Interaction of the chemotherapeutic agent oxaliplatin and the tyrosine kinase inhibitor dasatinib with the organic cation transporter 2.

Oxaliplatin (OHP) is effective in colorectal cancer treatment but induces peripheral neurotoxicity (OHP-induced peripheral neurotoxicity, OIPN), diminishing survivor quality of life. Organic cation transporter 2 (OCT2) is a key OHP uptake pathway in dorsal root ganglia. Competing for OCT2-mediated OHP uptake, such as with the tyrosine kinase inhibitor dasatinib, may mitigate OHP side effects. We investigated OHP and dasatinib interaction with OCT2 in human embryonic kidney 293 (HEK293) cells expressing OCT2 within a 10-3 to 10-7 M concentration range. Uptake competition experiments using fluorescent organic cation 4-(4-dimethylaminostyryl)-N-methylpyridinium (ASP+, 1 µM) and mass spectrometry (MS) to determine cellular platinum content indicated that OHP (100 µM) is an OCT2 substrate, mediating OHP cellular toxicity. ASP+ and MS analysis revealed dasatinib as a non-transported inhibitor of hOCT2 (IC50 = 5.9 µM) and as a regulator of OCT2 activity. Dasatinib reduced transporter Vmax, potentially via Y544 phosphorylation suppression. MS analysis showed cellular dasatinib accumulation independent of hOCT2. Although 3 µM dasatinib reduced 100 µM OHP accumulation in hOCT2-HEK293 cells, co-incubation with dasatinib and OHP did not prevent OHP toxicity, possibly due to dasatinib-induced cell viability reduction. In summary, this study demonstrates OHP as an OCT2 substrate and dasatinib as a non-transported inhibitor and regulator of OCT2, offering potential for OIPN mitigation.

Pigmented dentinogenic ghost cell tumor: a unique case report and a review of the literature.

Dentinogenic ghost cell tumors are rare tumors, and few cases of them were reported in the literature. The presence of pigment in odontogenic lesions is a rare unexplained histological finding. In this report, we describe a unique case of a 7-year-old girl that was referred to the Department of Oral and Maxillofacial Surgery complaining of a left mandibular swelling. Clinical examination revealed a huge, ulcerated mass. Both incisional and excisional biopsies revealed a benign infiltrative odontogenic tumor with admixed ameloblast-like cells and pigmented ghost cells, consistent with a pigmented dentinogenic ghost cell tumor. To the best of our knowledge, this is the youngest case of intraosseous dentinogenic ghost cell tumor reported in the English literature and the second report of a pigmented variant. This rare variant should be included in the differential of pigmented odontogenic lesions to avoid misinterpretation, especially in small biopsies.

Incidence and outcomes of surgical pulmonary embolectomy in the UK.

BACKGROUND: Surgical pulmonary embolectomy is rarely used for the treatment of massive acute pulmonary embolism. The aim of this study was to assess the incidence and outcomes of this operation by undertaking a retrospective analysis of a large national registry in the UK. METHODS: All acute pulmonary embolectomies performed between 1996 and 2018 were captured in the National Institute of Cardiovascular Outcomes Research central database. Trends in the number of operations performed during this interval and reported in-hospital outcomes were analysed retrospectively. Multivariable logistic regression was used to identify independent risk factors for in-hospital death. RESULTS: All 256 patients treated surgically for acute pulmonary embolism during the study interval were included in the analysis. Median age at presentation was 54 years, 55.9% of the patients were men, 48.0% had class IV heart failure symptoms, and 37.5% had preoperative cardiogenic shock. The median duration of bypass was 73 min, and median cross-clamp time was 19 min. Cardioplegic arrest was used in 53.1% of patients. The median duration of hospital stay was 11 days. The in-hospital mortality rate was 25%, postoperative stroke occurred in 5.4%, postoperative dialysis was required in 16%, and the reoperation rate for bleeding was 7.5%. Risk-adjusted multivariable analysis revealed cardiogenic shock (OR 2.54, 95% c.i. 1.05 to 6.21; P = 0.038), preoperative ventilation (OR 5.85, 2.22 to 16.35; P < 0.001), and duration of cardiopulmonary bypass exceeding 89 min (OR 7.82, 3.25 to 20.42; P < 0.001) as significant independent risk factors for in-hospital death. CONCLUSION: Surgical pulmonary embolectomy is rarely performed in the UK, and is associated with significant mortality and morbidity. Preoperative ventilation, cardiogenic shock, and increased duration of bypass were significant predictors of in-hospital death.

A blood clot in the lung can prevent the lungs from working properly and put pressure on the heart to work harder. Small clots can be treated with medications taken at home and are not a danger to life. Larger blood clots can put a lot of pressure on the heart and need immediate hospital treatment. Large blood clots can be treated with 'clot busting' medications, the delivery of a small tube into the blood vessels of the lung to suck up the clot or deliver medications directly on to its surface, and finally a form of open-heart surgery. With this surgery, a surgeon opens the chest, make a cut into the large vessels containing the clot, and physically removes the large piece of obstructing clot. The aim of this study was to describe and analyse the outcomes of this operation done in the UK over a long period. A database was used to find out how often and where this operation took place and its results. The available data were studied to try to understand how helpful this operation is to patients with lung blood clots. Between 1996 and 2018, 256 people had this operation. One in four patients did not survive the operation, 5.4% developed a clot or bleed in the brain, 16% needed to go on to a dialysis machine, and 7.5% had to be rushed back into theatre because of bleeding. Needing a ventilator machine for help with breathing, being in a sudden state of heart failure, and a long time on the heart bypass machine were all linked with patients who did not survive. This operation is rarely performed in the UK, and is often linked to a high chance of death or serious complication. In this study, the points described above were linked to a bad outcome.

The effect of cardioplegic supplementation with sildenafil on cardiac energetics in a piglet model of cardiopulmonary bypass and cardioplegic arrest with warm or cold cardioplegia.

Cardioplegic cardioprotection strategies used during paediatric open-heart surgery remain suboptimal. Sildenafil, a phosphodiesterase 5 (PDE-5) inhibitor, has been shown to be cardioprotective against ischemia/reperfusion injury in a variety of experimental models and this study therefore tested the efficacy of supplementation of cardioplegia with sildenafil in a piglet model of cardiopulmonary bypass and arrest, using both cold and warm cardioplegia protocols. Piglets were anaesthetized and placed on coronary pulmonary bypass (CPB), the aorta cross-clamped and the hearts arrested for 60 min with cardioplegia with or without sildenafil (10 nM). Twenty minutes after removal of cross clamp (reperfusion), attempts were made to wean the pigs from CPB. Termination was carried out after 60 min reperfusion. Throughout the protocol blood and left ventricular tissue samples were taken for analysis of selected metabolites (using HPLC) and troponin I. In both the cold and warm cardioplegia protocols there was evidence that sildenafil supplementation resulted in faster recovery of ATP levels, improved energy charge (a measure of metabolic flux) and altered release of hypoxanthine and inosine, two purine catabolites. There was no effect on troponin release within the studied short timeframe. In conclusion, sildenafil supplementation of cardioplegia resulted in improved cardiac energetics in a translational animal model of paediatric CPB surgery.

Recommendations for developing effective and safe paediatric and congenital heart disease services in low-income and middle-income countries: a public health framework.

The global burden of paediatric and congenital heart disease (PCHD) is substantial. We propose a novel public health framework with recommendations for developing effective and safe PCHD services in low-income and middle-income countries (LMICs). This framework was created by the Global Initiative for Children's Surgery Cardiac Surgery working group in collaboration with a group of international rexperts in providing paediatric and congenital cardiac care to patients with CHD and rheumatic heart disease (RHD) in LMICs. Effective and safe PCHD care is inaccessible to many, and there is no consensus on the best approaches to provide meaningful access in resource-limited settings, where it is often needed the most. Considering the high inequity in access to care for CHD and RHD, we aimed to create an actionable framework for health practitioners, policy makers and patients that supports treatment and prevention. It was formulated based on rigorous evaluation of available guidelines and standards of care and builds on a consensus process about the competencies needed at each step of the care continuum. We recommend a tier-based framework for PCHD care integrated within existing health systems. Each level of care is expected to meet minimum benchmarks and ensure high-quality and family centred care. We propose that cardiac surgery capabilities should only be developed at the more advanced levels on hospitals that have an established foundation of cardiology and cardiac surgery services, including screening, diagnostics, inpatient and outpatient care, postoperative care and cardiac catheterisation. This approach requires a quality control system and close collaboration between the different levels of care to facilitate the journey and care of every child with heart disease. This effort was designed to guide readers and leaders in taking action, strengthening capacity, evaluating impact, advancing policy and engaging in partnerships to guide facilities providing PCHD care in LMICs.

Validation of the German Registry for Acute Aortic Dissection Type A Score in predicting 30-day mortality after type A aortic dissection surgery.

OBJECTIVES: No reliable scores are available to predict mortality following surgery for type A acute aortic dissection (TAAAD). Recently, the German Registry of Acute Aortic Dissection Type A (GERAADA) score has been developed. We aim to compare how the GERAADA score performs in predicting operative mortality for TAAAD to the European System for Cardiac Operative Risk Evaluation (EuroSCORE) II. METHODS: We calculated the GERAADA score and EuroSCORE II in patients who underwent TAAAD repair at the Bristol Heart Institute. As there are no precise criteria to calculate the GERAADA score, we used 2 methods: a Clinical-GERAADA score, which evaluated malperfusion with clinical and radiological evidence, and a Radiological-GERAADA score, where malperfusion was assessed by computed tomography scan alone. RESULTS: 207 consecutive patients had surgery for TAAAD, and the observed 30-day mortality was 15%. The Clinical-GERAADA score showed the strongest discriminative power with an area under the curve (AUC) of 0.80 [95% confidence interval (CI) 0.71-0.89], while the Radiological-GERAADA score had an AUC of 0.77 (95% CI 0.67-0.87). EuroSCORE II showed acceptable discriminative power with an AUC of 0.77 (95% CI 0.67-0.87). CONCLUSIONS: Clinical GERAADA score performed better than the other scores and it is specific and easy to use in the context of a TAAAD. Further validation of the new criteria for malperfusion is needed.

Left ventricular pseudoaneurysm in Lemierre's syndrome: a case report.

Background: Lemierre's syndrome is an infectious phenomenon characterized by oropharyngeal infection with bacteraemia, thrombophlebitis, and distant septic emboli. Septic emboli are a recognized cause of a Type 2 myocardial infarction, with a left ventricular pseudoaneurysm being a rare but important complication of this. Case summary: A 19-year-old male presented with acute confusion, fevers, and a cough. Blood cultures were positive for Fusobacterium necrophorum and initial imaging showed a cavitating pneumonia. Further evaluation revealed septic emboli in the distal digits and brain. The patient initially responded to antibiotic therapy but developed chest pain with increased troponin levels. An electrocardiogram showed inferolateral ST elevation. A transthoracic echocardiogram (TTE) showed hypokinaesia of the mid to apical lateral wall, and a computed tomography (CT) scan showed a pericardial effusion with a possible purulent effusion or abscess. The patient underwent surgical drainage of a sterile effusion. A post-operative TTE and CT demonstrated a left ventricular pseudoaneurysm that was surgically repaired. The venous thrombus was encountered intra-operatively confirming a diagnosis of Lemierre's syndrome. The patient completed the regimen of antibiotics and showed a good post-operative recovery. Discussion: This is the first case described of left ventricular pseudoaneurysm as a complication of Lemierre's syndrome. It highlights not only the importance of serial, multimodality imaging in both diagnostic workup and identification of complications, but also the importance of a multidisciplinary team in the management of patients with complex and rare presentations.

In-hospital outcomes predictors and trends of redo sternotomy aortic root replacements: insights from a UK registry analysis.

Background: Redo sternotomy aortic root surgery is technically demanding, and the evidence on outcomes is mostly from retrospective, small sample, single-centre studies. We report the trend, early clinical results and outcome predictors of redo aortic root replacement over 20 years in the United Kingdom. Methods: We retrospectively analysed collected data from the UK National Adult Cardiac Surgery Audit (NACSA) on all redo sternotomy aortic root replacements performed between 30th January 1998 and 19th March 2019. We analysed trends in the volume of operations, characteristics of hospital survivors vs. non-survivors, and predictors of in-hospital outcomes. Results: During the study period, 1,107 redo sternotomy aortic root replacements were performed (median age 59, 26% of patients were females). Eighty-four per cent of cases (N = 931) underwent a composite root replacement, 11% (N = 119) had homograft root replacement and valve-sparing root replacement was performed in 5.1% (N = 57) of cases. There was a steady increase in the volume of redo sternotomy root replacements beyond 2006, from an annual volume of 22 procedures in 2006 to 106 procedures in 2017. Hospital mortality was 17% (n = 192), postoperative stroke or TIA occurred in 5.2% (n = 58), and postoperative dialysis was required in 11% (n = 109) of patients. Return to the theatre for bleeding/tamponade was required in 9% (n = 102) and median in-hospital stay was 9 days. Age >59 (OR: 2.99, CI: 1.92-4.65, P < 0.001), recent myocardial infarction (OR: 6.42, CI: 2.24-18.41, P = 0.001) were associated with increased in-hospital mortality. Emergency surgery (OR: 3.95, 2.27-6.86, P < 0.001), surgery for endocarditis (OR: 2.05, CI: 1.26-3.33, P = 0.001), salvage coronary artery bypass grafting (OR: 2.20, CI: 1.37-3.54, P < 0.001), arch surgery (OR: 2.47, CI: 1.30-3.61, P = 0.018) and aortic cross-clamp longer than 169 min (OR: 2.17, CI: 1.00-1.01, P = 0.003) were associated with increased risk of mortality. We found no effect of the centre or surgeon volume on mortality (P > 0.05). Conclusions: Redo sternotomy aortic root replacement still carries significant morbidity and mortality and is sporadically performed across surgeons and centres in the UK.

Surgical outcomes and optimal approach to treatment of aortic valve endocarditis with aortic root abscess.

OBJECTIVES: To evaluate the impact of aortic root abscess (ARA) on the postoperative outcomes of surgically managed infective endocarditis (IE) and to inform optimal surgical approach. METHODS: Between 2009 and 2020, 143 consecutive patients who underwent surgical management for aortic-valve IE were included in a retrospective cohort study. Multivariable and propensity-weighted analyses were used to adjust for demographic imbalances between those without (n = 93; NARA) and with an ARA (n = 50). Additionally, empirical subgroup analysis appraised the two most used surgical techniques; patch reconstruction (PR) and aortic root replacement (ARR). RESULTS: Demographic characteristics were similar between ARA and NARA except for logistic EuroSCORE, previous valve surgery, and multivalvular infection. In-hospital mortality was 8% and 12% in NARA and ARA, respectively (p = .38), with mortality rates consistently nonsignificantly higher in ARA across all time periods. The overall reoperation rate was also higher in ARA (27% vs. 14%; p = .09) and ARA was shown to be associated with late reoperation (odds ratio [OR] = 2.74; 95% confidence interval [CI] = 1.18-6.36). Patients treated with an ARR showed a 16% increase in late mortality when compared with PR (40% vs. 24%; p = .27) and a 17% lower reoperation rate (14% vs. 31%; p = .24). Propensity-weighted analysis identified ARR as a significant protective factor for reoperation (hazard ratio = 0.05; 95% CI = 0.01-0.34). CONCLUSIONS: The presence of an ARA in aortic valve endocarditis was not associated with significantly higher early and late mortality but is linked with a higher reoperation rate at our institution. ARR in ARA is protective from reoperation so should be considered best practice in this setting.

Blood lactate predicts mortality after surgical repair of type A acute aortic dissection.

BACKGROUND: Ischemia and malperfusion are strong predictors of poor postoperative outcomes in type A acute aortic dissection (TAAAD). Serum lactate is an accurate surrogate point-of-care marker of malperfusion. The aim of this study is to investigate the correlation between lactate, in-hospital outcomes, and 1-year survival following TAAAD repair. METHODS: One hundred and thirty-two patients underwent operative repair of TAAAD over a 4-year period at our institution 128 patients had serum lactate measurements at three stages peri-operatively-preoperatively, at the end of cardiopulmonary bypass (post-CPB) and 6 h postintensive care unit (ICU) admission. The primary outcomes were in-hospital mortality and 1-year survival. The secondary outcomes were the incidences of in-hospital morbidities. RESULTS: Patients were divided into two groups: 88 (68.8%) with normal lactate and 40 (31.2%) with elevated lactate (>2.2 mmol/L). Lactate measured preoperatively (odds ratio 1.52, 95% confidence interval 1.17-2.07, p < .01), post-CPB (1.34, 1.14-1.64, p < .01) and 6 h post-ICU admission (1.29, 1.08-1.55, p < .01) was an independent predictor of in-hospital mortality. Following adjustment for the Penn Classification, lactate continued to have a significant correlation with in-hospital mortality at all three timepoints. There was a higher incidence of complications in the elevated lactate group and especially hemofiltration (20% vs. 9.1%, p = .08). 1-year survival was similar in both groups (p = .23). CONCLUSIONS: There is a direct correlation between elevated serum lactate and postoperative mortality after TAAAD repair, which is independent of the Penn Classification status on admission.

Endoscopic Robotic Retrieval of a Migrated Subclavian Vein Stent from the Right Ventricle.

A 54-year-old woman with end-stage renal disease on hemodialysis with access through a right arm arteriovenous fistula presented with right arm swelling. Venography demonstrated right subclavian vein stenosis. A balloon angioplasty of the stenotic vein was unsuccessful, and she subsequently underwent stent placement with balloon angioplasty. Ten days following the procedure, she developed acute shortness of breath. Transthoracic echocardiogram demonstrated the migration of the venous stent into the right ventricle. Using an endoscopic robotic approach, the stent was successfully extracted from the beating heart.

Case Report and Supporting Documentation: Acute Kidney Injury Manifested as Oliguria Is Reduced by Intravenous Magnesium Before Cisplatin.

After more than four decades of post-approval, cisplatin is still an important treatment for numerous cancers. However, acute kidney injury (AKI), defined as significant impairment of renal filtration as discussed below, is the major limiting side effect of cisplatin, occurring in approximately 30% of patients (25-33% after the first course). Cisplatin also damages the kidneys' ability to reabsorb magnesium in 40-100% of patients, with collateral health risks due to subsequent hypomagnesemia. Multiple methods and drugs have been proposed for preventing cisplatin-induced AKI, including saline infusion with or without mannitol, which has not always prevented AKI and has been found to activate a cellular stress response in renal tubular cells. While numerous reports and trials, as well as the National Comprehensive Cancer Network (NCCN), support premedication with magnesium and hydration, this practice has not been universally accepted. Many clinics administer intravenous magnesium (IV) only after identification of hypomagnesemia post-cisplatin treatment, thus placing patients at risk for AKI and chronic renal loss of magnesium. We present the following case report and additional supporting evidence identifying the immediate effect of IV magnesium prior to intraperitoneal cisplatin for cycle 4 because of documented hypomagnesemia resulting in normalization of oliguria, which had been experienced for the first three cycles. The patient subsequently requested and received IV magnesium before cisplatin for the next two cycles with continuation of normal urinary output. The effect of pretreatment with IV magnesium on urine output following cisplatin has not been previously reported and further supports pre-cisplatin administration. In addition, two recent meta-analyses of clinical trials and pre-clinical research are reviewed that demonstrate effectiveness of magnesium pretreatment to preventing AKI without reducing its chemotherapeutic efficacy. This case report with additional evidence supports the adoption of administration of 1-3 g IV magnesium before cisplatin as best practice to prevent cisplatin induced AKI and hypomagnesemia regardless of patient baseline serum magnesium levels.

Perspectives of Surgeons from Atlanta, USA.

BACKGROUND: The COVID-19 pandemic in late 2019 quickly stretched health care system across the globe. Mortalities, shortages in health care system capacity, and lack of experience in similar circumstances required innovation in the way health care is delivered. Health care systems changed operating schedules, staff work pattern, and how patients are cared for. The effects of these changes reached patients, staff and training in different ways. METHODS: We searched the Pubmed and EMBASE for articles related to COVID-19. We also searched local emails and information provided to staff during the pandemic RESULTS: The COVID-19 pandemic affected organizations, patients, and staff. The organizations and staff had to adapt to the times to provide a safe and appropriate service to our patients. CONCLUSION: The pandemic challenged and changed the way we work as health care providers, and how we train the future surgeons. Changes in the system were effective.

Management of the aortic root in type A aortic dissection: A valve sparing approach.

BACKGROUND: Type A acute aortic dissection (TAAAD) is rapidly fatal without emergency repair. Surgical outcomes have improved over the years with improvements in technique and postoperative care. Classically, supracomissural aortic replacement has been the standard of care. However, reintervention rates, particularly on the aortic root in certain groups of patients, shifted the focus towards improving long-term results of surgical repair. With regard to the aortic root, root replacement has been the gold standard. However, the surgical community realized that valve replacement in itself is a disease, and valve sparing aortic root replacement (VSRR) took center stage in the care of these patients. METHODS: We searched the Pubmed and EMBASE databases for articles related to VSRR and composite valve conduit (CVC) root replacement, and the long-term results of these techniques in TAAAD. RESULTS: Supracomissural repair is limited by reintervention, and CVC results are affected by complications related to the prosthetic valve. Conversely, VSRR is associated with good short-term outcomes, improvement in quality of life, and it is durable. CONCLUSION: VSRR is a sound technique in TAAAD in experienced hands.

Rapid Regulation of Human Multidrug and Extrusion Transporters hMATE1 and hMATE2K.

Vectorial transport of organic cations (OCs) in renal proximal tubules is mediated by sequential action of human OC transporter 2 (hOCT2) and human multidrug and toxic extrusion protein 1 and 2K (hMATE1 and hMATE2K), expressed in the basolateral (hOCT2) and luminal (hMATE1 and hMATE2K) plasma membranes, respectively. It is well known that hOCT2 activity is subjected to rapid regulation by several signaling pathways, suggesting that renal OC secretion may be acutely adapted to physiological requirements. Therefore, in this work, the acute regulation of hMATEs stably expressed in human embryonic kidney cells was characterized using the fluorescent substrate 4-(4-(dimethylamino)styryl)-N-methylpyridinium (ASP+) as a marker. A specific regulation of ASP+ transport by hMATE1 and hMATE2K measured in uptake and efflux configurations was observed. In the example of hMATE1 efflux reduction by inhibition of casein kinase II, it was also shown that this regulation is able to modify transcellular transport of ASP+ in Madin-Darby canine kidney II cells expressing hOCT2 and hMATE1 on the basolateral and apical membrane domains, respectively. The activity of hMATEs can be rapidly regulated by some intracellular pathways, which sometimes are common to those found for hOCTs. Interference with these pathways may be important to regulate renal secretion of OCs.

Balloon-Anchoring Technique to Stabilize Target Vessel Catheterization in Complex Endovascular Aortic Repair.

Purpose: To describe a bailout technique to stabilize target vessel catheterization in branched endovascular aortic repair. Technique: The technique is demonstrated in a 75-year-old patient with a 75-mm symptomatic type III thoracoabdominal aortic aneurysm that was treated with a t-Branch endograft. If a catheter cannot be advanced for exchange to a more stable guidewire after target vessel catheterization, the balloon-anchoring technique can be applied to stabilize the through-the-branch hydrophilic guidewire. Through a femoral access a catheter and hydrophilic wire are passed outside the device into the target vessel and exchanged with a stiff wire; a semicompliant balloon is advanced over the Rosen wire and inflated in the target vessel, stabilizing the through-the-branch hydrophilic wire and facilitating its exchange with a stiff wire over a catheter or advancement of the bridging covered stent directly. Conclusion: The balloon-anchoring technique adds to the spectrum of bailout techniques that can be applied in cases of challenging target vessel access.

Transcatheter mitral valve-in-valve implantation in a pediatric patient.

An 11-year-old girl, with 25 mm mosaic tissue valve presented with clinical and echocardiographic appearance of stenotic mitral valve prosthesis. Her condition was treated via a transcatheter valve-in-valve implantation using a 23 mm Edwards Sapien 3, with satisfactory outcome.

Successful Reconstruction of the Right Ventricular Outflow Tract by Implantation of Thymus Stem Cell Engineered Graft in Growing Swine.

Graft cellularization holds great promise in overcoming the limitations associated with prosthetic materials currently used in corrective cardiac surgery. In this study, the authors evaluated the advantages of graft cellularization for right ventricular outflow tract reconstruction in a novel porcine model. After 4.5 months from implantation, improved myocardial strain, better endothelialization and cardiomyocyte incorporation, and reduced fibrosis were observed in the cellularized grafts compared with the acellular grafts. To the authors' knowledge, this is the first demonstration of successful right ventricular outflow tract correction using bioengineered grafts in a large animal model.