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Computational fluid dynamics (CFD) simulations can be leveraged to understand clinically relevant problems in cardiovascular flows. This dissertation explores two applications of CFD modeling to physiological flows: intracranial flow in the Circle of Willis (CoW) during vasospasm and intraventricular flow in the presence of a left ventricular assist device (LVAD).The CoW is a redundant network of blood vessels that perfuses the cerebral tissue. Flow in the collateral pathways that form this ring-like vascular structure can change in the presence of vessel constriction or occlusion. After a bleeding event in the subarachnoid space, vessels in the CoW sometimes involuntarily constrict, in a phenomenon known as vasospasm, which limits blood flow to the tissue, potentially causing infarct. The role of collateral pathways in the response to vasospasm is not well-understood. This dissertation investigates the relationship between changes in flow rate and direction in the collateral pathways, the anatomical variant of the CoW, and localization and severity of vasospasm across the network. Patient-specific CFD simulations were created in a cohort of 25 vasospasm patients, leveraging computed tomographic angiography (CTA) scans to generate models of the vasculature and transcranial Doppler ultrasound (TCD) measurements to apply boundary conditions. Bayesian analysis accounted for parameter uncertainty introduced by the medical data and was used to optimize the model parameters applied in the final simulation. Diameters, velocities, and flow rates were benchmarked against literature values, and virtual angiography performed by tracking a passive scalar, advected by the fluid velocity computed in the CFD simulations, was compared to clinical angiography, showing good agreement. Two metrics for vasospasm severity – percent changes in resistance and viscous dissipation – correlated closely with angiographic severity and helped identify regions of localization of vasospasm within the CoW and quantify overall severity.The second application of CFD in this thesis is on intraventricular flows. LVADs are centrifugal pumps implanted in the left ventricle (LV) of advanced heart failure patients. While pump designs have improved significantly over time, the risk of thromboembolic events remains high. Third generation pumps incorporate a pulsatility mode that modulates the rotational speed of the device impeller to promote in-pump washout. The role that this pulsatility mode plays in intraventricular washout is an active area of research. This dissertation studied how the temporal synchronization of the pulsatility mode with the native cardiac cycle affects the degree of intraventricular washout, which can have important implications for platelet activation and aggregation that subsequently can lead to thrombus formation. Lagrangian particle tracking was integrated into CFD simulations to model the hemodynamic environment experienced by platelets moving through the LV. Boundary conditions were defined using the time-varying flow rate from an equivalent particle image velocimetry (PIV) experiment. Regions of stasis were identified from examining velocity fields and calculating the stagnation index, which is an Eulerian quantification of stasis. Eulerian metrics from the CFD simulations agreed closely with PIV results. The optimal timing of the pulsatility mode with the cardiac cycle that maximizes intraventricular washout was identified.

Patients with advanced heart failure are implanted with a left ventricular assist device (LVAD) as a bridge-to-transplantation or destination therapy. Despite advances in pump design, the risk of stroke remains high. LVAD implantation significantly alters intraventricular hemodynamics, where regions of stagnation or elevated shear stresses promote thrombus formation. Third generation pumps incorporate a pulsatility mode that modulates rotational speed of the pump to enhance in-pump washout. We investigated how the timing of the pulsatility mode with the cardiac cycle affects intraventricular hemodynamic factors linked to thrombus formation. Computational fluid dynamics simulations with Lagrangian particle tracking to model platelet behavior in a patient-specific left ventricle captured altered intraventricular hemodynamics due to LVAD implantation. HeartMate 3 incorporates a pulsatility mode that modulates the speed of the pump every two seconds. Four different timings of this pulsatility mode with respect to the cardiac cycle were investigated. A strong jet formed between the mitral valve and inflow cannula. Blood stagnated in the left ventricular outflow tract beneath a closed aortic valve, in the near-wall regions off-axis of the jet, and in a large counterrotating vortex near the anterior wall. Computational results showed good agreement with particle image velocimetry results. Synchronization of the pulsatility mode with peak systole decreased stasis, reflected in the intraventricular washout of virtual contrast and Lagrangian particles over time. Temporal synchronization of HeartMate 3 pulsatility with the cardiac cycle reduces intraventricular stasis and could be beneficial for decreasing thrombogenicity.

Advances in left ventricular assist devices (LVADs) have improved hemocompatibility and durability, making this technology a viable lifesaving long-term treatment option for individuals with advanced heart failure (HF). Despite these improvements, the rate of stroke in LVAD patients remains high. The inflow cannula design impacts Left Ventricle (LV) hemodynamics, potentially creating thrombogenic flow patterns. This research aims to analyze the LV hemodynamic differences of two LVAD inflow cannula designs: one protruding 16 mm into the LV (HeartMate III, HM3) and the other flush with the myocardium (Evaheart 2, EVA2). Both inflow cannulae were virtually implanted into the apex of a 3D reconstructed LV from a HF patient. The aortic valve (AV) remained closed and a flow rate of 5 L/min was maintained using pulsatile waveforms adapted to each pumps’ characteristics. Computational fluid dynamic simulation analysis focuses on Eulerian and Lagrangian metrics to estimate LV washout and quantify blood stasis. The EVA2 high flow rate pulsatility, related to the inherently high dependency on preload designed into the pump performance, improves LV washout especially near the closed AV and the flush cannula prevents stasis at the apex. However, the evaluation of the effect of pump characteristics and cannula design separately demonstrated the dominant role of the pump characteristics (i.e. the H-Q curves) in reducing stasis.

The Circle of Willis (CoW) is a ring-like network of blood vessels that perfuses the brain. Flow in the collateral pathways that connect major arterial inputs in the CoW change dynamically in response to vessel narrowing or occlusion. Vasospasm is an involuntary constriction of blood vessels following subarachnoid hemorrhage (SAH), which can lead to stroke. This study investigated interactions between localization of vasospasm in the CoW, vasospasm severity, anatomical variations, and changes in collateral flow directions. Patient-specific computational fluid dynamics (CFD) simulations were created for 25 vasospasm patients. Computed tomographic angiography scans were segmented capturing the anatomical variation and stenosis due to vasospasm. Transcranial Doppler ultrasound measurements of velocity were used to define boundary conditions. Digital subtraction angiography was analyzed to determine the directions and magnitudes of collateral flows as well as vasospasm severity in each vessel. Percent changes in resistance and viscous dissipation were analyzed to quantify vasospasm severity and localization of vasospasm in a specific region of the CoW. Angiographic severity correlated well with percent changes in resistance and viscous dissipation across all cerebral vessels. Changes in flow direction were observed in collateral pathways of some patients with localized vasospasm, while no significant changes in flow direction were observed in others. CFD simulations can be leveraged to quantify the localization and severity of vasospasm in SAH patients. These factors as well as anatomical variation may lead to changes in collateral flow directions. Future work could relate localization and vasospasm severity to clinical outcomes like the development of infarct.

Blood velocities measured by Transcranial Doppler (TCD) are dependent on the angle between the incident ultrasound beam and the direction of blood flow (known as the Doppler angle). However, when TCD examinations are performed without imaging the Doppler angle for each vessel segment is not known. We have measured Doppler angles in the basal cerebral arteries examined with TCD using three-dimensional (3D) vessel models generated from computed tomography angiography (CTA) scans. This approach produces angle statistics that are not accessible during non-imaging TCD studies. We created 3D models of the basal cerebral arteries for 24 vasospasm patients. Standard acoustic windows were mapped to the specific anatomy of each patient. Virtual ultrasound transmit beams were generated that originated from the acoustic window and intersected the centerline of each arterial segment. Doppler angle measurements were calculated and compiled for each vessel segment. Doppler angles were smallest for the middle cerebral artery M1 segment (median 24.6°) and ophthalmic artery (median 25.0°), and largest for the anterior cerebral artery A2 segment (median 76.4°) and posterior cerebral artery P2 segment (median 75.8°). The ophthalmic artery had the highest proportion of Doppler angles that were less than 60° (99%) while the anterior cerebral artery A2 segment had the lowest proportion of Doppler angles that were less than 60° (10%). These angle measurements indicate the expected deviation between measured and true velocities in the cerebral arteries, highlighting specific segments that may be prone to underestimation of velocity.

BackgroundOvarian adult granulosa cell tumours are low-grade malignant sex cord–stromal neoplasm with a low recurrence rate. Prognostic factors for recurrence include tumor stage, tumor rupture in Stage I neoplasms and the presence of residual tumors after surgery. However, in recurrent tumors, prognostic factors for overall survival (OS) are lacking. In the present paper, we conducted a systematic meta-analysis with the aim to assess prognostic factors for OS in patients with recurrent GCT.MethodsElectronic databases were searched for all studies assessing prognostic factors in recurrent adult granulosa cell tumor of the ovary. Student T test, Fisher’s exact test and Kaplan–Meier survival analysis with long-rank test were used to assess differences among groups; a p value < 0.05 was considered significant.ResultsEleven studies analyzing 102 recurrent tumors were included in the systematic review. Tumor stage and localization of recurrent tumors were significantly associated with OS on Kaplan–Meier analysis; Cox regression analysis showed a HR of 0.879 for the stage II, of 3.052 for the stage III, and of 2.734 for stage IV tumor was significantly associated with OS (p = 0.037); observed HRs for abdominal and thoracic locations were of 2.405 and of 4.024, respectively.ConclusionsIn conclusion, the present article emphasizes the prognostic significance of tumor stage > II and extrapelvic anatomic sites of recurrences in patients with recurrent granuolase cell tumors of the ovary.

Chronic endometritis (CE) is the persistent inflammation of the endometrial lining associated with infertility and various forms of reproductive failures. The diagnosis of CE is based on the histological evidence of stromal plasma cells; however, standardized methods to assess plasma cells are still lacking. In the present paper, we aimed to determine the most appropriate plasma cell threshold to diagnose CE based on pregnancy outcomes. Three electronic databases were searched from their inception to February 2022 for all studies comparing pregnancy outcomes between patients with CE and patients without CE. The relative risk (RR) of pregnancy, miscarriage, and/or live birth rates were calculated and pooled based on the plasma cell threshold adopted. A p-value < 0.05 was considered significant. Nine studies adopting different thresholds (1 to 50 plasma cells/10 HPF) were included. In the meta-analysis, we only found a significant association between miscarriage rate and a plasma cell count ≥ 5/10 HPF (RR = 2.4; p = 0.007). Among studies not suitable for meta-analysis, CE showed an association with worsened pregnancy only when high thresholds (10 and 50/10 HPF) were adopted. In conclusion, our study suggests that the presence of plasma cells at low levels (<5/10 HPF) may not predict worsened pregnancy outcomes. Based on these findings, a threshold of ≥5 plasma cells/10 HPF may be more appropriate to diagnose CE.

Background: chemotherapy response score (CRS) is widely used to assess the response of ovarian high-grade serous carcinoma (HGSC) to chemotherapy and is based on pathological examination of omental specimens. We aimed to assess the prognostic value of CRS assessed on the uterine adnexa. Methods: a systematic review and meta-analysis were performed by searching three electronic databases from 2015 inception to September 2021. We included all studies reporting either hazard ratio (HR) with 95% confidence interval (CI) for progression-free survival (PFS) or primary PFS data, for both adnexal and omental CRS in HGSC. HRs with 95% CI were extracted and pooled by using a significant p-value < 0.05. Statistical heterogeneity was assessed by using Higgins’ I2. Results: six studies with 691 HGSC patients were included. Adnexal CRS3 vs. CRS1-2 significantly stratified PFS, with a HR of 0.572 (0.447–0.733; p < 0.001). Omental CRS3 vs. CRS1-2 significantly stratified PFS with a similar HR (HR = 0.542; 95% CI 0.444–0.662; p < 0.001). Statistical heterogeneity was 0% in both analyses. Conclusions: adnexal CRS significantly stratifies PFS in HGSC and might be used when omental CRS is not assessable.

Background: The diagnostic role of Wilms’ tumor 1 (WT1) is well known in gynaeco-pathological setting, since it is considered a specific marker of serous histotype and adnexal origin. Moreover, its oncogenic role has been recently highlighted in many cancers and it has also been regarded as a promising target antigen for cancer immunotherapy. However, the relationship between its expression and prognostic role in uterine cancer remains unclear. We analyzed the diagnostic and prognostic role of WT1 expression in patients with uterine carcinoma by completing a search using PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines and the PICOS (Participants, Intervention, Comparison, Outcomes, Study Design) model through PubMed, Scopus and Web of Science databases to identify studies that fit our search criteria. The objective of the current meta-analysis was to investigate the diagnostic and prognostic role of WT1 expression in patients with uterine carcinoma. Materials and Methods: A literature search was performed of the PubMed, Scopus, and Web of Science databases for English-language studies published from January 2000 to April 2020. Studies were considered eligible if they evaluated the WT1 expression in uterine carcinoma. Results: In total, 35 articles were identified that used uterine carcinoma criteria and provided data for 1616 patients. The overall rate of WT1 expression in uterine carcinoma was 25%. The subgroup analysis of uterine cancer types revealed that WT1 was expressed differently among different histotypes (endometrioid, clear cell, serous carcinoma and carcinosarcoma). Discussion and Conclusions: The WT1 immunohistochemical expression is not limited to serous histotype and/or ovarian origin. In fact, a significant proportion of endometrial adenocarcinomas can also show WT1 immunoreactivity. Moreover, our study suggests that WT1 may be a potential marker to predict the prognosis of patients with uterine cancer, but more studies are needed to confirm its role in clinical practice.

Background. Extra-mammary Paget’s disease (EMPD) is a rare neoplasm of epithelial origin, whose precise incidence is not clear. Starting from what is already known, we performed a systematic review and meta-analysis to investigate in male and female patients the immunohistochemical expression of biological markers that could serve as potential prognostic/therapeutic factors, including only human epidermal growth factor receptor 2 (HER2/neu), Estrogen Receptor (ER), Progesterone Receptor (PR), and Androgen Receptor (AR). Methods. A literature search was performed of the PubMed, Scopus, and Web of Science databases for English-language studies published from January 2000 to June 2020. Results. A total of 27 studies with 713 patients assessed the role of HER2/neu, AR, ER, and PR expression in male and female with EMPD. The overall rate of HER2/neu expression was 30%, the expression’s rate for ER and AR was 13% and 40%, respectively, and the overall rate for PR was 8%. The subgroup analysis revealed that there is a different expression of molecular markers between male and female patients. Conclusions. This study revealed that AR status and HER2/neu overexpression/amplification have been shown as two fundamental pathogenetic pathways in both female and male patients affected by EMPD.