Citations

Abstract Objective . To investigate similarities and differences in the formalism, processing, and the results of relative biological effectiveness (RBE) calculations with a biological weighting function (BWF), the microdosimetric kinetic model (MKM) and subsequent modifications (non-Poisson MKM, modified MKM). This includes: (a) the extension of the V79-RBE 10% BWF to model the RBE for other clonogenic survival levels; (b) a novel implementation of MKMs as weighting functions; (c) a benchmark against Chinese Hamster lung fibroblast (V79) in vitro data; (d) a study on the effect of pre- or post- processing the average biophysical quantities used for the RBE calculations; (e) a possible modification of the modified MKM parameters to improve the model accuracy at high linear energy transfer (LET). Methodology . Lineal energy spectra were simulated for two spherical targets (diameter = 0.464 or 1.0 μ m) using PHITS for 1 H, 4 He, 12 C, 20 Ne, 40 Ar, 56 Fe and 132 Xe ions. The results of the in silico calculations were compared with published in vitro data. Main results . All models appear to underestimate the RBE α of hydrogen ions. All MKMs generally overestimate the RBE 50% , RBE 10% and RBE 1% for ions with an LET greater than ∼200 keV μ m −1 . This overestimation is greater for small surviving fractions and is likely due to the assumption of a radiation-independent quadratic term of clonogenic survival ( ß ). The overall RBE trends seem to be best described by the novel ‘post-processing average’ implementation of the non-Poisson MKM. In case of calculations with the non-Poisson MKM, pre- or post- processing the average biophysical quantities affects the computed RBE values significantly. Significance . This study presents a systematic analysis of the formalism and results of widely used microdosimetric models of clonogenic survival for ions relevant for cancer particle therapy and space radiation protection. Points for improvements were highlighted and will contribute to the development of upgraded biophysical models.

ABSTRACT Introduction Literature concerning corporotomy location in multi-component inflatable penile prosthetic surgery via a penoscrotal approach is scarce if not non-existent. However, corporotomy location represents an important issue that may influence immediate and long-term outcomes regarding patient and partner satisfaction as well as device durability. Objective To report practices in low- and high-volume penile implant centers regarding corporotomy location. Methods Data from 18 (13 European and 5 American) implant centers were collected retrospectively between September 1st, 2018 and August 31st, 2019. Variables included: intraoperative proximal and distal corpus cavernosum length measurement, total corporal length measurement, total penile implant cylinder length, and length of rear tip extenders. Additionally, patient characteristics, indication for penile implant, operative time, type of implant utilized, reservoir characteristics and short term complications were reported. Results 809 virgin penile implant cases were included in the analysis. Mean age of participants was 61.5 +/- 9.6 years old. In total, 299 AMS 700TM (Boston Scientific) and 510 Coloplast Titan® devices were implanted. The mean proximal/distal corporal measurement ratio during corporotomy was 0.93 +/- 0.29. A statistically significant correlation between lower proximal /distal measurement ratio and higher age (p=0.0013), lower BMI (p<0.0001), use of rear tip extenders (RTE) (p=0.04), lower RTE length (p<0.0001) and absence of diabetes (p=0.0004) was reported. In a 3-month follow up period 49 complications and 37 revision procedures were reported. Conclusions This is the first study reporting and evaluating the current practices regarding corporotomy location during IPP placement in a multicenter cohort, particularly when including such a high number of patients. Nevertheless, the retrospective design limits the study outcomes. Even in experienced hands proximal length measurement in relation to distal length measurement in penoscrotal IPP surgery is in many cases sub-optimal, particularly when the tubing-cylinder connection of each device is taken into account. Disclosure No

Abstract Improving the chances of curing patients with cancer who have had surgery to remove metastatic sites of disease is a priority area for cancer research. Pexa-Vec (Pexastimogene Devacirepvec; JX-594, TG6006) is a principally immunotherapeutic oncolytic virus that has reached late-phase clinical trials. We report the results of a single-center, nonrandomized biological end point study (trial registration: EudraCT number 2012-000704-15), which builds on the success of the presurgical intravenous delivery of oncolytic viruses to tumors. Nine patients with either colorectal cancer liver metastases or metastatic melanoma were treated with a single intravenous infusion of Pexa-Vec ahead of planned surgical resection of the metastases. Grade 3 and 4 Pexa-Vec–associated side effects were lymphopaenia and neutropaenia. Pexa-Vec was peripherally carried in plasma and was not associated with peripheral blood mononuclear cells. Upon surgical resection, Pexa-Vec was found in the majority of analyzed tumors. Pexa-Vec therapy associated with IFNα secretion, chemokine induction, and resulted in transient innate and long-lived adaptive anticancer immunity. In the 2 patients with significant and complete tumor necrosis, a reduction in the peripheral T-cell receptor diversity was observed at the time of surgery. These results support the development of presurgical oncolytic vaccinia virus-based therapies to stimulate anticancer immunity and increase the chances to cure patients with cancer.

Hodgkin lymphoma (HL) is an uncommon malignancy of B-cell origin. Classical HL (cHL) and nodular lymphocyte–predominant HL are the 2 main types of HL. The cure rates for HL have increased so markedly with the advent of modern treatment options that overriding treatment considerations often relate to long-term toxicity. These NCCN Guidelines Insights discuss the recent updates to the NCCN Guidelines for HL focusing on (1) radiation therapy dose constraints in the management of patients with HL, and (2) the management of advanced-stage and relapsed or refractory cHL.

Background: In REDUCE LAP-HF II (A Study to Evaluate the Corvia Medical, Inc IASD System II to Reduce Elevated Left Atrial Pressure in Patients With Heart Failure), implantation of an atrial shunt device did not provide overall clinical benefit for patients with heart failure with preserved or mildly reduced ejection fraction. However, prespecified analyses identified differences in response in subgroups defined by pulmonary artery systolic pressure during submaximal exercise, right atrial volume, and sex. Shunt implantation reduces left atrial pressures but increases pulmonary blood flow, which may be poorly tolerated in patients with pulmonary vascular disease (PVD). On the basis of these results, we hypothesized that patients with latent PVD, defined as elevated pulmonary vascular resistance during exercise, might be harmed by shunt implantation, and conversely that patients without PVD might benefit. Methods: REDUCE LAP-HF II enrolled 626 patients with heart failure, ejection fraction ≥40%, exercise pulmonary capillary wedge pressure ≥25 mm Hg, and resting pulmonary vascular resistance <3.5 Wood units who were randomized 1:1 to atrial shunt device or sham control. The primary outcome—a hierarchical composite of cardiovascular death, nonfatal ischemic stroke, recurrent HF events, and change in health status—was analyzed using the win ratio. Latent PVD was defined as pulmonary vascular resistance ≥1.74 Wood units (highest tertile) at peak exercise, measured before randomization. Results: Compared with patients without PVD (n=382), those with latent PVD (n=188) were older, had more atrial fibrillation and right heart dysfunction, and were more likely to have elevated left atrial pressure at rest. Shunt treatment was associated with worse outcomes in patients with PVD (win ratio, 0.60 [95% CI, 0.42, 0.86]; P =0.005) and signal of clinical benefit in patients without PVD (win ratio, 1.31 [95% CI, 1.02, 1.68]; P =0.038). Patients with larger right atrial volumes and men had worse outcomes with the device and both groups were more likely to have pacemakers, heart failure with mildly reduced ejection fraction, and increased left atrial volume. For patients without latent PVD or pacemaker (n=313; 50% of randomized patients), shunt treatment resulted in more robust signal of clinical benefit (win ratio, 1.51 [95% CI, 1.14, 2.00]; P =0.004). Conclusions: In patients with heart failure with preserved or mildly reduced ejection fraction, the presence of latent PVD uncovered by invasive hemodynamic exercise testing identifies patients who may worsen with atrial shunt therapy, whereas those without latent PVD may benefit.

INTRODUCTION: Despite studies showing improved safety, efficacy, and cost-effectiveness of endoscopic resection for nonmalignant colorectal polyps, colectomy rates for nonmalignant colorectal polyps have been increasing in the United States and Europe. Given this alarming trend, we aimed to investigate whether colectomy rates for nonmalignant colorectal polyps are increasing or declining in a large, integrated, community-based healthcare system with access to advanced endoscopic resection procedures. METHODS: We identified all individuals aged 50–85 years who underwent a colonoscopy between 2008 and 2018 and were diagnosed with a nonmalignant colorectal polyp(s) at the Kaiser Permanente Northern California integrated healthcare system. Among these individuals, we identified those who underwent a colectomy for nonmalignant colorectal polyps within 12 months after the colonoscopy. We calculated annual colectomy rates for nonmalignant colorectal polyps and stratified rates by age, sex, and race and ethnicity. Changes in rates over time were tested by the Cochran-Armitage test for a linear trend. RESULTS: Among 229,730 patients who were diagnosed with nonmalignant colorectal polyps between 2008 and 2018, 1,611 patients underwent a colectomy. Colectomy rates for nonmalignant colorectal polyps decreased significantly from 125 per 10,000 patients with nonmalignant polyps in 2008 to 12 per 10,000 patients with nonmalignant polyps in 2018 ( P < 0.001 for trend). When stratified by age, sex, and race and ethnicity, colectomy rates for nonmalignant colorectal polyps also significantly declined from 2008 to 2018. DISCUSSION: In a large, ethnically diverse, community-based population in the United States, we found that colectomy rates for nonmalignant colorectal polyps declined significantly over the past decade likely because of the establishment of advanced endoscopy centers, improved care coordination, and an organized colorectal cancer screening program.

Abstract Background Magnetic Resonance Imaging (MRI) is the mainstay for neurosurgical oncology but not for informing us about glioma biology. An obstacle to developing MR-based glioma biomarkers is the absence of rigorous correlation between MRI features and glioma biology as assessed in multi-regional biopsies, within and across patients. Methods We directly addressed this obstacle by collating a unique cohort of 202 MRI-localized biopsies from 58 patients. We define a low-dimensional transcriptional pseudotime continuum along which heterogeneous high-grade glioma (HGG) samples organize both within and across patients. Results We observe three polarized transcriptional tissue states: infiltrated brain, immune/inflammatory, and proliferative associated with patterns of cohabitation of cellular subpopulations. The states and deconvolved populations show correlation with enhancement status on T1Gd MRI. Moreover, discrete MRI habitats, regions sharing common imaging features, defined as combinations of high or low signal intensity across multiparametric MRI revealed 14 MRI habitats. We order the MRI habitats according to the average pseudotime on the transcriptional continuum. We find that MRI habitats with low pseudotime (associated with early tumor development and diffusely invaded brain tissue) localized at the periphery of the tumor whilst high pseudotime either proliferative or immune/inflammatory states were towards the core of the lesion. We find that composition of MRI habitats are impacted by MGMT status and patient sex. Conclusion This suggests that ongoing aggregation of MRI-localized biopsies may augment our projection of biology onto MRI habitats to support tracking of the evolution of cellular ecologies within and across each patient’s tumor over time. Key Points Trajectory inference of HGG samples reveals a continuum connecting three polarized tissue states reflecting transitions in cellular population ecologies and gene set enrichment Combining multiparametric MRI features into regional MRI habitats reveal clinically-distinct patterns of cell co-habitation and tissue state MGMT methylation status shifts the cellular patterns of cohabitation within MRI habitats Importance of the Study Regional heterogeneity is a defining characteristic of high-grade glioma (HGG). Mapping the transcriptomic biology of multiregionally sampled MRI-localized biopsies from high-grade gliomas onto a low-dimensional space reveals a continuum between three primary tissue states: infiltrated brain, immune/inflammatory, and proliferative. Each state is associated with distinct cell cohabitation ecologies. Transitions between the tissue states coordinate with changes in tumor composition, revealing potential direct connections between tumor biology shifts and their manifestation on clinical imaging.

Abstract Objective. 4D-CBCT provides phase-resolved images valuable for radiomics analysis for outcome prediction throughout treatment courses. However, 4D-CBCT suffers from streak artifacts caused by under-sampling, which severely degrades the accuracy of radiomic features. Previously we developed group-patient-trained deep learning methods to enhance the 4D-CBCT quality for radiomics analysis, which was not optimized for individual patients. In this study, a patient-specific model was developed to further improve the accuracy of 4D-CBCT based radiomics analysis for individual patients. Approach. This patient-specific model was trained with intra-patient data. Specifically, patient planning 4D-CT was augmented through image translation, rotation, and deformation to generate 305 CT volumes from 10 volumes to simulate possible patient positions during the onboard image acquisition. 72 projections were simulated from 4D-CT for each phase and were used to reconstruct 4D-CBCT using FDK back-projection algorithm. The patient-specific model was trained using these 305 paired sets of patient-specific 4D-CT and 4D-CBCT data to enhance the 4D-CBCT image to match with 4D-CT images as ground truth. For model testing, 4D-CBCT were simulated from a separate set of 4D-CT scan images acquired from the same patient and were then enhanced by this patient-specific model. Radiomics features were then extracted from the testing 4D-CT, 4D-CBCT, and enhanced 4D-CBCT image sets for comparison. The patient-specific model was tested using 4 lung-SBRT patients’ data and compared with the performance of the group-based model. The impact of model dimensionality, region of interest (ROI) selection, and loss function on the model accuracy was also investigated. Main results. Compared with a group-based model, the patient-specific training model further improved the accuracy of radiomic features, especially for features with large errors in the group-based model. For example, the 3D whole-body and ROI loss-based patient-specific model reduces the errors of the first-order median feature by 83.67%, the wavelet LLL feature maximum by 91.98%, and the wavelet HLL skewness feature by 15.0% on average for the four patients tested. In addition, the patient-specific models with different dimensionality (2D versus 3D) or loss functions (L1 versus L1 + VGG + GAN) achieved comparable results for improving the radiomics accuracy. Using whole-body or whole-body+ROI L1 loss for the model achieved better results than using the ROI L1 loss alone as the loss function. Significance. This study demonstrated that the patient-specific model is more effective than the group-based model on improving the accuracy of the 4D-CBCT radiomic features analysis, which could potentially improve the precision for outcome prediction in radiotherapy.

Abstract Melioidosis, an infection caused by Burkholderia pseudomallei, has a very high risk of mortality when treated, with an even higher risk of fatality if undiagnosed or not treated appropriately. It is endemic to Asia, Australia, South America, and the Caribbean; however, the number of melioidosis cases reported in the United States has been increasing. Therefore, physicians should be aware of this clinical entity and its possible presentations. Mycotic aneurysms due to B. pseudomallei are extremely rare, accounting for ~1%–2% of cases. Here we describe a rare case of melioidosis presenting as a mycotic aneurysm in the United States, highlight the potential for diagnostic challenges and epidemiologic concerns, and provide a review of mycotic aneurysm cases due to B. pseudomallei published to date.