A systematic review and meta-analysis of BRCA1/2 mutation for predicting the effect of platinum-based chemotherapy in triple-negative breast cancer

IntroductionPlatinum-based chemotherapy (PBC) remains the mainstay of treatments for triple-negative breast cancer (TNBC). TNBC is a heterogeneous group, the issue of whether BRCA1/2 mutation carriers have a particular sensitivity to platinum agents is inconclusive. We conducted a meta-analysis to explore the relationship between BRCA1/2 mutation and PBC susceptibility in individuals with TNBC, aiming to gain more information on the size of the benefit of PBC in BRCA1/2 mutation carriers.Materials and methodsAll studies applying PBC with a subgroup of BRCA1/2 status were included. All endpoints, including pCR and RCB in the neoadjuvant phase, DFS in the adjuvant phase, ORR, PFS, and OS in the advanced phase, were assessed using HRs and 95% Cl.ResultsFrom the 22 studies included, there were 2158 patients with TNBC, with 392 (18%) bearing the BRCA1/2 gene mutation. Based on 13 studies applying neoadjuvant PBC, we discovered that BRCA1/2 mutation was substantially associated with a 17.6% increased pCR rate (HR 1.32, 95% CI 1.17–1.49, p < 0.00001; I² = 51%). Same result was observed in RCB0/I index (HR 1.38, 95% CI 1.08–1.76, P = 0.009; I² = 0%). The meta-analysis of 6 trials addressing advanced therapy revealed that ORR rates were significantly higher in patients with BRCA1/2 mutation (HR 1.91, 95% CI 1.48–2.47, p < 0.00001; I² = 32%), as well as PFS(HR 1.13, 95% CI 0.81–1.57, P = 0.47; I² = 0%) and OS (HR 1.89, 95% CI 1.22–2.92, P = 0.004; I² = 0%).ConclusionAccording to our meta-analysis of 22 trials in TNBC, BRCA1/2 mutation carriers were significantly more sensitive to PBC regimens, especially in neoadjuvant and advanced therapy.     

Comparison of conventional magnetic resonance imaging and diffusion-weighted imaging in the differentiation of bone plasmacytoma from bone metastasis in the extremities

PurposeTo compare conventional magnetic resonance imaging (MRI) and diffusion-weighted imaging (DWI) in the differentiation of bone plasmacytoma from bone metastasis in the extremities.Materials and methodsA total of 65 patients with 27 bone plasmacytomas (11 men; mean age, 63.6 ± 8.2 [SD] years) and 38 patients with bone metastases (20 men; mean age, 64.1 ± 11.5 [SD] years) were retrospectively included. Plasmacytomas and metastases were compared for size, peritumoral edema, signal intensity (SI), SI pattern, apparent diffusion coefficient (ADC) values and standard deviation (SD) of ADC. Receiver operating characteristic analysis with area under the curve (AUC) was used to calculate sensitivity, specificity, and accuracy of MRI and DWI for the diagnosis of plasmacytoma according to a defined cut-off value.ResultsOn conventional MRI, plasmacytomas showed less peritumoral edema (22% vs. 71%; P < 0.001), were more often hyperintense on T1-weighted image (48% vs. 18%; P = 0.022) and more homogeneous on T2-weighted image (78% vs. 26%; P < 0.001) and contrast-enhanced T1-weighted images (70% vs. 25%; P = 0.001) than bone metastases. Mean ADC value and SD of ADC were significantly lower in bone plasmacytomas (760.1 ± 196.9 [SD] μm²/s and 161.5 ± 62.7 [SD], respectively) than in bone metastases (1214.2 ± 382.6 [SD] μm²/s and 277.0 ± 110.3 [SD], respectively) (P < 0.001). Using an ADC value ≤ 908.3 μm²/s, DWI yielded 88% sensitivity and 78% specificity for the diagnosis of plasmacytoma. ADC value yielded best area under the curve (AUC = 0.913), followed by SD of ADC (AUC = 0.814) and homogeneity on T2-weighted images (AUC = 0.757). The combination of conventional MRI and DWI (AUC = 0.894) showed improved diagnostic performance over conventional MRI alone (AUC= 0.843) for discriminating between plasmacytoma and metastasis.ConclusionConventional MRI in combination with DWI can be useful to discriminate between bone plasmacytoma and bone metastasis in the extremities.     

Peripheral cytotoxic T lymphocyte predicts first-line progression free survival in HER2-positive advanced breast cancer

BackgroundThe role of peripheral blood lymphocyte (pBL) in breast cancer has long been studied. However, the predictive role of pBL in advanced breast cancer (ABC) is poorly understood.MethodsA total of 303 patients with ABC were consecutively recruited at our center between January 2015 and September 2019. At baseline, pBL subtypes were detected in all patients with 229 blood samples available for circulating tumor DNA (ctDNA) detection. pBL was analyzed through flow cytometry. ctDNA-based gene mutations were detected using next generation sequencing. The cutoff value of pCTL was estimated by X-tile software. Progression free survival (PFS) was estimated by Kaplan-Meier curve and Cox hazard proportion regression model, with difference detection by log-rank test.ResultsMedian follow-up time of the study was 21.0 months. The median age of diagnosis was 52.0 years. Among the pBL subtypes, only pCTL level was found predictive for PFS in the HER2+ patients whom received anti-HER2 therapy (13.1 vs. 5.6 months, P = 0.001). However, the predictive role of pCTL was not found in HR-positive (P = 0.716) and TNBC (P = 0.202). pCTL high associated with suppressive immune indictors including lower CD4/CD8 ratio (P = 0.004) and high level of Treg cell (P = 0.004). High occurrence of FGFR1 amplification which has been reported as immune suppressor was also found in HER2+ patients with pCTL high (22.2% vs. 4.3%, P = 0.048).ConclusionsHigher pCTLs level associated with shorter PFS and FGFR1 mutation in HER2+ ABC patients.     

Evaluation of efficacy and safety of PARP inhibitors in breast cancer: A systematic review and meta-analysis

BackgroundMany breast cancer clinical trials with PARPi have been completed or are currently carried out, either by monotherapy or combined with chemotherapy. We aim to assess the efficacy and safety of PARPi in breast cancer patients as compared to chemotherapy.MethodsA comprehensive literature search of PubMed, EMBASE, CENTRAL, conference meetings and clinical trial registry was performed. The primary outcomes were progression-free survival (PFS), overall survival (OS), overall response rate (ORR). The secondary outcome was safety profile. The comparative effects were measured using hazard ratio (HR) or relative risk (RR) with 95% confidence interval. Subgroup analyses were conducted based on types of intervention and baseline characteristics of patients.ResultsSix RCTs (n = 1953) were included. Two RCTs were recognized as high risk. PARPi was associated with an improved PFS (HR, 0.65; 95% CI, 0.56–0.74), OS (HR, 0.86; 95% CI, 0.73–1.01), and a higher ORR (RR, 1.38; 95% CI, 1.05–1.82). PARPi, however, significantly increased risk of grade 3–4 thrombocytopenia (RR, 1.63; 95% CI, 1.06–2.52). Monotherapy was observed with lower risk of disease progression and higher ORR rate than combination therapy, 0.56 to 0.65 and 2.21 to 1.05, respectively. For patients without prior platinum treatment, PARPi significantly improved PFS (HR, 0.64; 95% CI, 0.52–0.79).ConclusionsPARPi was observed with a significantly improved efficacy in aspects of PFS and ORR, but also higher risk of grade 3–4 thrombocytopenia as compared to chemotherapy. PARPi was a better choice for patients who had not received previous platinum treatment.     

Outcomes of open repairs of chronic distal aortic dissection anatomically amenable to endovascular repairs

ObjectiveTo review short-term outcomes and long-term survival and durability after open surgical repairs for chronic distal aortic dissections in patients whose anatomy was amenable to thoracic endovascular aortic repair (TEVAR).MethodsBetween February 1991 and August 2017, we repaired chronic distal dissections in 697 patients. Of those patients, we enrolled 427 with anatomy amenable to TEVAR, which included 314 descending thoracic aortic aneurysms (DTAAs) and 105 extent I thoracoabdominal aortic aneurysms (TAAAs). One hundred eighty-five patients (44%) had a history of type A dissection, and 33 (7.9%) had a previous DTAA/TAAA repair. Variables were assessed with logistic regression for 30-day mortality and Cox regression for long-term mortality. Time-to-event analysis was performed using Kaplan-Meier methods.ResultsThirty-day mortality was 8.4% (n = 36). In all, 22 patients (5.2%) developed motor deficit (paraplegia/paraparesis), and 17 (4.0%) experienced stroke. Multivariable analysis identified low estimated glomerular filtration rate (eGFR; <60 mL/min/1.73 m²), previous DTAA/TAAA repair, and chronic obstructive pulmonary disease (COPD) as associated with 30-day mortality. Patients without all 3 risk factors had a 30-day mortality rate of 2.6%. During a median follow-up of 6.5 years, 160 patients died. The survival rate was 81% at 1 year and 61% at 10 years. Cox regression analysis identified preoperative aortic rupture, eGFR <60 mL/min/1.73 m², previous DTAA/TAAA repair, COPD, and age >60 years as predictive of long-term mortality. Forty-five patients required subsequent aortic procedures, including 8 reinterventions to the treated segment. Freedom from any aortic procedures was 85% at 10 years, and aortic procedure-free survival was 45% at 10 years. Hereditary aortic disease was the sole predictor for any aortic interventions (hazard ratio, 3.2; P = .004).ConclusionsOpen surgical repair provided satisfactory low neurologic complication rates and durable repairs in chronic distal aortic dissection. Patients without low eGFR, redo, and COPD are the low-risk surgical candidates and may benefit from open surgical repair at centers with similar experience to ours. Patients with hereditary aortic disease warrant close surveillance.     

Derivation and Validation of a Machine Learning Algorithm for Predicting Venous Thromboembolism in Injured Children

BackgroundVenous thromboembolism (VTE) causes significant morbidity in pediatric trauma patients. We applied machine learning algorithms to the Trauma Quality Improvement Program (TQIP) database to develop and validate a risk prediction model for VTE in injured children.MethodsPatients ≤18 years were identified from TQIP (2017–2019, n = 383,814). Those administered VTE prophylaxis ≤24 h and missing the outcome (VTE) were removed (n = 347,576). Feature selection identified 15 predictors: intubation, need for supplemental oxygen, spinal injury, pelvic fractures, multiple long bone fractures, major surgery (neurosurgery, thoracic, orthopedic, vascular), age, transfusion requirement, intracranial pressure monitor or external ventricular drain placement, and low Glasgow Coma Scale score. Data was split into training (n = 251,409) and testing (n = 118,175) subsets. Machine learning algorithms were trained, tested, and compared.ResultsLow-risk prediction: For the testing subset, all models outperformed the baseline rate of VTE (0.15%) with a predicted rate of 0.01–0.02% (p < 2.2e⁻¹⁶). 88.4–89.4% of patients were classified as low risk by the models.High-risk predictionAll models outperformed baseline with a predicted rate of VTE ranging from 1.13 to 1.32% (p < 2.2e⁻¹⁶). The performance of the 3 models was not significantly different.ConclusionWe developed a predictive model that differentiates injured children for development of VTE with high discrimination and can guide prophylaxis use.Level of EvidencePrognostic, Level II.Type of StudyRetrospective, Cross-sectional.     

Is hemiarch replacement adequate in acute type A aortic dissection repair in patients with arch branch vessel dissection without cerebral malperfusion?

ObjectiveThe study objective was to determine if hemiarch replacement is an adequate arch management strategy for patients with acute type A aortic dissection and arch branch vessel dissection but no cerebral malperfusion.MethodsFrom January 2008 to August 2019, 479 patients underwent open acute type A aortic dissection repair. After excluding those with aggressive arch replacement (n = 168), cerebral malperfusion syndrome (n = 34), and indeterminable arch branch vessel dissection (n = 1), 276 patients with an acute type A aortic dissection without cerebral malperfusion syndrome who underwent hemiarch replacement comprised this study. Patients were then divided into those with arch branch vessel dissection (n = 133) and those with no arch branch vessel dissection (n = 143).ResultsThe median age of the entire cohort was 62 years, with the arch branch vessel dissection group being younger (60 vs 62 years, P = .048). Both groups had similar aortic arch and descending thoracic aortic diameters, with significantly more DeBakey type I dissections (100% vs 80%) in the arch branch vessel dissection group. The arch branch vessel dissection group had more aortic root replacement (36% vs 27%, P = .0035) and longer aortic crossclamp times (153 vs 128 minutes, P = .007). Postoperative outcomes were similar between the arch branch vessel dissection and no arch branch vessel dissection groups, including stroke (10% vs 5%, P = .12) and operative morality (7% vs 5%, P = .51). The arch branch vessel dissection group had a significantly greater cumulative incidence of reoperation (8-year: 19% vs 4%, P = .04) with a hazard ratio of 2.89 (95% confidence interval, 1.01-8.27; P = .048), which was similar between groups among only DeBakey type I dissections (8-year: 19% vs 5%, P = .11). The 8-year survival was similar between the arch branch vessel dissection and no arch branch vessel dissection groups (76% vs 74%, P = .30).ConclusionsHemiarch replacement was adequate for patients with acute type A aortic dissection with arch branch vessel dissection without cerebral malperfusion syndrome, but carried a higher risk of late reoperation.     

Safety and oncologic efficacy of percutaneous MRI-guided cryoablation of intraparenchymal renal cancers

PurposeThe purpose of this study was to evaluate the safety and oncologic efficacy of percutaneous magnetic resonance imaging (MRI)-guided cryoablation of intraparenchymal renal cancer.Materials and methodsBetween February 2009 and August 2019, 31 consecutives patients with 31 entirely intraparenchymal biopsy-proven renal cancers were treated with cryoablation under MRI-guidance in our institution, and were retrospectively included. There were 20 men and 11 women with a mean age of 68.5 ± 12.5 (SD) (range: 40–91 years). Patient, tumor- and procedure-related, and follow-up data were retrospectively collected and analyzed. Local recurrence free (LRFS), metastasis free (MFS), disease free (DFS), cancer specific (CSS), and overall survivals (OS) were calculated.ResultsPrimary and secondary technical efficacy rates were 94% and 100%, respectively. Median follow-up was 27 months. Seven (7/31; 23%) minor complications were noted in 7 patients. Patients showed a significant decline of the estimated glomerular filtration rate (eGFR) between baseline and nadir (mean basal eGFR 65.9 ± 22.4 [SD] mL/min/1.73 m² vs. mean nadir eGFR 52.8 ± 26.0 [SD] mL/min/1.73 m²; P < 0.001), but only two showed a clinically significant renal function decline. Three-year estimates of primary and secondary LRFS, MFS, and DFS were 64% (95% confidence interval [CI]: 47–87%), 89% (95% CI: 78–99%), 83% (95% CI: 77–98%), and 45% (95% CI: 28–73%), respectively. No patients died due to renal cancer evolution (three-year CSS of 100%; 95% CI: 100–100%). One patient died 52 months after the percutaneous treatment due to cryoablation-unrelated causes (three-year OS of 100%; 95% CI: 100–100%).ConclusionMRI-guided percutaneous cryoablation for intraparenchymal renal cancer offers good oncologic outcomes with acceptable complication rates and renal function worsening.     

Ministernotomy compared with right anterior minithoracotomy for aortic valve surgery

ObjectivesMinisternotomy and right anterior minithoracotomy are the 2 main techniques applied for minimally invasive aortic valve replacement. The goal of this study is to compare early and long-term outcomes of both techniques.MethodsThe data of 2419 patients undergoing isolated minimally invasive aortic valve replacement between 1999 and 2019 were prospectively collected. Retrospectively, patients were divided into the ministernotomy group (n = 1352) and the minithoracotomy group (n = 1067).ResultsAfter propensity score matching, 986 patients remained in each group. Operation time and rate of conversion to full sternotomy were significantly higher in the minithoracotomy group than in the ministernotomy group (184.6 ± 45.2 vs 241.3 ± 68.6, relative risk, 2.54, P = .005 and .09 vs .23, relative risk, 1.45, P = .013, respectively). The 30-day mortality, excluding cardiac death, was lower in the ministernotomy group than in the minithoracotomy group (0.012 vs 0.028, relative risk, 1.41, P = .011, respectively); the intensive care unit length of stay (12.4 vs 16.5, relative risk, 1.62, P = .037, respectively) and hospital length of stay (5.4 vs 8.7, relative risk, 1.74 P = .028, respectively) were significantly longer in the minithoracotomy group. The minithoracotomy surgical approach was the strongest independent predictor of early mortality (odds ratio, 4.24 [1.67-7.35], P = .002). The actuarial survival by Kaplan–Meier analysis at 1, 3, 5, 10, and 20 years was significantly better in the ministernotomy group than in the minithoracotomy group (P = .0001). Actuarial freedom from reoperation at 5 years was 97.3% ± 4.4% in the ministernotomy group versus 95.8% ± 5.2% in the minithoracotomy group (P = .087).ConclusionsMinimally invasive aortic valve replacement using ministernotomy is associated with reduced operative time, intensive care unit stay, hospital length of stay, and postoperative morbidities and incisional pain, and improves early and long-term mortality.     

Prognostic factors for progression-free survival of the filum terminale ependymomas in adults

ObjectiveTo define the prognostic factors for progression and to determine the impact of the histological grading (according to the World Health Organization) on the progression-free survival (PFS) of filum terminale ependymomas.MethodsA retrospective chart review of 38 patients with ependymoma of the filum terminale was performed, focusing on demographic data, preoperative symptoms, tumor size, quality of resection, presence of a tumor capsule, and histological grade.ResultsGross total resection (GTR) was achieved in 30 patients (78.9%). Histopathological analysis found 21 (55.3%) myxopapillary grade I ependymoma (MPE), 16 (42.1%) ependymoma grade II (EGII), and 1 (2.6%) ependymoma grade III. There was no significant difference between the mean ± SD volume of MPE (5840.5 ± 5244.2 mm³) and the one of EGII (7220.3 ± 6305.9 mm³, p = 0.5). The mean ± SD follow-up was 54.1 ± 38.4 months. At last follow-up, 30 (78.9%) patients were free of progression. In multivariate analysis, subtotal resection (p = 0.015) and infiltrative tumor (p = 0.03) were significantly associated with progression. The PFS was significantly higher in patients with encapsulated tumor than in patients with infiltrative tumor (log-rank p = 0.01) and in patients who had a GTR in comparison with those who had an incomplete resection (log-rank p = 0.05). There was no difference in PFS between patient with MPE and EGII (p = 0.1).ConclusionThe progression of ependymoma of the filum terminale highly depends on the quality of resection, and whether the tumor is encapsulated. Except for anaplastic grade, histopathological type does not influence progression.     

The efficacy and safety of paclitaxel plus bevacizumab therapy in breast cancer patients with visceral crisis

BackgroundVisceral crisis in metastatic breast cancer (MBC) is defined as severe organ dysfunction requiring rapidly efficacious therapy. Although weekly paclitaxel plus bevacizumab (wPTX + BV) achieves a high response rate in human epidermal growth factor receptor 2 (HER2)-negative MBC, the efficacy and safety of wPTX + BV for visceral crisis is unclear.MethodsWe retrospectively investigated patients with MBC with visceral crisis who received wPTX + BV. Visceral crisis was defined as follows: liver dysfunction (aspartate or alanine aminotransferase >200 U/L or total bilirubin >1.5 mg/dl), respiratory dysfunction (carcinomatous lymphangiomatosis, SpO₂ <93% in ambient air or required thoracentesis), superior vena cava (SVC) syndrome, or bone marrow carcinomatosis. The primary outcome was the proportion of patients on-treatment with wPTX + BV after 12 weeks. We also investigated time to treatment failure (TTF), overall survival (OS), objective response rate (ORR), and adverse events.ResultsA total of 44 patients with respiratory dysfunction (n = 29), liver dysfunction (n = 10), bone marrow carcinomatosis (n = 7), and SVC syndrome (n = 2) were eligible for this investigation. The proportion of patients on-treatment with wPTX + BV after 12 weeks was 63% (30/44), and the other patients discontinued wPTX + BV because of adverse events (n = 5) and disease progression (n = 9). Median TTF and OS, and the ORR were 131 days and 323 days, and 41%, respectively. No treatment-related death occurred.Conclusion: wPTX + BV achieved favorable efficacy and safety for treating patients with visceral crisis and may therefore be considered an option for the treatment of this acutely severe clinical condition.     

Risk of Surgical Mitral Valve Repair for Primary Mitral Regurgitation

BackgroundRisk estimation for surgical intervention is an essential component of heart team shared decision-making. However, current mitral valve (MV) surgery risk models used in practice lack etiologic or procedural specificity. The purpose of this study was to establish a comprehensive method for assessment of operative risk of MV repair of primary mitral regurgitation (MR).MethodsA novel etiology and procedure-specific algorithm identified 53,462 consecutive (July 2014 to June 2020) intention-to-treat MV repair patients with primary MR from The Society of Thoracic Surgeons Adult Cardiac Surgery Database. Risk models were fit for 30-day operative mortality, mortality and/or major morbidity, and conversion-to-replacement (CONV). As-treated mortality and morbidity models were derived separately.ResultsEvent rates for mortality (n = 619; 1.16%), mortality plus morbidity (n = 4746; 8.88%), and CONV (n = 3399; 6.36%) were low. Mortality was higher in CONV patients vs repair (3.18% vs 1.02%). All event rates were lower with increasing program volumes. The mortality risk model had excellent discrimination (AUC: 0.807) and calibration and confirmed very low mortality risk for isolated MV repair for primary MR, with mean mortality risk of 1.16% and median of 0.55% (interquartile range: 0.30%-1.17%) with 90th and 95th percentiles 2.48% and 3.99%, respectively. The mortality risk was <0.5% in patients <65 years of age, with 97% of the total population across age groups having a risk of <3%. Only 1 in 4 patients age 75 or older had >3% estimated risk of mortality.ConclusionsThis etiologic and procedure-specific risk model establishes that the contemporary mortality risk of MV repair for primary MR is <1% for the vast majority of patients.     

Impact of left ventricular ejection fraction on the outcomes of open repair of descending thoracic and thoracoabdominal aneurysms

ObjectiveTo discern the impact of depressed left ventricular ejection fraction (LVEF) on the outcomes of open descending thoracic aneurysm (DTA) and thoracoabdominal aneurysms (TAAA) repair.MethodsRestricted cubic spline analysis was used to identify a threshold of LVEF, which corresponded to an increase in operative mortality and major adverse events (MAE: operative death, myocardial infarction, stroke, spinal cord injury, need for tracheostomy or dialysis). Logistic and Cox regression were performed to identify independent predictors of MAE, operative mortality, and survival.ResultsDTA/TAAA repair was performed in 833 patients between 1997 and 2018. Restricted cubic spline analysis showed that patients with LVEF <40% (n = 66) had an increased risk of MAE (odds ratio [OR], 2.17; 95% confidence interval [CI], 1.22-3.87; P < .01) and operative mortality (OR, 2.72; 95% CI, 1.21-6.12; P = .02) compared with the group with LVEF ≥40% (n = 767). The group with LVEF <40% had a worse preoperative profile (eg, coronary revascularization, 48.5% vs 17.3% [P < .01]; valvular disease, 82.8% vs 49.39% [P < .01]; renal insufficiency, 45.5% vs 26.1% [P < .01]; respiratory insufficiency, 36.4% vs 21.2% [P = .01]) and worse long-term survival (35.5% vs 44.7% at 10 years; P = .01). Nonetheless, on multivariate regression, depressed LVEF was not an independent predictor of operative mortality, MAE, or survival.ConclusionsLVEF is not an independent predictor of adverse events in surgery for DTA.     

MicroRNA-145-loaded poly(lactic-co-glycolic acid) nanoparticles attenuate venous intimal hyperplasia in a rabbit model

BackgroundMicroRNA-145 (miR-145) reportedly alters the phenotype of vascular smooth muscle cells (VSMCs) from a proliferative to a contractile state. So far, viral or plasmid vectors have been experimentally used to transduce microRNAs into VSMCs. We hypothesized that a simple ex vivo microRNA delivery system using miR–145-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles (PLGA NPs) could control the VSMC phenotype and prevent intimal hyperplasia.MethodsJugular vein grafts of male Japanese white rabbits were soaked in phosphate-buffered saline, control microRNA (cont-miR)-loaded PLGA NP solution or miR–145-loaded PLGA NP solution for 30 minutes (n = 8 for each). Vein grafts were implanted in the ipsilateral carotid artery and assessed 2 weeks after the implantation.ResultsQuantitative polymerase chain reaction analysis showed significantly higher miR-145 expression in the miR–145-treated group. The neointimal area was significantly smaller in the miR–145-treated group (phosphate-buffered saline-treated vs cont–miR-treated vs miR–145-treated group; 1.63 ± 0.52 mm² vs 1.67 ± 0.49 mm² vs 0.88 ± 0.34 mm², respectively; P < .01 for the miR–145-treated vs the cont–miR-treated group). In the miR–145-treated group, Ki–67-positive cells were significantly fewer, indicating lower VSMC proliferation. An inflammation-related molecule, CD40 expression was significantly reduced by miR–145-loaded PLGA NP treatment.ConclusionsLocal and sustained release of miR-145 by PLGA NPs attenuated intimal hyperplasia in the rabbit model by maintaining VSMCs in a contractile state. This simple ex vivo miR-145 delivery system would be promising toward broader clinical application.     

Remote Ischaemic Pre-Conditioning Reduces Intestinal Ischaemia Reperfusion Injury in a Newborn Rat

ObjectiveRemote ischaemic conditioning (RIC) has been shown to reduce ischaemia-reperfusion injury(IRI) in multiple organ systems. IRI is seen in multiple bowel pathologies in the newborn, including NEC. We investigated the potential of RIC as a novel therapy for various intestinal pathologies in the newborn.MethodsWe used an established intestinal IRI model in rat pups which results in similar intestinal injury to necrotising enterocolitis (NEC). Animals were randomly allocated to IRI only(n = 14), IRI + RIC(n = 13) or sham laparotomy(n = 10). The macroscopic extent of intestinal injury is reported as a percentage of total small bowel. Injury severity was measured using Chiu-Park scoring. Neutrophil infiltration/activation was assayed by myeloperoxidase activity. Immunohistochemistry was used to assess the expression of hypoxia-inducible factor alpha (HIF-1α). Data are median (interquartile range).ResultsAnimals that underwent RIC showed a decreased extent of macroscopic injury from 100%(85–100%) in the IRI only group to 58%(15–84%, p = 0.003) in the IRI + RIC group. Microscopic injury score was significantly lower in animals that underwent RIC compared to IRI alone (3.5[1.25–5] vs 5.5[4–6], p = 0.014). Intestinal myeloperoxidase activity in animals exposed to IRI was 3.4 mU/mg of tissue (2.5–3.7) and 2.1 mU/mg(1.5–2.8) in the IRI + RIC group(p = 0.047). HIF-1α expression showed a non-significant trend towards reduced expression in the IRI + RIC group.ConclusionsRIC reduces the extent and severity of bowel injury in this animal model, supporting the hypothesis that RIC has therapeutic potential for intestinal diseases in the newborn.     

Results of staged repair of aortic disease in patients with Marfan syndrome

ObjectiveWe present our open surgical strategies for staged replacement of the thoracic and thoracoabdominal aorta in patients with Marfan syndrome.MethodsBetween October 1999 and December 2017, 82 patients with Marfan syndrome underwent 118 aortic repairs. We divided the aorta into 4 segments for categorization: (1) the aortic root, (2) aortic arch, (3) descending thoracic, and (4) abdominal aorta. Procedures were categorized according to the types of surgery. Staged repair was defined as a subsequent operation on a different segment of the aorta after initial repair (n = 111, 94.1%), and reoperation was defined as an operation on the same segment (n = 7, 5.9%).ResultsThe mean age at initial operation was 41.7 ± 14.9 years. Staged repairs included aortic root replacement (n = 42, 36%), total arch replacement (n = 11, 9.3%), combined aortic root and total arch replacement (n = 13, 11%), descending aorta replacement (n = 4, 3.4%), thoracoabdominal aortic repair (n = 36, 31%), and extensive arch-descending or thoracoabdominal repair (n = 5, 4.2%). Four patients received 3 staged repairs. Operative mortality was 0.8% (1/118). Stroke occurred in 1.7% (2/118), and spinal cord injury occurred in 1.7% (2/117). Overall survival was 95.8 ± 2.4% at 10-years. Twenty-four patients underwent replacement of the whole aorta after 2.5 ± 3.8 years following initial repair.ConclusionsOur strategies for staged replacement of the thoracic and thoracoabdominal aorta in patients with Marfan syndrome resulted in excellent early- and long-term outcomes.     

Outcomes after endovascular versus open thoracoabdominal aortic aneurysm repair: A population-based study

ObjectiveWe sought to determine the early and late outcomes of endovascular versus open thoracoabdominal aortic aneurysm repair.MethodsWe performed a multicenter population-based study across the province of Ontario, Canada, from 2006 to 2017. The primary end point was mortality. Secondary end points were time to first event of a composite of mortality, permanent spinal cord injury, permanent dialysis, and stroke, the individual end points of the composite, patient disposition at discharge, hospital length of stay, myocardial infarction, and secondary procedures at follow-up.ResultsA total of 664 adults undergoing surgical repair of a thoracoabdominal aortic aneurysm (endovascular: n = 303 [45.5%] vs open: n = 361 [54.5%]) were identified using an algorithm of administrative codes validated against the operative records. Propensity score matching resulted in 241 patient pairs. Endovascular repairs increased during the study and currently comprise more than 50% of total repairs. In the matched sample, open repair was associated with a higher incidence of in-hospital death (17.4% vs 10.8%, P = .04), complications (26.1% vs 17.4%, P = .02), discharge to rehabilitation facilities (18.7% vs 10.0%, P = .02), and longer length of stay (12 [7-21] vs 6 [3-13] days, P < .01). Long-term mortality was not significantly different (hazard ratio, 1.09; 95% confidence interval, 0.78-1.50), nor were the other secondary end points, with the exception of secondary procedures, which were higher in the endovascular group (hazard ratio, 2.64; 95% confidence interval, 1.54-4.55). At 8 years, overall survival was 41.3% versus 44.6% after endovascular and open repair (P = .62).ConclusionsEndovascular repair was associated with improved early outcomes but higher rates of secondary procedures after discharge. Long-term survival after thoracoabdominal aortic aneurysm repair is poor and independent of repair technique.     

Impact of body mass index on overall survival in patients with metastatic breast cancer

BackgroundHigh Body mass index (BMI) is a risk factor for breast cancer among postmenopausal women and an adverse prognostic factor in early-stage. Little is known about its impact on clinical outcomes in patients with metastatic breast cancer (MBC).MethodsThe National ESME-MBC observational cohort includes all consecutive patients newly diagnosed with MBC between Jan 2008 and Dec 2016 in the 18 French comprehensive cancer centers.ResultsOf 22 463 patients in ESME-MBC, 12 999 women had BMI data available at MBC diagnosis. Median BMI was 24.9 kg/m² (range 12.1–66.5); 20% of women were obese and 5% underweight. Obesity was associated with more de novo MBC, while underweight patients had more aggressive cancer features. Median overall survival (OS) of the BMI cohort was 47.4 months (95% CI [46.2–48.5]) (median follow-up: 48.6 months). Underweight was independently associated with a worse OS (median OS 33 months; HR 1.14, 95%CI, 1.02–1.27) and first line progression-free survival (HR, 1.11; 95%CI, 1.01; 1.22), while overweight or obesity had no effect.ConclusionOverweight and obesity are not associated with poorer outcomes in women with metastatic disease, while underweight appears as an independent adverse prognostic factor.     

Asymptomatic degenerative mitral regurgitation repair: Validating guidelines for early intervention

IntroductionMitral repair for asymptomatic (New York Heart Association [NYHA] class I) degenerative mitral regurgitation (MR) is supported by the guidelines, but is not performed often. We sought to determine outcomes for asymptomatic patients when compared with those with symptoms.MethodsBetween 2004 and 2018, 1027 patients underwent mitral replacement (22) or repair with or without other cardiac surgery (1005), the latter being grouped by NYHA class: I (n = 470; 47%), II (n = 408; 40%), or III/IV (n = 127; 13%). Statistical analyses included propensity score matching and weighting, and multistate models.ResultsThe proportion of patients designated as NYHA class I undergoing surgery increased steadily during this period (P < .001). Overall, 30-day mortality was 0.4%, and zero for patients designated NYHA class I. Unadjusted 10-year survival was significantly greater in patients designated NYHA class I compared with II and III/IV (P < .001). Freedom from reoperation at 10 years was 99.8% overall, and 100% for patients designated NYHA class I. In patients designated as NYHA class I, predischarge and 10-year moderate MR were 0.7% and 20.1%, whereas more than moderate was zero and 0.6%. Preoperative ejection fraction less than 60% was associated with late mortality (P = .025). After covariate-adjustments, freedom from MR and tricuspid regurgitation were not statistically significantly different by NYHA class. However, overall survival was significantly worse in patients with NYHA class III/IV, compared with class II.ConclusionsMitral repair in asymptomatic patients is safe and durable. Careful monitoring until class II symptoms is appropriate. However, repair before ejection fraction decreases below 60% is important for late overall survival.     

Impacts of clinicopathological factors on efficacy of trastuzumab deruxtecan in patients with HER2-positive metastatic breast cancer

BackgroundThe previous second-line treatment for HER2-positive metastatic breast cancer were ado-trastuzumab emtansine (T-DM1); however, its activity is decreased in tumors with heterogenous, reduced, or loss of HER2 expression. Trastuzumab deruxtecan (T-DXd) has recently been developed as a novel antibody-drug conjugate to overcome resistance to T-DM1. However, clinical evidence on its ability to overcome this resistance is limited.Materials and methodsWe retrospectively analyzed data for patients with HER2-positive metastatic breast cancer who received T-DXd at our institution from April 2020 to March 2021. We evaluated the associations between clinicopathological and molecular biomarkers and the efficacy of T-DXd.ResultsTwenty-two patients were enrolled in this study. The median progression-free survival (PFS) was 9.7 months (95% confidence interval [CI], 7.0–not reached [NR]), and the objective response rate (ORR) was 61.9%. The ORR and PFS were comparable between patients with HER2 immunohistochemistry scores of 3+ and 2+/1+ at initial diagnosis (ORR: 50.0% vs. 72.7%, p = 0.39; median PFS, 9.7 months [95%CI, 2.6–NR] vs. 8.3 months [95%CI, 7.1–NR]; hazard ratio, 1.86 [95%CI, 0.53–6.57], p = 0.34). Two patients with heterogenous HER2 expression had a partial response or long stable disease (≥6 months). Three of four patients with re-biopsy samples after anti-HER2 targeted therapy and with latest HER2 immunohistochemistry scores of 1+ experienced partial responses (75.0%) to T-DXd, but none had responded to prior T-DM1.ConclusionsT-DXd demonstrated favorable activity in clinical practice. Moreover, T-DXd showed meaningful benefit in patients with heterogeneity, reduction, or loss of HER2 expression.