Evaluation of Hemodynamic Properties After Chimney and Fenestrated Endovascular Aneurysm Repair.

BACKGROUND: Fenestrated (FEVAR) and chimney (ChEVAR) endovascular aortic repair have been applied in anatomically suitable complex aortic aneurysms. However, local hemodynamic changes may occur after repair. This study aimed to compare FEVAR's and ChEVAR's hemodynamic properties, focusing on visceral arteries. METHODS: Preoperative and postoperative computed tomography angiographies have been used to reconstruct patient-based models. Data of 3 patients, for each modality, were analyzed. Following geometric reconstruction, computational fluid dynamics simulations were used to extract near-wall and intravascular hemodynamic indicators, such as pressure drops, velocity, wall shear stress, time averaged wall shear stress, oscillatory shear index, relative residence time, and local normalized helicity. RESULTS: An overall improvement in hemodynamics was detected after repair, with either technique. Preoperatively, a disturbed prothrombotic wall shear stress profile was recorded in several zones of the sac. The local normalized helicity results showed a better organization of the helical structures at postoperative setting, decreasing thrombus formation, with both modalities. Similarly, time averaged wall shear stress increased and oscillatory shear index decreased postoperatively, signaling nondisturbed blood flow. The relative residence time was locally reduced. The flow in visceral arteries tended to be more streamlined in ChEVAR, compared to evident recirculation regions at renal and superior mesenteric artery fenestrations (P = 0.06). CONCLUSIONS: ChEVAR and FEVAR seem to improve hemodynamics toward normal values with a reduction of recirculation zones in the main graft and aortic branches. Visceral artery flow comparison revealed that ChEVAR tended to present lower recirculation regions at parallel grafts' entries while FEVAR showed less intense flow regurgitation in visceral stents.

Computational Study of Abdominal Aortic Aneurysm Walls Accounting for Patient-Specific Non-Uniform Intraluminal Thrombus Thickness and Distinct Material Models: A Pre- and Post-Rupture Case.

An intraluminal thrombus (ILT) is present in the majority of abdominal aortic aneurysms, playing a crucial role in their growth and rupture. Although most computational studies do not include the ILT, in the present study, this is taken into account, laying out the whole simulation procedure, namely, from computed tomography scans to medical image segmentation, geometry reconstruction, mesh generation, biomaterial modeling, finite element analysis, and post-processing, all carried out in open software. By processing the tomography scans of a patient's aneurysm before and after rupture, digital twins are reconstructed assuming a uniform aortic wall thickness. The ILT and the aortic wall are assigned different biomaterial models; namely, the first is modeled as an isotropic linear elastic material, and the second is modeled as the Mooney-Rivlin hyperelastic material as well as the transversely isotropic hyperelastic Holzapfel-Gasser-Ogden nonlinear material. The implementation of the latter requires the designation of local Cartesian coordinate systems in the aortic wall, suitably oriented in space, for the proper orientation of the collagen fibers. The composite aneurysm geometries (ILT and aortic wall structures) are loaded with normal and hypertensive static intraluminal pressure. Based on the calculated stress and strain distributions, ILT seems to be protecting the aneurysm from a structural point of view, as the highest stresses appear in the thrombus-free areas of the aneurysmal wall.

Phase 2 study of epigenetic priming with decitabine followed by cytarabine for acute myeloid leukemia in older patients.

Acute myeloid leukemia (AML) in older patients has a poor prognosis, low complete remission (CR) rates, and poor overall survival (OS). Preclinical studies have shown synergistic effects of epigenetic priming with hypomethylating agents followed by cytarabine. Based on these data, we hypothesized that an induction regimen using epigenetic priming with decitabine, followed by cytarabine would be effective and safe in older patients with previously untreated AML. Here, we conducted a phase 2 trial in which older patients with previously untreated AML received an induction regimen consisting of 1 or 2 courses of decitabine 20 mg/m2 intravenously (IV) for 5 days followed by cytarabine 100 mg/m2 continuous IV infusion for 5 days. Forty-four patients (median age 76 years) were enrolled, and CR/CRi was achieved by 26 patients (59% of all patients, 66.7% of evaluable patients). Fourteen of 21 (66.7%) patients with adverse cytogenetics achieved CR including six out of seven evaluable patients with TP53 mutations. The 4- and 8-week mortality rates were 2.3% and 9.1%, respectively, with median OS of 10.7 months. These results suggest epigenetic priming with decitabine followed by cytarabine should be considered as an option for first-line therapy in older patients with AML. This trial was registered at www.clinicaltrials.gov as # NCT01829503.

Mechanics of ascending aortic aneurysms based on a modulus of elasticity dependent on aneurysm diameter and pressure.

The mechanical stresses and strains are examined, in ascending thoracic aortic aneurysm (aTAA) models, in a patient-specific aTAA as well as in healthy thoracic aortic models, via Finite Element Analysis. The aneurysms are assumed spherical, 1.5 mm thick, with diameters between 47 mm and 80 mm, eccentrically positioned. The geometry and wall thickness distribution of the aorta along its length are based on open literature data for an average patient age of 66.25 years, accounting for the Body Surface Area (BSA) parameter. The vessel wall material is assumed isotropic and incompressible, with its Young's modulus varying with the aneurysm diameter and the applied intraluminal pressure (120 mmHg to 240 mmHg). In the aTAAs, peak stresses were found to increase nonlinearly with aneurysm diameter (for a given pressure) tending to reach a plateau, appearing at the proximal area of the aneurysm, whereas lower stresses were found at its distal part and even smaller at the aneurysm maximum diameter. Regarding the patient-specific aTAA model, the peak stresses appeared at the distal part of the aneurysm where a tear of the intima layer was detected during surgical intervention. Peak strains exhibited for each pressure a maximum at a certain aneurysm diameter beyond which they dropped so that essentially the vessel wall's distensibility was thus reduced. Examining more than 100 geometry cases and employing a failure stress criterion, the rupture diameter thresholds were estimated to be 65, 52.5, 50 and 47.5 mm for a pressure of 120, 160, 200 and 240 mmHg respectively.

Rapid Emergence of Potentially Transmissible Severe Acute Respiratory Syndrome Coronavirus 2 With Resistance to Combination Monoclonal Antibody Therapy.

Prolonged coronavirus disease 2019 may generate new viral variants. We report an immunocompromised patient treated with monoclonal antibodies who experienced rebound of viral RNA and emergence of an antibody-resistant (>1000-fold) variant containing 5 mutations in the spike gene. The mutant virus was isolated from respiratory secretions, suggesting the potential for secondary transmission.

Therapy With Allogeneic Severe Acute Respiratory Syndrome Coronavirus-2-Specific T Cells for Persistent Coronavirus Disease 2019 in Immunocompromised Patients.

We administered severe acute respiratory syndrome coronavirus-2 viral-specific T cells (VSTs) under emergency investigational new drug applications to 6 immunocompromised patients with persistent coronavirus disease 2019 (COVID-19) and characterized clinical and virologic responses. Three patients had partial responses after failing other therapies but then died. Two patients completely recovered, but the role of VSTs in recovery was unclear due to concomitant use of other antivirals. One patient had not responded to 2 courses of remdesivir and experienced sustained recovery after VST administration. The use of VSTs in immunocompromised patients with persistent COVID-19 requires further study.

Intravascular Lymphoma - The Creepy Crawler: A Case Series and Brief Literature Review.

BACKGROUND: Intravascular large B-cell lymphoma (IVLBCL) is a rare subtype of extranodal B-cell lymphoma, which has traditionally been associated with poor outcomes. Despite increasing recognition, IVLBCL requires a high degree of clinical suspicion on the part of the clinician for its diagnosis. CASE SERIES: We present four patient cases: A 69-year-old female with constitutional symptoms and cognitive decline; a 78-year-old female with kidney injury and constitutional symptoms whose disease rapidly progressed to multiorgan failure and death; a 70-year-old asymptomatic female with an incidentally found, enlarged thyroid; and a 63-year-old male with cytopenia and constitutional symptoms. Retrospective chart analysis was performed on these four patients diagnosed with IVLBCL at our Institute to identify the pathognomonic features of the disease and compare these to the published evidence. IVLBCL has a heterogeneous presentation, as seen in our four patients. The disease is characterized by the exclusive presence of malignant cells inside the blood vessels and lack of organ infiltration. Traditional preliminary diagnostic modalities such as imaging are usually inconclusive, given the paucity of lymphomatous aggregates. A bone marrow biopsy, random skin biopsies, or a focal organ biopsy in appropriate cases is required for diagnosis. Immunosuppression might play a role in the pathogenesis. Timely initiation of aggressive cancer-directed therapy was associated with improved outcomes. Monitoring for disease response and relapse continues to be a challenge. CONCLUSION: Our mini-series highlights the significance of timely diagnosis and intervention in IVLBCL and emphasizes the importance of further research to determine its association with immunosuppression.

Rates and Predictors of Nonadherence to the Post-Allogeneic Hematopoietic Cell Transplantation Medical Regimen in Patients and Caregivers.

Allogeneic hematopoietic cell transplantation (HCT) requires a complex, multicomponent medical regimen after hospital discharge. Patients must manage multiple medications; care for their catheter; minimize exposure to sources of potential infection; follow diet, exercise, and self-care guidelines; and attend frequent follow-up medical appointments. Their caregivers are tasked with helping them manage the regimen. Despite the importance of this management in preventing adverse clinical outcomes, there has been little study of regimen nonadherence and its predictors. We sought to prospectively determine rates and predictors of nonadherence to components of the post-HCT medical regimen during the first 8 weeks after hospital discharge. Patients (n = 92) and their caregivers (n = 91) (total n = 183) completed interview assessments pre-HCT, and at 4 weeks and 8 weeks after hospital discharge post-HCT. Sociodemographic factors (eg, age, sex), patient clinical status (eg, disease type, donor type), patient and caregiver self-reported health-related factors (eg, medical comorbidities), and patient and caregiver psychosocial factors (eg, anxiety, depression, HCT task-specific and general self-efficacy, relationship quality) were assessed pre-HCT. Nonadherence to each of 17 regimen tasks was assessed at 4 and 8 weeks after hospital discharge via self and caregiver collateral reports. Nonadherence rates varied among tasks, with 11.2% to 15.7% of the sample reporting nonadherence to immunosuppressant medication, 34.8% to 38.6% to other types of medications, 14.6% to 67.4% to required infection precautions, and 27.0% to 68.5% to lifestyle-related behaviors (eg, diet/exercise). Nonadherence rates were generally stable but worsened over time for lifestyle-related behaviors. The most consistent nonadherence predictors were patient and caregiver pre-HCT perceptions of lower HCT task efficacy. Higher caregiver depression, caregiver perceptions of poorer relationship with the patient, having a nonspousal caregiver, and having diseases other than acute myelogenous leukemia also predicted greater nonadherence in 1 or more areas. Rates of nonadherence varied across tasks, and both patient and caregiver factors, particularly self-efficacy, predicted nonadherence. The findings highlight the importance of considering not only patient factors, but also caregiver factors, in post-HCT regimen nonadherence.

Patient-reported outcomes in relapsed/refractory multiple myeloma treated with melflufen plus dexamethasone: analyses from the Phase II HORIZON study.

Relapsed/refractory multiple myeloma (RRMM) is known to have a high burden of disease and complications associated with refractoriness to prior lines of therapy. Severe pain and fatigue symptoms and impairments in physical and emotional functioning have been strongly linked to reduced health-related quality of life (HRQoL) in patients with RRMM. Assessment of patient reported-outcome measures from the pivotal, Phase II HORIZON study (OP-106; NCT02963493) in patients with RRMM (n = 64) demonstrated that melphalan flufenamide (melflufen) plus dexamethasone treatment preserved HRQoL. Patients had clinically meaningful improvements, even after eight treatment cycles, in relevant scales such as global health status/QoL, physical functioning, emotional functioning, pain, and fatigue. Patients with triple-class-refractory disease (n = 50) displayed similar improvements. Patient-reported outcome deterioration was delayed for a substantial amount of time in patients who experienced a response to melflufen plus dexamethasone treatment relative to patients who did not experience a response. These findings support the notion that treatment with melflufen plus dexamethasone may sustain or improve HRQoL over time in patients with RRMM, including in patients with triple-class-refractory disease for whom outcomes are generally worse. The clinical benefits observed in patients from the HORIZON trial are encouraging and supportive of translation into real-world practice.

A prospective study of the use of central venous catheters in patients newly diagnosed with acute myeloid leukemia treated with induction chemotherapy.

PURPOSE: Central venous catheters (CVCs) are widely used in acute myeloid leukemia (AML) patients. Complications associated with CVCs are frequently encountered and contribute to morbidity and mortality. Prospective studies investigating and comparing complications of different types of CVCs in AML patients and their effects on the quality of life are limited. METHODS: We conducted a prospective observational study and evaluated the complications associated with the use of CVCs in adult AML patients during induction chemotherapy and evaluated quality of life outcomes as reported by the patients during and after their hospitalization. RESULTS: Fifty newly diagnosed patients with AML (median age, 59 years) who received intensive induction chemotherapy were enrolled in the study. Twenty-nine patients (58%) had a peripherally inserted central catheters (PICCs) placed and 21 (42%) patients received a Hickmann tunneled central catheter (TCC). Three percent of cases developed catheter-related thrombosis in PICCs and no thrombosis in TCCs. Catheter-related bloodstream infection was diagnosed in 8% of patients. CVC occlusion occurred in 44 patients (88%). The total number of occlusion events was 128; 97% of patients with PICCs and 76% of patients with TCCs (p = 0.003). All patients reported that the use of CVC simplified their course of treatment. Most patients reported similar restrictions in activity associated with TCCs and PICCs. CONCLUSION: The present study demonstrates that thrombosis and catheter-related bloodstream infections remain important complications of CVCs in AML patients. Occlusion rates were higher with the use of PICCs and the use of CVCs impacted the quality of life.

Remodeling effects of carotid artery stenting versus endarterectomy with patch angioplasty in terms of morphology and hemodynamics.

BACKGROUND: Carotid endarterectomy (CEA) remains the first-line treatment option of symptomatic and asymptomatic carotid stenosis, while stenting (CAS) is reserved for selected patients at high surgical risk. Here, we compare the vascular remodeling process in CEA- and CAS-treated patients with respect to morphological and hemodynamic features, because of their possible engagement in carotid atherosclerosis. METHODS: Twelve (12) patients were included, half with patched CEA and half with CAS. Pre- and post-operative 3D image-based models of the carotid bifurcation were anatomically characterized in terms of flare, tortuosity, and curvature. Individual computational fluid dynamics simulations allowed to quantify the postoperative hemodynamic milieu in terms of (1) wall shear stress and (2) helical flow. RESULTS: Carotid flare increased in all cases, but a more marked increase emerged after CEA compared to CAS. Tortuosity and curvature increased after CEA but decreased after CAS. CEA patients presented with significantly higher postoperative tortuosity than CAS patients. CEA was associated with a worse (non-statistically significant) score in all flow disturbance indicators vs. CAS. CONCLUSION: The increased flare and tortuosity of the carotid bifurcation after CEA vs. CAS is a marked difference in the vascular remodeling process between the two modalities. CAS seems to induce a less pro-restenosis hemodynamic environment compared to CEA. The emerged differences stimulate further analysis on a larger cohort with long-term outcomes, to shed light on the clinical impact of the observations.

Computational Fluid Dynamic Analysis Supports the Hemodynamic Stability of Hybrid Combinations With the AFX Bifurcate and Nitinol-Based Proximal Segments in Solutions of Failed Endovascular Aneurysm Repair.

Hybrid endograft combinations of two or more different types of covered stents are rarely reported to treat complex abdominal aortic aneurysm cases or primary and secondary endoleaks. Clinical and laboratory data regarding the clinical efficacy and mechanical stability of such combinations are lacking. Based on a recently published case report, we describe and comment on the hemodynamic profile of a representative simulated hybrid case of AFX and Nitinol-based proximal cuff and support the stability of this combination in non-angulated cases.

Modeling and Computational Comparison of the Displacement Forces Exerted between the AFX Unibody Aortic Stent Graft and its Hybrid Combination with a Nitinol-based Proximal Aortic Cuff.

BACKGROUND: The bifurcated AFX (Endologix, Inc, Irvine, CA, USA) aortic stent-graft is the sole unibody endograft for the management of Abdominal Aortic Aneurysms (AAA). In order to improve the AFX central sealing and clinical efficacy in challenging cases, a replacement of the central chromium-cobaltium AFX extension with a Nitinol-based proximal aortic cuff has been suggested. Yet, comparative data regarding the hemodynamic performance of this design is missing. Aim of this study was to compare the displacement forces (DF) acting on the hybrid AFX-Endurant design, with the classic AFX and Endurant endografts, in angulated and non-angulated cases based on patient-specific Computational Fluid Dynamics (CFD) simulations. METHODS: 3D endograft models of 11 treated AAA cases were reconstructed from Computed Tomography Angiography (CTA) imaging data: 5 cases of AFX, 3 cases of the combination AFX-Endurant and 3 cases of the classic Endurant design. The DF on the main-body, the iliac limbs, and the entire stent-graft was calculated by processing the velocity and pressure fields generated by pulsatile CFD simulations. RESULTS: The range of total DF (acting on the whole endograft structure) in the AFX, hybrid AFX-Endurant and Endurant group was 2.5-5.2N, 2.0-5.9N and 1.9-2.9N respectively, with the maximum total DF being lower for Endurant. The DF on the main-body of the classic and hybrid AFX cases were higher than the right and left iliac limbs (2.5-4.9N vs. 0.6-5.3N and 0.7-3.6N respectively). Conversely, the DF on the main-body of the Endurant cases was comparable to the force exerted on the right and left limbs. When separating the cases with respect to their neck angulation, the DF on all endograft parts (main-body, limbs) and on the endograft as a whole were lower for the hybrid AFX-Endurant group compared to the classic AFX and Endurant groups, for cases with almost straight neck. CONCLUSION: The off-label use of the hybrid AFX-Endurant stent-graft does not seem superior to the conventional AFX or Endurant endografts in angulated cases but was associated with lower DF than AFX or Endurant in non-angulated cases. The clinical value and utility of these findings remain to be elucidated.

Melflufen and Dexamethasone in Heavily Pretreated Relapsed and Refractory Multiple Myeloma.

PURPOSE: Melphalan flufenamide (melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and rapidly and selectively releases alkylating agents into tumor cells. The phase II HORIZON trial evaluated the efficacy of melflufen plus dexamethasone in relapsed and refractory multiple myeloma (RRMM), a population with an important unmet medical need. PATIENTS AND METHODS: Patients with RRMM refractory to pomalidomide and/or an anti-CD38 monoclonal antibody received melflufen 40 mg intravenously on day 1 of each 28-day cycle plus once weekly oral dexamethasone at a dose of 40 mg (20 mg in patients older than 75 years). The primary end point was overall response rate (partial response or better) assessed by the investigator and confirmed by independent review. Secondary end points included duration of response, progression-free survival, overall survival, and safety. The primary analysis is complete with long-term follow-up ongoing. RESULTS: Of 157 patients (median age 65 years; median five prior lines of therapy) enrolled and treated, 119 patients (76%) had triple-class-refractory disease, 55 (35%) had extramedullary disease, and 92 (59%) were refractory to previous alkylator therapy. The overall response rate was 29% in the all-treated population, with 26% in the triple-class-refractory population. In the all-treated population, median duration of response was 5.5 months, median progression-free survival was 4.2 months, and median overall survival was 11.6 months at a median follow-up of 14 months. Grade ≥ 3 treatment-emergent adverse events occurred in 96% of patients, most commonly neutropenia (79%), thrombocytopenia (76%), and anemia (43%). Pneumonia (10%) was the most common grade 3/4 nonhematologic event. Thrombocytopenia and bleeding (both grade 3/4 but fully reversible) occurred concomitantly in four patients. GI events, reported in 97 patients (62%), were predominantly grade 1/2 (93%); none were grade 4. CONCLUSION: Melflufen plus dexamethasone showed clinically meaningful efficacy and a manageable safety profile in patients with heavily pretreated RRMM, including those with triple-class-refractory and extramedullary disease.

Outcomes of Patients With Acute Myeloid Leukemia Who Relapse After 5 Years of Complete Remission.

Leukemia relapse 5 years after achieving first complete remission (CR1) is uncommon in patients with acute myeloid leukemia (AML). In this study, we evaluated the outcomes of AML patients with late relapse at our institution and reviewed the literature for these patients. The study cohort consisted of nine AML patients with late relapse. The median interval between CR1 and AML relapse was 6.1 years (range: 5.116.2 years). At relapse, the karyotype was different from the initial AML diagnosis in 50% of patients. At the time of AML relapse, seven patients received induction chemotherapy and two patients received hypomethylating agents with an overall CR rate of 66%. The median time to relapse after achieving second CR (CR2) was 16.5 months [95% confidence interval (CI): 9.4, NA]. The median overall survival after first relapse was 28.6 months (95% CI: 7.3, 3.466.5 months). Despite initial CR after reinduction therapy, relapse rates are still high, suggesting that alternative strategies for postremission therapies are warranted in CR2. These approaches include the use of allogeneic hematogenic cell transplantation and the use of newly approved AML agents as maintenance therapy in nontransplant eligible patients.

Endograft Specific Haemodynamics After Endovascular Aneurysm Repair: Flow Characteristics of Four Stent Graft Systems.

OBJECTIVES: The implication of haemodynamics in the occurrence of complications after endovascular aneurysm repair (EVAR) has been raised in the literature. Different aortic stent graft configurations may lead to different haemodynamic properties. The current study deals with the post-operative haemodynamic variability between four stent graft systems with different structure, material, and type of fixation. METHODS: Computed tomography data of 32 patients were used, equally distributed among the four endograft groups, namely the AFX, Endurant, Excluder, and Nellix. Velocity, wall shear stress (WSS), and helicity statistics were calculated, in regions around the flow division where disturbances are expected. The haemodynamic data were compared between and within the groups. RESULTS: The morphology of AAAs pre-operatively did not vary significantly among the four groups. Before the flow division, lowest velocity was observed in Endurant cases and highest in Nellix cases. Endurant induced the lowest peak WSS and Nellix the highest (p = .03). The helicity levels were low in AFX and Nellix cases and high in Endurant and Excluder cases. After the flow division, the trend in the results was preserved. Nellix induced the highest velocity and WSS, followed closely by Excluder and AFX. There was a significant increase of helicity before and after flow division in AFX (p <0.001, R2 = 0.09) and Nellix (p <0.001) cases. CONCLUSIONS: It has been shown that different types of endografts induce variable haemodynamic conditions around the flow division. The parallel limb structure, featured by Nellix, seems to induce favourable flow conditions in terms of velocity and WSS, while helical flow before the flow division is suppressed. High WSS is generally considered to be a desirable flow characteristic in endovascular devices, whereas helicity extremes (very low or high) are potentially a negative sign. Endurant, with the stiffer material and the short neck structure, was associated with the lowest blood velocity and WSS values but preserved high helicity levels. The AFX and Excluder, which include the same material, induced similar haemodynamic conditions.

In-stent graft helical flow intensity reduces the risk of migration after endovascular aortic repair.

During the last years endovascular aneurysm repair (EVAR) became the elective treatment for abdominal aortic aneurysms (AAAs) thanks to lower mortality and morbidity rates than open surgery. In face of these advantages, stent-graft performances are still clinically suboptimal. In particular, post-surgical complications derive from device migration as a consequence of the hemodynamic forces acting on the endograft. In this regard, while the importance of hemodynamic surface forces is well recognized, the role of the in-stent flow is still unclear. Here we hypothesize that in-stent helical blood flow patterns might influence the distribution of the displacement forces (DFs) acting on the stent-graft and, ultimately, the risk of stent migration. To test this hypothesis, the hemodynamics of 20 post-EVAR models of patients treated with two different commercial endografts was analyzed using computational hemodynamics. The main findings of the study indicate that: (1) helical flow intensity decreases the risk of endograft migration, as given by an inverse correlation between helicity intensity (h2) and time-averaged displacement forces (TADFs) (p < 0.05); (2) unbalanced counter-rotating helical structures in the legs of the device contribute, in particular along the systole, to significantly suppress TADFs (p < 0.01); (3) as expected, helical flow intensity is positively correlated with pressure drop and resistance to flow (p < 0.001). The findings of this study suggest that a design strategy promoting in-stent helical flow structures could contribute to minimize the risk of migration of implanted EVAR devices.