Physics-based in silico modelling of microvascular pulmonary perfusion in COVID-19.

Due to its ability to induce heterogenous, patient-specific damage in pulmonary alveoli and capillaries, COVID-19 poses challenges in defining a uniform profile to elucidate infection across all patients. Computational models that integrate changes in ventilation and perfusion with heterogeneous damage profiles offer valuable insights into the impact of COVID-19 on pulmonary health. This study aims to develop an in silico hypothesis-testing platform specifically focused on studying microvascular pulmonary perfusion in COVID-19-infected lungs. Through this platform, we explore the effects of various acinar-level pulmonary perfusion abnormalities on global lung function. Our modelling approach simulates changes in pulmonary perfusion and the resulting mismatch of ventilation and perfusion in COVID-19-afflicted lungs. Using this coupled modelling platform, we conducted multiple simulations to assess different scenarios of perfusion abnormalities in COVID-19-infected lungs. The simulation results showed an overall decrease in ventilation-perfusion (V/Q) ratio with inclusion of various types of perfusion abnormalities such as hypoperfusion with and without microangiopathy. This model serves as a foundation for comprehending and comparing the spectrum of findings associated with COVID-19 in the lung, paving the way for patient-specific modelling of microscale lung damage in emerging pulmonary pathologies like COVID-19.

Long-Term Survival of Patients With Glioblastoma of the Pineal Gland: A ChatGPT-Assisted, Updated Case of a Multimodal Treatment Strategy Resulting in Extremely Long Overall Survival at a Site With Historically Poor Outcomes.

We present an updated case report of a patient with glioblastoma isolated to the pineal gland with an overall survival greater than five years and no progression of focal central nervous system (CNS) deficits since initial presentation. The patient underwent radiotherapy up to 60 Gy with concurrent and adjuvant temozolomide with the use of non-standard treatment volumes that included the ventricular system. The utilization of ventricular irradiation as well as the addition of bevacizumab at disease recurrence may have encouraged this unusually long survival by preventing/delaying leptomeningeal spread. We also present an updated review of the literature, which shows a median survival of six months, reinforcing the patients atypical disease trajectory. Finally, we utilize OpenAI's language model ChatGPT to aid in synthesizing this manuscript. In doing so, we demonstrate that ChatGPT is apt at creating concise summaries of relevant literature and topic subjects, however its output is often repetitive with similar sentence/paragraph structure, less than ideal grammar and poor syntax requiring editing. Thus, in its current iteration, ChatGPT is a helpful aid that cuts down on the time spent in data acquisition and processing but is not a replacement for human input in the creation of quality medical literature.

Cardiac toxicity in patients with lung cancer receiving thoracic radiotherapy and immunotherapy.

Background: Immune checkpoint inhibitors (ICIs) are used to treat locally-advanced and metastatic lung cancer, which can lead to severe immunogenic-related cardiotoxicities. We assessed the risk of cardiotoxicity in ICI-treated lung cancer patients with or without cardiac radiation from thoracic radiotherapy. Methods: Retrospective data was collected on Stage III-IV lung cancer patients who received ICIs between 2015 and 2018. All cardiotoxicities associated with ICI were assessed in correlation with the timing of radiotherapy (RT) in relation to ICI, and the mean RT heart dose. The rate of cardiac events in relation to RT timing and heart dose was compared using multiple logistic regression including the Framingham risk score and steroid use prior to ICI therapy. Results: Of 194 ICI-treated patients evaluated, 55.2% (n=107/194) patients had received thoracic RT at a median dose of 60.4 Gy (range, 15-75). Cardiotoxicities such as non-ST elevated myocardial infarction and new onset supraventricular tachycardias were observed in 13 (12.2%) of those who had thoracic RT versus 9 (10.3%) who did not (p=0.87). 38 patients who received RT concurrently with ICI did not develop any cardiotoxicity whereas 14.1% (n=22/156) of those who did not receive concurrent RT developed cardiotoxicities (univariate, p=0.030; multivariate, p=0.055). There were no significant differences in the mean heart RT dose, Framingham risk score, and steroid treatment between patients that received concurrent RT with ICI versus non-concurrent RT/ICI. Conclusion: ICI-related cardiotoxicities were not significantly associated with patients who received concurrent thoracic radiotherapy in this retrospective review. Further validation of prospective studies is needed to confirm these results.

GammaTile Brachytherapy Combined With External Beam Radiation Therapy for the Treatment of a Partially Resected Secondary Glioblastoma (WHO Grade 4 IDH-Mutant Astrocytoma): Matching External Beam Dose Gradient to Brachytherapy Dose Fall-Off.

Reirradiation of recurrent glioblastomas is most commonly managed with hypofractionated external beam radiation with a modest overall effect. GammaTile, which is a Cesium-131 source embedded in collagen mesh, is an approach that allows the surgical bed of resectable intracranial tumors to receive a greater biological dose than is possible with any form of external beam radiation therapy (EBRT). In this case report, a 28-year-old male presents with a WHO grade 4 isocitrate dehydrogenase (IDH)-mutant astrocytoma (formerly secondary glioblastoma) of the left occipital/parietal lobe after receiving 45 Gy and two cycles of adjuvant temozolomide four years prior for a grade 3 IDH-mutant astrocytoma. The patient proceeded to undergo craniotomy with maximal safe resection and application of GammaTile to a dose of 60 Gy at 5mm depth. Shortly afterward, he developed symptomatic progression of disease in the bilateral splenium and left thalamus/basal ganglia. We irradiated the undertreated residual disease with EBRT to a dose of 35 Gy in 10 fractions without introducing excessive dose to the GammaTile irradiated volume. This was achieved by creating one portion of the planning target volume with a homogeneous dose and another part where the delivered dose decreased with the GammaTile dose buildup. Treatment planning utilized the Gradient Optimization feathering technique with non-coplanar volumetric modulated arc therapy. The resulting composite between the hypofractionated EBRT and GammaTile dose distribution created an approximate dose equivalent of 50 Gy in 2 Gy fractions to the residual disease with no hot spots or areas of under coverage. This is the first report showing the feasibility of combining GammaTile with dose-matched EBRT volumes in a reproducible manner to sub-totally resected, recurrent intracranial neoplasms.

Development and preclinical testing of a novel biodegradable hydrogel vaginal packing technology for gynecologic high-dose-rate brachytherapy.

PURPOSE: We evaluated the performance of a novel hydrogel-based strategy developed for clinical use as vaginal packing using phantoms and cadavers, and to compare the hydrogel to gauze and balloon packing. MATERIAL AND METHODS: The biocompatible hydrogel is based on a thiol-Michael addition reaction, with delivery of reagents into the vaginal cavity using a custom-made system. Soft-cured cadavers were used for soft tissue-like mechanical properties. Two cadavers with intact uteri had magnetic resonance imaging (MRI) compatible with tandem and ovoids. For one cadaver, the temperature of the vaginal canal was measured before hydrogel application, during polymerization, and after hydrogel removal. The hydrogel packing and applicator was kept in a second cadaver, which was imaged using computed tomography (CT) and MRI. The hydrogel packing and imaging was repeated for an open multichannel MRI compatible, titanium-based vaginal cylinder placed in a post-hysterectomy cadaver. RESULTS: The gel reaction occurred within 90 seconds, indicating polymerization at clinical quantities with a 5°C increase in vaginal temperature. CT and MRI imaging identified the hydrogel readily and showed a conformance to anatomy with few air pockets. The entire hydrogel packing was readily retrieved upon completion of imaging. CONCLUSIONS: The novel strategy for polyethylene glycol (PEG)-based hydrogel intra-vaginal packing was able to rapidly polymerize in human cadavers with minimal heat production. Delivery was efficient and able to fill the contours of the vaginal cavity and displace tissue away from the applicator axis. The hydrogel has favorable imaging characteristics on CT and MRI, and shows a potential for clinical use, warranting additional studies for the use in humans.

Effect of evolocumab on cholesterol synthesis and absorption.

The effects of cholesterol-lowering drugs, including those that reduce cholesterol synthesis (statins) and those that reduce cholesterol absorption (ezetimibe), on cholesterol absorption and synthesis are well understood. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are a novel class of cholesterol-lowering drugs that robustly reduce LDL-cholesterol (LDL-C), but little is known about their effects on cholesterol absorption and synthesis. We evaluated how treatment with evolocumab, a fully human monoclonal IgG2 antibody to PCSK9, affects markers of cholesterol synthesis and absorption by measuring these markers in patients from an evolocumab clinical trial. At 2 weeks, changes in ß-sitosterol/total cholesterol (TC) from baseline were 4% for placebo, 10% for evolocumab 140 mg (nonsignificant vs. placebo), and 26% for evolocumab 420 mg (P < 0.001 vs. placebo). Changes in campesterol/TC at week 2, relative to baseline between placebo and evolocumab, were all nonsignificant. Evolocumab had a modest effect on markers of cholesterol synthesis. At 2 weeks, changes in desmosterol/TC were 1% for placebo, 7% for evolocumab 140 mg (nonsignificant vs. placebo), and 15% for evolocumab 420 mg (P < 0.01 vs. placebo). Changes from baseline in lathosterol/TC at week 2 between placebo and evolocumab were nonsignificant. These results suggest that evolocumab has a modest effect on cholesterol synthesis and absorption despite significant LDL-C lowering.

PCSK9 inhibition-mediated reduction in Lp(a) with evolocumab: an analysis of 10 clinical trials and the LDL receptor's role.

Lipoprotein (a) [Lp(a)] is independently associated with CVD risk. Evolocumab, a monoclonal antibody (mAb) to proprotein convertase subtilisin/kexin type 9 (PCSK9), decreases Lp(a). The potential mechanisms were assessed. A pooled analysis of Lp(a) and LDL cholesterol (LDL-C) in 3,278 patients from 10 clinical trials (eight phase 2/3; two extensions) was conducted. Within each parent study, biweekly and monthly doses of evolocumab statistically significantly reduced Lp(a) at week 12 versus control (P < 0.001 within each study); pooled median (quartile 1, quartile 3) percent reductions were 24.7% (40.0, 3.6) and 21.7% (39.9, 4.2), respectively. Reductions were maintained through week 52 of the open-label extension, and correlated with LDL-C reductions [with and without correction for Lp(a)-cholesterol] at both time points (P < 0.0001). The effect of LDL and LDL receptor (LDLR) availability on Lp(a) cell-association was measured in HepG2 cells: cell-associated LDL fluorescence was reversed by unlabeled LDL and Lp(a). Lp(a) cell-association was reduced by coincubation with LDL and PCSK9 and reversed by adding PCSK9 mAb. These studies support that reductions in Lp(a) with PCSK9 inhibition are partly due to increased LDLR-mediated uptake. In most situations, Lp(a) appears to compete poorly with LDL for LDLR binding and internalization, but when LDLR expression is increased with evolocumab, particularly in the setting of low circulating LDL, Lp(a) is reduced.

Systematic Review of the Relationship between Acute and Late Gastrointestinal Toxicity after Radiotherapy for Prostate Cancer.

A small but meaningful percentage of men who are treated with external beam radiation therapy for prostate cancer will develop late gastrointestinal toxicity. While numerous strategies to prevent gastrointestinal injury have been studied, clinical trials concentrating on late toxicity have been difficult to carry out. Identification of subjects at high risk for late gastrointestinal injury could allow toxicity prevention trials to be performed using reasonable sample sizes. Acute radiation therapy toxicity has been shown to predict late toxicity in several organ systems. Late toxicities may occur as a consequential effect of acute injury. In this systematic review of published reports, we found that late gastrointestinal toxicity following prostate radiotherapy seems to be statistically and potentially causally related to acute gastrointestinal morbidity as a consequential effect. We submit that acute gastrointestinal toxicity may be used to identify at-risk patients who may benefit from additional attention for medical interventions and close follow-up to prevent late toxicity. Acute gastrointestinal toxicity could also be explored as a surrogate endpoint for late effects in prospective trials.

Biomarkers as predictors of response to treatment with motesanib in patients with progressive advanced thyroid cancer.

CONTEXT: Antiangiogenic therapies have shown potential in the treatment of advanced thyroid cancer, but it is uncertain which patients are most likely to benefit from therapy. OBJECTIVE: This prespecified exploratory analysis investigated whether baseline levels and/or changes in circulating biomarkers could predict tumor response and/or progression-free survival (PFS) among patients enrolled in a phase 2 study of motesanib in advanced thyroid cancer. DESIGN/SETTING/PATIENTS: Patients with progressive locally advanced or metastatic medullary or differentiated thyroid cancer received motesanib 125 mg once daily for up to 48 wk in a phase 2 interventional study. Samples for assessment of circulating biomarkers of angiogenesis or apoptosis were collected at study wk 1 (baseline), 2, 4, 8, 16, 24, 32, 40, 48, and 4 wk after cessation of motesanib treatment. Tumor response was assessed per Response Evaluation Criteria in Solid Tumors by independent review. RESULTS: Change from baseline in serum placental growth factor (PlGF) after 1 wk of treatment correlated with best tumor response (Kendall rank correlation, 0.28; P < 0.0001). Using a Fisher exact test, the most significant separation between patients who had an objective response and those who did not was at a 4.7-fold increase in PlGF. The response rate among patients with a greater than 4.7-fold increase in PlGF was 30% compared with 3% below this threshold. There was also a significant separation between responders and nonresponders at a 1.6-fold decrease in soluble vascular endothelial growth factor (VEGF) receptor 2 after 3 wk of treatment. Patients with baseline serum VEGF less than 671 pg/ml had significantly longer PFS times than the remainder of patients. CONCLUSIONS: Changes in PlGF and soluble VEGF receptor 2 levels after initiation of therapy predicted response to motesanib in patients with advanced differentiated thyroid cancer or metastatic medullary thyroid cancer. Lower baseline VEGF levels were associated with longer PFS.

Conatumumab, a fully human agonist antibody to death receptor 5, induces apoptosis via caspase activation in multiple tumor types.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) binds to death receptors 4 and 5 (DR4, DR5) to transduce apoptotic signals. Conatumumab (AMG 655) is an investigational, fully human monoclonal agonist antibody (IgG(1)) to human DR5, which induces apoptosis via caspase activation. In this study, we demonstrate that conatumumab binds to DR5, activating intracellular caspases in vitro in the presence of a cross-linker. We also show that conatumumab has activity in vivo and inhibits tumor growth in colon (Colo205 and HCT-15), lung (H2122) and pancreatic (MiaPaCa2/T2) xenograft models. Conatumumab also enhances the antitumor activity of chemotherapeutics in vivo. Caspase activation in Colo205 tumors is dose-dependent and correlated with serum concentrations of conatumumab. We demonstrate for the first time that increases in serum caspase-3/7 activity and levels of M30 (neoepitope of caspase-cleaved cytokeratin-18) are linked to activation of the extrinsic apoptotic pathway using conatumumab in a preclinical model. These data suggest that conatumumab has potential as a therapeutic agent for treating patients with multiple tumor types, and that serum caspase-3/7 and M30 levels may serve as biomarkers of conatumumab activity.