Neonatal heart transplantation in the United States: Trends and outcomes.

BACKGROUND: Heart transplantation in the neonatal period is associated with excellent survival. However, outcomes data are scant and have been obtained primarily from two single-center reports within the United States. We sought to analyze the outcomes of all neonatal heart transplants performed in the United States using the United Network for Organ Sharing (UNOS) dataset. METHODS: The UNOS dataset was queried for patients who underwent infant heart transplantation from 1987 to 2021. Patients were divided into two groups based on age - neonates (<=31 days), and older infants (32 days-365 days). Demographic and clinical characteristics were analyzed and compared, along with follow up survival data. RESULTS: Overall, 474 newborns have undergone heart transplantation in the United States since 1987. Freedom from death or re-transplantation for neonates was 63.5%, 58.8% and 51.6% at 5, 10, and 20 years, respectively. Patients in the newborn group had lower unadjusted survival compared to older infants (p < .001), but conditional 1-year survival was higher in neonates (p = .03). On multivariable analysis, there was no significant difference in survival between the two age groups (p = .43). Black race, congenital heart disease diagnosis, earlier surgical era, and preoperative mechanical circulatory support use were associated with lower survival among infant transplants (p < .05). CONCLUSIONS: Neonatal heart transplantation is associated with favorable long-term clinical outcomes. Neonates do not have a significant survival advantage over older infants. Widespread applicability is limited by the small number of available donors. Efforts to expand the donor pool to include non-standard donor populations ought to be considered.

Sublobar resection is equivalent to lobectomy for T1a non-small cell lung cancer in the elderly: a Surveillance, Epidemiology, and End Results database analysis.

BACKGROUND: Anatomic lobectomy with mediastinal lymph node dissection is considered the optimal management for early stage non-small cell lung cancer (NSCLC). Limited lung resection may be preferable in the elderly population, who are more likely to have poor pulmonary reserve and multiple comorbidities. Our primary objective was to compare the survival of patients aged ≥ 75 y who underwent sublobar resection or lobectomy for stage IA NSCLC. MATERIALS AND METHODS: We queried the Surveillance, Epidemiology, and End Results database for patients aged ≥ 75 y who were diagnosed with stage IA NSCLC from 1998-2007. Patients were divided into three groups based on the type of surgery performed (wedge resection, segmentectomy, and lobectomy). Kaplan-Meier analysis and Cox proportional hazard model were used for survival analysis. RESULTS: A total of 1640 patients were analyzed. Lobectomy was performed in 1051 patients, 119 underwent segmentectomy, and 470 patients had wedge resection. Overall and cancer-specific survival were significantly lower in the wedge resection group as compared with those in lobectomy (P < 0.05). However, for T1a tumors, no significant difference was found in risk adjusted 5-y cancer-specific survival for patients who underwent wedge resection, segmentectomy (hazard ratio, 1.009; 95% confidence interval 0.624-1.631; P = 0.972), or lobectomy (hazard ratio, 0.98; 95% confidence interval, 0.691-1.388; P = 0.908). CONCLUSIONS: Sublobar resection is not inferior to lobectomy for T1a N0 M0 NSCLC in the elderly and should be considered a viable alternative in this high-risk population.

BCL-2 modulates the unfolded protein response by enhancing splicing of X-box binding protein-1.

Accumulation of unfolded proteins within the endoplasmic reticulum (ER) triggers a highly conserved stress response mechanism termed the unfolded protein response (UPR). The UPR is a complex series of signaling pathways controlled by ER localized transmembrane receptors, PERK, ATF6 and IRE1α. Following activation IRE1α splices XBP-1 mRNA facilitating the formation of a potent transcription factor, spliced XBP-1. The BCL-2 family members, BAX and BAK, in addition to the mitochondrion also localize to the ER and have been demonstrated to directly interact with IRE1α promoting its activity. In this study we show that in addition to BAX and BAK, the anti-apoptotic BCL-2 protein can regulate IRE1α activity. Enhanced splicing of XBP-1 was observed in BCL-2 overexpressing cells implicating BCL-2 in the complex regulation of IRE1α activity.

Pulmonary Artery Banding and Arch Repair vs Norwood for Unbalanced Atrioventricular Canal Defect.

BACKGROUND: The outcomes of single-ventricle palliation in unbalanced atrioventricular canal defect with coarctation of aorta (uAVC+CoA) have not been well studied. Systemic ventricle outflow tract obstruction has a propensity to develop in these patients after aortic arch repair with pulmonary artery banding (arch-PAB), which may adversely affect survival and Fontan candidacy. METHODS: A retrospective review was performed of patients who underwent single-ventricle palliation for uAVC+CoA from 2000 to 2022. Patients were divided into 2 groups based on initial palliation: (1) arch-PAB and (2) Norwood procedure. Demographic and clinical characteristics were analyzed and compared along with survival data. RESULTS: Stage 1 palliation for uAVC+CoA was performed in 41 patients. Arch-PAB was performed in 14 infants and Norwood in 27 infants. Arch-PAB patients had more chromosomal abnormalities (28.6 vs 7.4%, P < .009) and less severe systemic ventricle outflow tract obstruction on baseline echocardiogram (0.0 vs 70.4%, P < .001). Survival to stage 3 palliation was lower for the arch-PAB group (28.6% vs 66.6%, P = .02). Arch-PAB remained a significant risk factor for mortality (hazard ratio, 2.93; 95% CI, 1.05-8.53; P = .04) after adjusting for chromosomal abnormalities and atrioventricular valve regurgitation. After arch-PAB, systemic ventricle outflow tract obstruction was diagnosed in 13 of 14 patients. Echocardiography underestimated the degree of outflow tract obstruction in 10 of 13 arch-PAB patients. CONCLUSIONS: Arch-PAB has worse outcomes than Norwood for uAVC+CoA. Systemic ventricle outflow tract obstruction develops in almost all patients after arch-PAB. Outflow tract obstruction is underestimated by the echocardiogram and requires a high index of suspicion, along with advanced imaging, to ensure timely diagnosis and management.

Mitral Valve Replacement in Infants and Children: Experience Using a 15-mm Mechanical Valve.

BACKGROUND: Reports using a 15-mm mechanical valve for mitral valve replacement (MMVR) in children are limited. We review our center's operative and postoperative experience with this valve. METHODS: We performed a single-center retrospective chart review identifying patients having undergone MMVRs between 2009 and 2022. We analyzed short- and long-term outcomes using descriptive statistics. RESULTS: Fifteen patients underwent 16 MMVRs with no operative deaths. The median age and weight at the time of operation was 6.2 months (interquartile range [IQR] 4.4-13.7), and 5.16 kg (IQR 4.5-6.9), respectively. Ten implants (66%) were placed in the supraannular position. Median postoperative duration of intubation was 1.5 days (IQR 1.0-3.75), cardiac intensive care unit length of stay was 6 days (IQR 3-13.5), and overall hospital length of stay was 17.0 days (IQR 12-48.5). Three patients (20%) experienced major adverse events postoperatively. Four of 13 patients discharged home (31%) required readmission within 30 days for subtherapeutic/supratherapeutic international normalized ratio values. There were no surgical mortalities and 4 late mortalities (27%). Six patients underwent subsequent MMVR at a median time to second MMVR of 6.8 (IQR 3.6-8.9) years. There are 6 patients with the original 15-mm MVR at a median time of 4.7 years since placement. CONCLUSIONS: We present the largest single-center cohort of patients having undergone 15-mm MMVR. Our experience is distinguished by a lower rate of major adverse events than previously reported, durability of the device, and a rapid postoperative recovery time. Appropriate and consistent anticoagulation is a notable challenge in this age group.

Treatment outcomes and prognostic factors of esthesioneuroblastoma-a retrospective study from South India.

Esthesioneuroblastoma (ENB) or olfactory neuroblastoma is a rare malignant neoplasm arising from the neural crest cells of the olfactory epithelium. The optimum treatment for this rare disease is still unclear. Most of the available literature on this rare head and neck tumour is limited to small retrospective series and single institutional reports. We conducted a retrospective study to investigate the clinical profile, treatment outcomes and prognostic factors of patients with ENB treated at a tertiary cancer centre in south India. Patients with a histopathological diagnosis of ENB treated from 2000 to 2019 were included. Patient demographics, tumour characteristics, stage, treatment details and outcome data were identified from medical records. Overall survival (OS) and disease-free survival (DFS) were estimated using the Kaplan-Meier method and the log-rank test was used for comparison. The prognostic factors were identified using Cox regression analysis. Forty-two patients underwent treatment for ENB from 2000 to 2019. Twenty-six patients underwent surgery. Twelve patients received radical radiotherapy (RT) while 24 patients underwent adjuvant radiation. After a median follow-up of 71 months, the estimated OS and DFS at 4 years were 64.4% and 54%, respectively. The estimated 4-year OS for modified Kadish A, B, C and D stages was 75.0%, 90.9%, 56.4% and 0%, respectively. Modified Kadish stage, nodal involvement, orbital invasion, intracranial extension, surgery, RT treatment and use of chemotherapy were significant predictors of OS and DFS in univariate Cox regression analysis. Orbital invasion and RT treatment were significant predictors of DFS in the multivariate analysis as well. However, only RT treatment came out to be a significant predictor for OS in multivariate Cox regression analysis. Surgery is the mainstay of treatment. Adjuvant RT may improve local control and survival in advanced cases. Advanced modified Kadish stage, lymph node involvement and orbital invasion are associated with poor outcomes.

Lysosomal destabilization and cathepsin B contributes for cytochrome c release and caspase activation in embelin-induced apoptosis.

XIAP is an important antiapoptotic protein capable of conferring resistance to cancer cells. Embelin, the small molecular inhibitor of XIAP, possesses wide spectrum of biological activities with strong inhibition of nuclear factor kappa B and downstream antiapoptotic genes. However, the mechanism of its cell death induction is not known. Our studies using colon cancer cells lacking p53 and Bax suggest that both lysosomes and mitochondria are prominent targets of embelin-induced cell death. Embelin induced cell-cycle arrest in G(1) phase through p21, downstream of p53. In the absence of p21, the cells are sensitized to death in a Bax-dependent manner. The loss of mitochondrial membrane potential induced by embelin was independent of Bax and p53, but lysosomal integrity loss was strongly influenced by the presence of p53 but not by Bax. Lysosomal role was further substantiated by enhanced cathepsin B activity noticed in embelin-treated cells. p53-dependent lysosomal destabilization and cathepsin B activation contribute for increased sensitivity of p21-deficient cells to embelin with enhanced caspase 9 and caspase 3 activation. Cathepsin B inhibitor reduced cell death and cytochrome c release in embelin-treated cells indicating lysosomal pathway as the upstream of mitochondrial death signaling. Deficiency of cell-cycle arrest machinery renders cells more sensitive to embelin with enhanced lysosomal destabilization and caspase processing emphasizing its potential therapeutic importance to address clinical drug resistance.

Likelihood of Aortic Valve Preservation During Repair of Acute Type A Aortic Dissection.

BACKGROUND: We sought risk factors for replacement of the aortic valve with or without the root (AVR/root) in the setting of acute type A aortic dissection (ATAD) repair. METHODS: All ATAD repairs at our institution from January 2005 to June 2018 were reviewed. Baseline characteristics were recorded. For patients with aortic valve preservation we documented the degree of aortic insufficiency (AI) postoperatively and on subsequent echocardiograms when available. Logistic regression was used to determine the association between preoperative characteristics and the odds ratio of AVR/root. RESULTS: A total of 206 patients underwent repair of ATAD. Thirty-four were excluded for no documented AI grading. Forty-six underwent AVR/root during repair of the ATAD (including 40 root replacements). Of 126 that did not undergo AVR/root, 42 (33.33%) had follow-up echocardiograms at a median of 68 months postoperatively and 2 required reintervention for valve insufficiency. Increase in degree of AI, bicuspid valve morphology, size of the aortic root, and connective tissue disorder were significantly associated with increased risk of AVR/root. Of 130 patients without connective tissue disorder, bicuspid aortic valve, aortic root aneurysm, or intimal root tear, the rate of valve preservation was 65/65 (100%), 25/29 (86.2%), and 22/40 (55%) for those presenting with mild, moderate, and severe AI, respectively. DISCUSSION: Degree of preoperative AI, bicuspid valve morphology, size of the aortic root, and connective tissue disorder significantly correlate with failure of aortic valve preservation in patients with ATAD. The vast majority of tricuspid valves in patients without connective tissue disorder or aortic root pathology can be salvaged.

Likelihood of Aortic Valve Preservation During Repair of Acute Type A Aortic Dissection.

BACKGROUND: We sought risk factors for replacement of the aortic valve with or without the root (AVR/root) in the setting of acute type A aortic dissection (ATAD) repair. METHODS: All ATAD repairs at our institution from January 2005 to June 2018 were reviewed. Baseline characteristics were recorded. For patients with aortic valve preservation, we documented the degree of aortic insufficiency (AI) postoperatively and on subsequent echocardiograms when available. Logistic regression was used to determine the association between preoperative characteristics and the odds ratio of AVR/root. RESULTS: 206 patients underwent repair of ATAD. Thirty-four were excluded for no documented AI grading. Forty-six underwent AVR/root during repair of the ATAD (including 40 root replacements). Of 126 that did not undergo AVR/root, 42 (33.33%) had follow-up echocardiograms at a median of 68 months postoperatively, 2 required reintervention for valve insufficiency. An increase in the degree of AI, bicuspid valve morphology, size of the aortic root, and connective tissue disorder was significantly associated with increased risk of AVR/root. Of 130 patients without connective tissue disorder, bicuspid aortic valve, aortic root aneurysm or intimal root tear, the rate of valve preservation was 65/65 (100%), 25/29 (86.2%), and 22/40 (55%) for those presenting with mild, moderate, and severe AI, respectively. CONCLUSION: The degree of preoperative AI, bicuspid valve morphology, size of the aortic root, and connective tissue disorder significantly correlate with the failure of aortic valve preservation in patients with ATAD. The vast majority of tricuspid valves in patients without connective tissue disorder or aortic root pathology can be salvaged.

Interaction Between Ischemic Time and Donor Age on Adult Heart Transplant Outcomes in the Modern Era.

BACKGROUND: We examined the effect of cold ischemic interval on modern outcomes to determine whether advances in patient management have made an impact. METHODS: Using the United Network of Organ Sharing database, we reviewed adult heart transplants between January 2000 and March 2016. We divided donor age into terciles: younger than 18 years, 18 to 33 years, and 34 years and older. Within each tercile, transplants were divided by cold ischemic interval of less than 4 hours, 4 to 6 hours, and more than 6 hours. Survival curves were compared between cold ischemic interval categories within each tercile. Covariate-adjusted and donor age-stratified Cox proportional hazards regression models were used to estimate overall mortality and graft failure hazards ratios. RESULTS: Of 29,192 transplants, no significant differences between cold ischemic interval groups in survival or graft failure were apparent in the group aged younger than 18. For donors older than 18, significant differences were found for survival and graft failure with cold ischemic interval exceeding 4 hours in both univariate and multivariate analysis, and survival functions at different ischemic intervals continued to diverge beyond 1 year. The interaction effect between donor age and cold ischemic interval on overall mortality was not significant when analyzed as continuous variables, however younger donor age appeared to attenuate increase in overall mortality with longer cold ischemic intervals. CONCLUSIONS: Despite advances in perioperative management during the past 30 years, for donors older than 18 years, cold ischemic interval exceeding 4 hours is associated with gradual but significantly diminished survival that persists well beyond the perioperative period. Comparison to historical data suggests that advances in management have somewhat attenuated the hazard associated with longer ischemic times.

Primary Transplantation for Congenital Heart Disease in the Neonatal Period: Long-term Outcomes.

BACKGROUND: Primary transplantation was developed in the 1980s as an alternative therapy to palliative reconstruction of uncorrectable congenital heart disease. Although transplantation achieved more favorable results, its utilization has been limited by the availability of donor organs. This review examines the long-term outcomes of heart transplantation in neonates at our institution. METHODS: The institutional pediatric heart transplant database was queried for all neonatal heart transplants performed between 1985 and 2017. Follow-up was obtained from medical records and an annually administered questionnaire. Overall survival and time to development of complications were estimated using the Kaplan Meier method. Univariate and multivariate analyses were performed to identify independent predictors of survival. RESULTS: Heart transplantation was performed in 104 neonates. Median age was 17 days. Hypoplastic left heart syndrome (classic or variant) was the primary diagnosis in 77.8% of patients. Survival at 10 years and 25 years was 73.9% and 55.8%, respectively. At 20 years, freedom from allograft vasculopathy and lymphoproliferative disease was 72.0% and 81.9%, respectively. Freedom from re-transplantation was 81.4% at 20 years. Eight patients (7.6%) developed end-stage renal disease. By multivariate analysis, lower glomerular filtration rate and allograft vasculopathy were the only significant predictors of death. CONCLUSIONS: Neonatal heart transplantation remains a durable therapy with very acceptable long-term survival. Children transplanted in the newborn period have the potential to reach adulthood with minimal need for reintervention.

Neonatal heart transplantation.

Neonatal heart transplantation was developed and established in the 1980's as a durable modality of therapy for complex-uncorrectable heart disease. Patients transplanted in the neonatal period have experienced unparalleled long-term survival, better than for any other form of solid-organ transplantation. However, the limited availability of neonatal and young infant donors has restricted the indications and applicability of heart transplantation among newborns in the current era. Indications for heart transplantation include congenital heart disease not amenable to other forms of surgical palliation, and cardiomyopathy, including some primary tumors. Use of ABO-incompatible transplants, and organs with prolonged cold ischemic time or marginal function have all been associated with good outcomes in infants. These extended strategies to increase the donor pool may also someday include donation after determination of circulatory death and the use of anencephalic donors. The operative techniques for donors and recipients of neonatal heart transplantation are unique and have been well-described. Immunosuppression protocols for neonates need not include induction and are largely steroid-free. Newborn and young infant transplant recipients have fewer episodes of rejection, less coronary allograft vasculopathy, less post-transplant lymphoproliferative disease and less renal dysfunction than their older counterparts. Long-term outcomes have been very encouraging in terms of graft survival, patient survival, and quality of life. Our review highlights the history, current indications, techniques and outcomes of heart transplantation in this immunologically-privileged subset of patients.