Citations

Exhausted-like CD8 + resident memory T cells in the lung limit immune activation–driven fibrosis.

BackgroundEsophageal carcinoma is the eighth most common cancer in the world. Volumetric‐modulated arc therapy (VMAT) is widely used to treat distal esophageal carcinoma due to high conformality to the target and good sparing of organs at risk (OAR). It is not clear if small‐spot intensity‐modulated proton therapy (IMPT) demonstrates a dosimetric advantage over VMAT. In this study, we compared dosimetric performance of VMAT and small‐spot IMPT for distal esophageal carcinoma in terms of plan quality, plan robustness, and interplay effects.Methods35 distal esophageal carcinoma patients were retrospectively reviewed; 19 patients received small‐spot IMPT and the remaining 16 of them received VMAT. Both plans were generated by delivering prescription doses to clinical target volumes (CTVs) on phase‐averaged 4D‐CT's. The dose‐volume‐histogram (DVH) band method was used to quantify plan robustness. Software was developed to evaluate interplay effects with randomized starting phases for each field per fraction. DVH indices were compared using Wilcoxon rank‐sum test. For fair comparison, all the treatment plans were normalized to have the same CTVhigh D95% in the nominal scenario relative to the prescription dose.ResultsIn the nominal scenario, small‐spot IMPT delivered statistically significantly lower liver Dmean and V30Gy[RBE], lung Dmean, heart Dmean compared with VMAT. CTVhigh dose homogeneity and protection of other OARs were comparable between the two treatments. In terms of plan robustness, the IMPT and VMAT plans were comparable for kidney V18Gy[RBE], liver V30Gy[RBE], stomach V45Gy[RBE], lung Dmean, V5Gy[RBE], and V20Gy[RBE], cord Dmax and , liver Dmean, heart V20Gy[RBE], and V30Gy[RBE], but IMPT was significantly worse for CTVhigh D95%, , and D5%‐D95%, CTVlow D95%, heart Dmean, and V40Gy[RBE], requiring careful and experienced adjustments during the planning process and robustness considerations. The small‐spot IMPT plans still met the standard clinical requirements after interplay effects were considered.ConclusionsSmall‐spot IMPT decreases doses to heart, liver, and total lung compared to VMAT as well as achieves clinically acceptable plan robustness. Our study supports the use of small‐spot IMPT for the treatment of distal esophageal carcinoma.

236 Background: Hepatobiliary cancer (HBC), including cholangiocarcinoma, affects over 40,000 people in the U.S. each year, and results in over 30,000 cancer deaths annually. Despite continuing advances in next-generation sequencing (NGS), the understanding of germline genetic risk as it relates to these malignancies remains limited, and guidelines for the germline testing of these patients are lacking. We report the spectrum of pathogenic/likely pathogenic (P/LP) germline genetic variants observed in patients with HBC, and the clinical utility related to germline genetic test results. Methods: We retrospectively studied a consecutive series of 267 patients referred to Invitae for germline genetic testing based on a personal history of HBC, per an IRB approved protocol. Patients were evaluated with a multigene panel of up to 135 genes chosen by the ordering providers. De-identified clinical and family history information were reviewed as provided by clinicians. Results: Among 267 HBC patients 15% (n = 41) had P/LP variants identified in genes including MUTYH, ATM, CHEK2, BAP1, BRCA1, MLH1, BRCA2, PALB2, TP53, APC, CDH1, MSH6, and PMS2 (12% excluding MUTYH heterozygotes). Amongst patients with a family history (FH) of HBC, P/LP rate was 13%; for patients with a FH of cancers other than HBC, P/LP rate was 16%; for patients with no reported FH, P/LP rate was 13%. Conclusions: In this study, 15% of HBC patients had P/LP variants in cancer-risk genes. The clinical utility of these germline P/LP variants includes 32% of patients who were eligible for ongoing clinical treatment trials based on their germline test results (NCT02286687), 60% with clinical management recommendations per current NCCN guidelines, and cascade testing of at risk family members. These data justify comprehensive germline multigene panel testing in all HBC patients, in view of the potential impact on clinical management for a substantial fraction of positive patients as well as facilitating cascade testing for risk assessment of family members.

Abstract DNA methylation is instrumental for gene regulation. Global changes in the epigenetic landscape have been recognized as a hallmark of cancer. However, the role of DNA methylation in epithelial ovarian cancer (EOC) remains unclear. In this study, high-density genetic and DNA methylation data in white blood cells from the Framingham Heart Study (N = 1,595) were used to build genetic models to predict DNA methylation levels. These prediction models were then applied to the summary statistics of a genome-wide association study (GWAS) of ovarian cancer including 22,406 EOC cases and 40,941 controls to investigate genetically predicted DNA methylation levels in association with EOC risk. Among 62,938 CpG sites investigated, genetically predicted methylation levels at 89 CpG were significantly associated with EOC risk at a Bonferroni-corrected threshold of P < 7.94 × 10−7. Of them, 87 were located at GWAS-identified EOC susceptibility regions and two resided in a genomic region not previously reported to be associated with EOC risk. Integrative analyses of genetic, methylation, and gene expression data identified consistent directions of associations across 12 CpG, five genes, and EOC risk, suggesting that methylation at these 12 CpG may influence EOC risk by regulating expression of these five genes, namely MAPT, HOXB3, ABHD8, ARHGAP27, and SKAP1. We identified novel DNA methylation markers associated with EOC risk and propose that methylation at multiple CpG may affect EOC risk via regulation of gene expression. Significance: Identification of novel DNA methylation markers associated with EOC risk suggests that methylation at multiple CpG may affect EOC risk through regulation of gene expression.

PurposeIntensity‐modulated proton therapy (IMPT) is known to be sensitive to patient setup and range uncertainty issues. Multiple robust optimization methods have been developed to mitigate the impact of these uncertainties. Here, we propose a new robust optimization method, which provides an alternative way of robust optimization in IMPT, and is clinically practical, which will enable users to control the balance between nominal plan quality and plan robustness in a user‐defined fashion.MethodWe calculated nine individual dose distributions which corresponded to one nominal and eight extreme scenarios caused by patient setup and proton beam's range uncertainties. For each voxel, the normalized dose interval (NDI) is defined as the full dose range variation divided by the maximum dose in all uncertainty scenarios (NDI = [max – min dose]/max dose), which was then used to calculate the normalized dose interval volume histogram (NDIVH) curves. The areas under the NDIVH curves were used to quantify plan robustness. A normalized dose interval volume constraint (NDIVC) applied to the target was incorporated to specify the desired robustness which was user‐defined. Users could then explore the trade‐off between nominal plan quality and plan robustness by adjusting the position of the NDIVCs on the NDIVH curves freely. We benchmarked our method using one lung, five head and neck (H&N), and three prostate cases by comparing our results to those derived using the voxel‐wise worst‐case robust optimization.ResultsUsing the benchmark cases, our new method achieved quality IMPT plans comparable to those derived from the voxel‐wise worst‐case robust optimization for both nominal plan quality and plan robustness in general; even more conformal and more homogeneous target dose distributions in some cases, if proper NDIVCs were applied. The AUC under NDIVH, as a precise quantitative index of plan robustness, was consistent with DVH bandwidths. Additionally, we demonstrated the feasibility of adjusting the position of NDIVCs in the NDIVH curves which allowed users to explore the trade‐off between nominal plan quality and plan robustness.ConclusionsThe NDIVH‐based robust optimization method provided a novel and individualized way of robust optimization in IMPT, and enables users to adjust the balance between nominal plan quality and plan robustness in a user‐defined fashion. This method is applicable for continued improvement and developing the next generation of IMPT planning algorithms in the future.

PurposeAt our institution, all proton patient plans undergo patient‐specific quality assurance (PSQA) prior to treatment delivery. For intensity‐modulated proton beam therapy, quality assurance is complex and time consuming, and it may involve multiple measurements per field. We reviewed our PSQA workflow and identified the steps that could be automated and developed solutions to improve efficiency.MethodsWe used the treatment planning system's (TPS) capability to support C# scripts to develop an Eclipse scripting application programming interface (ESAPI) script and automate the preparation of the verification phantom plan for measurements. A local area network (LAN) connection between our measurement equipment and shared database was established to facilitate equipment control, measurement data transfer, and storage. To improve the analysis of the measurement data, a Python script was developed to automatically perform a 2D–3D γ‐index analysis comparing measurements in the plane of a two‐dimensional detector array with TPS predictions in a water phantom for each acquired measurement.ResultsDevice connection via LAN granted immediate access to the plan and measurement information for downstream analysis using an online software suite. Automated scripts applied to verification plans reduced time from preparation steps by at least 50%; time reduction from automating γ‐index analysis was even more pronounced, dropping by a factor of 10. On average, we observed an overall time savings of 55% in completion of the PSQA per patient plan.ConclusionsThe automation of the routine tasks in the PSQA workflow significantly reduced the time required per patient, reduced user fatigue, and frees up system users from routine and repetitive workflow steps allowing increased focus on evaluating key quality metrics.

AbstractPurposeTo compare dosimetric performance of volumetric‐modulated arc therapy (VMAT) and small‐spot intensity‐modulated proton therapy for stage III non‐small‐cell lung cancer (NSCLC).Methods and MaterialsA total of 24 NSCLC patients were retrospectively reviewed; 12 patients received intensity‐modulated proton therapy (IMPT) and the remaining 12 received VMAT. Both plans were generated by delivering prescription doses to clinical target volumes (CTV) on averaged 4D‐CTs. The dose‐volume‐histograms (DVH) band method was used to quantify plan robustness. Software was developed to evaluate interplay effects with randomized starting phases of each field per fraction. DVH indices were compared using Wilcoxon rank sum test.ResultsCompared with VMAT, IMPT delivered significantly lower cord Dmax, heart Dmean, and lung V5 Gy[RBE] with comparable CTV dose homogeneity, and protection of other OARs. In terms of plan robustness, the IMPT plans were statistically better than VMAT plans in heart Dmean, but were statistically worse in CTV dose coverage, cord Dmax, lung Dmean, and V5 Gy[RBE]. Other DVH indices were comparable. The IMPT plans still met the standard clinical requirements with interplay effects considered.ConclusionsSmall‐spot IMPT improves cord, heart, and lung sparing compared to VMAT and achieves clinically acceptable plan robustness at least for the patients included in this study with motion amplitude less than 11 mm. Our study supports the usage of IMPT to treat some lung cancer patients.

BackgroundPreoperative prediction of tumor recurrence is important in the management of patients with hepatocellular carcinoma (HCC).PurposeTo investigate whether tumor stiffness derived by magnetic resonance elastography (MRE) could predict early recurrence of HCC after hepatic resection.Study TypeRetrospective.PopulationIn all, 99 patients with pathologically confirmed HCCs after surgical resection.Field Strength/Sequence3.0T; preoperative MRE with 60‐Hz mechanical vibrations using an active acoustic driver.AssessmentRegions of interest (ROIs) were manually drawn in the tumors to measure mean tumor stiffness. Surgical specimens were reviewed for histological grade, capsule, vascular invasion, and surgical margins. The early recurrence of HCC was defined as that occurring within 2 years after resection.Statistical TestsCox proportional hazard models were used to evaluate risk factors associated with the time to early recurrence.ResultsHCCs with recurrence had higher tumor stiffness, higher rate of advanced T stage, vascular invasion, lower rate of capsule formation, larger tumor size, higher aspartate aminotransferase (AST), and hepatitis B virus (HBV)‐DNA level and aspartate aminotransferase / alanine aminotransferase ratio (P = 0.031, 0.007, 0.01, <0.001, 0.015, 0.034, 0.01, and 0.014, respectively) than HCCs without recurrence. Vascular invasion (hazard ratio [HR] = 2.922; 95% confidence interval [CI]: [1.079, 7.914], P = 0.035) and mean tumor stiffness (HR = 1.163; 95% CI: [1.055, 1.282], P = 0.002) were risk factors associated with early recurrence. Each 1‐kPa increase in tumor stiffness was associated with a 16.3% increase in the risk for tumor recurrence.Data ConclusionThe mean stiffness of HCCs may be a useful, noninvasive, quantitative biomarker for the prediction of early HCC recurrence after hepatic resection.Level of Evidence: 4Technical Efficacy: Stage 5J. Magn. Reson. Imaging 2019;49:719–730.