Evaluating the clinical acceptability of deep learning contours of prostate and organs-at-risk in an automated prostate treatment planning process.

BACKGROUND: Radiation treatment is considered an effective and the most common treatment option for prostate cancer. The treatment planning process requires accurate and precise segmentation of the prostate and organs at risk (OARs), which is laborious and time-consuming when contoured manually. Artificial intelligence (AI)-based auto-segmentation has the potential to significantly accelerate the radiation therapy treatment planning process; however, the accuracy of auto-segmentation needs to be validated before its full clinical adoption. PURPOSE: A commercial AI-based contouring model was trained to provide segmentation of the prostate and surrounding OARs. The segmented structures were input to a commercial auto-planning module for automated prostate treatment planning. This study comprehensively evaluates the performance of this contouring model in the automated prostate treatment planning process. METHODS AND MATERIALS: A 3D U-Net-based model (INTContour, Carina AI) was trained and validated on 84 computed tomography (CT) scans and tested on an additional 23 CT scans from patients treated in our local institution. Prostate and OARs contours generated by the AI model (AI contour) were geometrically evaluated against reference contours. The prostate contours were further evaluated against AI, reference, and two additional observer contours for comparison using inter-observer variation (IOV) and 3D boundaries discrepancy analyses. A blinded evaluation was introduced to assess subjectively the clinical acceptability of the AI contours. Finally, treatment plans were created from an automated prostate planning workflow using the AI contours and were evaluated for their clinical acceptability following the Radiation Therapy Oncology Group-0815 protocol. RESULTS: The AI contours demonstrated good geometric accuracy on OARs and prostate contours, with average Dice similarity coefficients (DSC) for bladder, rectum, femoral heads, seminal vesicles, and penile bulb of 0.93, 0.85, 0.96, 0.72, and 0.53, respectively. The DSC, 95% directed Hausdorff distance (HD95), and mean surface distance for the prostate were 0.83 ± 0.05, 6.07 ± 1.87 mm, and 2.07 ± 0.73 mm, respectively. No significant differences were found when comparing with IOV. In the double-blinded evaluation, 95.7% of the AI contours were scored as either "perfect" (34.8%) or "acceptable" (60.9%), while only one case (4.3%) was scored as "unacceptable with minor changes required." In total, 69.6% of the AI contours were considered equal to or better than the reference contours by an independent radiation oncologist. Automated treatment plans created from the AI contours produced similar and clinically acceptable dosimetric distributions as those from plans created from reference contours. CONCLUSIONS: The investigated AI-based commercial model for prostate segmentation demonstrated good performance in clinical practice. Using this model, the implementation of an automated prostate treatment planning process is clinically feasible.

Comparison of outcomes of stereotactic body radiation therapy delivered with three different technologies to the lung.

PURPOSE/OBJECTIVES: Since the inception of stereotactic body radiation therapy (SBRT), treatment delivery has been performed with volumetric modulated arc therapy (VMAT), helical tomotherapy (HT) and noncoplanar static fields (SF). The purpose of this study is to compare SBRT delivery among these treatment modalities to the lung. MATERIALS/METHODS: A retrospective review of SBRT treatments of 30 to 60 Gy in 1 to 5 fractions from 2007 to 2015 was performed. Dosimetric parameters included V5, V20, D2cm, gross tumor volume (GTV) and planning target volume (PTV) size and coverage, rib/esophageal minimum/maximum doses, R30Gy, R50%, and the conformality index (CI). Clinical outcomes evaluated included local control, pneumonitis and other toxicities. ANOVA, Student's t-test and Kruskal-Wallis test were used to compare the parameters among modalities. Kaplan-Meier estimates of time-to-local failure were produced. RESULTS: 176 Treatments included 106 SF, 36 VMAT and 34 HT. HT had better PTV coverage (p=0.0166) but higher lung V5 and esophageal doses (p<0.001 and p=0.0032). R30Gy, R50%, and CI were significantly better with VMAT SBRT (p<0.001). Clinically, Grade 2+ pneumonitis was associated with larger median GTV's of 21.39 cc versus 7.65 cc (p=0.0016), larger median PTV's of 65.62 cc versus 31.75 cc (p=0.0030), and higher V20 6.62% versus 4.08% (p=0.0408). For patients surviving >1 year, overall local failure rate was 9.4%. Actuarial control rates trended toward statistical significance with time to local failure with VMAT being the most favorable group on the Kaplan-Meier curve (p=0.0733). CONCLUSION: VMAT showed superior conformality compared to the other modalities. Among the modalities examined, HT had higher values for parameters associated with toxicity such as V5 and maximum esophageal dose, but all were within acceptable limits. There was a trend to better local control with VMAT.

Extracellular redox state shift: A novel approach to target prostate cancer invasion.

AIM: Extracellular superoxide dismutase (ECSOD) and the cysteine/glutamate transporter (Cys)/(xCT) are tumor microenvironment (TME) redox state homeostasis regulators. Altered expression of ECSOD and xCT can lead to imbalance of the TME redox state and likely have a profound effect on cancer invasion. In the present study, we investigated whether ECSOD and xCT could be therapeutic targets for prostate cancer (PCa) invasion. RESULTS: Immunohistochemistry of tumor microarray PCa tissues (N = 165) with high Gleason scores indicated that xCT protein expression is significantly increased while ECSOD protein expression is significantly decreased. Metastatic PCa indicated ECSOD protein expression is significantly decreased in epithelial area whereas xCT protein expression is significantly increased in stromal area. Furthermore, inhibition of extracellular O2•- by overexpression of ECSOD or alteration of the extracellular Cys/CySS ratio by knockdown of xCT protein inhibited PCa cell invasion. Simultaneous overexpression of ECSOD and knockdown xCT inhibited PCa cell invasion more than overexpression of ECSOD or knockdown of xCT alone. In the co-culturing system, simultaneous overexpression of ECSOD and knockdown of xCT in prostate stromal WPMY-1 cells inhibited PCa cell invasiveness more than overexpression of ECSOD alone. The decrease in PCa invasion correlated with increased of extracellular H2O2 levels. Notably, overexpression of catalase in TME reversed the inhibitory effect of ECSOD on cancer cell invasion. CONCLUSION: Impaired ECSOD activity and an upregulated of xCT protein expression may be clinical features of an aggressive PCa, particularly metastatic cancers and/or those with a high Gleason score. Therefore, shifting the extracellular redox state toward an oxidizing status by targeted modulation of ECSOD and xCT, in both cancer and stromal cells, may provide a greater strategy for potential therapeutic interventions of aggressive PCa.

'District nurses' hands are tied by poor procurement decisions'.

In March last year my husband Steve woke up in agony, with pain in his right foot and leg. His toes had turned blue, and after a dash to the local emergency department, we were quickly referred to the vascular team at a leading London hospital.

Temporal self-regulation of transposition through host-independent transposase rodlet formation.

Transposons are highly abundant in eukaryotic genomes, but their mobilization must be finely tuned to maintain host organism fitness and allow for transposon propagation. Forty percent of the human genome is comprised of transposable element sequences, and the most abundant cut-and-paste transposons are from the hAT superfamily. We found that the hAT transposase TcBuster from Tribolium castaneum formed filamentous structures, or rodlets, in human tissue culture cells, after gene transfer to adult mice, and ex vivo in cell-free conditions, indicating that host co-factors or cellular structures were not required for rodlet formation. Time-lapsed imaging of GFP-laced rodlets in human cells revealed that they formed quickly in a dynamic process involving fusion and fission. We delayed the availability of the transposon DNA and found that transposition declined after transposase concentrations became high enough for visible transposase rodlets to appear. In combination with earlier findings for maize Ac elements, these results give insight into transposase overproduction inhibition by demonstrating that the appearance of transposase protein structures and the end of active transposition are simultaneous, an effect with implications for genetic engineering and horizontal gene transfer.

Role of reverse phenotyping in interpretation of next generation sequencing data and a review of INPP5E related disorders.

INTRODUCTION: Next Generation Sequencing (NGS) is a useful tool in diagnosis of rare disorders but the interpretation of data can be challenging in clinical settings. We present results of extended studies on a family of multiple members with global developmental delay and learning disability, where another research group postulated the underlying cause to be a homozygous RABL6 missense variant. METHODS AND RESULTS: Using data from the Exome Variant Server, we show that missense RABL6 variants are unlikely to cause early onset rare developmental disorder. Protein structural analysis, cellular functional studies and reverse phenotyping proved that the condition in this family is due to a homozygous INPP5E mutation. An in-depth review of mutational and phenotypic spectrum associated with INPP5E demonstrated that mutations in this gene lead to a range of cilliopathy-phenotypes. DISCUSSION: We use this study as an example to demonstrate the importance of careful clinical evaluation of multiple family members, reverse phenotyping, considering the unknown phenotypic variability of rare diseases, utilizing publically available genomic databases and conducting appropriate bioinformatics and functional studies while interpreting results from NGS in uncertain cases. We emphasize that interpretation of NGS data is an iterative process and its dynamic nature should be explained to patients and families. Our study shows that developmental delay, intellectual disability, hypotonia and ocular motor apraxia are common in INPP5E-related disorders and considerable intra-familial phenotypic variability is possible. We have compiled the INPP5E mutational spectrum and provided novel insights into their molecular mechanisms.