort and the matched-pair cohort were 23% and 24%, respectively, both of which were lower than that of patients in the historical cohort (37%), although no statistical significance was observed. These results led to a low 3-year overall survival in patients in the historical cohort (58%) compared to those in the clinical cohort (71%) and the matched-pair cohort (73%). These results suggest that a single dose of rituximab could be effectively used to desensitize patients and prevent the onset of primary PGF in patients who receive HLA-mismatched allografts. This study is registered at http://www.chictr.org.cn/ChiCTR-OPC-15006672. Disclosures No relevant conflicts of interest to declare.

Extracorporeal Mass Exchange Technology Platform for Temporary Liver Support: A Clinical Feasibility Study on a Device and the Cell Source Primary Human Liver Cells

Clinical feasibility phase-I study data are discussed on the use and the safety of a modular mass exchanger for temporary extracorporeal treatment of liver failure; and the use of the cell source primary human liver cells isolated from discarded transplant organs as a metabolic module in this mass exchanger. This technology platform can be compared with the mass exchange functions of a human placenta before giving birth. The "maternal blood side" can be used with various sources/modules of metabolic support including artificial (e.g. absorber) or biological elements (e.g. cells), separated by membrane compartments. These keep the source of metabolic support from contact with the patient, including the immune cells, while allowing exchange of soluble or protein-bound plasma components for therapy. Each of the multiple independent membrane compartments are bundled towards the in/outlets but interwoven to form a decentralized multi-compartment mass exchanger within an effector module compartment. The use of liver cells as a metabolic module in this compartment results in its function as a bioreactor. A combination with further modules outside of the mass exchanger was demonstrated through a continuous SPAD for detoxification. Nine patients (5 m, 4 f) with a median age of 43 years (range 11-55 years) were treated with a total of 11 metabolic modules in 12 sessions, with overall treatment times ranging from 11 to 216 hours. Patients suffered from acute-on-chronic liver failure (AoCLF, n=3), acute liver failure (ALF, n=3) and primary non-function graft after liver transplantation (PNF, n=3). Treatment resulted in a one-year survival of 78%. The results showed a significant decrease in thrombocytes and fibrinogen. No severe adverse effects were found. One patient (AoCLF) recovered without transplantation and remained alive for the one-year follow-up. Six patients (3 ALF, 2 PNF, and 1 AoCLF) were successfully bridged to transplantation, and two (1 AoCLF, 1 PNF) died within ten days after termination of therapy. Total and conjugated bilirubin, ammonia, urea and creatinine were significantly reduced by the end of therapy, compared to baseline. The MELD score decreased significantly, whereas no significant improvements were observed in APACHE-II, APACHE-III, SOFA and Child-Pugh scores. Conclusion: The mass exchanger technology platform, the Core Module used with primary human liver cells as Metabolic Module, proved to be clinically feasible and safe. Further clinical studies are required to prove the efficacy of such therapies. However, the clinical impact of using human liver cells as a Metabolic Module is limited and a reliable, biocompatible and effective metabolic source is in need.

Clinical significance on monitoring different immune cell chimerism of patients after allogeneic hematopoietic stem cell transplantation

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) has been widely used in the treatment of hematologic diseases and other malignant solid tumors. However, there are also a series of problems after allo-HSCT, such as the recurrence of the primary disease, graft rejection (GR), graft versus host disease(GVHD) and so on, which may lead to the failure of transplantation, and are currently important problems affecting the efficacy of allo-HSCT. Dynamic monitoring of chimeric state of donor and recipient cells and timely corresponding clinical treatment have great significance to reduce the recurrence of disease, GR and GVHD. The chimeric state of T cells is related to the occurrence of GVHD after transplantation, and the higher the chimeric rate of T cells in the early stage, the more likely GVHD will occur. The chimeric state of B cells is often correlated with the recurrence after transplantation. In this paper, the clinical significance of dynamic monitoring of chimeric rate of patients after allo-HSCT was elaborated from the monitoring of chimeric rate of different immune cell subgroups and the factors influencing chimeric state, so as to further guide clinical treatment and intervention. Key words: Hematopoietic stem cell transplantation; Transplantation, homologous; Chimerism; Immunity, cellular; Graft vs host disease; Graft rejection