Secondary Graft Research Articles

Post-engraftment Bloodstream Infections After Allogeneic Hematopoietic Cell Transplantation: Risk Factors and Association with Mortality.

Bloodstream infections (BSIs) are major cause of morbidity and mortality after allogeneic hematopoietic cell transplantation (allo-HCT). This study aimed to analyze the incidence, etiology, risk factors and outcomes of post-engraftment BSI in allo-HCT recipients. The retrospective study included 261 patients with documented engraftment after first allo-HCT performed from January 2018 till September 2021. Of 261 patients 29 (11.1%) developed at least one post-engraftment BSIs episode with a median time to post-engraftment BSI of 49 days (range, 1 - 158 days from the engraftment). A total of 45 pathogens were isolated from blood - 64.4% (n = 29) were represented by Gram-negative bacteria, and 35.6% (n = 16) - by Gram-positive bacteria. Secondary graft failure (hazard ratio [HR]: 39.93; 95% confidence interval [CI]: 7.64-208.74; P <0.001), secondary poor graft function (HR: 18.07; 95% CI: 3.53 - 92.44; P <0.001), and acute gut graft-versus-host-disease (GvHD) grade II-IV (HR: 29.86; 95% CI: 10.53 - 84.68; P <0.001) were associated with the higher risk of Gram-negative post-engraftment BSIs. Overall 30-day survival after post-engraftment BSIs was 71.4%. By multivariate analysis post-engraftment BSIs (HR: 3.09; 95% CI: 1.29 - 7.38; P = 0.011), and acute gut GvHD grade II-IV (HR: 6.60; 95% CI: 2.78 - 15.68; P <0.001) were associated with the higher 180-day non-relapse mortality risk. Gram-negative bacteria prevailed in the etiology of post-engraftment BSIs with secondary graft failure. secondary poor graft function. and acute gut GvHD being the main predisposing factors for their development. Post-engraftment BSIs were associated with the higher risk of non-relapse mortality after allo-HCT.

Outcomes of permanent canines on the cleft side after secondary alveolar grafting using different materials in complete unilateral cleft lip and palate.

The prevalence of impaction of the permanent canine on the cleft side (PCCS) ranges from 12-35% after alveolar bone grafting (ABG). PCCSs usually develop above other permanent teeth in the alveolar process, gradually becoming vertical until they reach the occlusal plane. The type of cleft, hypodontia of lateral incisor on the cleft side, slower PCCS root development, and genetic factors are predictors of impaction and/or its ectopic eruption. To compare the behavior of PCCS in individuals with complete unilateral cleft lip and palate (UCLP) subjected to secondary alveolar grafting (SAG) with different materials. This retrospective longitudinal study analyzed 120 individuals undergoing SAG with iliac crest bone, rhBMP-2, and mandibular symphysis. The individuals were selected at a single center and equally divided into three groups. Panoramic radiographs were analyzed by the Dolphin Imaging 11.95 software to measure PCCS angulation and PCCS height from the occlusal plane at two different timepoints. No statistical significance was found between grafting materials (P=0.416). At T1, the PCCS height from the occlusal plane was greater for rhBMP-2 and mandibular symphysis compared to iliac crest bone. The lateral incisor on the cleft side was not related to success or lack of eruption of PCCS (P=0.870). Impaction rates of PCCS were similar for the materials studied. Absence of the lateral incisor on the cleft side did not prevent spontaneous eruption of PCCSs.

Primarni graft parcijalne debljine kože za pokrivanje mekotkivnih defekata šake i prstiju - ne oklevajte

Introduction: Hand injuries often result in soft tissue defects. The treatment of these defects belongs to the most difficult challenges in reconstructive surgery. There are numerous options for covering soft tissue defects, including flaps and skin grafts. Material and methods: This retrospective observational study included seventeen patients with 24 skin defects of the hand, who were treated by primary split-thickness skin graft (STSG) in a single center. The average follow-up period was 6 months. The age of the patients ranged from 36 to 80 years. The majority of patients (n=16) were males, and one patient was female. Skin defects varied in size from 7x8mm to 39x40mm. Primary goals were STSG survival, recipient site infection, and donor site morbidity. Secondary goals were cosmetic appearance and time needed for complete wound healing. Results: All 24 wounds healed successfully in a mean of 28,11±9,94 days. There were no graft infections. Partial graft loss occurred in one case. There was no major donor site morbidity reported. Six patients described the cosmetic result as good (score 3), 10 patients dde-scribed it as acceptable (score 2), and one patient described it as poor (score 1). Conclusion: Split thickness skin graft is an excellent option for immediate treatment of hand and finger skin defects. This method is simple , has less consequences than secondary grafts, requires minimum equipment and can sometimes be done in the emergency room, without hospitalization. Therefore, there is no need to be afraid of primary skin grafting.

Role of Masquelet’s technique in the induction of membrane and secondary bone grafting in patients of long bone fractures with bone loss

Role of Masquelet’s technique in the induction of membrane and secondary bone grafting in patients of long bone fractures with bone loss

Closure of maxillary lateral incisor agenesis space in unilateral cleft lip and palate: a digital model assessment

To compare dental positional and gingival parameters of maxillary anterior teeth in unilateral cleft lip and palate (UCLP) after orthodontic treatment with canine substitution due to lateral incisor agenesis. This split-mouth study comprised 57 subjects with UCLP (31 male, 26 female) and agenesis of maxillary lateral incisor at the cleft side, from a single center. Canine substitution was completed after the secondary alveolar bone graft. Dental models were taken between 2 to 6 months after debonding (mean age: 20.4 years). The following variables were measured in the maxillary anterior teeth: crown height, width, proportion, and symmetry, as well as steps between incisal edges, gingival margins, tooth mesiodistal angulation and labiolingual inclination. Paired t-tests with Bonferroni post-hoc correction was used for comparisons between cleft and non-cleft sides (p<0.05). At the cleft side, canines replacing missing lateral incisors had a higher crown height (0.77mm) and an increased width (0.67mm), and first premolars showed a shorter crown height (1.39mm). Asymmetries were observed in the gingival level of central and lateral incisors, with a greater clinical crown at the cleft side (0.61 and 0.81mm, respectively). Cleft side central incisors were more upright than their contralaterals (2.12º). Maxillary anterior teeth demonstrated positional, size and gingival height differences between cleft and non-cleft side after space closure of maxillary lateral incisor agenesis. Slight asymmetries in tooth position and gingival margin in the maxillary anterior teeth should be expected after orthodontic treatment in UCLP patients.

Upper Extremity Wounds Treated with Biodegradable Temporizing Matrix versus Collagen-Chondroitin Silicone Bilayer

Objective This study aims to compare outcomes between Novosorb Biodegradable Temporizing Matrix (BTM) and Integra collagen-chondroitin silicone for upper-extremity wound reconstruction.Methods This retrospective study analyzed adult patients who underwent wound reconstruction with either BTM or Integra at our institution between 2015 and 2020.Results Forty-eight patients were included: 31 (64.6%) BTM and 17 (35.4%) Integra. Mean age was 44.0 (range: 18–68) years. Age, race, sex, smoking, comorbidities, and defect size were similar between groups. Wound etiologies included 12 (25.0%) burn, 22 (45.8%) trauma, and others. Median template size was 133 cm2 for BTM and 104 cm2 for Integra (p = 0.526). Skin grafting was performed after 14 (45.2%) and 14 (82.4%) wounds treated with BTM and Integra, respectively (p = 0.028). Template complications of infection and dehiscence were comparable. Skin-graft complications occurred in five (35.7%) and three (21.4%) wounds in BTM and Integra, respectively (p = 0.031). Skin-graft failure rates were comparable (p = 0.121). Mean number of secondary procedures required after template placement was higher in the Integra group (BTM, 1.0; Integra, 1.9; p = 0.090). Final healing was achieved in 17 (54.8%) BTM and 11 (64.7%) Integra wounds (p = 0.694). Median time to healing was 4.1 months after BTM and 2.6 months after Integra placement (p = 0.014).Conclusion Compared with Integra, BTM achieved comparable wound healing and complication rates. Fewer secondary procedures and skin grafts were observed in BTM wounds, likely as a result of the coronavirus disease 2019 pandemic. At our institution, 100 cm2 of product costs $850 for BTM and $3,150 for Integra, suggesting BTM as an economical alternative to fulfill the high functional and aesthetic requirements of upper-extremity wounds.

Descemet membrane endothelial keratoplasty in eyes with glaucoma.

Endothelial keratoplasty has become the standard for the treatment of endothelial dysfunction. In Descemet membrane endothelial keratoplasty (DMEK), only the endothelium and Descemet membrane are transplanted, providing superior outcomes compared to Descemet stripping endothelial keratoplasty (DSEK). A substantial subset of patients who require DMEK have comorbid glaucoma. Even in eyes with complex anterior segment such as eyes with previous trabeculectomy or tube shunts, DMEK can restore meaningful vision and outperforms DSEK in terms of visual recovery, decreased rejection rate, and the need for high dose of topical steroids. However, accelerated endothelial cell loss and secondary graft failure have been described in eyes with previous glaucoma surgery, namely trabeculectomy and drainage device. During DMEK and DSEK procedures, raised intraocular pressure is required to attach the graft, which could worsen preexisting glaucoma or cause de novo glaucoma. Mechanisms of postoperative ocular hypertension include delayed air clearance, pupillary block, steroid response, and damage to angle structures. Medically treated glaucoma has increased risk for postoperative ocular hypertension. By understanding these additional complications and making appropriate modifications in surgical techniques and postoperative management, DMEK can be performed successfully and achieve very good visual outcome in eyes with glaucoma. Such modifications include precisely controlled unfolding technique, iridectomies that can help avoid pupillary block, tube shunts that can be trimmed to facilitate graft unfolding, air fill tension that can be adjusted, and postoperative steroid regimens that can be modified to decrease the risk for steroid response. Long-term survival of the DMEK graft, however, is shorter in eyes with previous glaucoma surgery than those without, as observed after other types of keratoplasty.

Erratum.

Figures 1 and 2 were inadvertently switched and printed with the wrong legends in “Does absence of maxillary lateral incisor affect the status of maxillary canine before and after secondary alveolar bone grafting in patients with unilateral alveolar cleft?,” by Hyunseung Hong, Il-Hyung Yang, Jin-Young Choi, Jong-Ho Lee, Jee Hyeok Chung, Sukwha Kim, and Seung-Hak Baek.Angle Orthod.2022;92:683– 690. These have been corrected in the online version.

Post-Transplant Cyclophosphamide, Tacrolimus, and Mycophenolate Mofetil As the New Standard for Graft-Versus-Host Disease (GVHD) Prophylaxis in Reduced Intensity Conditioning: Results from Phase III BMT CTN 1703

Introduction: Controlling both GVHD and disease relapse is essential for allogeneic hematopoietic cell transplantation (alloHCT) success. For three decades, the standard GVHD prophylaxis strategy has been a calcineurin inhibitor such as tacrolimus (Tac) plus methotrexate (MTX). Although several approaches have been tried in recent years to improve upon Tac/MTX, intensifying immunosuppression frequently comes with an increased risk of serious infections or relapse and usually no effect on chronic GVHD even if acute GVHD is reduced. The Blood and Marrow Transplant Clinical Trials Network (BMT CTN) previously completed a phase II study comparing three novel GVHD prophylaxis regimens to contemporaneous controls receiving Tac/MTX (BMT CTN 1203) in order to determine the most promising novel GVHD prophylaxis approach with reduced intensity conditioning (RIC). The most promising GVHD prophylaxis regimen in BMT CTN 1203 was a 3-drug combination of post-transplant cyclophosphamide (PTCy), tacrolimus, and mycophenolate mofetil (PTCy/Tac/MMF). Here, we report the results of the randomized phase III study comparing outcomes of alloHCT in those randomized to receive PTCy/Tac/MMF versus standard Tac/MTX. Patients and Methods: Eligible adults (age 18+) with hematologic malignancies undergoing RIC alloHCT with an 6/6 matched related (N=128), 8/8 matched unrelated (N=288), or 7/8 single mismatch (N=15) peripheral blood stem cell donor, satisfactory organ function, and adequate performance status were randomized 1:1 to receive PTCy/Tac/MMF (N=214) or Tac/MTX (N=217), stratified by transplant center and Disease Risk Index (DRI). The primary endpoint of the study was GVHD/relapse or progression-free survival (GRFS), a time-to-event outcome defined as grade III-IV acute GVHD, chronic GVHD requiring systemic immune suppression, disease relapse or progression, or death by any cause. The primary hypothesis was that PTCy/Tac/MMF has a ≥15% higher GRFS at 1 year than Tac/MTX in the intent-to-treat population. Secondary endpoints included the incidence/severity of acute and chronic GVHD, engraftment/chimerism, relapse/progression, infections, and survival. Results: The 2 study arms were well balanced by patient sex, age, Karnofsky performance status, disease risk, comorbidities, donor match, conditioning regimen, and post-transplant maintenance therapy (Figure panel A). In the multivariate Cox regression model of the primary endpoint, the PTCy treatment group had a significantly lower hazard of GRFS than Tac/MTX (hazard ratio 0.641, 95% confidence interval [CI] 0.492 to 0.835, p=0.001). The adjusted 1-year GRFS rate was 52.7% (95% CI: 45.8%, 59.2%) for the PTCy arm and 34.9% (95% CI: 28.6%, 41.3%) for the control arm, Figure panel B). The lower proportion of GRFS events in the PTCy arm was due to a reduction in both acute and chronic GVHD. The Day 100 grade III-IV acute GVHD was 6.3% vs 14.7% (p=0.001), and chronic GVHD rate at 1 year was 21.9% vs 35.1% (p=0.005) for PTCy vs Tac/MTX, respectively. There was no difference in the relapse/progression rate at 1 year (20.8% vs 20.2%, p=0.9), or OS rate at 1 year post transplant (76.8% vs 72.6% , p=0.3), in PTCy vs Tac/MTX. The cumulative incidence of engraftment was lower for PTCy for neutrophils ≥ 500/mm3 by day +28 (90.3% vs 93.4%, p=0.03), platelets ≥ 50,000/mm3 by day +100 (79.5% vs 83.7%, p<0.001), and lymphocytes ≥ 1000/mm3 by 1 year (47.1% vs 63.2%, p<0.001). Grade 3 infection rates were similar between the arms (12.2% for PTCy vs 13.3%, p=0.8) but grade 2 infections were greater for PTCy (33.7% vs 23.5%, p=0.002). There was no difference in CMV reactivation between the treatment arms (7.3% for PTCy vs 7.1%, p=0.8). There was no significant difference in proportion of chimerism at day +100 (>95% donor in 68.6% for PTCy vs 67.8%, p=0.2) or secondary graft failure between the arms (2.9% for PTCy vs 0.9%, p=0.2). Conclusions: BMT CTN 1703 met its primary endpoint, demonstrating a higher 1-year GRFS with PTCy/Tac/MMF compared to Tac/MTX owing to significant improvements in GVHD risk without increased risk of relapse or death. PTCy/Tac/MMF, which has become standard of care for mismatched transplants, should also become the standard of care for GVHD prophylaxis from closely-matched donors receiving reduced intensity conditioning. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Long-Term Follow-Up of Biological Reconstruction with Free Fibular Graft after Resection of Extremity Diaphyseal Bone Tumors

This study aimed to evaluate the clinical outcomes and complications of reconstruction with a composite free fibula inside other biological grafts. We retrospectively reviewed 26 patients who underwent reconstruction after bone tumor resection of the diaphysis of the long bone. Surgical data, time to bony union, functional outcomes, and complications were evaluated in all cases. The median follow-up was 72.5 months. The limb salvage rate was 100%. Primary osseous union was achieved in 90.4% of the junctions. The union rates at the metaphyseal and diaphyseal junctions were 100% and 85.7%, respectively (p = 0.255). The mean time of bony union in the upper (87.5%) and lower (91.7%) extremity was 4.6 ± 1.6 months and 6.9 ± 2 months, respectively. The mean MSTS score was 27.2 ± 3.2, with a mean MSTS rating of 90.7%. Complications occurred in 15.4% of the cases. The administration of vascularized or non-vascularized grafts did not significantly influence the union time (p = 0.875), functional outcome (p = 0.501), or blood loss (p = 0.189), but showed differences in operation time (p = 0.012) in lower extremity reconstruction. A composite free fibula inside other biological grafts provides a reasonable and durable option for osseous oncologic reconstruction of the long bone diaphysis of the extremities with an acceptable rate of complications. A higher union rate was achieved after secondary bone grafting. In lower-extremity reconstruction, two plates may be considered a better option for internal fixation. Vascularizing the fibula did not significantly affect the union time.

The chameleon of herpetic keratitis

AbstractIn Europe, herpes simplex virus type I (HSV) is a common cause of keratitis. The disease may be well treated if the ophthalmologist is aware of the various types of clinical expressions of this typical unilateral chameleon, and treatment is adjusted accordingly. Types of expression include 1. epithelial keratitis (dendritica/ geographica), 2. stromal keratitis (necrotizing “ulcer” “vs. non‐necrotizing = interstitial keratitis”), 3. endotheliitis (= “disciform keratitis”), 4. so‐called “metaherpetic keratitis” (= neurotrophic keratopathy), 5. (vascularized) corneal scars. In the acute phase, concomitant ocular hypertension should be treated predominantly without surgery (no prostaglandin analoga!). After keratoplasty and in case of severe recurrences of herpetic keratitis, systemic acyclovir application (2 × 400 mg/day) for at least 1 year is indispensable! In 1.5% of corneal excisions during keratoplasty, HSV PCR is positive without clinical suspicion of herpetic keratitis. This may be one reason for primary or secondary graft failure and needs adequate treatment.

Infectious Crystalline Keratopathy after Penetrating Keratoplasty with Light and Electron Microscopic Examination.

To highlight the typical histological and ultrastructural features of severe infectious crystalline keratopathy (ICK) in a corneal graft, which required excimer laser-assisted repeat penetrating keratoplasty (PKP) and to present the challenging treatment conditions associated with ICK. An 85-year-old female patient underwent PKP for secondary graft failure after Descemet membrane endothelial keratoplasty (DMEK) for Fuchs' endothelial corneal dystrophy in the left eye. One year later, white branched opacities were observed in the superficial corneal stroma of the graft without surrounding inflammation in the left eye. The patient underwent excimer laser-assisted repeat PKP (8.0/8.1 mm) in the left eye after prolonged refractory topical anti-infectious treatment for 1 month. The corneal explant was further examined by light and transmission electron microscopy (TEM). The light microscopic examination of the corneal explant demonstrated aggregates of coccoid bacteria in the superficial and mid-stromal region that were positive for periodic acid-Schiff (PAS) and Gram stain. The bacterial aggregates extended into the interlamellar spaces, showed a spindle-shaped appearance, and were not surrounded by an inflammatory cellular reaction. TEM demonstrated lamellae separation within the anterior corneal stroma with spindle-shaped aggregates of bacteria, which were embedded in an extracellular amorphous matrix with incipient calcification, being consistent with a biofilm. No inflammatory cellular reaction was evident by TEM. At discharge from hospital, the corrected visual acuity was 20/80 in the left eye. ICK is often challenging due to the difficult diagnosis and treatment conditions. The refractory courses are mainly attributed to a biofilm formation, which inhibits effective topical anti-infectious treatment. In such cases, (repeat) PKP may be necessary to completely remove the pathology, prevent recurrences, and improve vision.

Anterior Dental Implant in Grafted Cleft Alveolus: A Clinical Comparison Between Intramembranous and Endochondral Bone Graft.

Alveolar bone graft is usually performed during the early mixed dentition phase, at the chronological age of 6 to 8 years old, to reconstruct the cleft alveolus. As the appropriate time for implant placement is after completion of full growth, it can result in a likelihood of resorption. The aim of this study is to compare the clinical outcomes of anterior dental implants with delayed bone grafting using iliac crest (endochondral) and mandibular ramus or symphysis (intramembranous) bone in adolescents to adulthood patients with cleft alveolus. This study included 10 patients with cleft alveolus who underwent delayed bone grafting with autogenous block bone and particulate cancellous bone and marrow (PCBM) from the mandibular ramus and symphysis with dental implant placement, and iliac crest. The success of the treatment was evaluated through clinical and radiographic examination including marginal bone loss measurement of the implants. All patients underwent delayed bone grafting between the ages of 11 and 21.1 years (mean age: 15.1±4.3y). The implant diameters ranged from 3.8 to 4.5mm and the lengths ranged from 8.0 to 11.5mm. All of the implants were integrated successfully and survived during the 3-year follow-up period. Delayed bone grafting followed by implant placement showed long-term stability with satisfactory esthetic and functional rehabilitation. One of the main advantages of delayed bone grafting is to achieve adequate bone support for future dental implant placements with less bone resorption compared with those of primary, early secondary, and secondary bone grafting.

Secondary Autologous Fat Grafting for the Treatment of Chin Necrosis as a Consequence of Prone Position in COVID-19 Patients.

Due to the spread of the coronavirus disease 2019 pandemic, an increasing number of ill patients have been admitted to intensive care unit requiring mechanical ventilation. Although prone positioning is considered beneficial, long periods in this position may induce important complications, including pressure ulcers in high-risk and uncommon body areas. We report five cases of pressure ulcer necrosis of the chin in coronavirus disease 2019 patients as a consequence of mechanical ventilation in prone positioning using autologous fat grafting (AFG) as a secondary technique. A series of five patients with secondarily-healed chin necrosis treated by AFG between February and June 2020 were reviewed. All patients had been treated initially with surgical debridement followed by conservative treatment. Secondary AFG was performed to reduce patient's pain, improve chin contour-projection, and minimize cosmetic sequelae and scarring. Patient satisfaction was assessed using a five-point Likert scale (0-4). Vancouver scale was used to evaluate the chin scars clinically. The average amount of fat injected into the chin area was 8.1 ± 2.0 ml. At 6-month follow-up, all patients were mostly satisfied (average Likert-scale 3.2 ± 0.4). Based on the Vancouver scale, improvement of the chin scar from 9.5 ± 0.8 to 4.7 ± 0.8 was found. We report a positive experience with secondary AFG for correction of painful and unaesthetic scarring and contour abnormality following surgical debridement and secondary-intention healing of chin pressure ulcers.

G-CSF Improves Stable Engraftment in Adults with Sickle Cell Disease Undergoing Nonmyeloablative Hematopoietic Stem Cell Transplantation

Allogeneic hematopoietic stem cell transplantation (HSCT) is curative in patients with sickle cell disease (SCD). HSCT using nonmyeloablative conditioning leads to a mixed chimerism that improves the SCD phenotype but may be complicated by the continued need for immunosuppression and graft loss. Granulocyte colony stimulating factor (G-CSF) may stimulate progenitor cells and is used post-HSCT to reduce the duration of neutropenia and the risk of neutropenic fever. G-CSF has been generally avoided in patients with SCD due to its risk of promoting vaso-occlusion (PMID 19513902). Starting in 7/2016, our institution administered G-CSF after day +5 post-HSCT on the days when the ANC was < 500 x103/µL. In this study, we evaluated whether G-CSF is safe and can improve the duration of neutropenia, infection risk, and donor chimerisms in adults with SCD undergoing non-myeloablative HSCT. We included 34 adults with SCD that underwent allogeneic HSCT from an HLA-matched sibling donor in our institution and were conditioned with alemtuzumab and total body irradiation (TBI) (PMID 33534948) between 11/2011 and 8/2021. Medical records were individually reviewed for data extraction. Linear and categorical outcomes were compared by G-CSF use with the Kruskal-Wallis and chi-square test, respectively. We also compared the Kaplan-Meier curves for discontinuation of immunosuppression with the log-rank method. Median and interquartile range (IQR) are provided. The median age of our cohort was 33 years (IQR, 26 - 45 years), 18 (53%) patients were female, and 30 (88%) had hemoglobin SS genotype. We did not observe statistically significant differences in baseline characteristics between the SCD patients that received G-CSF versus did not receive G-CSF for median age (37 years vs. 32 years), female gender (69% vs. 43%), hemoglobin SS genotype (85% vs. 90%) or median CD34+ dose (8.6 vs. 8.1 x 106/kg), respectively. In the 13 SCD patients that received G-CSF, the median day when it was initiated was day +10 (IQR, 7 - 17) and for a median of 3 days (IQR, 2 - 7 days). The maximum pain score during hospitalization was not significantly different in the SCD group that received G-CSF (median 8, IQR, 7 - 10) compared to those that did not receive G-CSF (median 10, IQR, 9 - 10). Median time to neutrophil engraftment (G-CSF: day 16 vs. no G-CSF: day 22) and duration of neutropenia (G-CSF: 7 days vs. no G-CSF: 9 days) were relatively similar between the 2 groups, while the incidence of neutropenic fevers trended lower with G-CSF treatment (8% vs. 29%, respectively, P=0.1). Whole blood or myeloid chimerism values were significantly higher in the SCD patients that received G-CSF at day +30, +90, +180, and 1 year post-HSCT (Figure 1A). Secondary graft loss was not observed after we implemented G-CSF while 4 out of 21 (19%) of patients experienced secondary graft failure who did not receive post-HSCT G-CSF. Furthermore, in those patients with stable engraftment, we observed a trend for more patients who received G-CSF being successfully tapered off immunosuppression (11/13, 85%) versus those that did not receive G-CSF (10/17, 59%) (Figure 1B). In conclusion, administration of G-CSF to patients with SCD undergoing HSCT conditioned with alemtuzumab/TBI was associated with significantly higher whole blood or myeloid donor chimerism values. This benefit was achieved without a significant increase in pain scores during the hospitalization for HSCT and was associated with trends for a greater proportion of patients discontinuing immunosuppression and less secondary graft loss. Future studies investigating the effects of G-CSF on donor myeloid progenitor cells and on T-cell clearance may guide strategies to improve outcomes for curative therapies in adults with SCD. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Methods of plastic surgery of the alveolar process in children with congenital cleft lip and palate

Alveolar cleft is a tornado-shaped bone defect in the maxillary arch. The treatment goals for alveolar cleft are stabilization and provision of bone continuity to the maxillary arch, permitting support for tooth eruption, eliminating oronasal fistulas, providing an improved esthetic result, and improving speech. Treatment protocols vary in terms of the operative time, surgical techniques, and graft materials. Early approaches including boneless bone grafting (gingivoperiosteoplasty) and primary bone graft fell into disfavor because they impaired facial growth, and they remain controversial. Secondary bone graft (SBG) is not the most perfect method, but long-term follow-up has shown that the graft is absorbed to a lesser extent, does not impede facial growth, and supports other teeth. Accordingly, SBG in the mixed dentition phase (6–11 years) has become the preferred method of treatment. The most commonly used graft material is cancellous bone from the iliac crest. Recently, many researchers have investigated the use of allogeneic bone, artificial bone, and recombinant human bone morphogenetic protein, along with growth factors because of their ability to decrease donor-site morbidity. Further investigations of bone substitutes and additives will continue to be needed to increase their effectiveness and to reduce complications.

Comparison of Hematopoietic Stem Cell Transplantation and Immunosuppressive Therapy for Patients with Severe Hepatitis-Associated Aplastic Anemia

Background：Hepatitis-associated aplastic anemia (HAAA) is known as a rare variant of acquired aplastic anemia, characterized by a syndrome of bone marrow failure following the development of hepatitis. Immunosuppressive therapy (IST) or hematopoietic stem cell transplantation (HSCT) could provide lifesaving opportunities for severe HAAA patients. However, to date, no cohort has characterized treatment outcome and long-term survival between those patients receiving IST and HSCT. In this study, we aim to retrospectively evaluate the outcome of these two therapies for severe HAAA in China. Methods: Patients consecutively diagnosed as severe HAAA between August 2008 and Jan 2021 were enrolled in this study. The definition of severe HAAA is that severe aplastic anemia developed within three months after documented hepatitis. The enrollments were patients who received HSCT or IST as a first-line treatment. Patients with HSCT were conditioned as described previously with cyclophosphamide (Cy, 120-150 mg/kg, divided doses on days -6 to -2), and rabbit ATG (Thymoglobulin®, Genzyme, Cambridge, MA) (2.5mg/kg once i.v. daily on days -6 to -2) or p-ALG (Anti-lymphocyte Immunoglobulin®, Wuhan Institute of Biological Products Co., Ltd., China) (20mg/kg once i.v. daily on days -6 to -2), Fludarabine 150 mg/m2 i.v.in divided doses on days -6 to -2, with or without Busulfan (Bu, 0.8 mg/kg four times i.v. daily on days -7 and -6). IST consisted of both rabbit ATG (rATG) (3~3.75mg/kg once i.v. daily on 5 days), porcine antilymphocyte globulin (pALG)(20mg/kg once i.v. daily on 5 days), combined with a six-month course of cyclosporine (3mg per kilogram per day orally, with adjustment of the dose to maintain a blood level between 200 and 400 ng per milliliter). Probabilities of overall survival (OS), failure-free survival (FFS), and treatment-related-mortality (TRM) were calculated by Kaplan-Meier method. Results and Discussion: This study retrospectively included 94 consecutive HAAA patients, including 68 patients underwent HSCT and 26 patients receiving IST. The IST and HSCT groups were similar with respect to age and gender ratio. The median follow up were 1752 (±153.62, 95%CI 1450.90~2053.10) days, and 2648 (±321.41, 95%CI 2018.05-3277.96) days among alive patients in the IST and HSCT group, respectively. In HSCT group, all patients achieved neutrophil engraftment. No primary or secondary graft failures (GF) was documented. Compared with patients receiving alternative donor HSCT (n=11), patients in matched sibling donor HSCT (MSD-HSCT) group (n=15) had a significant lower cumulative incidence of acute graft versus host disease (aGVHD) (20±10.33% vs 56.4±15.47%, p=0.048), and lower incidence of cytomegalovirus (CMV) reactivation group (72.73% vs 13.33%, p=0.004). No clinical significance of chronic graft versus host disease (cGVHD) incidence group (43.4±18.85% vs 50±35.4%, p=0.78) and bacterial/fungus infection (26.67% vs 36.36%, p=0.683) was found between MSD-HSCT group and alternative donor-HSCT. Attributable causes of death were pneumonias and severe infection in patients receiving HSCT. In IST group, the hematology response rate to treatment evaluated at 3m, 6m and 12m was 27.68%, 52.94%, and 60.23%, respectively. There were thirteen patients were non-evaluable, including six patients transferred to perform HSCT, two patients were diagnosed MDS/AML transformation and one patient relapsed. The 5-year overall survival (OS) and failure-free survival (FFS) rate was 85.5±4.44% (95% CI, 0.772, 0.946) and 69.6± 5.35% (95% CI, 0.599,0.809) of all enrolled HAAA patients, respectively (Figure 1). For patients receiving different therapy, the 5-year OS rates were 92.86 ± 6.88% in MSD-HSCT group, 72.7± 13.43% in alternative donor-HSCT, and 84.1 ± 7.28% in the IST group (P = 0.56). Otherwise, the 5-year estimated FFS rate was 56.0± 11.51% in the IST group, compared with 92.86 ± 6.88% in the MSD-HSCT group and 72.7± 13.43% in alternative donor-HSCT group (P = 0.10). The cumulative incidence of treatment-related-mortality (TRM) of MSD-HSCT, alternative-HSCT and IST was 7.1±6.9% (95% CI, 80.30-100), 27.3±13.4% (95% CI, 50.60-100), 14±5.54% % (95% CI, 7.58-97.6) (p=0.22), respectively. Even there was no difference between the HSCT and IST groups in OS, MSD-HSCT group still showed superior FFS. Patients receiving alternative donor HSCT, and IST showed comparable OS and FFS. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Outcomes of Non-Myeloablative HLA-Haploidentical Bone Marrow Transplant with Thiotepa and Post-Transplant Cyclophosphamide in Children and Adults with Sickle Cell Disease, a Phase II Trial: Vanderbilt Global Haploidentical Transplant Learning Collaborative (VGC2)

Introduction: Related reduced-intensity HLA-Haploidentical bone marrow transplant (haplo-BMT) expands the donor pool to approximately 90% of children and adults with sickle cell disease (SCD). In 2013, we developed the multi-institutional Vanderbilt Global Haploidentical Learning Collaborative to optimize haplo-BMT for SCD. In a Phase II clinical trial, we developed a protocol focused on improving engraftment rates by augmenting the original Hopkins haplo-BMT approach (Bolaños-Meade et al. Blood 2012) with thiotepa. We initially demonstrated durable engraftment in 93% (14/15) of participants (including 2 with previous graft rejection) and a 100% overall survival after a median follow-up of 13.3 months (de la Fuente et al. BBMT 2019). We present the results of our phase-II trial (ClinicalTrials.gov identifier NCT01850108). Material and methods: The trial opened in October 2013, and each site has a standalone Institutional Review Board-approved protocol with institutional-specific eligibility criteria and a data-sharing agreement with Vanderbilt University Medical Center. A DSMB assessed the aggregate results for participant safety and clinical trial futility. Collaborators met via videoconferencing initially weekly and then bi-weekly to discuss best practices. The common conditioning regimen included: thymoglobulin 4.5 mg/kg, thiotepa 10 mg/kg, fludarabine 150 mg/m2, cyclophosphamide 29 mg/kg and TBI 2Gy. Graft-versus-host disease (GVHD) prophylaxis included post-transplant cyclophosphamide 100 mg/kg, mycophenolate mofetil, and sirolimus. Bone marrow was the donor source and was primed with filgrastim (5-10 μg/kg/d x5 days) in 11% (9/80) of haploidentical donors. Primary and secondary graft failure was defined as <5% donor myeloid/lymphoid whole blood chimerism at Day>28 and >Day+28 (after initial engraftment), respectively. Primary endpoints were 1-year and 2-year EFS. Primary or secondary graft failure and death were considered events. Safety stopping rules were implemented, independent of age, based on graft failure, death, grade III or IV acute GVHD, or moderate or severe chronic GVHD. Local treating physicians classified the severity of chronic GVHD. Results: At the interim analysis of May 1, 2022, we report results from patients enrolled from 8/14/2014 - 2/28/2022. Final enrollment is a total of 80 participants from 7 sites, 45% were male. Donors were siblings (42.5%), parents (53.8%), daughters (2.5%) and cousins (1.3%); 83.8% (n=67) had sickle cell trait. Participants clinical and laboratory data are listed in table 1. Graft failure occurred in 12.5% (10/80) of the participants, with 4 primary and 6 secondary graft failures, table 2. All graft failures were in participants <18 years of age, and all had autologous reconstitution. For engrafted participants, the median whole blood chimerism values for D+180 and D+365 post-transplant was 100% (n=67; IQR: 99.8 - 100; Range 30.0 - 100) and 100% (n=50; IQR: 100 - 100; Range 95.0 - 100), respectively. Among engrafted participants, 97.7% (43/44) were off immunosuppression at D+365 post-transplant. The incidence of grades III-IV acute and moderate/severe chronic GVHD were 8.8% (7/80) each. The median follow-up time was 1.4 years, based on the time of graft failure, death, or May 1, 2022. Mortality was 5.0% (4/80), Table 2. A Kaplan-Meier analysis for survival found no difference by age group <18 years or >18 years of age (p=0.760). Kaplan-Meier based probability of overall survival was 96.7% (95% CI 87.1% - 99.2%) at one year and 94.3% (95% CI 83.0% - 98.2%) at two years. Results of the final analysis of primary and secondary endpoints (1- and 2-year EFS) will be submitted for publication after all participants have been followed for a minimum of one year (anticipated 2/23). Conclusion: Our Vanderbilt Global Haploidentical learning collaborative is a successful and efficient approach to sharing best practices and implementing curative therapy for SCD. After 8 years, we have shown low mortality rate and 100% engraftment in adults using our haplo-BMT regimen. Three new research questions have emerged in the consortium: 1. What strategies can we develop to address the high graft failure in children? 2. How can we optimize supportive care practices and minimize severe infectious complications in adults? 3. What are the heart, lung, kidney, and other late-health effects after curative therapy? Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Efficacy and Safety of Allogenic Hematopoietic Stem Cell Transplant in Paroxysmal Nocturnal Hemoglobinuria: A Single Centre Study from Pakistan

Background: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired disorder of clonal hematopoiesis1 .The resulting abnormalities in complement regulatory proteins can manifest as hemolysis, thrombosis, and marrow failure2. The management and clinical outcomes of patients with PNH significantly changed with the development of complement inhibitor therapies3. Allogenic Hematopoietic stem cell transplant (HSCT) despite being the sole curative option for PNH is not recommended as first line therapy owing to its toxicities 4,5. Current indications for HSCT include a suboptimal response to eculizumab, severe AA/PNH, clonal evolution to myelodysplastic syndrome (MDS), or acute myelogenous leukemia2. However, in low and middle income countries (LMIC) where complement inhibitor therapies are not available, allogenic HSCT still remains the only treatment option for classical PNH as well as for PNH in the setting of another specified bone marrow disorder. Objective: To analyze the efficacy and safety of Allogenic HSCT in patients with paroxysmal nocturnal hemoglobinuria (PNH). Study design: Observational, retrospective study. Place and duration of study: Armed Forces Bone Marrow Transplant Centre/ National Institute of Blood and Marrow Transplant (AFBMTC/NIBMT) Rawalpindi, Pakistan, from June 2008 till February 2022. Methodology: From June 2008 till February 2022, a total of 65 patients of PNH were registered at AFBMTC/NIBMT. Out of these16 patients underwent allogenic HSCT and were included in the final retrospective analysis. PNH diagnosis was confirmed by flow cytometry by the demonstration of GPI-negative cells in at least two cell lineages i.e neutrophils, red blood cells (RBCs) in 62.5% (n=10) patients and by fluorescent aerolysin (FLAER)-based assay in 37.5% (n=6) patients. Median time from diagnosis to transplant was 380 days. All patients received HLA identical sibling donor HSCT. Stem cell source was Bone marrow harvest (BMH), BMH plus peripheral blood stem cell (PBSC) and PBSC alone in 81% (n=13), 12.5% (n=2) and 6% (n=1) patients respectively. Graft versus host disease (GVHD) prophylaxis was with Antithymocyte globulin (ATG) + Cyclosporin (CSA) in patients receiving NMA conditioning or ATG + CSA + short term Methotrexate (MTX) in those receiving MAC. Results: Median age of the study cohort was 24 years (range, 18 to 42 years) and all were male. 68.7% (n=11) patients received immunosuppressive therapy before HSCT with partial or no response. History of thrombosis prior to HSCT was present in only one patient (cPNH). Allogenic HSCT done for classical PNH (cPNH) in 75% (n=12) patients and for PNH in the setting of another specified bone marrow disorder (PNH/AA) in 25% (n=4) patients. Patients with classical PNH received Myeloablative conditioning (MAC) i.e Flu150Bu12.8IV (75%, n=9), Bu16Cy120 (8.3%, n=1), or Flu150Cy200 (8.3 %, n=1) except for one patient who received Flu150Cy160. Patients with PNH/AA, received non myeloablative conditioning (NMA) i.e Flu150Cy120, except for one who received Flu150Bu12.8IV. Out of 16 patients, 94% (n=15) patients achieved successful engraftment with full donor chimerism. One patient (cPNH) had Primary graft failure. Median time to neutrophil and platelet engraftment was day +12 and day +22 respectively. Disease relapse was monitored by donor chimerism till Day +180 post BMT and thereafter by peripheral blood counts. PNH clone post BMT was not tested. Incidence of acute GVHD grade I/II involving skin and gut, was 25% (n=4). No incidence of chronic GVHD was noted. One patient (PNH/AA) had secondary graft failure on Day +46. With a median post-transplant follow-up of 15 months (range, 4 to 157) overall survival (OS) was 93.7% and disease-free survival (DFS) was 87.5%. Conclusion: In resource constrained, LMIC, where complement inhibitor therapies are currently unavailable, allogenic HSCT remains the valid option for treatment of PNH, with good overall survival rate and acceptable treatment related toxicites. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Splenic Irradiation Prior to Allogeneic Hematopoietic Cell Transplantation for Patients with Myelofibrosis

Background: Myelofibrosis (MF) is a clonal stem cell neoplasm characterized by excess fibrous tissue formation in the bone marrow. Allogeneic hematopoietic cell transplantation (HCT) is the only curative treatment for MF. Patients with MF often have compensatory splenic extramedullary hematopoiesis leading to splenomegaly, which is associated with delayed engraftment and decreased survival post-HCT. Several Janus kinase (JAK) inhibitors are approved to treat splenomegaly and systemic symptoms in MF patients. However, JAK inhibitor therapy does not always lead to complete resolution of splenomegaly. Therefore, splenic irradiation (RT) prior to HCT may benefit patients with persistent splenomegaly, yet research investigating outcomes of this therapeutic approach is limited. Methods: We conducted a single-center, retrospective cohort study of MF patients to characterize the feasibility of splenic RT and assess engraftment rates and post-transplant outcomes with this approach. Forty-eight MF patients who underwent HCT at Massachusetts General Hospital between 2011 to 2021 were identified using an institutional transplant database. Patient disease- and transplant-related characteristics were summarized according to splenic RT within 3 months prior to transplant. Results: Baseline disease- and transplant-related characteristics are displayed in Table 1. Among all patients, twenty-nine (60%) were male, and the median age was 67 years (range, 53-77). All patients received reduced intensity conditioning, with a majority (81%) receiving fludarabine with melphalan. Seventy-three percent of patients had a JAK2 mutation and 46% received ruxolitinib (RUX) prior to HCT. A total of 17 (35%) patients received splenic RT prior to transplant. Splenic RT ranged from 2 daily doses of 1 Gy to 5 daily doses of 1.5 Gy, with total radiation ranging from 2 Gy to 7.5 Gy. Splenic RT was administered at a median of 13 days prior to transplant (range, 7-69 days). All splenic RT patients had splenomegaly prior to transplant, and 11 (65%) were treated with RUX prior to HCT. Patients receiving splenic RT had significantly larger spleen sizes prior to transplant (23.1 v. 17.3 cm, p<0.01), and were more likely to have at least one high molecular risk (HMR) mutation than patients in the no RT group (83% v. 33%, p=0.01). For the entire cohort, the median days to neutrophil engraftment and platelet engraftment was 14 and 23, respectively. Among splenic RT patients, there was one case of primary graft failure and one case of secondary graft failure. The median days to neutrophil engraftment was 15 (IQR, 13-19) for the RT group and 13 (IQR, 12-14) for the no RT group (p=0.07). The median days to platelet engraftment was 32 (IQR, 25-108) for the RT group and 22 (IQR, 18-25) for the no RT group (p<0.01). Three splenic RT patients (18%) died early without platelet engraftment. When RUX was accounted, patients with RT and RUX had a substantially delayed platelet engraftment compared to no RT and/or no RUX (69.5 days vs 19.5-22.5 days, p=0.03) [Figure 1]. For the entire cohort, the 3-year overall survival (OS) and progression-free survival (PFS) was 67% (95%CI: 50%-79%) and 61% (95%CI: 45%-74%), respectively. The cumulative incidence of non-relapse mortality (NRM) and relapse was 26% (95%CI: 13%-40%) and 13% (95%CI: 5%-24%), respectively. Despite delayed platelet engraftment, survival outcomes were not different between RT and no RT, regardless of pre-HCT RUX exposure. Conclusion: Splenic RT administration prior to HCT appears feasible and associated with acceptable engraftment and clinical outcomes for MF patients with splenomegaly at the time of transplant. The persistence of massive splenomegaly at transplant following pre-transplant RUX is likely indicative of higher risk disease and remains associated with longer time to platelet engraftment, despite the addition of splenic RT. Larger prospective studies are required to fully assess the clinical impact of splenic RT in the transplant setting, especially in combination with other therapeutic strategies. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal