Volume Regression Research Articles

Contribution of neoadjuvant chemotherapy and radiation therapy (intensity-modulated radiation therapy with concurrent chemotherapy versus stereotactic body radiation therapy alone) on tumor volume regression in patients with borderline resectable or locally advanced pancreatic ductal adenocarcinoma: A single institution experience.

707 Background: Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis with a minority of patients (pts) eligible for curative resection. Pts with borderline resectable or locally advanced (BR/LA) PDAC frequently receive neoadjuvant chemotherapy (NAC) +/- radiation therapy (RT) to improve resectability. Here, we report the individual contribution of NAC and RT (either intensity modulated RT + concurrent chemotherapy (IMRT+CC) or stereotactic body RT (SBRT) alone) on tumor regression by measuring tumor volumes. Methods: We performed a single institution retrospective review of PDAC pts who underwent resection between 2011-2021 and were part of a tumor biobank registry. Tumor measurements were performed at baseline, post-NAC, and post-RT by five independent, blinded abdominal radiologists. Analyses were performed using paired t-tests, two-proportion z-tests, log-rank tests, and Mann-Whitney U test. Results: We identified 49 BR/LA pts who received NAC followed by RT who had complete pre- and post-treatment imaging. Fifteen pts received IMRT+CC and 28 received SBRT. The effect of NAC on tumor volumes (-29.2% vs -26.3%, p=0.66; mean percent change) and maximum diameter (-9.2% vs -12.0%, p=0.58) was similar within the IMRT+CC and SBRT groups. Both IMRT+CC (-7.12 cm3, p=0.003) and SBRT (-2.70 cm3, p=0.001) resulted in significant tumor regressions. IMRT+CC achieved a significantly greater overall mean percent change in tumor volume (-53.4% vs -28.8%, p=0.024) and maximum diameter (-30.4% vs -16.2%, p=0.020) compared to SBRT. Pts receiving IMRT+CC or SBRT had similar tumor volumes (10.88 vs 11.74 cm3, p=0.87, respectively) and maximum diameter (3.45 vs 3.17 cm, p=0.48) prior to RT. IMRT+CC resulted in improved tumor volume response (>30% regression; 80.0% vs 46.4%; p=0.033) but not an improved response rate by RECIST criteria (46.7% vs 21.4%; p=0.085). Mean resected tumor volumes (by pathological review) for those receiving IMRT+CC (n=9) and SBRT (n=23) were 4.34 vs 13.1 cm3 (p=0.049). The R0 (86.7% vs 85.7%, p=0.93) and N0 (73.3% vs 53.6%, p=0.21) resection rates between the two groups were similar. Compared to SBRT, IMRT+CC resulted in an improved recurrence free survival (RFS; 2.36 vs 1.31 years; p=0.026), but did not meet statistical significance for an overall survival benefit (mOS; 2.85 vs 2.03 years, p=0.19). Conclusions: We found that IMRT+CC yielded superior radiographic volumetric regression and improved RFS but did not significantly impact mOS. Correspondingly, resected tumors from patients treated with IMRT+CC were smaller than those obtained from patients treated with SBRT. The role of IMRT+CC and SBRT in PDAC remains to be clearly defined.

Cerebral venous sinus thrombosis manifesting as chronic spontaneous subdural hematoma: case report and review of the literature

BackgroundCerebral venous sinus thrombosis (CVST) is a rare form of stroke that is mainly seen in young women. It is frequently associated with hemorrhagic venous infarction and subarachnoid hemorrhage. There are few reports of CVST associated with chronic non-traumatic subdural hematoma (SDH). The diagnosis of CVST with spontaneous SDH is difficult because of the variability of its clinical features. The management of SDH associated with CVST is controversial and not well-established.Case presentationWe report a 26-year-old woman with positive COVID-19 serology who presented with superior longitudinal sinus thrombosis associated with chronic spontaneous SDH. She was managed conservatively and treated with anticoagulation and corticosteroids. A follow-up angioscan 1 month after treatment showed regression of the SDH volume with partial repermeabilisation of the thrombosed sinus. Three months later, the follow-up angioscan showed complete resolution of the chronic SDH and superior longitudinal sinus thrombosis with restoration of venous flow.ConclusionsCVST can also present with spontaneous chronic SDH. The management of SDH concomitant with CVST remains controversial due to the rarity of its presentation and the risks associated with the use of anticoagulation.

One-year follow-up after active aortic aneurysm sac treatment with shape memory polymer devices during endovascular aneurysm repair

ObjectiveTo determine the safety and efficacy of treating abdominal aortic aneurysm (AAA) sacs with polyurethane shape memory polymer (SMP) devices during endovascular aneurysm repair (EVAR), using a technique to fully treat the target lumen after endograft placement (aortic flow volume minus the endograft volume). SMP devices self-expand in the sac to form a porous scaffold that supports thrombosis throughout its structure. MethodsTwo identical prospective, multicenter, single-arm studies were conducted in New Zealand and the Netherlands. The study population was adult candidates for elective EVAR of an infrarenal AAA (diameter of ≥55 mm in men and ≥50 mm in women). Key exclusion criteria were an inability to adequately seal a common iliac artery aneurysm, patent sac feeding vessels of >4 mm, and a target lumen volume of <20 mL or >135 mL. Target lumen volumes were estimated by subtracting endograft volumes from preprocedural imaging-based flow lumen volumes. SMP devices were delivered immediately after endograft deployment via a 6F sheath jailed in a bowed position in the sac. The primary efficacy end point was technical success, defined as filling the actual target lumen volume with fully expanded SMP at the completion of the procedure. Secondary efficacy outcome measures during follow-up were the change in sac volume and diameter, rate of type II endoleak and type I or III endoleaks, and the rate of open repair and related reinterventions, with data collection at 30 days, 6 months, and 1 year (to date). Baseline sac volumes and diameters for change in sac size analyses were determined from 30-day imaging studies. Baseline and follow-up volumes were normalized by subtraction of the endograft volume. ResultsOf 34 patients treated with SMP devices and followed per protocol, 33 patients were evaluable at 1 year. Preprocedural aneurysm volume was 181.4 mL (95% confidence interval [CI], 150.7-212.1 mL) and preprocedural aneurysm diameter was 60.8 mm (95% CI, 57.8-63.9 mm). The target lumen volume was 56.3 mL (95% CI, 46.9-65.8 mL). Technical success was 100% and the ratio of SMP fully expanded volume to estimated target lumen volume was 1.4 ± 0.3. Baseline normalized sac volume and diameter were 140.7 mL (95% CI, 126.6-154.9 mL) and 61.0 mm (95% CI, 59.7-62.3 mm). The adjusted mean percentage change in normalized volume at 1 year was −28.8% (95% CI, −35.3 to −22.3%; P < .001). The adjusted mean change in sac diameter at 1 year was −5.9 mm (95% CI, −7.5 to −4.4 mm; P < .001). At 1 year, 81.8% of patients (95% CI, 64.5%-93.0%) achieved a ≥10% decrease in normalized volume and 57.6% of patients (95% CI, 39.2%-74.5%) achieved a ≥5 mm decrease in diameter. No device- or study procedure-related major adverse events occurred through 1 year after the procedure. ConclusionsTreatment of AAA sacs with SMP devices during EVAR resulted in significant sac volume and diameter regression at 1 year with an acceptable safety profile in this prospective study.

Efficacy of intensive therapy for massive intraoperative blood loss in children: experience of the Morozov Hospital

To evaluate the effectiveness of intensive therapy for massive intraoperative blood loss in children. A retrospective analysis of primary medical records of 39 children with massive intraoperative blood loss was performed. Patients were divided into two groups (younger 1 year (n=18) and older 1 year (n=21)). Each group was divided into two subgroups (blood loss <10% and >100% of total blood volume). We analyzed total intraoperative infusion, qualitative composition of transfusions, reinfusion of washed autologous erythrocytes and vasopressor support. In postoperative period, we assessed hemoglobin, platelets, albumin, fibrinogen, lactate, prothrombin index, duration of mechanical ventilation, severity of organ dysfunction (pSOFA score) after 1 and 3 days, ICU stay and incidence of repeated blood transfusions. With regard to transfusion volume, we found a general pattern (3 parts of crystalloids, 2 parts of erythrocyte-containing components and 1 part of fresh frozen plasma in all groups with the exception of children older 1 year with blood loss >100% of total blood volume. The last ones had ratio 3:5:1 due to large volume of reinfusion of washed autologous erythrocytes. In all groups, target levels of hemoglobin, platelets, albumin and prothrombin index were achieved. Serum fibrinogen was slightly lower in the group with blood loss >100% of total blood volume. There was a direct relationship between blood loss and ICU stay (Spearman's test rs=0.421, p<0.05), as well as duration of mechanical ventilation (Spearman's test rs=0.509, p<0.05). Mean pSOFA score upon admission to intensive care unit was 3-4 points in both groups with blood loss <100% of total blood volume. In patients with blood loss >100% of total blood volume, this indicator averaged 9 points and regressed to 3-4 points over the next 72 hours. Intraoperative intensive therapy contribute to minimal severity of postoperative organ dysfunction in children with blood loss < 100% of total blood volume and rapid regression of multiple organ failure in patients with blood loss exceeding this indicator.

Impact of Recurrent Mitral Regurgitation on Left Ventricular Mass Regression and Cardiac Events following Mitral Valve Repair.

Mitral valve regurgitation results in volume overload, followed by left ventricular remodeling. Variation of reverse remodeling following mitral repair influences the clinical outcomes. We aimed to evaluate the association between recurrent mitral regurgitation and mass regression following mitral valve repair and the impact on major adverse cardiovascular events. A retrospective cohort study was conducted on 164 consecutive patients with severe mitral regurgitation who underwent elective mitral valve repair. Subgroups were classified based on the presence of recurrent mitral regurgitation exceeding moderate severity. The hemodynamic parameters were evaluated according to geometry, mass, and function with Doppler echocardiography before and after surgery. Cox regression analysis was performed to evaluate the association between hemodynamics and mass regression and clinical outcomes. The results for MR indicated 110 cases with non-recurrent MR and 54 with recurrent MR, along with 31 major adverse cardiovascular events. The tracked echocardiographic results revealed less reduction in dimension and volume, along with less mass regression in the recurrent MR subgroup. Significant differences were revealed in the relative change of the LV end-diastolic volume index and relative mass regression between subgroups. The relative change in the LVEDVI was proportionally correlated with relative mass regression. Cox regression analysis identified correlations with major adverse cardiovascular events, including suture annuloplasty, recurrent mitral regurgitation, tracked LV mass, relative LV mass regression, and systolic dysfunction. LV mass regression and relative change of the LV end-diastolic volume could be risk predictors of recurrent mitral regurgitation. The extent of LV mass regression is correlated with adverse cardiac events.

Modeling of permeability impairment dynamics in porous media: A machine learning approach

The prediction of clogging and permeability impairment dynamics in porous media is crucial for the optimization of various industrial and natural processes. This paper presents a novel machine learning-based approach for predicting the dynamics of throat clogging and permeability impairment due to fine migration within realistic porous media under varying hydro-physical conditions. A Computational Fluid Dynamics-Discrete Element Method (CFD-DEM) numerical framework, employing a four-way coupling scheme, was used to generate the data for training and validation of the Machine Learning Model (MLM). One hundred and twenty distinct CFD-DEM simulations were performed to generate over 190,000 data points, at throat level, for the training of the MLM. Simulation cases encompassing ranges of porous media geometry, fine particle size, flow velocity, fine particle concentration, grains surface roughness, and fines and grains zeta potential. Geometries of porous media were extracted from high-resolution 3D images of natural sand obtained using micro-computed tomography imaging. The developed MLM predicts the temporal evolution of clogged throats and permeability impairment. The MLM was established by connecting three Machine Learning Sub-Models (MLSMs). The first is a throat-classification MLSM; which classifies the throats based on their location and size to identify clogged throats. Subsequently, a pore volume regression MLSM is implemented to identify the pore volume at which each clogged throat becomes clogged. Finally, the permeability impairment regression MLSM predicts the permeability reduction based on the clogged throat's information and pore volumes associated with clogging. The throats classification in the final MLM showed an accuracy of 95% in predicting clogged throats when compared to direct CFD-DEM simulations whereas the prediction of the permeability impairment had an R-squared value of 0.99. The MLM developed in this study stands as a robust framework for precisely quantifying key microscale parameters; where its predictions were used to quantify the significance of altering the hydro-physical parameters on the microscale parameters of the clogging dynamics. The proposed MLM provides an accurate and fast prediction of porous media clogging and permeability impairment dynamics, with potential applications in various industries, including oil and gas, environmental engineering, and material science.

Treatment with sacubitril/valsartan and improvement of ventricular-arterial coupling in heart failure with reduced ejection fraction

Abstract Background Treatment with the angiotensin receptor-neprilysin inhibitor sacubitril/valsartan (S/V) in patients with heart failure and reduced ejection fraction (HFrEF) reduces mortality and heart failure (HF) hospitalizations. The specific hemodynamic mechanisms underlying these beneficial effects are currently unclear. Purpose This study aimed to assess the effects of S/V treatment on left ventricular (LV) end-systolic elastance (Ees), effective arterial elastance (Ea), and the ventricular-arterial coupling ratio (Ea/Ees) in patients with HFrEF using non-invasive pressure-volume analysis. Methods 117 patients with symptomatic HF and LVEF &amp;lt;40% in whom treatment with S/V was initiated were enrolled in this multicenter German prospective study. We used transthoracic echocardiography with simultaneous arm-cuff blood pressure measurements for non-invasive pressure-volume loop analyses. Primary endpoints were changes in Ees, Ea, and Ea/Ees ratio after six months of S/V treatment. Results The mean age was 65 (±13) years and 30% were female. In 54.7% of the patients, the etiology of HF was ischemic, and 45.3% was non-ischemic. 58.4% had first HF diagnosis at baseline. 102 patients with complete clinical and echocardiographic data at baseline and after six months of follow-up were analyzed. Among those, 62% were on target dose of S/V. Six months of S/V treatment resulted in a significant increase of Ees (0.66 mmHg/ml, IQR [0.45;0.94] vs. 0.78 mmHg/ml [0.57;1.10], p=0.001) and decrease of Ea (1.76 mmHg/ml [1.48;2.13] vs. 1.62 mmHg/ml [1.36;1.96], p=0.014). Hence, the Ea/Ees ratio significantly improved (2.52 [1.88;4.05] vs. 1.93 [1.50;2.63], p&amp;lt;0.001). In addition, LV volumes and pressure improved significantly with a regression of the LV end-systolic volume (LVESV: 142 ml [115;180] vs. 96 ml [65;124]), end-diastolic volume (LVEDV: 216 ml [179;247] vs. 165 ml [132;200]) and LV end-diastolic pressure (LVEDP: 19.6 mmHg [18.2;22.4] vs. 17.8 mmHg [16.6;19.9]), p&amp;lt;0.001 respectively. The LVEF increased from a median of 33% (27;37) to 43% (36;49), p&amp;lt;0.001. NT-proBNP level decreased from (median) 1771 pg/ml [838;5211] to 724 pg/ml [300;1575] and mean 6-minute walking distance increased from 371m (±125) to 423 m (±122), p&amp;lt;0.001 respectively. The percentage of patients with NYHA class III changed from 25.6% to 5.9%. Conclusion In a 6-months treatment period, initiation of sacubitril/valsartan in patients with heart failure and reduced ejection fraction was associated with reduction of LV volumes, improved LV function, reduction in afterload and fewer heart failure symptoms. These new data indicate that beyond reverse LV remodeling, improvement of LV contractility and ventricular-arterial coupling may contribute to the favorable clinical outcomes on treatment with sacubitril/valsartan in chronic heart failure.

Influence of moderate prosthesis–patient mismatch on long-term outcomes in patients with severe aortic stenosis with paradoxically reduced gradients against the background of reduced stroke volume after aortic valve replacement with a biological prosthesis: retrospective comparative study

OBJECTIVE: Our aim was to evaluate the impact of moderate prosthesispatient mismatch on long-term results after aortic valve replacement in patients with severe aortic stenosis with paradoxically reduced gradients against the background of a reduced stroke volume of the left ventricle.&#x0D; MATERIALS AND METHODS: We analyzed data from 88 patients with symptomatic severe aortic stenosis meeting the criteria: paradoxically reduced gradients against the background of a reduced stroke volume of the left ventricle. Patients were divided into 2 groups: Group 1 (n=42, mean age 674 years) with paradoxically reduced gradients against the background of reduced stroke volume of the left ventricle, with a moderate patientprosthesis mismatch; Group 2 (n=46, mean age 686 years) with paradoxically reduced gradients against the background of reduced stroke volume of the left ventricle, without patientprosthesis discrepancy. All patients underwent transthoracic echocardiographic evaluation.&#x0D; RESULTS: The average follow-up period was 84 (quarterly interval 7598) months, during the follow-up period 35 (40%) deaths were registered. There were no significant differences in in-hospital mortality: 2 (4.7%) and 2 (4.3%), respectively (p=0.2). In the long-term follow-up period, there was a significant difference in survival and hospitalization rates for exacerbation of heart failure between patients with and without patientprosthesis mismatch: 46 and 71%, 37 and 72%, respectively (p0.001). In the long-term follow-up period, patients with patientprosthesis mismatch showed a trend towards slower regression of left ventricle mass and left atrial volume, as well as a slower recovery of global longitudinal deformation of the left ventricle and exercise tolerance compared with patients without patientprosthesis mismatch. There were no significant differences in the incidence of stroke (90% and 91%; p=0.7). According to the results of Cox regression, the left ventricular stroke volume index and the aortic valve effective orifice area index were independent predictors of lethal events and the risk of hospitalization for exacerbation of heart failure.&#x0D; CONCLUSION: Moderate patientprosthesis mismatch in patients with paradoxically reduced gradients associated with reduced left ventricular stroke volume is independently associated with increased mortality and increased hospitalization for exacerbations of heart failure.

Clinical evaluation of intralesional umbilical cord-derived mesenchymal stem cells, conditioned medium and triamcinolone acetonide injection for keloid treatment: A pilot study.

Topical keloid therapy is performed with triamcinolone acetonide (TA) intralesional injection. However, the recurrence rate is high with various side effects. Mesenchymal stem cells (MSCs) have high proliferative abilities and reduce the activity and proliferation of fibroblast cells in keloids. To overcome the costs and limitations, conditioned medium (CM) is used. This study aims to evaluate feasibility of intralesional injection of umbilical cord MSC (UC-MSC) and conditioned medium (UC-CM) compared to TA for keloid therapy. Twenty-four patients with keloids who met the inclusion criteria were included, randomized into three treatment groups and then got assessed for the sociodemographic data, keloid volume, histopathology (type 1:3 collagen ratio), interleukin-10 (IL-10) levels and Patient and Observer Scar Assessment Scale (POSAS) score during visits. Largest volume regression occurred in the UC-MSC group, followed by UC-CM and then the TA group (UC-MSC: 45.32% ± 2.61%; UC-CM: 43.61% ± 3.67%; TA: 28.34% ± 3.81%; p = 0.003). Similar pattern was also observed in increase in IL-10 levels, the decrease in POSAS scores and the reduction of type 1:3 collagen ratio. Hence, UC-MSC and UC-CM are promisingly more effective than TA for keloid therapy, showcasing their superiority in reducing keloid volume, symptoms and type 1:3 collagen ratio, as well as increasing the levels of IL-10.

Prognostic Value of Tumor Volume Reduction during Radiotherapy in Patients with Locally Advanced Cervical Cancer in Different Risk Groups

To evaluate the risk factors of patients with locally advanced cervical cancer (LACC) undergoing radical radiotherapy (with or without concurrent chemotherapy) and to assess the prognostic value of tumor volume regression (TVR) based on magnetic resonance imaging (MRI) in different risk groups. A retrospective analysis was performed on 176 individuals diagnosed with stage IIA-IVA cervical cancer (CC) who underwent radical intensity-modulated radiotherapy in our center between January 2012 and December 2020. The tumor volume before radiotherapy (TVp) and before brachytherapy (TVmid) were evaluated based on three-dimensional MRI images, TVR = (TVp -TVmid)/TVp × 100%. Kaplan-Meier curves were used to assess patient's overall survival (OS) and progression-free survival (PFS). Prognostic factors were identified using Cox proportional hazards models. For the entire cohort, patients with TVR ≥ 94% had better 5-year OS (82.7% vs 49.8%, p<0.001) and 5-year PFS (82.5% vs 51.1%, p<0.001) compared to TVR < 94%. Patients with TVR ≥ 94% were more likely to receive concurrent chemoradiotherapy (CCRT) than those with TVR < 94% (70.1% vs 40.5%, p<0.05). Among patients undergoing CCRT, those with a TVR ≥ 94% had a better prognosis than those with a TVR < 94%. However, among patients who received RT alone, those with TVR ≥ 94% had better PFS but no statistically significant difference in OS. Likewise, among patients with CYFRA21-1 < 7.7 ng/ml, patients with TVR ≥ 94% had a better prognosis. However, TVR was not a prognostic factor in patients with CYFRA21-1 ≥ 7.7 ng/ml. Both CYFRA21-1 (OS, PFS interaction, p<0.001) and FIGO stage (PFS interaction, p = 0.035) were found to significantly impact predictive effects of TVR. In LACC patients with CRYFA21-1 < 7.7 ng/ml who received CCRT, TVR was an important prognostic factor. However, in patients with CRYFA21-1 ≥ 7.7 ng/ml who received RT alone, the prognostic value of TVR needs to be further explored.

Evaluation of Changes in Circulating Cell-Free DNA as an Early Predictor of Response to Chemoradiation in Rectal Cancer-A Pilot Study.

Background and Objectives: The objective of this study was to investigate quantitative changes in cell-free DNA (cfDNA) found in the bloodstream of patients with locally advanced rectal cancer who received neoadjuvant long-course chemoradiation, assuming a change in DNA fragments release during therapeutic stress. Materials and Methods: This was a prospective observational study that involved 49 patients who had three distinct pathologies requiring neoadjuvant chemoradiation: 18 patients with breast cancer, 18 patients with cervical cancer, and 13 patients with rectal cancer. Both breast cancer and cervical cancer patients were used as a control groups. Breast cancer patients were used as a control group as irradiation targeted healthy tissue after the tumor resection (R0), while cervical cancer patients were used as a control group to evaluate the effect of chemoradiation regarding cfDNA in a different setting (squamous cell carcinomas) and a different tumor burden. Rectal cancer patients were the study group, and were prospectively evaluated for a correlation between fragmentation of cfDNA and late response to chemoradiation. Blood samples were collected before the initiation of treatment and after the fifth radiation dose delivery. cfDNA was quantified in peripheral blood and compared with the patients' clinicopathological characteristics and tumor volume. Conclusion: Thirteen patients with locally advanced rectal cancer (T3/T4/N+/M0) were included in the study, and all of them had their samples analyzed. Eight were male (61.54%) and five were female (38.46%), with an average age of 70.85 years. Most of the patients had cT3 (53.85%) or cT4 (46.15%) tumors, and 92.31% had positive lymph nodes (N2-3). Of the thirteen patients, only six underwent surgery, and one of them achieved a pathological complete response (pCR). The mean size of the tumor was 122.60 mm3 [35.33-662.60 mm3]. No significant correlation was found between cfDNA, tumor volume, and tumor regression grade. cfDNA does not seem to predict response to neoadjuvant chemoradiotherapy and it is not correlated to tumor volume or tumor regression grade.

Impact of Intensive Low-Density Lipoprotein Cholesterol-Lowering Therapy on Coronary Artery Plaques in Acute Coronary Syndrome

Acute coronary syndrome (ACS) is associated with a high incidence of unstable plaques beyond the culprit lesion, leading to early recurrence of cardiovascular events. Coronary computed tomography angiography (CCTA) can be used to noninvasively observe plaques throughout the coronary arteries. To evaluate the impact of intensive low-density lipoprotein cholesterol (LDL-C)-lowering therapy on quantitative changes in coronary plaque, assessed using CCTA in a study population with ACS. In total, 81 consecutive patients with ACS who underwent CCTA at discharge and at 1-year follow-up from April 2018 to March 2020 were analyzed. The patients were divided into 2 groups: those who achieved LDL-C <70 mg/100 ml and those who did not. Changes in plaque morphology within and between the 2 groups were compared using CCTA. A total of 198 vessels were analyzed. The calcified plaque volume was significantly increased in the LDL-C <70 group (65.8 ± 80.1 mm3 to 73.6 ± 83.7 mm3, p=0.007), whereas no significant change was observed in the LDL-C ≥70 group (106.9 ± 161.7 mm3 to 105.7 ± 137.5 mm3, p=0.552). Percent change in low-attenuation plaque volume in the LDL <70 group was significantly lower than in the LDL-C ≥70 group (17.2 ± 90.9% vs 84.4 ± 162.6%, p=0.020). Receiver operating characteristic curve analysis demonstrated that the target LDL-C level for low-attenuation plaque volume regression was 64 mg/100 ml. In conclusion, noninvasive CCTA demonstrated that intensive LDL-C lowering in high-risk patients with ACS could potentially lead to plaque stabilization.

Association between Serum Oxysterols and Coronary Plaque Regression during Lipid-Lowering Therapy with Statin and Ezetimibe: Insights from the CuVIC Trial.

Several clinical trials using intravascular ultrasound (IVUS) evaluation have demonstrated that intensive lipid-lowering therapy by statin or a combination therapy with statin and ezetimibe results in significant regression of coronary plaque volume. However, it remains unclear whether adding ezetimibe to statin therapy affects coronary plaque composition and the molecular mechanisms of plaque regression. We conducted this prospective IVUS analysis in a subgroup from the CuVIC trial. The CuVIC trial was a prospective randomized, open, blinded-endpoint trial conducted among 11 cardiovascular centers, where 260 patients with coronary artery disease who received coronary stenting were randomly allocated into either the statin group (S) or the combined statin and ezetimibe group (S＋E). We enrolled 79 patients (S group, 39 patients; S＋E group, 40 patients) in this substudy, for whom serial IVUS images of nonculprit lesion were available at both baseline and after 6-8 months of follow-up. After the treatment period, the S＋E group had significantly lower level of low-density lipoprotein cholesterol (LDL-C; 80.9±3.7 vs. 67.7±3.8 mg/dL, p=0.0143). Campesterol, a marker of cholesterol absorption, and oxysterols (β-epoxycholesterol, 4β-hydroxycholesterol, and 27-hydroxycholesterol) were also lower in the S ＋E group. IVUS analyses revealed greater plaque regression in the S＋E group than in the S group (-6.14% vs. -1.18% for each group, p=0.042). It was noteworthy that the lowering of campesterol and 27-hydroxycholesterol, but not LDL-C, had a significant positive correlation with plaque regression. Compared with statin monotherapy, ezetimibe in combination with statin achieved significantly lower LDL-C, campesterol, and 27-hydroxycholesterol, which resulted in greater coronary plaque regression.

Portal Dynamics After Living Donor Liver Transplant in Pediatric Recipients: A 10-Year Follow-Up Retrospective Study

It may be difficult for pediatric patients to evaluate the impact of liver transplantation (LT) on splenomegaly due to the natural growth course. The long-term dynamics of portal vein (PV) size and PV flow after LT in pediatric patients are unclear. We aimed to evaluate the long-term transition of the splenic size, PV size, and PV flow velocity in pediatric patients who underwent successful living donor liver transplantation (LDLT) and survived >10 years. From October 2004 to December 2010, 39 pediatric patients (25 boys; 14 girls) underwent LDLT, received pre-LDLT and post-LDLT computed tomography scans and long-term ultrasound sonography follow-up, and survived >10 years without additional intervention at our institution. We analyzed the short- to mid-term and long-term impact of LDLT on splenic size, PV size, and PV flow velocity over time. The PV diameter increased throughout the 10-year follow-up (P < .001). The PV flow velocity increased 1 day after LDLT (P< .001); proceeded to decrease 3 days after LDLT, reaching a low point 6 to 9 months after LDLT; and remained stable throughout the 10-year follow-up. Regression of the splenic volume at 6 to 9 months after LDLT (P < .001) was noted. However, the splenic size steadily increased on long-term follow-up. Although LDLT has a significant short-term reduction effect on splenomegaly, the long-term transitional trend of the splenic size and PV diameter may increase along with children's growth. The PV flow reached a stable status 6 to 9 months after LDLT and remained so until 10 years after LDLT.

Mesiotemporal Volumetry, Cortical Thickness, and Neuropsychological Deficits in the Long-term Course of Limbic Encephalitis.

Limbic encephalitis (LE) is an autoimmune disease often associated with temporal lobe epilepsy and subacute memory deficits. It is categorized into serologic subgroups, which differ in clinical progress, therapy response, and prognosis. Using longitudinal MRI analysis, we hypothesized that mesiotemporal and cortical atrophy rates would reveal serotype-specific patterns and reflect disease severity. In this longitudinal case-control study, all individuals with antibody-positive (glutamic acid decarboxylase 65 [GAD], leucine-rich glioma-inactivated protein 1 [LGI1], contactin-associated protein 2 [CASPR2], and N-methyl-d-aspartate receptor [NMDAR]) nonparaneoplastic LE according to Graus' diagnostic criteria treated between 2005 and 2019 at the University Hospital Bonn were enrolled. A longitudinal healthy cohort was included as the control group. Subcortical segmentation and cortical reconstruction of T1-weighted MRI were performed using the longitudinal framework in FreeSurfer. We applied linear mixed models to examine mesiotemporal volumes and cortical thickness longitudinally. Two hundred fifty-seven MRI scans from 59 individuals with LE (34 female, age at disease onset [mean ± SD] 42.5 ± 20.4 years; GAD: n = 30, 135 scans; LGI1: n = 15, 55 scans; CASPR2: n = 9, 37 scans; and NMDAR: n = 5, 30 scans) were included. The healthy control group consisted of 128 scans from 41 individuals (22 female, age at first scan [mean ± SD] 37.7 ± 14.6 years). The amygdalar volume at disease onset was significantly higher in individuals with LE (p ≤ 0.048 for all antibody subgroups) compared with that in healthy controls and decreased over time in all antibody subgroups, except in the GAD subgroup. We observed a significantly higher hippocampal atrophy rate in all antibody subgroups compared with that in healthy controls (all p ≤ 0.002), except in the GAD subgroup. Cortical atrophy rates exceeded normal aging in individuals with impaired verbal memory, while those who were not impaired did not differ significantly from healthy controls. Our data depict higher mesiotemporal volumes in the early disease stage, most likely due to edematous swelling, followed by volume regression and atrophy/hippocampal sclerosis in the late disease stage. Our study reveals a continuous and pathophysiologically meaningful trajectory of mesiotemporal volumetry across all serogroups and provides evidence that LE should be considered a network disorder in which extratemporal involvement is an important determinant of disease severity.

Forecasting Individual Patients' Best Time for Surgery in Colon-Rectal Cancer by Tumor Regression during and after Neoadjuvant Radiochemotherapy.

The standard treatment of locally advanced rectal cancer is neoadjuvant chemoradiotherapy before surgery. For those patients experiencing a complete clinical response after the treatment, a watch-and-wait strategy with close monitoring may be practicable. In this respect, the identification of biomarkers of the response to therapy is extremely important. Many mathematical models have been developed or used to describe tumor growth, such as Gompertz's Law and the Logistic Law. Here we show that the parameters of those macroscopic growth laws, obtained by fitting the tumor evolution during and immediately after therapy, are a useful tool for evaluating the best time for surgery in this type of cancer. A limited number of experimental observations of the tumor volume regression, during and after the neoadjuvant doses, permits a reliable evaluation of a specific patient response (partial or complete recovery) for a later time, and one can evaluate a modification of the scheduled treatment, following a watch-and-wait approach or an early or late surgery. Neoadjuvant chemoradiotherapy effects can be quantitatively described by applying Gompertz's Law and the Logistic Law to estimate tumor growth by monitoring patients at regular intervals. We show a quantitative difference in macroscopic parameters between partial and complete response patients, reliable for estimating the treatment effects and best time for surgery.

A self-healable and injectable hydrogel for pH-responsive doxorubicin drug delivery in vitro and in vivo for colon cancer treatment

Hydrogels are three-dimensional solid-like structures with a wide range of applications in drug transport, tissue engineering, wound dressing, etc. We developed herein a new hydrogel by mixing 5′-guanosine monophosphate (5′-GMP) disodium salt (16 mM) and 1,4,5,8-naphthalene tetracarboxylic acid tetra potassium salt (NAP) (4 mM) in 4:1 (GMP:NAP) stoichiometry in aqueous media (pH ∼4 at 25 °C). The mechanical properties of the resulting hydrogel were investigated by rheological studies, which showed that the hydrogel formed at pH 4 is the most stable [storage modulus (Gꞌ) of ∼4000 Pa] and has higher endurance for the oscillatory strain (20% strain). Spectroscopic investigations provided insights into the unique self-assembly of 5′-GMP and NAP. Further, the composite exhibited pH-responsive hydrogelation over the pH range of 3–6, and the gel was transformed into a sol form at pH > 5. This stimuli-sensitive nature of the hydrogel was then exploited for the encapsulation and efficacious delivery of an anticancer drug, doxorubicin (DOX), specifically toward the colorectal cancer. Microscopic studies revealed the presence of a regular entangled fibrillar network for the hydrogels, which allowed for its exceptionally high drug loading capacity. The controlled release of DOX from the hydrogel was then studied at the physiological pH of the gastrointestinal tract, i.e. pH ∼7.4. The DOX-loaded hydrogel (DOX-Gel) exhibited a ∼82% release of DOX over 100 h at pH ∼7.4. The enhanced cellular toxicity of DOX was observed in CT-26 murine colorectal carcinoma cell lines treated with the DOX-loaded hydrogel compared to DOX only as manifested from the fluorescence-activated cell sortinganalyses and fluorescence microscopic studies. The fluorescence-activated cell sorting analysis showed a ∼4.5-fold increase in the drug internalization for the DOX-Gel as compared to DOX only formulations. The co-localization of DOX into the cell nucleus was confirmed from confocal microscopy. The in vivo drug delivery efficacy of this pH-responsive hydrogel was further assessed on an animal tumor model, Balb/c mice (n = 9). A significant regression of ∼87.5% in the tumor volume was observed after 21 days of DOX-gel administration, in contrast to DOX only formulation, which showed only a ∼46.0% regression in the tumor volume. The blood reports of the non-treated control mice and the mice treated with DOX only indicated a metastatic behavior in comparison with the mice treated with the DOX-Gel. This, the present system, is a self-healable, injectable hydrogel, which makes it an ideal drug delivery vehicle with stimuli-responsive controlled drug release capabilities even in vivo.

Abstract 1680: Characterization of sensitivity to single agents and combination treatments (VAC and VI) and development of acquired resistance in childhood rhabdomyosarcoma xenograft models

Abstract For childhood rhabdomyosarcoma (RMS), a tumor demonstrating characteristics of skeletal muscle lineage, survival has not changed significantly in over two decades. In a recent high-risk clinical trial (ARST0431) 25% of patients progressed during 52 weeks of chemo-radiation treatment, and 80% had tumor recurrence or progression within 24 months. Two drug modules comprise the core for treatment: VAC (vincristine, actinomycin-D, cyclophosphamide) and VI (vincristine, irinotecan). However, the molecular basis for intrinsic or acquired resistance to these combinations is poorly understood.To simulate clinical heterogeneity of RMS, we have developed 40 PDX/CDX xenograft models and using Single Mouse Testing (SMT) have characterized the sensitivity of each model to individual agents and to VAC/VI combinations. Tumor volume regression and Event-Free Survival (EFS) were used to assess chemosensitivity. To select for acquired resistance, tumor bearing mice were treated with one cycle of VAC or VI, tumor was transplanted upon regrowth when volume reached 400% of that on day 1 of treatment. The process was repeated for up to 5 cycles of therapy. Development of resistance was measured by decreased EFS and tumor progression during treatment. Parental and isogenic lines with acquired resistance were snap frozen for DNA and RNA sequencing. Sensitivity for each tumor models was assessed by EFS for treated vs untreated tumor and probability plotted against time (days) after initiating treatment. Each single agent significantly extended EFS compared to control EFS (P&amp;lt;0.001), consistent with known clinical activity. Of note VAC and VI combinations had greater than additive EFS (e.g. EFSVAC&amp;gt;&amp;gt;EFSvincristine + EFSactD + EFScyclophosphamide). The sensitivity of the 40 xenograft models to VAC ranged from Progressive Disease with EFS &amp;lt;42 days to Maintained Complete Response at 140 days. A similar range in sensitivity to VI was observed also, but the correlation between sensitivity to VAC and VI was poor (r=0.375) indicating greater sensitivity of a model to one combination than the other. Ten lines have been selected in vivo for acquired resistance to VAC and VI. Resistance was developed between cycle 2 and cycle 5 of treatment with a mean decrease in EFS of 65 +/- 15% compared to the EFS on drug cycle 1. In summary, we have characterized the sensitivity of 40 RMS xenograft models to single agents and VAC/VI combinations and have developed 20 models with acquired resistance to these combinations. Tumor tissue has been obtained from all 40 models and from 20 models with acquired drug resistance. Sequencing of these models is ongoing and preliminary results will be presented. Supported by 1 UO1 CA263981-01. Citation Format: Samson Ghilu, Peter J. Houghton, Siyuan Zheng, Raushan T. Kurmasheva. Characterization of sensitivity to single agents and combination treatments (VAC and VI) and development of acquired resistance in childhood rhabdomyosarcoma xenograft models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1680.

Synergistic action of lactoferrin in enhancing the safety and effectiveness of docetaxel treatment against prostate cancer.

Tumor metastasis is promoted by an immunosuppressive environment. Lactoferrin (Lf) is known to regulate immunological activity in tumor cells and inhibit processes associated with tumor metastasis. A delivery of lactoferrin with docetaxel (DTX) in prostate cancer cells in the form of DTX-loaded lactoferrin nanoparticles (DTX-LfNPs) would provide a dual activity wherein the lactoferrin affects metastasis and DTX chemotherapeutically inhibits mitosis and cell division. DTX-LfNPs were prepared using sol-oil chemistry, and particles were characterized using transmission electron microscopy. Antiproliferation activity was analyzed in prostate cancer Mat Ly Lu cells. The target localization and efficacy of DTX-LfNPs were studied in an orthotopic prostate cancer induced by Mat Ly Lu cells in a rat model. Biomarkers were estimated using ELISA and biochemical reactions. DTX was loaded in pure Lf nanoparticles without involving any chemical modification and conjugation, thus when these nanoparticles are delivered in cancer cells both DTX and Lf will be present in biologically active forms. DTX-LfNps exhibit a spherical morphology of dimension of 60 ± 10nm with DTX Encapsulation Efficiency of 62.06 ± 4.07%. Competition experiments using soluble Lf confirm that DTX-LfNPs enter prostate cancer cells through the Lf receptor. DTX-LfNPs exhibit an improved anti-proliferative activity by 2.5 times compared to DTX. Further, analysis of the bioavailability of the drug in the prostate showed that DTX-LfNPs increased drug bioavailability in the prostate by two times more than the DTX. The analysis of efficacy in the Mat Ly Lu cells-induced orthotopic prostate cancer model showed that DTX-LfNPs significantly enhanced the anti-cancer activity compared to DTX in terms of regression of weight and volume of prostate tissue, the efficacy was confirmed by histochemical analysis. Lf provides synergistic activity along with DTX in inhibiting metastasis as assessed by the reduction of lactate dehydrogenase, alkaline phosphatase, TNF alpha, and IFNγ. LfNPs facilitate higher DTX localization along with Lf-mediated protection from DTX-associated toxicity to neutrophils and kidneys as assessed by C-reactive protein, creatinine, and uric acid. Thus, DTX LfNPs show a dual action by enhancing DTX bioavailability in prostate along with Lf-mediated suppression of metastasis as well as DTX-associated toxicity. In conclusion, DTX-LfNPs enhance the bioavailability of DTX in the prostate along with Lf-assisted improvement in inhibition of tumor metastasis and drug-associated toxicity.

Importance of radiographic tumor regression during radiotherapy in squamous cell versus adenocarcinoma of the uterine cervix as assessed by MRI and cone beam CT

The purpose of this study was to evaluate the kinetics of tumor regression in cervical squamous cell carcinoma (SCC) and adenocarcinoma (AC) using computed tomography (CT) and magnetic resonance imaging (MRI), and to correlate rate of regression and residual tumor with progression and survival. Thirty-two patients with stage IB2-IVA cervical cancer were randomly selected from an institutional database with a 2:1 ratio of SCC to AC. All available on-treatment weekly cone beam CT (CBCT) and pre- and post-external beam MRIs were utilized to generate largest two-dimensional area of tumor and tumor gross tumor volumes (GTV), respectively. Tumor volume regression velocity and percent residual tumor were correlated to 5-year progression-free survival (PFS) and disease-specific survival (DSS) using threshold regression modeling. Kaplan-Meier and Fine-Grey estimators were used for survival and cumulative incidence analysis, respectively. With a median follow-up of 2.9 years, 32 patients were included, 22 (69%) with SCC and 10 (31%) with AC. All received concurrent chemoradiation followed by brachytherapy. The 2-year cumulative incidence (CI) of local progression for both SCC and AC was 10%, and 2-year CI of distant progression was 9% vs. 57% (p = 0.02). Deaths occurred in 3/22 (14%) with SCC and 7/10 (70%) with AC, with a 2-year DSS of 90% versus 60%, respectively. Extent and rate of regression on CBCTs were not correlated with progression or survival; however, consistent rates of tumor regression for both SCC and AC. Thresholds of ≥20% residual disease on post-external beam pre-brachytherapy MRI and regression velocity ≤1.8%/day were associated with worse PFS and DSS. This study showed cervical AC is associated with higher rates of distant progression and worse overall survival than SCC. Cervical AC tends to have a higher initial and residual tumor burden. Our identified thresholds of ≥20% residual tumor and tumor regression of ≤1.8%/day may help identify cases warranting dose escalation.