Unselected Series Of Patients Research Articles

Assessment of ferroptosis as a promising candidate for metastatic uveal melanoma treatment and prognostication.

Uveal melanoma (UM) is the most common primary intraocular tumour in adults. Local resection, radiation therapy, and enucleation are the current first-line, primary UM treatments. However, regardless of the treatment received, around 50% of UM patients will develop metastatic disease within five to 7years. In the largest published series of unselected patients with metastatic UM (mUM), the median survival time after diagnosis of metastasis was 3.6months, with less than 1% of patients surviving beyond 5years. Approved drugs for treatment of mUM include systemic treatment with tebentafusp-tebn or isolated hepatic perfusion (IHP) with melphalan. However, these drugs are only available to a subset of patients and improve survival by only a few months, highlighting the urgent need for new mUM treatments. Accurately predicting which patients are at high risk for metastases is also crucial. Researchers are developing gene expression signatures in primary UM to create reliable prognostic models aimed at improving patient follow-up and treatment strategies. In this review we discuss the evidence supporting ferroptosis, a non-apoptotic form of cell death, as a potential novel treatment target and prognosticator for UM.

Long-Term Survival After Single-Ventricle Palliation: A Swedish Nationwide Cohort Study.

Long-term survival after single-ventricle palliation and the effect of dominant ventricle morphology in large, unselected series of patients are scarcely reported. This nationwide cohort study included all children undergoing operation with single-ventricle palliation during their first year of life in Sweden between January 1994 and December 2019. Data were obtained from institutional records and assessment of underlying cardiac anomaly and dominant ventricular morphology was based on complete review of medical records, surgical reports, and echocardiographic examinations. Data on vital status and date of death were retrieved from the Swedish Cause of Death Register, allowing for complete data on survival. Among 766 included patients, 333 patients (43.5%) were classified as having left or biventricular dominance, and 432 patients (56.4%) as having right ventricular (RV) dominance (of whom 231 patients had hypoplastic left heart syndrome). Follow-up was 98.7% complete (10 patients emigrated). Mean follow-up was 11.3 years (maximum, 26.7 years). Long-term survival was significantly higher in patients with left ventricular compared with RV dominance (10-year survival: 91.0% [95% CI, 87.3%-93.6%] versus 71.1% [95% CI, 66.4%-75.2%]). RV dominance had a significant impact on outcomes after first-stage palliation but was also associated with impaired survival after completed total cavopulmonary connection. In total, 34 (4.4%) patients underwent heart transplantation. Of these 34 patients, 25 (73.5%) had predominant RV morphology. This study provides clinically relevant knowledge about the long-term prognosis in patients with different underlying cardiac anomalies undergoing single-ventricle palliation. RV dominance had a significant impact on outcomes after initial surgical treatment but was also associated with impaired survival after completed Fontan circulation. URL: https://www.clinicaltrials.gov; Unique identifier: NCT03356574.

Stereotactic Radiosurgery for Vestibular Schwannoma With Radiographic Brainstem Compression.

The safety of single-treatment stereotactic radiosurgery (SRS) for vestibular schwannoma (VS) with radiographic evidence of brainstem compression but without motor deficit is controversial. Data on linear accelerator (linac)-based SRS in this setting are scarce. We address this with an outcomes report from an unselected series of patients with VS with radiographic brainstem compression treated with linac SRS. We included 139 patients with unilateral VS (any size) with radiographic brainstem compression (all without serious brainstem neurological deficits). The SRS prescription dose was 12.5Gy (single fraction) using 6MV linac-produced photon beams, delivered with a multiple arc technique. Inclusion criteria required at least 1 year of radiographic follow-up with magnetic resonance imaging. The primary endpoint was freedom from serious brainstem toxicity (≥grade 3 Common Terminology Criteria for Adverse Events v5); the secondary was freedom from enlargement (tumor progression or any requiring intervention). We assessed serious cranial nerve complications, excluding hearing loss, defined as Common Terminology Criteria for Adverse Events v5 grade 3 toxicity. Median magnetic resonance imaging follow-up time was 5 years, and median tumor size was 2.5cm in greatest axial dimension and 5ml in volume. The median brainstem D0.03ml=12.6Gy and median brainstem V10Gy=0.4ml. At 5 years, the actuarial freedom from serious brainstem toxicity was 100%, and freedom from tumor enlargement (requiring surgery and/or due to progression) was 90%. Severe facial nerve damage in patients without tumor enlargement was 0.9%. Linac-based SRS, as delivered in our series for VS with radiographic brainstem compression, is safe and effective.

RADT-22. STEREOTACTIC RADIOSURGERY FOR VESTIBULAR SCHWANNOMA WITH RADIOGRAPHIC BRAINSTEM COMPRESSION

Abstract BACKGROUND The safety of single treatment stereotactic radiosurgery (SRS) for vestibular schwannoma (VS) with radiographic evidence of brainstem compression- but without motor deficit- is controversial. Data on linac-based SRS in this setting are scarce. We address this deficit in the literature with a report of outcome of an unselected series of patients with VS with radiographic brainstem compression treated with linac SRS our institution. METHODS We included patients with unilateral VS of any size with radiographic brainstem compression at the time of SRS. All patients were without serious brainstem neurologic deficits at the time of SRS. The SRS prescription dose was 12.5 Gy in a single fraction using 6MV photon beams produced by a linear accelerator and delivered with a multiple arc technique. Inclusion in this study required at least 1 year of radiographic follow-up with magnetic resonance imaging (MRI). The primary endpoint was freedom from serious brainstem toxicity (CTCAEv5 grade >3); secondary endpoint was freedom from tumor enlargement considered to represent tumor progression, or any type of enlargement requiring surgical intervention. We also assessed serious cranial nerve complications, excluding hearing loss, defined as CTCAEv5 grade 3 toxicity. RESULTS Among 139 patients, the median MRI follow-up time was 5 years and the median tumor size was 2.5 cm greatest axial dimension and 5cc in volume. The median brainstem D0.03cc = 12.6 Gy, and the median brainstem V10Gy = 0.4cc. At 5 years, the actuarial freedom from serious brainstem toxicity was 100% (zero cases), and freedom from tumor enlargement, either requiring surgery or due to progression, was 90%. The rate of grade 3 facial nerve damage in patients without tumor enlargement was 0.9% (1/113). CONCLUSION Linac-based SRS as delivered in our series for VS with radiographic brainstem compression is safe and effective.

Cancer risk in relatives of BRCA1/2 pathogenic variant carriers in a large series of unselected patients with breast cancer.

The spectrum and risk of cancer in relatives of BRCA1/2 pathogenic variant carriers in the Chinese population have not been established. A family history of cancer in 9903 unselected breast cancer patients was retrospectively analyzed. BRCA1/2 status was determined for all patients and relative risks (RRs) were calculated to evaluate cancer risk in relatives of the patients. The incidences of breast cancer in female relatives of BRCA1 carriers, BRCA2 carriers, and non-carriers were 33.0%, 32.2%, and 7.7%, respectively. The corresponding incidences of ovarian cancer were 11.5%, 2.4%, and 0.5%, respectively. The incidences of pancreatic cancer in male relatives of BRCA1 carriers, BRCA2 carriers, and non-carriers were 1.4%, 2.7%, and 0.6%, respectively. The corresponding incidences of prostate cancer were 1.0%, 2.1%, and 0.4%, respectively. The risks of breast and ovarian cancers in female relatives of BRCA1 and BRCA2 carriers were significantly higher than female relatives of non-carriers (BRCA1: RR = 4.29, P < 0.001 and RR = 21.95, P < 0.001; BRCA2: RR = 4.19, P < 0.001 and RR = 4.65, P < 0.001, respectively). Additionally, higher risks of pancreatic and prostate cancers were noted in male relatives of BRCA2 carriers than non-carriers (RR = 4.34, P = 0.001 and RR = 4.86, P = 0.001, respectively). Female relatives of BRCA1 and BRCA2 carriers are at increased risk for breast and ovarian cancers, and male relatives of BRCA2 carriers are at increased risk for pancreatic and prostate cancers.

BRCA-CRisk: A Contralateral Breast Cancer Risk Prediction Model for BRCA Carriers.

The absolute cumulative risk of contralateral breast cancer (CBC) for patients with BRCA1/2 variants is unknown. The purpose of this study was to develop a CBC risk prediction model for assessing CBC risk for BRCA1/2 carriers. The primary cohort of 491 patients with BRCA1/2 variants was derived from a large series of unselected patients with breast cancer. A nomogram was established on the basis of the results of a multivariate Cox regression analysis from this cohort. This model, named BRCA-CRisk, was further validated by an independent cohort of 205 patients with BRCA1/2 variants. Discrimination and calibration of the model were assessed. In the primary cohort of 491 patients, 66 developed contralateral breast cancer after a median follow-up of 7.0 years. Four variables were significantly associated with risk of CBC and were incorporated in the establishment of the BRCA-CRisk prediction model: younger age at first breast cancer (with continuous variable, P = .002), positive first-degree family history of breast and/or ovarian cancer (hazard ratio [HR], 1.89; 95% CI, 1.16 to 3.08; P = .011), variant located near the 3' region of BRCA (HR, 2.01; 95% CI, 1.23 to 3.30; P = .006), and endocrine therapy (HR, 0.54; 95% CI, 0.33 to 0.88; P = .013). The area under the time-dependent curves for the 5- and 10-year cumulative risks of CBC were 0.775 and 0.702, respectively. The model was well validated in the independent cohort of 205 BRCA1/2 carriers, with area under the curves of 0.750 and 0.691 for 5 and 10 years, respectively. BRCA-CRisk model provides a useful tool for assessing the absolute cumulative risk of CBC for BRCA1/2 carriers and may help carriers and clinicians optimally select risk-reducing strategies on the basis of individual CBC risk.

Characteristics of Germline CHEK2 Mutated Patients in a Large Cohort of 2322 Myeloid Malignancies

Background Checkpoint kinase 2 (CHEK2) is a critical mediator of the DNA damage response and plays a role in DNA double strand break-induced apoptosis and cell cycle arrest (Bartek, 2003). Deleterious germline CHEK2 variants (CHEK2germ) have been associated with an increased risk for breast, colon, prostate, thyroid and kidney cancers (Cybulski, 2004). Early studies suggested that germline CHEK2 variants also predispose to myeloid malignancies, including myelodysplastic syndromes (MDS) (Janiszewska, 2018). Recently, CHEK2 was identified as the most frequent germline mutated gene in a cohort of 391 adult patients with AML (Yang, 2022). However, more data is warranted to clarify the role of germline CHEK2 mutations in the development of myeloid malignancies. Here we analyzed the prevalence of germline CHEK2 variants in a large series of unselected patients diagnosed with myeloid malignancies and describe their clinical features. Methods Between February 2018 and June 2022, 2322 consecutive adult patients diagnosed at Saint-Louis hospital, Paris with a myeloid malignancy were included in the study. DNA obtained from bone marrow or peripheral blood cells was subjected to capture-based next-generation sequencing of genes recurrently mutated in myeloid malignancies, including CHEK2. In selected patients, germline mutation testing was performed using Sanger sequencing of DNA obtained from skin fibroblasts or sorted CD3-positive cells from peripheral blood. Results We identified a CHEK2 variant in 38 out of 2322 (1.6%) unrelated patients. We focused on the 24 patients with a variant allele frequency (VAF) equal or higher than 40%, highly suggestive of a germline origin, which was subsequently confirmed in all patients with available germline DNA. Of these, 16 variants (Fig1 A) were considered as pathogenic/likely pathogenic (P/LP) according to the American College of Medical Genetics as well as 3 missense variants which were semi-functional in an in-vivo, yeast-based, functional assay (Delimitsou, 2019). The 5 remaining variants were considered of unknown significance (VUS). Finally, 19 CHEK2germ variants were considered causal for the myeloid malignancy representing a frequency of 0.8% (19/2322). Noteworthy, two out of them (10.5%) had a second somatic hit in CHEK2. (Fig1 B) The median age of the 19 CHEK2germ patients was 75 years (42-87) at diagnosis of the hematological disease. According to the revised WHO classification, there were 7 (37%) MDS-MLD, 2 (11% ) MDS-RS, 4 (21%) MDS-EB, 3 (16%) MPN, 2 (11%) AML, and 1 (5%) ICUS. Karyotype was normal in 7 patients (39%), 8 patients had an isolated abnormality, 3 patients had a complex karyotype and one had cytogenetic failure. Additional driver mutations (Fig 1 B) were identified in most patients (18/19, 95%), however no particular association was noticed. Seven patients (37%) had a personal history of cancer (prostate n=4, breast n=1, thyroid n=1, colon n=1). Five patients (26%) had a family history of hematologic disorders (MPN, n=2, multiple myeloma n=2, ICUS n=1) and 7 patients (37%) of non-hematological cancer (breast n=2, brain n=2, lung n=1, ovary n=1, intestinal n=1). Eleven patients were classified as low-risk MDS according to the IPSS classification with a median survival of 5.6 years. They mainly received ESA (N=2) or lenalidomide (N=2). Among the 3 high-risk MDS patients 2 received hypomethylating agent with a survival of 5 and 1.7 years, the remaining one is still alive after sequential bone marrow transplant. One AML patient is still receiving hypomethylating agent with BCL2-inhibitor in complete remission with a follow up of 1.1 year, while the other AML patient died of relapse after 2 sequential bone marrow transplants. Regarding the 3 MPN patients, 1 is still alive after 1.3 year and the 2 others died 11.5 and 3.8 years after diagnosis. Conclusion This is the largest study addressing the frequency (0.8%) and characteristics of carriers of germline CHEK2 pathogenic variants within patients with myeloid disorders. Their presentation is rather heterogenous with a majority of low-risk MDS. They did not appear to have a more complex karyotype or a poorer prognosis and seems to be less frequent than previously suggested. Compared to more frequent genetic predisposition to myeloid malignancies like DDX41, CHEK2germ hematological malignancies did not seem to represent a specific entity, in line with recent debate on CHEK2germ solid cancer. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Comparison of the Range of Lumbar Cerebrospinal Fluid Pressure in Adults With Normal Cerebrospinal Fluid Pressure and in Idiopathic Intracranial Hypertension.

Lumbar puncture CSF pressure measurements in a large group of adults (116) having lumbar puncture (LP) for diagnostic reasons with no clinical indication of raised intracranial pressure were used to establish the normal range of CSF pressure. The cerebrospinal fluid (CSF) pressure was also measured in a smaller unselected series of patients (35) with the syndrome of idiopathic intracranial hypertension (IIH). All the lumbar punctures were performed by the same highly skilled operator, a consultant nurse, to ensure accuracy of measurement. The results showed that the mean CSF pressure was 18.7 cm H 2 O with a range of 1-29 cm H 2 O in the group with normal CSF pressure. Ninty-five percentage of values was below 29 cm H 2 O in the group with normal CSF pressure. In the series with IIH, the mean and range were 37.7 cm H 2 O and 29.5-66 cm H 2 O, respectively. The lowest recorded pressure in the IIH group was 29.5 cm H 2 O with 95% of values above 31. This is the first time that the normal range of CSF pressure and that found in a group of patients with IIH has been reported after LP performed by the same operator to ensure inaccuracy of measurement has not biased the results. It suggests that the current upper limit of normal adopted by the revised diagnostic criteria for IIH (25 cm H 2 O) may be too low. The range of normal CSF pressure and that found in patients with IIH in our study suggests that consideration should be given to revising the upper limit of normal CSF pressure to around 30 cm H 2 O.

Feasibility and Accuracy of the Automated Software for Dynamic Quantification of Left Ventricular and Atrial Volumes and Function in a Large Unselected Population.

We aimed to evaluate the feasibility and accuracy of machine learning-based automated dynamic quantification of left ventricular (LV) and left atrial (LA) volumes in an unselected population. We enrolled 600 unselected patients (12% in atrial fibrillation) clinically referred for transthoracic echocardiography (2DTTE), who also underwent 3D echocardiography (3DE) imaging. LV ejection fraction (EF), LV, and LA volumes were obtained from 2D images; 3D images were analyzed using dynamic heart model (DHM) software (Philips) resulting in LV and LA volume–time curves. A subgroup of 140 patients also underwent cardiac magnetic resonance (CMR) imaging. Average time of analysis, feasibility, and image quality were recorded, and results were compared between 2DTTE, DHM, and CMR. The use of DHM was feasible in 522/600 cases (87%). When feasible, the boundary position was considered accurate in 335/522 patients (64%), while major (n = 38) or minor (n = 149) border corrections were needed. The overall time required for DHM datasets was approximately 40 seconds. As expected, DHM LV volumes were larger than 2D ones (end-diastolic volume: 173 ± 64 vs. 142 ± 58 mL, respectively), while no differences were found for LV EF and LA volumes (EF: 55% ± 12 vs. 56% ± 14; LA volume 89 ± 36 vs. 89 ± 38 mL, respectively). The comparison between DHM and CMR values showed a high correlation for LV volumes (r = 0.70 and r = 0.82, p < 0.001 for end-diastolic and end-systolic volume, respectively) and an excellent correlation for EF (r = 0.82, p < 0.001) and LA volumes. The DHM software is feasible, accurate, and quick in a large series of unselected patients, including those with suboptimal 2D images or in atrial fibrillation.

CORR Insights®: No Difference in Functional, Radiographic, and Survivorship Outcomes Between Direct Anterior or Posterior Approach THA: 5-Year Results of a Randomized Trial.

CORR Insights®: No Difference in Functional, Radiographic, and Survivorship Outcomes Between Direct Anterior or Posterior Approach THA: 5-Year Results of a Randomized Trial.

Safety and feasibility of conduction system pacing in patients with congenital heart disease.

Conduction system pacing (CSP) has emerged as an ideal physiologic pacing strategy for patients with permanent pacing indications. We sought to evaluate the safety and feasibility of CSP in a consecutive series of unselected patients with congenital heart disease (CHD). Consecutive patients with CHD in which CSP was attempted were included. Safety and feasibility, implant tools and electrical parameters at implant and at follow-up were evaluated. A total of 20 patients were included (10 with a previous device). A total of 10 patients had complex forms of CHD, 9 moderate defects and 1 a simple defect. CSP was achieved in 75% of cases (10 His bundle pacing, 5 left bundle branch pacing) with left ventricular septal pacing in the remaining 5 patients. Procedure times and fluoroscopy times were prolongued (126 ± 82 min and 27 ± 30 min, respectively). Ventricular lead implant times widely varied ranging from 4 to 115 min, (mean 31 ± 28 min) and the use of multiple delivery sheaths was frequent (50%). The QRS width was reduced from 145 ± 36 ms at baseline to 116 ± 18 ms with CSP. Implant electrical parameters included: CSP pacing threshold 0.95 ± 0.65 V; R wave amplitude 9.2 ± 8.8 mV and pacing impedance 632 ± 183 Ohms, and remained stable at a median follow-up of 478 days (interquartile range: 225-567). Systemic ventricle systolic function and NYHA class (1.50 ± 0.51 vs. 1.10 ± 0.31; p = .008) significantly improved at follow-up. Lead revision was required in one patient at Day 4. Permanent CSP is safe and feasible in patients with CHD although implant technique is complex.

Comparison of Survival After Breast-Conserving Therapy vs Mastectomy Among Patients With or Without the BRCA1/2 Variant in a Large Series of Unselected Chinese Patients With Breast Cancer

Whether patients with breast cancer who carry a BRCA1/2 variant can safely undergo breast-conserving therapy (BCT) remains controversial. To compare survival rates after BCT vs mastectomy in BRCA1/2 variant carriers and noncarriers in a large series of unselected patients with breast cancer. In this cohort study, a large consecutive series of 8396 unselected patients with primary breast cancer underwent either BCT, mastectomy with radiotherapy, or mastectomy alone from October 1, 2003, to May 31, 2015, at the Breast Center of Peking University Cancer Hospital in China. All patients were assessed for BRCA1/2 germline variant status. Statistical analysis was performed from May 1 to September 30, 2020. The primary outcomes were breast cancer-specific survival (BCSS) and overall survival (OS); secondary outcomes included recurrence-free survival, distant recurrence-free survival, and ipsilateral breast tumor recurrence. Of these 8396 Chinese patients (8378 women [99.8% women]; mean [SD] age, 50.8 [11.4] years; 187 BRCA1 carriers, 304 BRCA2 carriers, and 7905 noncarriers), 3135 (37.3%) received BCT, 1511 (18.0%) received mastectomy with radiotherapy, and 3750 (44.7%) received mastectomy alone. After a median follow-up of 7.5 years (range, 0.3-16.6 years), both BRCA1 and BRCA2 variant carriers treated with BCT had similar rates of survival compared with those treated with mastectomy with radiotherapy (BCSS: hazard ratio [HR] for BRCA1, 0.58 [95% CI, 0.16-2.10]; P = .41; HR for BRCA2, 0.46 [95% CI, 0.15-1.41]; P = .17; OS: HR for BRCA1, 0.61 [95% CI, 0.18-2.12]; P = .44; HR for BRCA2, 0.72 [95% CI, 0.26-1.96]; P = .52) or mastectomy alone (BCSS: HR for BRCA1, 0.70 [95% CI, 0.22-2.20]; P = .54; HR for BRCA2, 0.59 [95% CI, 0.18-1.93]; P = .39; OS: HR for BRCA1, 0.77 [95% CI, 0.27-2.21]; P = .63; HR for BRCA2, 0.62 [95% CI, 0.22-1.73]; P = .37) after adjusting for clinicopathologic factors and adjuvant therapy. For noncarriers, patients receiving BCT had significantly better survival than those receiving mastectomy with radiotherapy (BCSS: HR, 0.45 [95% CI, 0.36-0.57]; P < .001; OS: HR, 0.46 [95% CI, 0.37-0.58]; P < .001) or mastectomy alone (BCSS: HR, 0.71 [95% CI, 0.57-0.89]; P = .003; OS: HR, 0.71 [95% CI, 0.58-0.87]; P < .001) in multivariable analyses. This study suggests that BRCA1/2 variant carriers treated with BCT have survival rates at least comparable to those treated with mastectomy with radiotherapy or mastectomy alone and that BCT could be an option for BRCA1/2 variant carriers when the tumor is clinically appropriate for BCT.

Vascular Abnormalities Detected with Chest CT in COVID-19: Spectrum, Association with Parenchymal Lesions, Cardiac Changes, and Correlation with Clinical Severity (COVID-CAVA Study).

Although vascular abnormalities are thought to affect coronavirus disease 2019 (COVID-19) patients’ outcomes, they have not been thoroughly characterized in large series of unselected patients. The Swiss national registry coronavirus-associated vascular abnormalities (CAVA) is a multicentric cohort of patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection who underwent a clinically indicated chest computed tomography (CT) aiming to assess the prevalence, severity, distribution, and prognostic value of vascular and non-vascular-related CT findings. Clinical outcomes, stratified as outpatient treatment, inpatient without mechanical ventilation, inpatient with mechanical ventilation, or death, will be correlated with CT and biological markers. The main objective is to assess the prevalence of cardiovascular abnormalities–including pulmonary embolism (PE), cardiac morphology, and vascular congestion. Secondary objectives include the predictive value of cardiovascular abnormalities in terms of disease severity and fatal outcome and the association of lung inflammation with vascular abnormalities at the segmental level. New quantitative approaches derived from CT imaging are developed and evaluated in this study. Patients with and without vascular abnormalities will be compared, which is supposed to provide insights into the prognostic role and potential impact of such signs on treatment strategy. Results are expected to enable the development of an integrative score combining both clinical data and imaging findings to predict outcomes.

Value of TAPSE normalized to right ventricular length as a substitute to speckle tracking-derived right ventricular free wall longitudinal strain assessment

Abstract Funding Acknowledgements Type of funding sources: None. Background The diagnostic and prognostic value of right ventricular strain assessed by speckle-tracking imaging (STI-RV) has recently emerged in various clinical situations and this parameter has been incorporated into echocardiographic guidelines. However, it suffers from several limitations including the fundamental but often unmet requirement of good image quality and from the need for dedicated software with inter-vendor variability. Purpose We hypothesized that RV free wall (fw) longitudinal shortening, i.e. the ratio of tricuspid annular plane systolic excursion (TAPSE) to end-diastolic RV longitudinal length (RVDL) could be used as a surrogate of RVfw strain, without suffering from the abovementioned limitations. We therefore compared -(TAPSE/RVDL) to STI-RVfw strain in a series of non-selected patients undergoing echocardiography. Patients and methods 144 consecutive ≥18 y-o patients in sinus rhythm referred to our echocardiographic laboratory underwent transthoracic echocardiography using a Vivid E9 platform (GE Vingmed, Horten, Norway). STI-RVfw strain was obtained using a RV focused apical four chamber view and -(TAPSE/RVDL) was obtained from the apical four-chamber view. Images and loop were stored digitally and analyzed offline using EchoPac 2.02 software (GE Vingmed). Results Poor image quality precluded the assessment of STI-RVfw strain - but not of -(TAPSE/RVDL) - in 27 patients (18.8%) and of both parameters in 4 patients (2.8%); the study group consisted in the remaining 113 patients. Among all tested RV function indices, -(TAPSE/RVDL) best correlated with STI-RVfw strain (Panel A), without significant bias between the two methods (Panel B). The area under the ROC-curve for -(TAPSE/RVDL) to detect abnormal STI-RVfw strain (using a threshold of -20.2%) was 0.97 [IC 95% 0.94-1], and sensitivity, specificity, negative and positive predictive value were 83%, 96%, 96%, and 83%, respectively. Conclusion In this unselected series of patients, the assessment of -(TAPSE/RVDL) performed reasonably well to predict abnormal STI-RVfw strain and was more often feasible than the latter. Its prognostic value should be prospectively tested. Abstract Figure 1

Feasibility and accuracy of the automated software for dynamic quantification of left ventricular and atrial volumes and function in a large unselected population

Abstract Funding Acknowledgements Type of funding sources: None. Objective. Preliminary studies showed the accuracy of machine learning based automated dynamic quantification of left ventricular (LV) and left atrial (LA) volumes. We aimed to evaluate the feasibility and accuracy of machine learning based automated dynamic quantification of LV and LA volumes in an unselected population. Methods. We enrolled 600 unselected patients (12% in atrial fibrillation) clinically referred for transthoracic echocardiography (2DTTE), who also underwent 3D echocardiography (3DE) imaging. LV ejection fraction (EF), LV and LA volumes were obtained from 2D images; 3D images were analysed using Dynamic Heart Model (DHM) software (Philips) resulting in LV and LA volume-time curves. A subgroup of 140 patients underwent also cardiac magnetic resonance (CMR) imaging. Average time of analysis, feasibility, and image quality were recorded and results were compared between 2DTTE, DHM and CMR. Results. The use of DHM was feasible in 522/600 cases (87%). When feasible, the boundary position was considered accurate in 335/522 patients (64%), while major (n = 38) or minor (n = 149) borders corrections were needed. The overall time required for DHM datasets was approximately 40 seconds, resulting in physiologically appearing LV and LA volume–time curves in all cases. As expected, DHM LV volumes were larger than 2D ones (end-diastolic volume: 173 ± 64 vs 142 ± 58 mL, respectively), while no differences were found for LV EF and LA volumes (EF: 55%±12 vs 56%±14; LA volume 89 ± 36 vs 89 ± 38 mL, respectively). The comparison between DHM and CMR values showed a high correlation for LV volumes (r = 0.70 and r = 0.82, p &amp;lt; 0.001 for end-diastolic and end-systolic volume, respectively) and an excellent correlation for EF (r= 0.82, p &amp;lt; 0.001) and LA volumes. Conclusions. The DHM software is feasible, accurate and quick in a large series of unselected patients, including those with suboptimal 2D images or in atrial fibrillation. Table 1 DHM quality Adjustment Feasibility Good Suboptimal Minor Major Total of patients (n, %) 522/600 (87%) 327/522 (62%) 195/522 (28%) 149/522 (29%) 38/522 (6%) Normal subjects (n, %) 39/40 (97%) 23/39 (57%) 16/39 (40%) 9/39 (21%) 1/39 (3%) Atrial Fibrillation (n, %) 59/73 (81%)* 28/59 (47%) 31/59 (53%) 15/59 (25%) 6/59 (10%) Valvular disease (n, %) 271/312 (87%) 120/271 (%) 151/271 (%) 65/271 (24%) 16/271 (6%) Coronary artery disease (n, %) 47/58 (81%)* 26/47 (46%) 21/47 (37%) 16/47 (34%) 5/47 (11%) Miscellaneous (n, %) 24/25 (96%) 18/24 (75%) 6/24 (25%) 5/24 (21%) 3/24 (12%) Feasibility of DHM, image quality and need to adjustments in global population and in each subgroup. Abstract Figure 1

Oncological Long-term Outcome After Whole-gland High-intensity Focused Ultrasound for Prostate Cancer—21-yr Follow-up

BackgroundOwing to the morbidity of established radical treatment options for prostate cancer, alternative whole-gland and focal treatment strategies have emerged. High-intensity focused ultrasound (HIFU) is one of the most studied sources for tissue ablation and has been used since the 1990s. ObjectiveTo provide 21-yr oncological long-term follow-up data of an unselected series of patients who underwent whole-gland HIFU for nonmetastatic prostate cancer. Design, setting, and participantsA total of 674 patients were treated between November 1997 and November 2012 in one university center. Outcome measurements and statistical analysisThe oncological outcome was assessed by biopsy failure–free survival (BFFS), salvage treatment–free survival (STFS), metastasis-free survival (MFS), cancer-specific survival (CSS), and overall survival (OS). Multivariable Cox proportional hazard regression analyses were performed to estimate the prognostic relevance of clinical variables. Results and limitationsIn total, 560 patients were included into the evaluation and the median follow-up was 15.1 yr, with a range up to 21.4 yr. At 15 yr, CSS rates for low-, intermediate-, and high-risk patients were 95%, 89%, and 65%, respectively; MFS, STFS-1 (salvage treatment other than HIFU), STFS-2 (salvage treatment including repeat HIFU), and BFFS rates were 91%, 85%, and 58%; 77%, 63%, and 29%; 67%, 52%, and 28%; and 82%, 73%, and 47%, respectively. Preoperative high-risk category was an independent predictor of inferior OS, CSS, MFS, STFS, and BFFS. ConclusionsAlthough whole-gland HIFU achieved good long-term cancer control in low- and intermediate-risk patients, high-risk patients should not be treated routinely by HIFU. Intermediate-risk patients achieve high CSS and MFS rates, but a relevant salvage treatment rate has to be reckoned with. Long-term data after whole-gland therapy might help derive implications for focal treatment sources and patient selection. Patient summaryLong-term data after whole-gland high-intensity focused ultrasound (HIFU) therapy are crucial to prove its oncological efficacy, and may help derive implications for focal treatment strategies and patient selection. In this context, whole-gland HIFU achieved good long-term cancer control up to 21 yr in low- and intermediate-risk prostate cancer (PCa) patients. Owing to considerably inferior long-term cancer control, it should not routinely be used in high-risk PCa patients.

68Ga-DOTATATE and 123I-mIBG as imaging biomarkers of disease localisation in metastatic neuroblastoma: implications for molecular radiotherapy.

Iodine-131-labelled meta-iodobenzylguanidine (I-mIBG) and lutetium-177-labelled DOTATATE (Lu-DOTATATE) are used for molecular radiotherapy of metastatic neuroblastoma. These are taken up by the noradrenaline transporter (NAT) and the somatostatin receptor subtype 2 (SSTR-2), respectively. Scintigraphy of iodine-123-labelled meta-iodobenzylguanidine (I-mIBG) and gallium-68 DOTATATE (Ga-DOTATATE) PET are used to select patients for therapy. These demonstrate the extent and location of tumour, and avidity of uptake by cells expressing NAT and SSTR-2, respectively. This study compared the similarities and differences in the anatomical distribution of these two imaging biomarkers in an unselected series of patients with metastatic neuroblastoma undergoing assessment for molecular radiotherapy. Paired whole-body planar I-mIBG views and Ga-DOTATATE maximum intensity projection PET scans of metastatic neuroblastoma patients were visually compared. The disease extent was assessed by a semiquantitative scoring method. Paired scans from 42 patients were reviewed. Ga-DOTATATE scans were positive in all patients, I-mIBG scans were negative in two. In two patients, there was a mismatch, with some lesions identified only on the I-mIBG scan, and others visible only on the Ga-DOTATATE scan. Ga-DOTATATE and I-mIBG scans yield complementary information. For a more comprehensive assessment, consideration could be given to the use of both I-mIBG and Ga-DOTATATE imaging scans. Because of the heterogeneity of distribution of molecular targets revealed by these techniques, a combination of both I-mIBG and Lu-DOTATATE molecular radiotherapy may possibly be more effective than either alone.

Neurologic Manifestations in a Prospective Unselected Series of Hospitalized Patients With COVID-19

An increasing number of neurologic problems are being described in coronavirus disease 2019 (COVID-19) disease, but their frequency and type have not been defined. In this study, we sought to determine the extent of neurologic manifestations of COVID-19 in a prospective series of unselected patients admitted to the general medicine wards of our hospitals due to COVID-19 and who were examined by a team of neurologists. Eight neurologists provided medical attention to patients hospitalized for COVID-19 to provide medical support to other hospital units tasked with the care of an increasingly larger influx of patients with COVID-19. A series of 100 consecutive, unselected patients were evaluated systematically, including a questionnaire that collected medical information derived from the initial examination and the medical history. Eighty-eight percent of the patients had 1 neurologic manifestation associated with COVID-19 during hospitalization. Most common were anosmia-dysgeusia and headache (44% each), myalgias (43%), and dizziness (36%). Less frequent were encephalopathy (8%), syncope (7%), seizures (2%), and ischemic stroke during the period of hospitalization (2%). Anosmia and headache associated with younger patients with less severe disease, and both were associated with each other and with serum inflammatory markers. Encephalopathy was associated with fever and syncope and with markers of inflammation. Neurologic disturbances are common in patients with COVID-19, particularly if patients are evaluated by neurologists. There is a wide variety of neurologic conditions, some of them severe, in the spectrum of COVID-19 disease that will benefit from an evaluation by practicing neurologists.

KRD (carfilzomib and lenalidomide plus dexamethasone) for the treatment of relapsed or refractory multiple myeloma in the real-life: a retrospective survey in 123 patients.

From April 2016, carfilzomib, in combination with lenalidomide and dexamethasone (KRD), became available for use in the daily practice in Italy for patients with relapsed or refractory multiple myeloma (RRMM). We performed a retrospective survey at 14 different institutions from Southern Italy in order to evaluate patient characteristics and treatment results from an unselected series of patients treated accordingly so far. One hundred and twenty-three consecutive patients were included, with a median of 2 previous lines of therapy (range 1-9) and a median age of 63years (range 39-82). At the time of analysis, median number of courses administered is 11 (range 1-34), and all patients are evaluable for response. Overall response rate including complete remission, very good partial remission, and partial remission is 85%. After a median follow-up of 27months, median overall and progression-free survival are 33 and 23months, respectively. Sixty-three patients are alive and between them, 45 (37%) are in continuous remission. Sixty patients have died (49%), mainly from progressive disease. There were 6 treatment-related deaths (5% of the whole patient population). Overall, hematological and non-hematological toxicity were manageable, mostly on outpatient basis. Arterial hypertension has been observed in 43 cases (35%) but did not lead to treatment interruption. Our data demonstrate that in real life, KRD is highly effective and well tolerated in the majority of patients with RRMM.

Capillary-venule malformation is a microfistulous variant of arteriovenous malformation

ObjectiveTo describe typical clinical presentation of patients with microfistular, capillary-venule (CV) malformation as a variant form of arteriovenous malformations (AVM). MethodsA retrospective clinical analysis of 15 patients with CV-AVM confirmed by a computational flow model enrolled in a prospective database of patients with congenital vascular malformation between January 2008 and May 2018. ResultsThe mean age of the patients at first time of presentation was 30 years with balanced sex ratio. Presentation was dominated by soft tissue hypertrophy (n = 12 [80.0%]) and atypical varicose veins (n = 11 [73.3%]). The anatomic location of enlarged varicose veins gave no uniform pattern and did not correspond with the typical picture of primary varicose vein disease. Most often, symptomatic CV-AVM was found at the lower extremities in this series of unselected patients. The most frequent compartment affected was the subcutis (n = 14 [93.3%]), involvement of muscle was recorded in one-third and cutis in one-fourth of patients. ConclusionsA high grade of clinical suspicion is needed to recognize CV-AVM and to prevent inadequate therapy owing to missed diagnosis.