Isocitrate dehydrogenase (IDH) 1 and 2 mutations predict better outcome in patients with acute myeloid leukemia undergoing allogeneic hematopoietic cell transplantation: a study of the ALWP of the EBMT.

Isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) mutations have uncertain prognostic implications in AML. We investigate the impact IDH1 and IDH2 mutations in AML patients undergoing allogeneic hematopoietic cell transplantation (allo-HCT) in first complete remission (CR1). In total, 1515 adult patients were included, 15.91% (n = 241) carried IDH1 mutation (mIDH1), and 26.27% (n = 398) IDH2 mutation (mIDH2) and 57.82% (n = 876) had no-IDH mutation. NPM1 was frequently encountered with IDH1 mutation (no-IDH group, n = 217, 24.8%, mIDH1, n = 103, 42.7%, mIDH2, n = 111, 27.9%, p < 0.0001). At day 180, the cumulative incidence (CI) of grade II-IV acute graft-versus-host disease (GVHD) was significantly lower in mIDH1 and mIDH2 compared to no-IDH groups (Hazard ratio [HR] = 0.66 (95% CI 0.47-0.91), p = 0.011; HR = 0.73 (95% CI 0.56-0.96), p = 0.025, respectively). In the mIDH1 group, overall survival (OS) was improved compared to no-IDH (HR = 0.68 (95% CI 0.48-0.94), p = 0.021), whereas mIDH2 was associated with lower incidence of relapse (HR = 0.49 (95% CI 0.34-0.7), p < 0.001), improved leukemia free survival (LFS) (HR = 0.7 (95% CI 0.55-0.9), p = 0.004) and OS (HR = 0.74 (95% CI 0.56-0.97), p = 0.027). In the subgroup of NPM1 wild type, only IDH2 was associated with improved outcomes. In conclusion, our data suggest that IDH1 and IDH2 mutations are associated with improved outcomes in patients with AML undergoing allo-HCT in CR1.

Rare coronary artery variants are associated with increased mortality and reinterventions following the arterial switch operation.

OBJECTIVE: To determine the influence of coronary anatomy on long-term outcomes of the arterial switch operation (ASO). METHODS: We retrospectively reviewed patients with transposition of the great arteries or Taussig-Bing anomaly who underwent ASO at our institution between 1992 and 2022. The primary endpoint was freedom from a composite of death, transplantation, and coronary reintervention. RESULTS: A total of 632 patients (median age, 5.0 days; interquartile range [IQR], 4.0-7.0 days) underwent ASO. Coronary anatomy included the following categories: usual (n = 411; 65%), circumflex (Cx) from sinus 2 (n = 89; 14%), inverted (n = 55; 9%), single sinus (n = 46; 7%), and intramural (n = 31; 5%). Overall operative mortality was 3% (n = 16) and highest in patients with intramural cardiac anatomy (n = 3; 10%), although it dropped to 0% in this group in the most recent decade. The median duration of follow-up was 14.5 years (IQR, 6.0-20.3 years). Twenty-year freedom from the primary endpoint was 95 ± 1% for usual anatomy, 99 ± 1% for Cx from sinus 2, 90 ± 4% for inverted, 91 ± 4% for single sinus, and 80 ± 9% for intramural (P < .001). Intramurals had the highest 20-year incidence of coronary reintervention (11 ± 8%). Cox modeling identified intraoperative coronary revision (hazard ratio [HR], 20.1; 95% confidence interval [CI], 9.4-53.9; P < .001), Taussig-Bing anomaly (HR, 4.9; 95% CI, 2.2-10.9; P < .001), and an intramural coronary artery (HR, 2.9; 95% CI, 1.0-8.2; P = .04) to be risk factors for the composite endpoint. CONCLUSIONS: Rare coronary artery variants-particularly intramural-are associated with increased mortality and coronary reinterventions after ASO. A low threshold for unroofing intramurals is likely associated with declining mortality and improved outcomes. Additional investigations are needed to determine the long-term fate of the coronary arteries after ASO.

Long-term outcomes of heart transplantation in adults with congenital heart disease: The impact of single-ventricle versus biventricular physiology.

Objective: Congenital heart disease is a risk factor for mortality after orthotopic heart transplantation; however, the impact of preoperative circulation type and primary congenital heart disease diagnosis remains poorly delineated. Methods: We retrospectively reviewed patients with adult congenital heart disease aged 16 years or more who underwent orthotopic heart transplantation at our institution between 2008 and 2022. Patients were categorized as having single-ventricle or biventricular circulation. The primary end point was 5-year post-transplant survival. Results: Sixty-one patients with adult congenital heart disease (single-ventricle: n = 26 [42.6%], biventricular: n = 35 [57.4%]) underwent orthotopic heart transplantation at 33.7 [interquartile range, 19.1-48.7] years. The most common congenital heart disease diagnosis was hypoplastic left heart syndrome (n = 11, 42.3%) in the single-ventricle group and congenitally corrected transposition of the great arteries (n = 7, 20.0%) in the biventricular group. Twenty-four patients previously underwent Fontan palliation. At transplant, patients in the single-ventricle group were younger (18.5 [interquartile range, 17.6-32.3] years vs 45.0 [interquartile range, 33.0-52.2] years, P < .001) and more likely to have biopsy-proven cirrhosis (46.2% vs 14.3%, P = .01) and protein-losing enteropathy (42.3% vs 2.9%, P < .001). Patients in the single-ventricle group also had longer bypass times (223.4 ± 65.3 minutes vs 187.4 ± 59.5 minutes, P = .03) and longer durations of mechanical ventilatory support (3.5 [interquartile range, 2.0-6.0] days vs 1.0 [interquartile range, 1.0-2.0] days, P < .001). Operative mortality was comparable (11.5% vs 8.6%, P = 1). Median follow-up was 6.0 [interquartile range, 2.4-10.0] years. Five-year survival was worse in the single-ventricle group (66.0% ± 10.0% vs 91.3% ± 4.8%, P = .03), as was freedom from major rejection (58.3% ± 10.2% vs 84.0% ± 6.6%, P = .02). In univariable analysis, hypoplastic left heart syndrome and Fontan circulation were risk factors for post-transplant mortality (hypoplastic left heart syndrome: hazard ratio, 5.0, P < .001; Fontan: hazard ratio, 3.5, P = .03). Conclusions: Adult patients with congenital heart disease undergoing heart transplant with single-ventricle physiology experienced a more complicated post-transplant course, with worse long-term survival and freedom from rejection. Multicenter studies are required to guide orthotopic heart transplantation decision-making in this complex cohort.

Ventricular Septation of the Double-Inlet Ventricle: Over Three Decades of Follow-Up.

There is renewed interest in septation of the double-inlet ventricle as an alternative to Fontan palliation. We examined our septation experience with over 30 years of follow-up. We retrospectively reviewed patients with double-inlet ventricle from 1990 to 2011. Patients with two adequate atrioventricular valves, a volume-overloaded ventricle, and no significant subaortic obstruction were septation candidates. Of 98 double-inlet ventricle patients, 9 (9.2%) underwent attempted septation via a one-stage (n = 2, 22.2%) or two-stage (n = 7, 77.8%) approach. Ages at primary septation were 7.5 and 20.2 months. In the staged group, median age at the first and second stage was 8.3 months [range 4.1-14.7] and 22.4 months [range 11.4-195.7], respectively. There were no operative mortalities. Median follow-up was 18.8 years [range 0.4-32.9] and 30-year transplant-free survival was 77.8% ± 13.9%. Both single stage patients are alive and in sinus rhythm; 1 underwent bilateral outflow tract obstruction repair 27 years later. Of 7 patients planned for two-stage septation, there was 1 interval mortality and 1 deferred the second stage. Five patients underwent the second stage; 1 required early reintervention for a residual neo-septal defect and 1 underwent right atrioventricular valve replacement 28 years later. Three patients required a pacemaker preoperatively (n = 1) or after partial septation (n = 2). At latest follow-up, 7 patients have normal biventricular function and no significant valvulopathy. All remain NYHA functional class I. Select double-inlet ventricles may be septated with excellent long-term outcomes. Reconsideration of this strategy is warranted to avoid the sequelae of Fontan circulation.

Preclinical in vivo assessment of the activity of AZD7442 anti-SARS-CoV-2 monoclonal antibodies against Omicron sublineages.

Therapeutic monoclonal antibodies have been successful in protecting vulnerable populations against SARS-CoV-2. However, their effectiveness has been hampered by the emergence of new variants. To adapt the therapeutic landscape, health authorities have based their recommendations mostly on in vitro neutralization tests. However, these do not provide a reliable understanding of the changes in the dose-effect relationship and how they may translate into clinical efficacy. Taking the example of EvusheldTM (AZD7442), we aimed to investigate how in vivo data can provide critical quantitative results and project clinical effectiveness. We used the Golden Syrian hamster model to estimate 90 % effective concentrations (EC90) of AZD7442 in vivo against SARS-CoV-2 Omicron BA.1, BA.2 and BA.5 variants. While our in vivo results confirmed the partial loss of AZD7442 activity for BA.1 and BA.2, they showed a much greater loss of efficacy against BA.5 than that obtained in vitro. We analyzed in vivo EC90s in perspective with antibody levels measured in a cohort of immunocompromised patients who received 300 mg of AZD7442. We found that a substantial proportion of patients had serum levels of anti-SARS-CoV-2 spike protein IgG above the estimated in vivo EC90 for BA.1 and BA.2 (21 % and 92 % after 1 month, respectively), but not for BA.5. These findings suggest that AZD7442 is likely to retain clinical efficacy against BA.2 and BA.1, but not against BA.5. Overall, the present study illustrates the importance of complementing in vitro investigations by preclinical studies in animal models to help predict the efficacy of monoclonal antibodies in humans.

PD-1 blockade and allogeneic hematopoietic stem cell transplantation in Hodgkin lymphoma, a matter of time: a national study on behalf of the Société Francophone de Greffe de Moelle et de Thérapie Cellulaire.

Not available.

Effects of exercise and doxorubicin on acute diaphragm neuromuscular transmission failure.

Doxorubicin (DOX) is a highly effective anthracycline antibiotic used to treat a wide variety of cancers including breast cancer, leukemia and lymphoma. Unfortunately, clinical use of DOX is limited due to adverse off-target effects resulting in fatigue, respiratory muscle weakness and dyspnea. The diaphragm is the primary muscle of inspiration and respiratory insufficiency is likely the result of both muscle weakness and neural impairment. However, the contribution of neuropathology to DOX-induced respiratory muscle dysfunction is unclear. We hypothesized that diaphragm weakness following acute DOX exposure is associated with neurotoxicity and that exercise preconditioning is sufficient to improve diaphragm muscle contractility by maintaining neuromuscular integrity. Adult female Sprague-Dawley rats were randomized into four experimental groups: 1) sedentary-saline, 2) sedentary-DOX, 3) exercise-saline or 4) exercise-DOX. Endurance exercise preconditioning consisted of treadmill running for 1 h/day at 30 m/min for 10 days. Twenty-four hours after the last bout of exercise, animals were treated with DOX (20 mg/kg, I.P.) or saline (equal volume). Our results demonstrate that 48-h following DOX administration diaphragm muscle specific force is reduced in sedentary-DOX rats in response to both phrenic nerve and direct diaphragm stimulation. Importantly, endurance exercise preconditioning in DOX-treated rats attenuated the decrease in diaphragm contractile function, reduced neuromuscular transmission failure and altered phrenic nerve morphology. These changes were associated with an exercise-induced reduction in circulating biomarkers of inflammation, nerve injury and reformation. Therefore, the results are consistent with exercise preconditioning as an effective way of reducing respiratory impairment via preservation of phrenic-diaphragm neuromuscular conduction.

Staged Ventricular Septation of the Double-Inlet Ventricle: How-I-Do-It.

Ventricular septation of the double-inlet ventricle is a largely abandoned operation due to poor historical outcomes. However, there has been renewed interest in septation as an alternative to Fontan palliation given its long-term sequelae. As one of the few centers to revisit septation in the early 1990s, our institution has long-term data on a series of patients with a double-inlet ventricle who underwent biventricular repair. This manuscript is a summary of our approach to staged septation of the double-inlet ventricle, with a focus on patient selection criteria, surgical techniques, perioperative considerations on timing of interventions, and long-term results. We believe that septation of the double-inlet ventricle should be reconsidered in patients with suitable anatomy in light of the known complications of Fontan palliation.

Transplantation for myelofibrosis patients in the ruxolitinib era: a registry study from the Société Francophone de Greffe de Moelle et de Thérapie Cellulaire.

In this SFGM-TC registry study, we report the results after stem cell transplantation (HSCT) in 305 myelofibrosis patients, in order to determine potential risk factors associated with outcomes, especially regarding previous treatment with ruxolitinib. A total of 102 patients were transplanted from an HLA-matched-sibling donor (MSD), and 143 patients received ruxolitinib. In contrast with previous studies, our results showed significantly worse outcomes for ruxolitinib patients regarding overall survival (OS) and non-relapse mortality (NRM), especially in the context of unrelated donors (URD). When exploring reasons for potential confounders regarding the ruxolitinib effect, an interaction between the type of donor and the use of ATG was found, therefore subsequent analyses were performed separately for each type of donor. Multivariable analyses did not confirm a significant negative impact of ruxolitinib in transplantation outcomes. In the setting of URD, only age and Fludarabine-Melphalan (FM) conditioning were associated with increased NRM. For MSD, only Karnoksfy <70% was associated with reduced OS. However, a propensity score analysis showed that ruxolitinib had a negative impact on OS but only in non-responding patients, consistent with previous data. To conclude, with all the precautions due to confounders and bias, ruxolitinib itself does not appear to increase mortality after HSCT.

Bone marrow graft versus peripheral blood graft in haploidentical hematopoietic stem cells transplantation: a retrospective analysis in1344 patients of SFGM-TC registry.

The use of peripheral blood (PB) or bone marrow (BM) stem cells graft in haploidentical hematopoietic stem cell transplantation with post-transplant cyclophosphamide (PTCy) for graft-versus-host disease (GVHD) prophylaxis remains controversial. Moreover, the value of adding anti-thymoglobulin (ATG) to PTCy is unknown. A total of 1344 adult patients received an unmanipulated haploidentical transplant at 37 centers from 2012 to 2019 for hematologic malignancy. We compared the outcomes of patients according to the type of graft, using a propensity score analysis. In total population, grade II-IV and III-IV acute GVHD (aGVHD) were lower with BM than with PB. Grade III-IV aGVHD was lower with BM than with PB + ATG. All outcomes were similar in PB and PB + ATG groups. Then, in total population, adding ATG does not benefit the procedure. In acute leukemia, myelodysplastic syndrome and myeloproliferative syndrome (AL-MDS-MPS) subgroup receiving non-myeloablative conditioning, risk of relapse was twice greater with BM than with PB (51 vs. 22%, respectively). Conversely, risk of aGVHD was greater with PB (38% for aGVHD II-IV; 16% for aGVHD III-IV) than with BM (28% for aGVHD II-IV; 8% for aGVHD III-IV). In this subgroup with intensified conditioning regimen, risk of relapse became similar with PB and BM but risk of aGVHD III-IV remained higher with PB than with BM graft (HR = 2.0; range [1.17-3.43], p = 0.012).

Aortic insufficiency following balloon aortic valvuloplasty does not impact long-term autograft durability after the Ross procedure.

OBJECTIVE: Preoperative aortic insufficiency (AI) is associated with inferior autograft durability after the Ross procedure. However, many patients with aortic stenosis (AS) undergo balloon aortic valvuloplasty (BAV) early and present with longstanding AI before Ross. We studied how BAV and subsequent valvular pathology impacts autograft durability. METHODS: Patients undergoing the Ross operation from 1993 to 2020 were identified. Those who underwent BAV before Ross were compared with patients who did not undergo BAV and underwent Ross for predominant AI (AI group) or AS (AS group). Those who underwent previous open surgical aortic valve intervention were excluded. Primary outcome of interest was autograft failure, defined as a composite of autograft reintervention or severe insufficiency. RESULTS: A total of 198 patients were included. Seventy-nine (39.9%) underwent BAV and subsequently underwent the Ross for predominant AI (45.6%) or AS (54.4%). Of patients who did not undergo BAV, 66 (33.3%) presented with predominant AI and 53 (26.8%) with AS. Freedom from autograft failure at 15 years was 90%, 92%, and 62% in BAV, AS, and AI groups, respectively. The AI group was at significantly increased risk of long-term autograft failure (hazard ratio, 5.6; P = .01), whereas the AS and BAV groups had similar, low risk (hazard ratio, 1.1; P = .91). Autograft durability was similar among patients who received BAV and presented with AS or AI before the Ross (P = .84). CONCLUSIONS: BAV before the Ross procedure is common in patients with AS. These patients have excellent long-term autograft durability regardless of preoperative valvular pathology and should strongly be considered for the Ross operation.

Liberal use of veno-arterial extracorporeal membrane oxygenation in combined sequential heart-liver transplantation.

Combined heart-liver transplantation (CHLT) is a rarely though increasingly performed procedure with evolving indications. Despite CHLT being performed at only a handful of centers, the use of intraoperative mechanical circulatory support to optimize hemodynamics and facilitate dual-organ transplantation varies widely. At our center, we liberally utilize veno-arterial extracorporeal membrane oxygenation (V-A ECMO) when a veno-venous shunt is anticipated to be insufficient in mitigating the hemodynamic perturbations associated with liver reperfusion. In this series, we describe our experience with V-A ECMO in sequential (heart-first) CHLT and demonstrate highly favorable outcomes with this strategy.

Long-term autograft dilation and durability after the Ross procedure are similar in infants, children, and adolescents with primary aortic stenosis.

BACKGROUND: Autograft durability and remodeling are thought to be superior in younger pediatric patients after the Ross operation. We sought to delineate the fate of autografts across the pediatric age spectrum in patients with primary aortic stenosis (AS). METHODS: We retrospectively reviewed patients age ≤18 years with primary AS who underwent the Ross operation between 1993 and 2020. Patients were categorized by age. The primary endpoint was autograft dimensional change, and secondary endpoints were severe neo-aortic insufficiency (AI) and autograft reintervention. RESULTS: A total of 119 patients underwent the Ross operation, including 37 (31.1%) in group I (age <18 months), 24 (20.2%) in group II (age 18 months-8 years), and 58 (48.7%) in group III (age 8-18 years). All groups exhibited similar annular growth rates within the first 5 postoperative years, followed by a collective decrease in annulus growth rates from year 5 to year 10. Group III experienced rapid sinus dilation in the first 5 years, followed by stabilization of the sinus z-score from year 5 to year 10, whereas groups I and II demonstrated stable sinus z-scores over 10 years. There were 4 early deaths (3.4%) and 2 late deaths (1.7%) at a median follow-up of 8.1 years (range, 0.01-26.3 years). At 15 years, the incidences of severe neo-AI (0.0 ± 0.0% vs 0.0 ± 0.0% vs 3.9 ± 3.9%; P = .52) and autograft reintervention (8.4 ± 6.0% vs 0.0 ± 0.0% vs 2.4 ± 2.4%; P = .47) were similar in the 3 groups. CONCLUSIONS: Age at the time of Ross operation for primary AS does not influence long-term autograft remodeling or durability. Other physiologic or technical factors are likely greater determinants of autograft fate.

Influence of preoperative aortic regurgitation on long-term autograft durability and dilatation in children and adolescents undergoing the Ross procedure.

OBJECTIVE: Primary aortic insufficiency (AI) is a risk factor for autograft reintervention in adults undergoing the Ross procedure. We sought to examine the influence of preoperative AI on autograft durability in children and adolescents. METHODS: From 1993 to 2020, 125 consecutive patients between ages 1 and 18 underwent a Ross procedure. The autograft was implanted using a full-root technique in 123 (98.4%) and included in a polyethelene terephthalate graft in 2 (1.6%). Patients with aortic stenosis (aortic stenosis group) (n = 85) were retrospectively compared with those with AI or mixed disease (AI group) (n = 40). Median length of follow-up was 8.2 years (interquartile range, 3.3-15.4 years). The primary end point was the incidence of severe AI or autograft reintervention. Secondary end points included changes in autograft dimensions analyzed using mixed-effect models. RESULTS: The incidence of severe AI or autograft reintervention was 39.0% ± 13.0% in the AI group and 8.8% ± 4.4% in the aortic stenosis group at 15 years (P = .02). Annulus z scores increased in both aortic stenosis and AI groups over time (P < .001). However, the annulus dilated at a faster rate in the AI group (absolute difference, 3.8 ± 2.0 vs 2.5 ± 1.7; P = .03). Sinus of Valsalva z scores increased in both groups as well (P < .001), but at similar rates over time (P = .11). CONCLUSIONS: Children and adolescents with AI undergoing the Ross procedure have higher rates of autograft failure. Patients with preoperative AI have more pronounced dilatation at the annulus. Akin to adults, a surgical aortic annulus stabilization technique that modulates growth is needed in children.

Strategies for the Surgical Management of Highly Aggressive Williams Syndrome Aortopathy: A Three Case Report.

Severe aortopathy in Williams syndrome can sometimes present with an initial ascending aortic pathology, followed in short order by more distal multilevel obstruction and recurrence requiring reintervention. In this series, an early, comprehensive surgical approach using a combination of various access and perfusion strategies yielded excellent long-term results.