Cardiovascular sequelae of trastuzumab and anthracycline in long-term survivors of breast cancer.

OBJECTIVES: Long-term follow-up of patients treated with trastuzumab largely focuses on those with reduced left ventricular ejection fraction (LVEF) on treatment completion. This study sought to evaluate the prevalence of cardiovascular risk factors, overt cardiovascular disease and cardiac imaging abnormalities using cardiac magnetic resonance (CMR), in participants with normal LVEF on completion of trastuzumab±anthracycline therapy at least 5 years previously. METHODS: Participants with human epidermal growth factor receptor 2-positive breast cancer treated with trastuzumab±anthracycline ≥5 years previously were identified from a clinical database. All participants had normal LVEF prior to, and on completion of, treatment. Participants underwent clinical cardiovascular evaluation, ECG, cardiac biomarker evaluation and CMR. Left ventricular systolic dysfunction (LVSD) was defined as LVEF <50%. RESULTS: Forty participants were recruited between 15 March 2021 and 19 July 2022. Median time since completion of trastuzumab was 7.8 years (range 5.9-10.8 years) and 90% received prior anthracycline. 25% of participants had LVSD; median LVEF was 55.2% (Q1-Q3, 51.3-61.2). 30% of participants had N-terminal pro-B-type natriuretic peptide >125 pg/mL and 8% had high-sensitivity cardiac troponin T >14 ng/L. 33% of participants had a new finding of hypertension. 58% had total cholesterol >5.0 mmol/L, 43% had triglycerides >1.7 mmol/L and 5% had a new diagnosis of diabetes. CONCLUSIONS: The presence of asymptomatic LVSD, abnormal cardiac biomarkers and cardiac risk factors in participants treated with trastuzumab and anthracycline at least 5 years previously is common, even in those with normal LVEF on completion of treatment. Our findings reinforce the relevance of comprehensive evaluation of cardiovascular risk factors following completion of cancer therapy, in addition to LVEF assessment.

Vascular mechanisms of post-COVID-19 conditions: Rho-kinase is a novel target for therapy.

BACKGROUND: In post-coronavirus disease-19 (post-COVID-19) conditions (long COVID), systemic vascular dysfunction is implicated, but the mechanisms are uncertain, and the treatment is imprecise. METHODS AND RESULTS: Patients convalescing after hospitalization for COVID-19 and risk factor matched controls underwent multisystem phenotyping using blood biomarkers, cardiorenal and pulmonary imaging, and gluteal subcutaneous biopsy (NCT04403607). Small resistance arteries were isolated and examined using wire myography, histopathology, immunohistochemistry, and spatial transcriptomics. Endothelium-independent (sodium nitroprusside) and -dependent (acetylcholine) vasorelaxation and vasoconstriction to the thromboxane A2 receptor agonist, U46619, and endothelin-1 (ET-1) in the presence or absence of a RhoA/Rho-kinase inhibitor (fasudil), were investigated. Thirty-seven patients, including 27 (mean age 57 years, 48% women, 41% cardiovascular disease) 3 months post-COVID-19 and 10 controls (mean age 57 years, 20% women, 30% cardiovascular disease), were included. Compared with control responses, U46619-induced constriction was increased (P = 0.002) and endothelium-independent vasorelaxation was reduced in arteries from COVID-19 patients (P < 0.001). This difference was abolished by fasudil. Histopathology revealed greater collagen abundance in COVID-19 arteries {Masson's trichrome (MT) 69.7% [95% confidence interval (CI): 67.8-71.7]; picrosirius red 68.6% [95% CI: 64.4-72.8]} vs. controls [MT 64.9% (95% CI: 59.4-70.3) (P = 0.028); picrosirius red 60.1% (95% CI: 55.4-64.8), (P = 0.029)]. Greater phosphorylated myosin light chain antibody-positive staining in vascular smooth muscle cells was observed in COVID-19 arteries (40.1%; 95% CI: 30.9-49.3) vs. controls (10.0%; 95% CI: 4.4-15.6) (P < 0.001). In proof-of-concept studies, gene pathways associated with extracellular matrix alteration, proteoglycan synthesis, and viral mRNA replication appeared to be upregulated. CONCLUSION: Patients with post-COVID-19 conditions have enhanced vascular fibrosis and myosin light change phosphorylation. Rho-kinase activation represents a novel therapeutic target for clinical trials.

Coronary perforation incidence, outcomes and temporal trends (COPIT): a systematic review and meta-analysis.

Coronary perforation is a potentially life-threatening complication of percutaneous coronary intervention (PCI). We studied incidence, outcomes and temporal trends following PCI-related coronary artery perforation (CAP). METHODS: Prospective systematic review and meta-analysis including meta-regression using MEDLINE and EMBASE to November 2020. We included 'all-comer' PCI cohorts including large PCI registries and randomised controlled trials and excluding registries or trials limited to PCI in high-risk populations such as chronic total occlusion PCI or cohorts treated only with atheroablative devices. Regression analysis and corresponding correlation coefficients were performed comparing perforation incidence, mortality rate, tamponade rate and the rate of Ellis III perforations against the midpoint (year) of data collection to determine if a significant temporal relationship was present. RESULTS: 3997 studies were screened for inclusion. 67 studies met eligibility criteria with a total of 5 568 191 PCIs included over a 38-year period (1982-2020). The overall pooled incidence of perforation was 0.39% (95% CI 0.34% to 0.45%) and remained similar throughout the study period. Around 1 in 5 coronary perforations led to tamponade (21.1%). Ellis III perforations are increasing in frequency and account for 43% of all perforations. Perforation mortality has trended lower over the years (7.5%; 95% CI 6.7% to 8.4%). Perforation risk factors derived using meta-regression were female sex, hypertension, chronic kidney disease and previous coronary bypass grafting. Coronary perforation was most frequently caused by distal wire exit (37%) followed by balloon dilation catheters (28%). Covered stents were used to treat 25% of perforations, with emergency cardiac surgery needed in 17%. CONCLUSION: Coronary perforation complicates approximately 1 in 250 PCIs. Ellis III perforations are increasing in incidence although it is unclear whether this is due to reporting bias. Despite this, the overall perforation mortality rate (7.5%) has trended lower in recent years. Limitations of our findings include bias that may be introduced through analysis of multidesign studies and registries without pre-specified standardised perforation reporting CMore research into coronary perforation management including the optimal use of covered stents seems warranted. PROSPERO REGISTRATION NUMBER: CRD42020207881.

Coronary Artery Perforations: Glasgow Natural History Study of Covered Stent Coronary Interventions (GNOCCI) Study.

Background The objective of the GNOCCI (Glasgow Natural History Study of Covered Stent Coronary Interventions) Study was to report the incidence and outcomes of coronary artery perforations over an 18-year period at a single, high-volume percutaneous coronary intervention center. We considered both the temporal trends and long-term outcomes of covered stent deployment. Methods and Results We evaluated procedural and long-term clinical outcomes following coronary perforation in a cohort of 43,343 consecutive percutaneous coronary intervention procedures. Procedural major adverse cardiac events were defined as a composite of death, myocardial infarction, stroke, target vessel revascularization, or cardiac surgery within 24 hours. A total of 161 (0.37%) procedures were complicated by coronary perforation of which 57 (35%) were Ellis grade III. Incidence increased with time over the study period (r=0.73; P<0.001). Perforation severity was linearly associated with procedural mortality (median 2.9-year follow-up): Ellis I (0%), Ellis II (1.7%), Ellis III/IIIB (21%), P<0.001. Procedural major adverse cardiac events occurred in 47% of patients with Ellis III/IIIB versus 13.5% of those with Ellis I/II perforations (odds ratio, 5.8; 95% CI, 2.7-12.5; P<0.001). Covered stents were associated with an increased risk of stent thrombosis at 2.9-year follow-up (Academic Research Consortium definite or probable; 9.1% versus 0.9%; risk ratio, 10.5; 95% CI, 1.1-97; P=0.04). Conclusions The incidence of coronary perforation increased between 2001 and 2019. Severe perforation was associated with higher procedural major adverse cardiac events and was an independent predictor of long-term mortality. Although covered stents are a potentially lifesaving treatment, the generation of devices used during the study period was limited by their efficacy and high risk of stent thrombosis. Registration Information Clinicaltrials.gov. Identifier: NCT03862352.

The Effect of High-Dose Radiation Therapy on Healthy Vertebral Bone Density.

Objective Increased rates of insufficiency fractures are reported after radiation therapy without well-defined causality. Here, we conduct a cross-sectional study on the density change of a non-lesioned vertebral bone after irradiation relative to a control bone in patients with spinal metastases. Methods Patients were identified who received radiation therapy for spinal metastases to a region, including an adjacent vertebra without identifiable malignancy on pre-treatment CT. Every patient had an untreated vertebra of a similar type available as a control. A Hounsfield-density calibration curve was used to measure the vertebral body density before and after treatment. Analysis of covariance was used to model vertebral bone density changes with respect to treatment status. Significance was established as p < 0.05. Results We identified 36 patients who fit the study criteria. The irradiated healthy bone received a median dose of 30 Gy. The median biologically effective dose (BED) was 60 Gy (α/ß = 3) and 39 Gy (α/ß = 10). Median follow-up imaging intervals between pre-treatment and follow-up CT scans was 13.4 months. Levene's test was used to confirm the equality of error variance assumption of ANCOVA (p = 0.093). The mean change in the density of the irradiated vertebral bone was -3.59% (95% CI = -8.51% - 1.32%, p = 0.149). Conclusions We found no significant change in vertebral bone density attributable to radiation treatment. Further work is needed to elucidate if increased fracture rates after radiation are due to factors other than bone density.

Multi-level multi-leaf collimators: Optimization of layer thicknesses and a feasibility study.

PURPOSE: The function of multi-leaf collimators (MLC) is to modulate and shape the intensity of a radiotherapy beam by either blocking or unblocking beamlets. A variation on this functionality is tested in this work wherein the MLC is split into layers, with each layer attenuating the beam by a different amount. In this design, full blocking of a beamlet occurs only if all layers are blocked. This work suggests that such a device, a multi-layer MLC (MLMLC), can deliver dose distributions like a single layer MLC can deliver while requiring less time and monitor units (MU) METHODS: Optimal fluences were made for prostate plans using the Eclipse v13.6. An algorithm was developed to create step-and-shoot MLMLC patterns to match these optimal fluences when using up to six layers of MLC. Twelve MLMLC plans were made in total. These patterns were imported back into Eclipse as equivalent tungsten compensators and doses were calculated. Dose-volume histogram (DVH) values, total monitor units (MU), and total time to deliver were compared between arc-style MLMLC plans and nine-field step and shoot IMRT plans created completely in Eclipse using a single layer MLC. RESULTS: When using three or more layers, specified DVH values between the two sets agreed to within 5% while requiring roughly half as much time to deliver and about 20% fewer MU. CONCLUSIONS: Demonstrated that having multi-layer MLC can deliver dose distributions like a single layer MLC with less time and monitor units.

Bone Density Changes Following Radiotherapy to Vertebral Metastases.

Introduction Patients have increasing longevity and time for bone healing following radiotherapy (RT) for treatment of bone metastases (BM). Attempts to assess the treatment response of bone metastases have been either limited or heavily subjective. Our goal was to try to quantitate cancer-involved bone changes after RT using changes in bone mineral density (BMD) from computer tomographic (CT) imaging. Methods Retrospectively, 117 spinal metastases were identified that received RT with follow-up CT scans >9 months following CT simulation. Contoured volumes included: the metastasis (gross tumor volume; GTV); the involved vertebra (gross bone volume; GBV); a total lytic volume (Lyt); a dominant lytic volume (Domlyt); a control volume, and the nearest uninvolved, unirradiated vertebra (control bone volume; CBV). The Hounsfield-density calibration curve was used to measure the density of these volumes before and after treatment. Results Whether using raw or control-adjusted changes, the absolute and percent change in density of the GBV, GTV, Lyt, and Domlyt volumes all significantly increased (each p<0.0001). The increase in the density of Domlyt volumes was greater than that of Lyt volumes (p=0.0465), which were greater than GTV (p=0.0065), which were greater than GBV (p<0.0001). On multivariate analysis, only the biologically effective dose (BED) dose significantly correlated with GTV density change (p=0.0175). K means clustering created groups by initial lesion size, GTV, or GBV density. A significant difference in GTV density change was not detected between any groups. Conclusion Increases in BMD are associated with healing regardless of lesion size or initial density. A prospective study to determine whether long-term control is related to early density measurements is needed.

Incidence of acute bronchospasm during systemic adenosine administration for coronary angiography.

BACKGROUND: Adenosine is frequently used during coronary angiography to induce hyperaemia and allow operators to perform quantitative measurements of lesion severity. Acute bronchospasm is a recognised side effect relating to the activation of 'off target' A2B receptors. The true incidence of severe bronchospasm relating to adenosine administration is not known. METHODS: Using an electronic patient database, we analysed 100,253 consecutive coronary angiograms over almost 19 years. Fractional flow reserve (FFR) was measured under systemic adenosine in 9,440 cases. RESULTS: Adenosine-related bronchospasm was reported in only five cases (0.05%). One case resulted in a life-threatening respiratory arrest. CONCLUSIONS: This study reveals the incidence of acute bronchospasm during FFR testing to be extremely low. Although rare, these reactions can be severe and are not simply limited to patients with brittle airways disease. Physicians should be aware of the utility of bolus intravenous aminophylline providing targeted therapy to reverse and treat adenosine-related bronchospasm.

Do Postoperative Antibiotics Decrease the Frequency of Inflammatory Complications Following Third Molar Removal?

PURPOSE: The purpose of this study was to answer the following clinical question: among patients who have their third molars (M3s) removed, do those who receive only postoperative antibiotics compared with those who receive no perioperative antibiotics have a lower frequency of postoperative inflammatory complications? MATERIALS AND METHODS: The authors designed and implemented a prospective cohort study and enrolled a sample of patients who had at least 1 M3 removed in an ambulatory private practice setting from June 2011 through May 2012 by oral and maxillofacial surgeons participating in a practice-based research collaborative. The predictor variable was postoperative antibiotic use categorized as postoperative antibiotics alone or no antibiotics. The primary outcome variable was the presence or absence of an inflammatory complication (ie, alveolar osteitis or surgical site infection) after M3 removal. Descriptive, bivariate, and multiple logistic regression statistics (adjusted for clustering within surgical practices) were computed to measure the association between postoperative antibiotic use alone and inflammatory complications after M3 removal, with statistical significance set at a P value less than or equal to .05. RESULTS: The study sample was composed of 1,877 patients having 5,631 M3s removed, of which 61% received postoperative antibiotics only. The overall inflammatory complication frequencies in the groups receiving postoperative antibiotic only and no antibiotic were 4.3 and 7.5%, respectively (P = .003). After adjusting for differences between the 2 study groups and clustering of patients within surgical practices, postoperative antibiotic use was associated with a 40% decreased risk of developing postoperative inflammatory complications (P = .04) with marginal statistical significance. CONCLUSIONS: The results of this study suggest that postoperative antibiotic therapy is associated with a statistically meaningful decreased risk of inflammatory complications after M3 removal compared with no antibiotic therapy.

Single fraction spine stereotactic ablative body radiotherapy with volumetric modulated arc therapy.

This study investigated a single institution's experience with volumetric modulated arc therapy (VMAT) directed stereotactic ablative body radiotherapy (SABR) for vertebral metastases. From 2010 to 2014, 95 lesions of spinal metastases in 73 patients were treated with SABR using VMAT. Clinical local control, pain level, and use of steroid medication were employed to evaluate treatment responses. The majority (79%) of patients were treated with a radiation dose of 20 Gy in a single fraction. However, when normal tissue constraints could not be achieved, the dose was reduced to 18 Gy (11%) or 16 Gy (8%) in 1 fraction. At the median follow up of 12.7 months (mean 18.0, range 1-56 months), clinical local control was 97% (92 out of 95). There was a mean 81% (median 100%, range 28-100%) decrease in subjective pain score. Seventy-seven percent of patients had a decrease in narcotic pain medication use. Pain was completely resolved at the treatment site for 69% (66/95) of patients. Prior to the SABR treatment, 33% (31/95) of patients had epidural extension of tumor. Among patients with epidural involvement, 45% (14/31) exhibited neurologic impairment prior to treatment. Twenty-three percent (7/31) experienced spinal cord compression. Prior to treatment, 34 patients experienced some form of neurologic impairment. Of these patients, 24% (8/34) experienced improved motor functioning; the remaining 76% (26/34) of patients' neurological dysfunction were stable. Our results indicate the SABR regimen using VMAT technique is clinically effective in achieving clinical local control and palliation. This is the first publication reporting clinical outcomes of VMAT directed SABR.

Spatial variations of multiple off-axial targets for a single isocenter SRS treatment in Novalis Tx linac system.

PURPOSE: To develop a method to evaluate the positional variations of multiple off-axial targets for a single isocenter stereotactic radiosurgery (SRS) treatment in Novalis Tx linac system.Method and Materials: Five metallic ball bearing (BB) markers were placed sparsely in 3D off-axial locations (non-coplanar) inside a skull phantom as the representatives of multiple targets mimicking multiple brain metastases. The locations of the BB markers were carefully chosen to minimize overlapping of each other in a portal imaging detector plane. The skull phantom was immobilized by a frameless mask and CT scanned with a BrainLab Head&Neck Localizer using a GE Optima multi-detector CT (MDCT) scanner. The CT images were exported to iPlan treatment planning software and a multiple target PTV was drawn by combining all the contours of the BB markers. The margin of the MLC opening was selected as 3 mm expansion outward. Four non-coplanar arc beams were placed to generate a single isocenter SRS plan to treat the PTV. The skull phantom was localized to the treatment position using ExacTrac 6D Patient Positioning system. The four dynamic conformal arc beams were delivered using Novalis Tx system with portal imaging acquisition mode per 10% temporal resolution. The locations of the BB markers were visualized and analyzed with respect to the MLC aperture in the treatment plan similar to the Winston-Lutz (WL) test. RESULTS: All the BB markers were clearly identified inside the MLC openings. The total positional errors for the MLC aperture were 0.61 ± 0.2 mm along the rotational path of the four arcs. CONCLUSION: This study verified that the spatial deviations of multiple off-axial targets for a single isocenter SRS treatment plan is within sub-millimeter range in Novalis Tx linac system. Accompanied with the WL test, this simple test will quality-assure the spatial accuracies of the isocenter as well as the positions of multiple off-axial targets for the SRS treatment using a single isocenter multiple target treatment plan.