Overcoming the Disparity in Mitral Valve Repair: A Sex-based Analysis of Long-term Outcomes.

BACKGROUND: Sex-disparities remain pervasive across most cardiovascular diseases and continue to demonstrate significantly worse early and late outcomes for women, especially after surgical repair. This study aims to investigate outcomes of mitral valve (MV) repair by sex and identify opportunities for improvement. METHODS: A single-centre retrospective analysis of consecutive patients undergoing MV repair was conducted, from May 2008 - February 2023. In-hospital and long-term outcomes, including survival and symptomatic disease recurrence (sMR) were examined by sex. Adjusted outcome analysis was performed using inverse-probability treatment weighting (IPTW). RESULTS: In total, 490 patients underwent MV repair (Median age 65 years [IQR 57-73 years] sternotomy n=128 [26%], minimally-invasive n=362 [74%]), including 343 males and 147 females. Median follow-up time was 5.4 years, with an interquartile range of 3.1 to 8.4 years. IPTW-adjusted 30-day outcomes for female versus males, including death (1.4% vs 0.6%, p=0.59) and MACE (8.2% vs 7.6%, p=0.81), were not significantly different. Survival for females vs males after mitral valve repair was 94.9% vs 98.0% at 2 years, 91.4% vs 97.8% at 4 years and 87.2 % vs 88.7% at 8 years (HR 0.52 [0.19-1.44]). Both unadjusted and IPTW-adjusted Cox-regression hazard ratios for survival and freedom from sMR demonstrated no significant difference between sexes at long-term follow up. CONCLUSIONS: These contemporary results are encouraging and suggest that a critical "bridging of the gap" between sexes is possible with comprehensive efforts including earlier detection and awareness and improved surgical techniques, though other factors may be important to explore further.

Hiatal hernia after robotic-assisted coronary artery bypass graft surgery.

BACKGROUND: The aim of the present study is to determine the incidence/progression of hiatal hernia (HH) after robotic-assisted coronary artery bypass grafting (RA-CABG) surgery. METHODS: We reviewed the pre- and post-operative computed tomography (CT) of 491 patients who underwent RA-CABG between 2000 and 2017. Post-operative CT was acquired prospectively in a research protocol. CT was reviewed to assess the presence and the size of HH. RESULTS: We found 444/491 (90.4%) had pre-operative CT, while 201/491 (40.9%) had post-operative CT. In total, 155/491 (31.6%) had both pre- and long-term post-operative CT with a mean follow-up of 6.2 (±3.5) years. HH was more prevalent on post-operative CT, 64/155 (41.3%) compared to pre-operative CT, 44/155 (28.4%), P<0.0001. The diameter of pre-existing HH 2.8 (±1.8) cm was significantly greater after surgery 3.9 (±2.5) cm, P<0.0001. As well the volume of the pre-existing HH 5.8 (4.4-9.2) mL (quartile) was significantly greater after surgery 14.1 (7.2-64.9) mL, P<0.0001. 20/155 (12.9%) had a newly developed HH after RA-CABG. A binary multivariate regression including HH risk factors showed that male gender is a predictor of developing a HH after RA-CABG with Hazard Ratio of 3.038, confidence interval (1.10-8.43), P=0.033. CONCLUSIONS: RA-CABG is associated with an increased risk of developing HH and increases the size of pre-existing HH.

Biallelic MADD variants cause a phenotypic spectrum ranging from developmental delay to a multisystem disorder.

In pleiotropic diseases, multiple organ systems are affected causing a variety of clinical manifestations. Here, we report a pleiotropic disorder with a unique constellation of neurological, endocrine, exocrine, and haematological findings that is caused by biallelic MADD variants. MADD, the mitogen-activated protein kinase (MAPK) activating death domain protein, regulates various cellular functions, such as vesicle trafficking, activity of the Rab3 and Rab27 small GTPases, tumour necrosis factor-α (TNF-α)-induced signalling and prevention of cell death. Through national collaboration and GeneMatcher, we collected 23 patients with 21 different pathogenic MADD variants identified by next-generation sequencing. We clinically evaluated the series of patients and categorized the phenotypes in two groups. Group 1 consists of 14 patients with severe developmental delay, endo- and exocrine dysfunction, impairment of the sensory and autonomic nervous system, and haematological anomalies. The clinical course during the first years of life can be potentially fatal. The nine patients in Group 2 have a predominant neurological phenotype comprising mild-to-severe developmental delay, hypotonia, speech impairment, and seizures. Analysis of mRNA revealed multiple aberrant MADD transcripts in two patient-derived fibroblast cell lines. Relative quantification of MADD mRNA and protein in fibroblasts of five affected individuals showed a drastic reduction or loss of MADD. We conducted functional tests to determine the impact of the variants on different pathways. Treatment of patient-derived fibroblasts with TNF-α resulted in reduced phosphorylation of the extracellular signal-regulated kinases 1 and 2, enhanced activation of the pro-apoptotic enzymes caspase-3 and -7 and increased apoptosis compared to control cells. We analysed internalization of epidermal growth factor in patient cells and identified a defect in endocytosis of epidermal growth factor. We conclude that MADD deficiency underlies multiple cellular defects that can be attributed to alterations of TNF-α-dependent signalling pathways and defects in vesicular trafficking. Our data highlight the multifaceted role of MADD as a signalling molecule in different organs and reveal its physiological role in regulating the function of the sensory and autonomic nervous system and endo- and exocrine glands.

Starch or Saline After Cardiac Surgery: A Double-Blinded Randomized Controlled Trial.

BACKGROUND: Despite decades of investigation, the balance of clinical risks and benefits of fluid supplementation with starch remain unresolved. Patient-centered outcomes have not been well explored in a "real-world" trial in cardiac surgery. OBJECTIVE: We sought to compare a starch-based fluid strategy with a saline-based fluid strategy in the cardiac surgery patient. DESIGN: A pragmatic blinded randomized controlled trial comparing starch-based with saline-based fluid strategy. SETTING: A large tertiary academic center in London Ontario between September 2009 and February 2011. PARTICIPANTS: Patients undergoing planned, isolated coronary revascularization. MEASUREMENTS: Serum creatinine and patient weight were measured daily postoperatively. METHODS: Patients were randomized to receive 6% hydroxyethyl starch (Voluven) or saline for perioperative fluid requirements. Fluid administration was not protocolized. Co-primary outcomes were incidence of acute kidney injury (AKI) and maximum postoperative weight gain. Secondary outcomes included bleeding, transfusion, inotropic and ventilator support, and fluid utilization. RESULTS: The study was prematurely terminated due to resource limitations. A total of 69 patients (19% female, mean age = 65) were randomized. Using RIFLE criteria for AKI, "risk" occurred in 12 patients in each group (risk ratio [RR] = 1.0; 95% confidence interval [CI] = 0.5-1.9; P = 1.00), whereas "injury" occurred in 7 of 35 (20%) and 3 of 34 (9%) of patients in the starch and saline groups, respectively (RR = 2.3; 95% CI = 0.6-8.1; P = .31). Maximum weight gain, bleeding and blood product usage, and overall fluid requirement were similar between groups. LIMITATIONS: The study had to be prematurely terminated due to resource limitations which led to a small sample size which was not sufficiently powered to detect a difference in the primary outcomes. CONCLUSIONS: This pragmatic double-blinded randomized controlled trial revealed a number of interesting hypothesis-generating trends and confirmed the feasibility of undertaking a logistically complex trial in a pragmatic fashion.

CONTEXTE: L'équilibre entre les avantages et les risques cliniques d'une supplémentation en fluides à base d'amidon n'est toujours pas établi malgré des décennies d'études. Les résultats des patients subissant une chirurgie cardiaque n'ont pas été explorés suffisamment dans le cadre d'un essai concret. OBJECTIF: Comparer deux stratégies de supplémentation liquidienne, une solution à base d'amidon et une solution saline, chez des patients subissant une chirurgie cardiaque. TYPE D'ÉTUDE: Un essai pragmatique, contrôlé, à répartition aléatoire et mené en double insu comparant deux stratégies de supplémentation liquidienne une solution à base d'amidon et une solution saline. CADRE: Un grand centre universitaire de soins tertiaires de London (Ontario) entre septembre 2009 et février 2011. SUJETS: Des patients subissant une revascularisation coronarienne planifiée et isolée. MESURES: La créatinine sérique et le poids du patient ont été mesurés quotidiennement à la suite de l'intervention. MÉTHODOLOGIE: Les patients ont été répartis aléatoirement pour recevoir du Voluven (solution d'amidon hydroxyéthylé à 6 %) ou une solution saline pour les fluidiques périopératoires. L'administration ne s'est pas faite selon un protocole établi. L'incidence d'insuffisance rénale aiguë (IRA) et un gain pondéral maximal après l'intervention constituaient les deux principaux résultats mesurés. Les résultats secondaires incluaient une hémorragie, l'utilisation de transfusion sanguine, d'inotrope, d'assistance respiratoire et l'administration de fluides. RÉSULTATS: L'étude a été interrompue prématurément par manque de ressources. Les 69 patients (19 % de femmes) répartis aléatoirement avaient en moyenne 65 ans. La classification RIFLE avait permis de détecter un « risque ¼ d'IRA chez 12 patients dans chacun des groupes (RC: 1,0; IC 95 %: 0,5-1,9; p=1,00) et une « insuffisance ¼ chez 7 patients sur 35 (20 %) du groupe « amidon ¼ et 3 patients sur 34 (9 %) du groupe « saline ¼ (RC: 2,3; IC 95 %: 0,6-8,1; p=0,31). Le gain pondéral maximal, le nombre d'hémorragies, l'utilisation de produits sanguins et les besoins liquidiens étaient similaires dans les deux groupes. LIMITES: L'étude a été interrompue prématurément en raison d'un manque de ressources. Par conséquent, le faible échantillon de patients s'avère insuffisamment puissant pour détecter des différences significatives entre les deux groupes. CONCLUSIONS: Cette étude a mis en lumière quelques tendances permettant d'émettre des hypothèses intéressantes. L'étude a également confirmé la possibilité d'entreprendre un essai logistique complexe de manière pragmatique.

Hybrid arch frozen elephant trunk repair: evidence from the Canadian Thoracic Aortic Collaborative.

BACKGROUND: The frozen elephant trunk (FET) technique has become an increasingly popular strategy for aortic reconstruction in the setting of extensive thoracic aortic aneurysms or dissections. The objective of this study is to report on the Canadian experience with the FET technique in both the elective and emergent settings. METHODS: A total of 167 consecutive patients (mean age 65±13 years, 30% female, 25% re-operation) underwent elective (70%) and non-elective (30%) aortic arch reconstruction with the FET technique between May 2008 and October 2019 in six centers of the Canadian Thoracic Aortic Collaborative (CTAC). In-hospital clinical endpoints and early imaging endpoints were prospectively collected and analyzed. RESULTS: All 167 patients underwent successful FET implantation. In-hospital mortality occurred in 14 patients (8%), stroke occurred in 22 patients (13%) and temporary and permanent spinal cord ischemia (SCI) occurred in 6 (3.6%) and 3 (1.8%) patients, respectively. Prolonged mechanical ventilation was required in 35 patients (21%), renal failure requiring dialysis in 14 patients (8%) and atrial fibrillation in 59 patients (36%). The median hospital and intensive care unit (ICU) lengths of stay were 3 [interquartile range (IQR): 1, 6] and 10 (IQR: 7, 17) days, respectively. The rate of type 1A endoleak was 3.6%, with the lowest rate in patients who underwent a total arch replacement with a hybrid FET graft (0%) and the highest among patients who had a hemiarch with antegrade thoracic endovascular aortic repair (TEVAR) deployment (25%). The rate of other types of endoleak and stent complications was comparatively low. CONCLUSIONS: The early CTAC experience with the FET operation demonstrates technical feasibility and good early clinical outcomes in elective and emergent patients. Further analysis is required to explore variations in technique and their potential impact on early and late outcomes.

Clinical spectrum of individuals with pathogenic NF1 missense variants affecting p.Met1149, p.Arg1276, and p.Lys1423: genotype-phenotype study in neurofibromatosis type 1.

We report 281 individuals carrying a pathogenic recurrent NF1 missense variant at p.Met1149, p.Arg1276, or p.Lys1423, representing three nontruncating NF1 hotspots in the University of Alabama at Birmingham (UAB) cohort, together identified in 1.8% of unrelated NF1 individuals. About 25% (95% confidence interval: 20.5-31.2%) of individuals heterozygous for a pathogenic NF1 p.Met1149, p.Arg1276, or p.Lys1423 missense variant had a Noonan-like phenotype, which is significantly more compared with the "classic" NF1-affected cohorts (all p < .0001). Furthermore, p.Arg1276 and p.Lys1423 pathogenic missense variants were associated with a high prevalence of cardiovascular abnormalities, including pulmonic stenosis (all p < .0001), while p.Arg1276 variants had a high prevalence of symptomatic spinal neurofibromas (p < .0001) compared with "classic" NF1-affected cohorts. However, p.Met1149-positive individuals had a mild phenotype, characterized mainly by pigmentary manifestations without externally visible plexiform neurofibromas, symptomatic spinal neurofibromas or symptomatic optic pathway gliomas. As up to 0.4% of unrelated individuals in the UAB cohort carries a p.Met1149 missense variant, this finding will contribute to more accurate stratification of a significant number of NF1 individuals. Although clinically relevant genotype-phenotype correlations are rare in NF1, each affecting only a small percentage of individuals, together they impact counseling and management of a significant number of the NF1 population.

Hybrid Coronary Revascularization Versus Off-Pump Coronary Artery Bypass Grafting: Comparative Effectiveness Analysis With Long-Term Follow-up.

Background Hybrid coronary revascularization (HCR) involves the integration of coronary artery bypass grafting (CABG) and percutaneous coronary intervention to treat multivessel coronary artery disease. Our objective was to perform a comparative analysis with long-term follow-up between HCR and conventional off-pump CABG. Methods and Results We compared all double off-pump CABG (n=216) and HCR (n=147; robotic-assisted minimally invasive direct CABG of the left internal thoracic artery to the left anterior descending artery and percutaneous coronary intervention to one of the non-left anterior descending vessels) performed at a single institution between March 2004 and November 2015. To adjust for the selection bias of receiving either off-pump CABG or HCR, we performed a propensity score analysis using inverse-probability weighting. Both groups had similar results in terms of re-exploration for bleeding, perioperative myocardial infarction, stroke, blood transfusion, in-hospital mortality, and intensive care unit length of stay. HCR was associated with a higher in-hospital reintervention rate (CABG 0% versus HCR 3.4%; P=0.03), lower prolonged mechanical ventilation (>24 hours) rate (4% versus 0.7%; P=0.02), and shorter hospital length of stay (8.1±5.8  versus 4.5±2.1 days; P<0.001). After a median follow-up of 81 (48-113) months for the off-pump CABG and 96 (53-115) months for HCR, the HCR group of patients had a trend toward improved survival (85% versus 96%; P=0.054). Freedom from any form of revascularization was similar between the 2 groups (92% versus 91%; P=0.80). Freedom from angina was better in the HCR group (73% versus 90%; P<0.001). Conclusions HCR seems to provide, in selected patients, a shorter postoperative recovery, with similar excellent short- and long-term outcomes when compared with standard off-pump CABG.

Reason and Timing for Conversion to Sternotomy in Robotic-Assisted Coronary Artery Bypass Grafting and Patient Outcomes.

OBJECTIVE: Conversion to sternotomy is a primary bailout method for robotically assisted coronary artery bypass grafting procedures. The aims of this study were to identify the primary reasons for conversion from robotically assisted coronary artery bypass grafting to sternotomy and to evaluate the in-hospital outcomes in such patients. METHODS: Prospectively collected data from February 2004 to April 2017 were reviewed for 72 patients (56 men; mean age = 63.8 years) who required conversion to sternotomy during a robotically assisted coronary artery bypass grafting procedure with planned endoscopic left internal thoracic artery harvest and anastomosis to the left anterior descending on the beating heart. RESULTS: The overall rate of conversion was 12.4% (72/581). Conversions occurred either during attempted endoscopic left internal thoracic artery harvest (31.9%), during endoscopic left anterior descending isolation (40.3%), during manual isolation and anastomosis of the left anterior descending (19.4%), or after anastomosis due to unsatisfactory flow (8.3%). Overall, the most common reason for conversion was an intramyocardial left anterior descending (43.1%). The median stay in the intensive care unit was 1 day (range = 0-20) and the median hospital length of stay was 5 days (range = 3-43). In-hospital complications included new atrial fibrillation (16.7%), need for blood transfusion (20.8%), mediastinitis (4.2%), postoperative myocardial infarction (2.8%), exploration for bleeding (2.8%), and 1 in-hospital death. CONCLUSIONS: The reasons for conversion were primarily related to anatomical factors that created difficulties for endoscopic left internal thoracic artery harvesting and left anterior descending identification. Patients who required conversion to sternotomy from robotically assisted coronary artery bypass grafting demonstrated acceptable outcomes and low complication rates.

Cardiac-Referenced Leukocyte Telomere Length and Outcomes After Cardiovascular Surgery.

Leukocyte telomere shortening reflects stress burdens and has been associated with cardiac events. However, the patient-specific clinical value of telomere assessment remains unknown. Moreover, telomere shortening cannot be inferred from a single telomere length assessment. The authors investigated and developed a novel strategy for gauging leukocyte telomere shortening using autologous cardiac atrial referencing. Using multitissue assessments from 163 patients who underwent cardiovascular surgery, we determined that the cardiac atrium-leukocyte telomere length difference predicted post-operative complexity. This constituted the first evidence that a single-time assessment of telomere dynamics might be salient to acute cardiac care.

Is There a Role for Diagonal Coronary Artery Stenting in Patients Undergoing Robotic Coronary Artery Bypass Graft Surgery?

BACKGROUND: The efficacy of diagonal coronary artery stenting in patients undergoing robotic left internal thoracic artery-to-left anterior descending (LITA-to-LAD) anastomosis is not well defined. The objective of this study was to assess graft and stent patency in a single-stage hybrid revascularization with LITA-to-LAD anastomosis and PCI to a diagonal coronary artery. METHODS: From 2004 to 2014, a total of 25 patients consented to robotic-assisted LITA harvesting and a small left anterior thoracotomy for off-pump coronary artery bypass anastomosis onto the LAD along with concomitant PCI to the diagonal coronary artery. PCI to the diagonal coronary artery was performed in the same fluoroscopy-equipped hybrid operating room. RESULTS: Patients were on average 66 ± 11 years with 32% female. Pre-operative characteristics of these patients included 8% with a grade 3 or 4 left ventricle, 16% with a recent MI, and 92% with CCS III/IV symptoms. There were no death, one patient required an intra-aortic balloon pump, and one patient required re-operation for bleeding. The average ICU stay was 1.1 ± 0.53 days, and the average hospital stay was 4.6 ± 2.4 days. Fitzgibbon Grade A LITA-to-LAD patency at 6-month follow-up was 100%. As well, at 6-month follow-up the DES to the diagonal coronary artery had a patency rate of 96%. CONCLUSIONS: Single-stage hybrid revascularization strategy for bifurcating lesions of the LAD and diagonal coronary arteries with LITA-to-LAD anastomosis and PCI to a diagonal coronary artery appears to have acceptable clinical results with excellent 6-month angiographic patency results.

Robotic-assisted coronary artery bypass surgery: an 18-year single-centre experience.

BACKGROUND: Minimally invasive robot-assisted direct coronary artery bypass (RADCAB) has emerged as a feasible minimally invasive surgical technique for revascularization that might offer several potential advantages over conventional approaches. We present our 18-year experience in RADCAB. METHODS: Between February 1998 and February 2016, 605 patients underwent RADCAB. Patients underwent post-procedural selective graft patency assessment using cardiac catheterization. RESULTS: The mortality rate was 0.3%. The rate of conversion to sternotomy for any cause was reduced from 16.0% of the first 200 cases to 6.9% of the last 405 patients. The patency rate of the LITA-to-LAD anastomosis was 97.4%. Surgical re-exploration for bleeding occurred in 1.8% of patients, and the transfusion rate was 9.2%. Average ICU stay was 1.2 ± 1.4 days, and average hospital stay was 4.8 ± 2.9 days. CONCLUSIONS: Robot-assisted coronary artery bypass grafting is safe, feasible and it seems to represent an effective alternative to traditional coronary artery bypass grafting in selected patients.

Whole body perfusion strategy for aortic arch repair under moderate hypothermia.

INTRODUCTION: Aortic arch reconstruction under moderate hypothermia is commonly performed with antegrade cerebral perfusion (ACP) for brain protection; however, hypothermia alone is often solely relied upon for visceral and lower body protection. We investigated whether the addition of simultaneous lower body perfusion to ACP (whole body perfusion - WBP) may ameliorate the metabolic derangements of moderate hypothermic circulatory arrest (MHCA). METHODS: Between 2008 and 2014, 106 consecutive patients underwent elective or emergent aortic arch surgery with MHCA, with either ACP only (44 patients, 66±12 years, 30% female) or WBP (62 patients, 61±15 years, 31% female). Primary outcomes included 30-day/in-hospital mortality, intensive care unit (ICU) and hospital lengths of stay (LOS) and specific parameters of metabolic recovery. RESULTS: There were no significant differences between the groups in 30-day/in-hospital mortality (ACP: 3 (6.8%), WBP: 2 (3.2%); p=0.65), stroke (ACP: 1 (2.3%), WBP: 1 (1.6%); p=1.0) or renal failure (ACP: 2 (4.5%), WBP: 1 (1.5%); p=0.57). In the WBP group, we identified a significant reduction in lactate level at ICU admission (ACP 5.5 vs. WBP 3.5 mmol/L; p=0.002), time to lactate normalization (p=0.014) and median ICU length-of-stay (ACP 3 vs. WBP 1 days; p=0.049). There was no difference in post-operative creatinine (ACP: 104, WBP: 107 µmol/L; p=0.66). After multivariable regression adjustment, perfusion strategy no longer remained an independent predictor of ICU discharge time (p=0.09), however, cardiopulmonary bypass time (p=0.02), age (p=0.012) and emergent surgery (p=0.02) were. CONCLUSIONS: A WBP strategy during aortic arch reconstruction with MHCA may be associated with more rapid normalization of metabolic parameters and reduced ICU length of stay compared to using ACP alone. Further evaluation with a randomized trial is warranted.

Ultrafast Track Robotic-Assisted Minimally Invasive Coronary Artery Surgical Revascularization.

OBJECTIVE: Contemporary anesthetic techniques have enabled shorter sedation and early extubation in off-pump and minimally invasive coronary artery bypass (CABG) surgery. Robotic-assisted CABG represents the optimal surgical approach for ultrafast track anesthesia, with patients able to bypass the cardiac surgical intensive care unit with recovery in the postanesthesia care unit (PACU) and inpatient ward. METHODS: In-hospital postoperative outcomes from ninety patients who underwent either elective or urgent robotically-assisted CABG at our institution were reviewed. These patients were carefully selected by a multidisciplinary team to undergo fast-track anesthesia: extubation in the operating room, 4-hour recovery in the postanesthesia care unit and transfer to the inpatient ward. Intrathecal, paravertebral local, and patient-controlled anesthesia techniques were used to facilitate transition to oral analgesics. RESULTS: Average patient age was 61 ± 9 years. Sixty-six patients (73%) were male. Seventy cases were elective, and 20 patients required urgent revascularization. All patients underwent intraoperative angiography after graft construction, which revealed Fitzgibbon class A grafts. There were no in-hospital mortalities. One patient required re-exploration for bleeding, through the same minimally invasive incision, did not require conversion to sternotomy for bleeding, and was transferred to the intensive care unit postexploration for bleeding for standard postoperative care. Postoperative complications were limited to one superficial wound infection. The mean hospital length of stay was 3.5 ± 1.17 days. CONCLUSIONS: In patients undergoing robotic-assisted CABG, ultrafast-track cardiac surgery with immediate postprocedure extubation and transfer to the inpatient ward has been demonstrated to be safe with no increase in perioperative morbidity or mortality. It requires a dedicated heart team with a carefully selected group of patients. Avoiding cardiac surgical intensive care unit expedites recovery, with possible avoidance of infection and early discharge from hospital.

Prognostic significance of baseline metabolic tumor volume in relapsed and refractory Hodgkin lymphoma.

Identification of prognostic factors for patients with relapsed/refractory Hodgkin lymphoma (HL) is essential for optimizing therapy with risk-adapted approaches. In our phase 2 study of positron emission tomography (PET)-adapted salvage therapy with brentuximab vedotin (BV) and augmented ifosfamide, carboplatin, and etoposide (augICE), we assessed clinical factors, quantitative PET assessments, and cytokine and chemokine values. Transplant-eligible patients with relapsed/refractory HL received 2 (cohort 1) or 3 (cohort 2) cycles of weekly BV; PET-negative patients (Deauville score ≤2) proceeded to autologous stem cell transplantation (ASCT) whereas PET-positive patients received augICE before ASCT. Serum cytokine and chemokine levels were measured at baseline and after BV. Metabolic tumor volume (MTV) and total lesion glycolysis were measured at baseline, after BV, and after augICE. Sixty-five patients enrolled (45, cohort 1; 20, cohort 2); 49 (75%) achieved complete response and 64 proceeded to ASCT. Three-year overall survival and event-free survival (EFS) were 95% and 82%, respectively. Factors predictive for EFS by multivariable analysis were baseline MTV (bMTV) (P < .001) and refractory disease (P = .003). Low bMTV (<109.5 cm3) and relapsed disease identified a favorable group (3-year EFS, 100%). For patients who received a transplant, bMTV and pre-ASCT PET were independently prognostic; 3-year EFS for pre-ASCT PET-positive patients with low bMTV was 86%. In this phase 2 study of PET-adapted therapy with BV and augICE for relapsed/refractory HL, bMTV and refractory disease were independent prognostic factors for EFS. Furthermore, bMTV improved the predictive power of pre-ASCT PET. Future studies should optimize efficacy and tolerability of salvage therapy by stratifying patients according to risk factors such as bMTV.

A Prospective Randomized Study of Endoscopic Versus Conventional Harvesting of the Radial Artery.

OBJECTIVE: The aims of the study were to determine whether endoscopic harvesting of the radial artery (RA) reduces morbidity due to pain, infection, and disability with improvement in satisfaction and cosmesis compared to the conventional technique and (2) to compare the 6-month angiographic patency of the RA harvested conventionally and endoscopically. METHODS: In a prospective randomized study, 119 patients undergoing coronary artery bypass grafting using the RA were randomized to have RA harvested either conventionally (n = 59) or endoscopically (n = 60). RESULTS: Radial artery harvest time (open wound time) was significantly reduced in the endoscopic group (36.5 ± 9.4 vs 57.7 ± 9.4 minutes, P < 0.001). Only one patient developed wound infection (1.6%) in the endoscopic group compared with six patients (10.2%), P = 0.061, in the conventional group. Although this was not statistically significant, clinically this was relevant in terms of reduction in postoperative morbidity. Postoperative pain in the arm incision was significantly lower in the endoscopic group at postoperative day 2 (P < 0.001) and at discharge (P < 0.001) and similar to the conventional open group at 6 weeks' follow-up (P = 0.103). Overall patient satisfaction and cosmesis were significantly better in the endoscopic group at postoperative day 2 (P < 0.001), at discharge (P < 0.001), and at 6 weeks' follow-up (P < 0.001). There was no difference in the arm disability postoperatively (P = 0.505) between the two groups. Six-month angiographic assessment of 23 patients (12 endoscopic and 11 open) revealed no difference in the patency rate (10/12 in endoscopic and 9/11 in open group). CONCLUSIONS: Endoscopic RA harvesting reduced the incidence of postoperative wound infection and wound pain and improved patient satisfaction and cosmesis compared with conventional harvesting technique. There was no difference in the 6-month angiographic patency of the RA harvested conventionally and endoscopically.

Is the Future of Coronary Arterial Revascularization a Hybrid Approach?: The Canadian Experience Across Three Centers.

OBJECTIVE: Hybrid coronary revascularization offers and combines the advantages of both surgical and percutaneous revascularization and eliminates at the same time the disadvantages of both procedures. The objective of this study was to assess graft and stent patency at 6 months, rate of bleeding, intensive care unit and hospital stay, rate of reintervention, and long-term clinical follow-up. METHODS: From March 2004 to November 2015, a total of 203 patients underwent robotic-assisted minimally invasive direct coronary artery bypass graft of the left internal thoracic artery to the left anterior descending artery and PCI of a non-left anterior descending vessel in a single or two stage, at three different centers. Patients underwent 6-month angiographic follow-up. The mean ± SD clinical follow-up was 77.82 ± 41.4 months. RESULTS: Successful hybrid coronary revascularization occurred in 196 of the 203 patients. One hundred forty-six patients underwent simultaneous surgical and percutaneous intervention. Nineteen patients underwent PCI before surgery, and 38 patient underwent PCI after surgery. No in-hospital mortality occurred. The mean ± SD ICU stay was 1 ± 1 days and the mean ± SD hospital stay was 5 ± 2 days. Only 13.3% of the patients required a blood transfusion. Six-month angiographic follow-up has been performed in the 95 patients, and it demonstrated a left internal thoracic artery anastomotic patency of 97.9% and stent patency of 92.6%. A total of 77.8 ± 41.4-month clinical follow-up demonstrated 95.1% survival, 92.6% freedom from angina, and 90.7% freedom from any form of coronary revascularization. CONCLUSIONS: Hybrid coronary revascularization seems to be a promising and safe revascularization strategy. It provides selected patients with an alternative, functionally complete revascularization with minimal surgical trauma and good long-term clinical outcomes.

Recurrent De Novo and Biallelic Variation of ATAD3A, Encoding a Mitochondrial Membrane Protein, Results in Distinct Neurological Syndromes.

ATPase family AAA-domain containing protein 3A (ATAD3A) is a nuclear-encoded mitochondrial membrane protein implicated in mitochondrial dynamics, nucleoid organization, protein translation, cell growth, and cholesterol metabolism. We identified a recurrent de novo ATAD3A c.1582C>T (p.Arg528Trp) variant by whole-exome sequencing (WES) in five unrelated individuals with a core phenotype of global developmental delay, hypotonia, optic atrophy, axonal neuropathy, and hypertrophic cardiomyopathy. We also describe two families with biallelic variants in ATAD3A, including a homozygous variant in two siblings, and biallelic ATAD3A deletions mediated by nonallelic homologous recombination (NAHR) between ATAD3A and gene family members ATAD3B and ATAD3C. Tissue-specific overexpression of borR534W, the Drosophila mutation homologous to the human c.1582C>T (p.Arg528Trp) variant, resulted in a dramatic decrease in mitochondrial content, aberrant mitochondrial morphology, and increased autophagy. Homozygous null bor larvae showed a significant decrease of mitochondria, while overexpression of borWT resulted in larger, elongated mitochondria. Finally, fibroblasts of an affected individual exhibited increased mitophagy. We conclude that the p.Arg528Trp variant functions through a dominant-negative mechanism that results in small mitochondria that trigger mitophagy, resulting in a reduction in mitochondrial content. ATAD3A variation represents an additional link between mitochondrial dynamics and recognizable neurological syndromes, as seen with MFN2, OPA1, DNM1L, and STAT2 mutations.

Comparison of isoflurane and sevoflurane in cardiac surgery: a randomized non-inferiority comparative effectiveness trial.

PURPOSE: Volatile anesthetics possess cardioprotective properties, but it is unknown if the cardioprotective effects extend equally to all members of the class. Although sevoflurane is a relatively newer anesthetic than isoflurane, its introduction into practice was not preceded by a head-to-head comparison with isoflurane in a trial focusing on clinically important outcomes. Our objective was to determine whether sevoflurane was non-inferior to isoflurane on a clinically important primary outcome in a heterogeneous group of adults undergoing cardiac surgery. METHODS: This was a pragmatic randomized non-inferiority comparative effectiveness clinical trial in 464 adults having coronary artery bypass graft and/or single valve surgery during November 2011 to March 2014. The intervention was maintenance of anesthesia with sevoflurane (n = 231) or isoflurane (n = 233) administered at a dose of 0.5-2.0 MAC throughout the entire operation. All caregivers were blinded except for the anesthesiologist and perfusionist. The primary outcome was a composite of intensive care unit (ICU) length of stay ≥ 48 hr and all-cause 30-day mortality. We hypothesized that sevoflurane would be non-inferior to isoflurane (non-inferiority margin < 10% based on an expected event rate of 25%). Secondary outcomes included prolonged ICU stay, 30- and 365-day all-cause mortality, inotrope or vasopressor usage, new-onset hemodialysis or atrial fibrillation, stroke, and readmission to the ICU. RESULTS: No losses to follow-up occurred. The primary outcome occurred in 25% of sevoflurane patients and 30% of isoflurane patients (absolute difference, -5.4%; one-sided 95% confidence interval, 1.4), thus non-inferiority was declared. Sevoflurane was not superior to isoflurane for the primary outcome (P = 0.21) or for any secondary outcomes. CONCLUSION: Sevoflurane is non-inferior to isoflurane on a composite outcome of prolonged ICU stay and all-cause 30-day mortality. Sevoflurane is not superior to isoflurane on any other of the clinically important outcomes. This trial was registered at clinicaltrials.gov; NCT01477151.

RéSUMé: OBJECTIF: Les agents anesthésiques volatils possèdent des propriétés cardioprotectrices, mais nous ne savons pas si ces effets cardioprotecteurs sont équivalents pour tous les agents de cette classe. Bien que le sévoflurane soit un anesthésique plus récent que l'isoflurane, son introduction dans notre pratique n'a pas été précédée par une comparaison directe à l'isoflurane dans une étude s'intéressant à d'importants critères d'évaluation cliniques. Notre objectif était de déterminer si le sévoflurane était non inférieur à l'isoflurane en relation à un critère d'évaluation principal important d'un point de vue clinique dans un groupe hétérogène d'adultes subissant une chirurgie cardiaque. MéTHODE: Nous avons réalisé une étude clinique randomisée et pragmatique d'efficacité comparative et de non-infériorité auprès de 464 adultes subissant des pontages coronariens et/ou une chirurgie valvulaire unique entre novembre 2011 et mars 2014. L'intervention consistait en le maintien de l'anesthésie à l'aide de sévoflurane (n = 231) ou d'isoflurane (n = 233) administré à une dose de 0,5-2,0 MAC tout au long de l'opération. Aucun intervenant ne connaissait l'agent utilisé, à l'exception de l'anesthésiologiste et du perfusionniste. Le critère d'évaluation principal était une composée de la durée de séjour à l'unité de soins intensifs (USI) ≥ 48 h et de la mortalité, toutes causes confondues, à 30 jours. Nous avons émis l'hypothèse que le sévoflurane ne serait pas inférieur à l'isoflurane (marge de non-infériorité < 10 % sur la base d'un taux de complications attendu de 25 %). Les critères d'évaluation secondaires comprenaient un séjour prolongé à l'USI, la mortalité toutes causes confondues à 30 et à 365 jours, l'utilisation d'inotropes ou de vasopresseurs, une hémodialyse ou une fibrillation auriculaire nouvelles, un accident vasculaire cérébral et une réadmission à l'USI. RéSULTATS: Nous n'avons perdu aucun patient au suivi. Le critère d'évaluation principal est survenu chez 25 % des patients ayant reçu du sévoflurane et 30 % des patients ayant reçu de l'isoflurane (différence absolue, −5,4 %; intervalle de confiance unilatéral 95 %, 1,4): la non-infériorité a donc été déclarée. Le sévoflurane n'était pas supérieur à l'isoflurane en ce qui touchait au critère d'évaluation principal (P = 0,21) ou aux critères d'évaluation secondaires. CONCLUSION: Le sévoflurane n'est pas inférieur à l'isoflurane selon un critère d'évaluation composé d'une durée de séjour prolongée à l'USI et de la mortalité toutes causes confondues à 30 jours. Le sévoflurane n'est pas supérieur à l'isoflurane en ce qui touche à n'importe quel autre critère clinique important. Cette étude a été enregistrée au ClinicalTrials.gov, numéro NCT01477151.

Higher-risk mitral valve operations after previous sternotomy: endoscopic, minimally invasive approach improves patient outcomes.

BACKGROUND: Reoperative mitral valve (MV) surgery is associated with significant morbidity and mortality; however, endoscopic minimally invasive surgical techniques may preserve the surgical benefits of conventional mitral operations while potentially reducing perioperative risk and length of stay (LOS) in hospital. METHODS: We compared the outcomes of consecutive patients who underwent reoperative MV surgery between 2000 and 2014 using a minimally invasive endoscopic approach (MINI) with those of patients who underwent a conventional sternotomy (STERN). The primary outcome was in-hospital/30-day mortality. Secondary outcomes included blood product transfusion, LOS in hospital and in the intensive care unit (ICU), and postoperative complications. RESULTS: We included 132 patients in our study: 40 (mean age 68 ± 14 yr, 70% men) underwent MINI and 92 (62 ± 13 yr, 40% men) underwent STERN. The MINI group had significantly more comorbidities than the STERN group. While there were no significant differences in complications, all point estimates suggested lower mortality and morbidity in the MINI than the STERN group (in-hospital/ 30-day mortality 5% v. 11%, p = 0.35; composite any of 10 complications 28% v. 41%, p = 0.13). Individual complication rates were similar between the MINI and STERN groups, except for intra-aortic balloon pump requirement (IABP; 0% v. 12%, p = 0.034). MINI significantly reduced the need for any blood transfusion (68% v. 84%, p = 0.036) or packed red blood cells (63% v. 79%, p = 0.042), fresh frozen plasma (35% v. 59%, p = 0.012) and platelets (20% v. 40%, p = 0.024). It also significantly reduced median hospital LOS (8 v. 12 d, p = 0.014). An exploratory propensity score analysis similarly demonstrated a significantly reduced need for IABP (p < 0.001) and a shorter mean LOS in the ICU (p = 0.046) and in hospital (p = 0.047) in the MINI group. CONCLUSION: A MINI approach for reoperative MV surgery reduces blood product utilization and hospital LOS. Possible clinically relevant differences in perioperative complications require assessment in randomized clinical trials.

CONTEXTE: Les réopérations de la valve mitrale (VM) sont associées à une morbidité et à une mortalité importantes. Cependant, il semblerait que les techniques chirurgicales endoscopiques à effraction minimale préservent les avantages des opérations traditionnelles de la VM tout en réduisant potentiellement les risques périopératoires et la durée d'hospitalisation. MÉTHODES: Nous avons comparé les résultats de patients consécutifs ayant subi une réopération de la VM entre 2000 et 2014 selon une approche endoscopique à effraction minimale (groupe MINI) à ceux de patients ayant subi une sternotomie classique (groupe STERN). Le résultat primaire à l'étude était la mortalité intrahospitalière ou dans les 30 premiers jours, et les résultats secondaires, la transfusion de produits sanguins, la durée du séjour à l'hôpital et à l'unité des soins intensifs (USI), ainsi que les complications postopératoires. RÉSULTATS: Nous avons retenu 132 patients : 40 (âge moyen de 68 ± 14 ans, 70 % d'hommes) dans le groupe MINI et 92 (âge moyen de 62 ± 13 ans, 40 % d'hommes) dans le groupe STERN. Les patients du groupe MINI présentaient un nombre significativement plus élevé de comorbidités que ceux du groupe STERN. Aucune différence significative n'a été observée quant aux complications, mais toutes les estimations ponctuelles pointaient vers une mortalité et une morbidité moindres dans le groupe MINI (mortalité intrahospitalière ou dans les 30 premiers jours : 5 % c. 11 %, p = 0,35; morbidité combinée à la présence d'au moins une complication parmi 10 possibles : 28 % c. 41 %, p = 0,13). Les taux de complications individuels étaient semblables chez les patients des 2 groupes, sauf pour l'exigence de ballon de contrepulsion intra-aortique (BCIA; 0 % c. 12 %, p = 0,034). L'approche MINI a réduit significativement le taux de transfusion de sang (68 % c. 84 %, p = 0,036) ou de concentrés de globules rouges (63 % c. 79 %, p = 0,042), de plasma frais congelé (35 % c. 59 %, p = 0,012) et de plaquettes (20 % c. 40 %, p = 0,024), en plus de diminuer significativement la durée médiane d'hospitalisation (8 jours c. 12 jours, p = 0,014). En outre, une analyse exploratoire du score de propension a révélé une réduction significative du BCIA (p < 0,001) ainsi qu'une durée moyenne de séjour à l'USI (p = 0,046) et à l'hôpital (p = 0,047) plus courte dans le groupe MINI. CONCLUSION: Le recours à l'approche endoscopique à effraction minimale pour les réopérations de la VM diminuerait le recours aux produits sanguins et la durée d'hospitalisation. En ce qui a trait aux complications périopératoires, il faudra procéder à des essais cliniques aléatoires pour évaluer les différences possiblement pertinentes sur le plan clinique.