Jiawei Chen

Deep convolutional neural network with transfer learning for rectum toxicity prediction in cervical cancer radiotherapy: a feasibility study

Better understanding of the dose-toxicity relationship is critical for safe dose escalation to improve local control in late-stage cervical cancer radiotherapy. In this study, we introduced a convolutional neural network (CNN) model to analyze rectum dose distribution and predict rectum toxicity. Forty-two cervical cancer patients treated with combined external beam radiotherapy (EBRT) and brachytherapy (BT) were retrospectively collected, including twelve toxicity patients and thirty non-toxicity patients. We adopted a transfer learning strategy to overcome the limited patient data issue. A 16-layers CNN developed by the visual geometry group (VGG-16) of the University of Oxford was pre-trained on a large-scale natural image database, ImageNet, and fine-tuned with patient rectum surface dose maps (RSDMs), which were accumulated EBRT  +  BT doses on the unfolded rectum surface. We used the adaptive synthetic sampling approach and the data augmentation method to address the two challenges, data imbalance and data scarcity. The gradient-weighted class activation maps (Grad-CAM) were also generated to highlight the discriminative regions on the RSDM along with the prediction model. We compare different CNN coefficients fine-tuning strategies, and compare the predictive performance using the traditional dose volume parameters, e.g. D 0.1/1/2cc, and the texture features extracted from the RSDM. Satisfactory prediction performance was achieved with the proposed scheme, and we found that the mean Grad-CAM over the toxicity patient group has geometric consistence of distribution with the statistical analysis result, which indicates possible rectum toxicity location. The evaluation results have demonstrated the feasibility of building a CNN-based rectum dose-toxicity prediction model with transfer learning for cervical cancer radiotherapy.

Sacral Neuromodulation for Refractory Bladder Pain Syndrome/Interstitial Cystitis: a Global Systematic Review and Meta-analysis

Bladder pain syndrome/interstitial cystitis (BPS/IC) is a common debilitating disease and there has not been consistently effective treatment. We aimed to evaluate all available literature regarding the efficacy and safety of sacral neuromodulation (SNM) for refractory BPS/IC. A comprehensive search of Pubmed, Web of Science and Cochrane Library through May 2016 was conducted. A total of 17 studies enrolling 583 patients were identified. Pooled analyses demonstrated that SNM was associated with great reduction in pelvic pain (weighted mean difference [WMD] −3.99; 95% confidence interval [CI] −5.22 to −2.76; p < 0.00001), Interstitial Cystitis Problem and Symptom Index scores (WMD −6.34; 95% CI −9.57 to −3.10; p = 0.0001; and WMD −7.17; 95% CI −9.90 to −4.45; p < 0.00001, respectively), daytime frequency (WMD −7.45; 95% CI −9.68 to −5.22; p < 0.00001), nocturia (WMD −3.01; 95% CI −3.56 to −2.45; p < 0.00001), voids per 24 hours (WMD −9.32; 95% CI −10.90 to −7.74; p < 0.00001) and urgency (WMD −1.08; 95% CI −1.79 to −0.37; p = 0.003) as well as significant improvement in average voided volume (WMD 95.16 ml; 95% CI 63.64 to 126.69; p < 0.0001). The pooled treatment success rate was 84% (95% CI 76% to 91%). SNM-related adverse events were minimal. Current evidence indicates that SNM might be effective and safe for treating refractory BPS/IC.

Ketamine-induced bladder fibrosis involves epithelial-to-mesenchymal transition mediated by transforming growth factor-β1

Bladder wall fibrosis is a major complication of ketamine-induced cystitis (KC), but the underlying pathogenesis is poorly understood. The aim of the present study was to elucidate the mechanism of ketamine-induced fibrosis in association with epithelial-to-mesenchymal transition (EMT) mediated by transforming growth factor-β1 (TGF-β1). Sprague-Dawley rats were randomly distributed into four groups, which received saline, ketamine, ketamine combined with a TGF-β receptor inhibitor (SB-505124) for 16 wk, or 12 wk of ketamine and 4 wk of abstinence. In addition, the profibrotic effect of ketamine was confirmed in SV-40 immortalized human uroepithelial (SV-HUC-1) cells. The ketamine-treated rats displayed voiding dysfunction and decreased bladder compliance. Bladder fibrosis was accompanied by the appearance of a certain number of cells expressing both epithelial and mesenchymal markers, indicating that epithelial cells might undergo EMT upon ketamine administration. Meanwhile, the expression level of TGF-β1 was significantly upregulated in the urothelium of bladders in ketamine-treated rats. Treatment of SV-HUC-1 cells with ketamine increased the expression of TGF-β1 and EMT-inducing transcription factors, resulting in the downregulation of E-cadherin and upregulation of fibronectin and α-smooth muscle actin. Administration of SB-505124 inhibited EMT and fibrosis both in vitro and vivo. In addition, withdrawal from ketamine did not lead to recovery of bladder urinary function or decreased fibrosis. Taken together, our study shows for the first time that EMT might contribute to bladder fibrosis in KC. TGF-β1 may have an important role in bladder fibrogenesis via an EMT mechanism.

Ketamine Analog Methoxetamine Induced Inflammation and Dysfunction of Bladder in Rats.

The novel synthetic psychoactive ketamine analog methoxetamine is reportedly being used for recreational purposes. As ketamine use can result in urinary dysfunction, we conducted the present study to investigate how methoxetamine affects the bladder. A cystometry investigation showed that female Sprague-Dawley rats experienced increased micturition frequency bladder dysfunction after receiving a daily intraperitoneal injection of 30 mg/kg methoxetamine or ketamine for periods of 4 or 12 weeks. Histologic examinations of rat bladder tissue revealed damaged urothelium barriers, as well as evidence of inflammatory cell infiltration and matrix deposition. The drug-treated rats showed significantly upregulated levels of pro-inflammatory cytokines such as IL-1β, IL-6, CCL-2, CXCL-1, CXCL-10, NGF, and COX-2. In addition, interstitial fibrosis was confirmed by increased levels of collagen I, collagen III, fibronectin and TGF-β. Besides direct toxic effect on human urothelial cells, methoxetaminealso induced the upregulation related cytokines. Our results indicate that long term methoxetamine treatment can induce bladder dysfunction and inflammation in rats. Methoxetamine was confirmed to produce direct toxic and pro-inflammatory effects on human urothelial cells. Methoxetamine-associated bladder impairment may be similar to ketamine-induced cystitis.

Urinary Microbiome and Psychological Factors in Women with Overactive Bladder

Objectives: Emerging evidence indicates that alterations to the urinary microbiome are related to lower urinary tract symptoms. Overactive bladder (OAB) is a common disorder with complex etiologies and usually accompanied by psychological diseases. More information concerning the urinary microbiome and psychological factors in OAB is required. The aim of this study was to characterize the female urinary microbiome associated with OAB and investigate the relationships between urinary microbiome and psychological factors. Methods: Thirty women with OAB and 25 asymptomatic controls were recruited and asked to finish the Overactive Bladder Symptom Score, Self-Rating Anxiety Scale and Self-Rating Depression Scale. Urine specimens were collected by transurethral catheterization and processed for 16S rRNA gene sequencing using Illumina MiSeq. Sequencing reads were processed using QIIME. LEfSe revealed significant differences in bacterial genera between controls and OAB patients. The relationships between the diversity of the urinary microbiome and psychological scores were identified by Pearsons correlation coefficient. Results: We found that bacterial diversity (Simpson index) and richness (Chao1) were lower in OAB samples compared to controls (P both = 0.038). OAB and control bacterial communities were significantly different (based on weighted UniFrac distance metric, R = 0.064, P = 0.037). LEfSe demonstrated that 7 genera were increased (e.g., Proteus and Aerococcus) and 13 were reduced (e.g., Lactobacillus and Prevotella) in OAB group compared to controls. There were negative correlations between scores on Self-Rating Depression Scale and both richness (Chao1, r = −0.458, P = 0.011) and diversity (Shannon index, r = −0.516, P = 0.003) of urinary microbiome in OAB group. Some bacterial genera of OAB women with anxiety or depression were significantly different from those without. Conclusions: The aberrant urinary microbiome with decreased diversity and richness may have strong implications in pathogenesis and treatment of OAB. Psychological conditions were correlated with characteristics of urinary microbiome in women with OAB. Further research is needed to understand the connection between central nervous system and urinary microbiome.

Profiling the Urinary Microbiota in Male Patients With Bladder Cancer in China

Mounting evidence indicates that microbiome plays an important role in the development and progression of cancer. The dogma that urine in healthy individuals must be sterile has been overturned. Dysbiosis of the urinary microbiome has been revealed responsible for various urological disorders, including prostate cancer. The link between chronic inflammation, microbiome and solid tumors has been established for various neoplastic diseases. However, a detailed and comprehensive analysis of urinary microenvironment of bladder cancer has not been yet reported. We performed this study to characterize the potential urinary microbial community possibly associated with bladder cancer. Mid-stream urine was collected from 31 male patients with bladder cancer and 18 non-neoplastic controls. DNA was extracted from urine pellet samples and processed for high throughput 16S rRNA amplicon sequencing of the V4 region using Illumina MiSeq. Sequencing reads were filtered using QIIME and clustered using UPARSE. We observed increased bacterial richness (Observed Species, Chao 1 and Ace indexes; cancer vs. control; 120.0 vs. 56.0; 134.5 vs. 68.3; and 139.6 vs. 72.9, respectively), enrichment of some bacterial genera (e.g., Acinetobacter, Anaerococcus, and Sphingobacterium) and decrease of some bacterial genera (e.g., Serratia, Proteus, and Roseomonas) in cancer group when compared to non-cancer group. Significant difference in beta diversity was found between cancer and non-cancer group, among different risk level, but not among different tumor grade. Enrichment of Herbaspirillum, Porphyrobacter, and Bacteroides was observed in cancer patients with high risk of recurrence and progression, which means these genera maybe potential biomarkers for risk stratification. The PICRUSt showed that various functional pathways were enriched in cancer group, including Staphylococcus aureus infection, glycerolipid metabolism and retinol metabolism. To our knowledge, we performed the most comprehensive study to date to characterize the urinary microbiome associated with bladder cancer. A better understanding of the role of microbiome in the development and progression of bladder cancer could pave a new way for exploring new therapeutic options and biomarkers.

An anthropomorphic abdominal phantom for deformable image registration accuracy validation in adaptive radiation therapy

Purpose To design and construct a three‐dimensional (3D) anthropomorphic abdominal phantom for geometric accuracy and dose summation accuracy evaluations of deformable image registration (DIR) algorithms for adaptive radiation therapy (ART). Method Organ molds, including liver, kidney, spleen, stomach, vertebra, and two metastasis tumors, were 3D printed using contours from an ovarian cancer patient. The organ molds were molded with deformable gels made of different mixtures of polyvinyl chloride (PVC) and the softener dioctyl terephthalate. Gels with different densities were obtained by a polynomial fitting curve that described the relation between the Hounsfield unit (HU) and PVC‐softener blending ratio. The rigid vertebras were constructed by molding of white cement and cellulose pulp. The final abdominal phantom was assembled by arranging all the fabricated organs inside a hollow dummy according to their anatomies, and sealed by deformable gel with averaged HU of muscle and fat. Fiducial landmarks were embedded inside the phantom for spatial accuracy and dose accumulation accuracy studies. Two channels were excavated to facilitate ionization chamber insertion for dosimetric measurements. Phantom properties such as deformable gel elasticity and HU stability were studied. The dosimetric measurement accuracy in the phantom was performed, and the DIR accuracies of three DIR algorithms available in the open source DIR toolkit‐DIRART were also validated. Results The constructed deformable gel showed elastic behavior and was stable in HU values over times, proving to be a practical material for the deformable phantom. The constructed abdominal phantom consisted of realistic anatomies in terms of both anatomical shapes and densities when compared with its reference patient. The dosimetric measurements showed a good agreement with the calculated doses from the treatment planning system. Fiducial‐based accuracy analysis conducted on the constructed phantom demonstrated the feasibility of applying the phantom for organ‐wise DIR accuracy assessment. Conclusions We have designed and constructed an anthropomorphic abdominal deformable phantom with satisfactory elastic property, realistic organ density, and anatomy. This physical phantom can be used for routine validations of DIR geometric accuracy and dose accumulation accuracy in ART.

Internal Motion Estimation by Internal-external Motion Modeling for Lung Cancer Radiotherapy

The aim of this study is to develop an internal-external correlation model for internal motion estimation for lung cancer radiotherapy. Deformation vector fields that characterize the internal-external motion are obtained by respectively registering the internal organ meshes and external surface meshes from the 4DCT images via a recently developed local topology preserved non-rigid point matching algorithm. A composite matrix is constructed by combing the estimated internal phasic DVFs with external phasic and directional DVFs. Principle component analysis is then applied to the composite matrix to extract principal motion characteristics, and generate model parameters to correlate the internal-external motion. The proposed model is evaluated on a 4D NURBS-based cardiac-torso (NCAT) synthetic phantom and 4DCT images from five lung cancer patients. For tumor tracking, the center of mass errors of the tracked tumor are 0.8(±0.5)mm/0.8(±0.4)mm for synthetic data, and 1.3(±1.0)mm/1.2(±1.2)mm for patient data in the intra-fraction/inter-fraction tracking, respectively. For lung tracking, the percent errors of the tracked contours are 0.06(±0.02)/0.07(±0.03) for synthetic data, and 0.06(±0.02)/0.06(±0.02) for patient data in the intra-fraction/inter-fraction tracking, respectively. The extensive validations have demonstrated the effectiveness and reliability of the proposed model in motion tracking for both the tumor and the lung in lung cancer radiotherapy.

Investigating rectal toxicity associated dosimetric features with deformable accumulated rectal surface dose maps for cervical cancer radiotherapy

BackgroundBetter knowledge of the dose-toxicity relationship is essential for safe dose escalation to improve local control in cervical cancer radiotherapy. The conventional dose-toxicity model is based on the dose volume histogram, which is the parameter lacking spatial dose information. To overcome this limit, we explore a comprehensive rectal dose-toxicity model based on both dose volume histogram and dose map features for accurate radiation toxicity prediction.MethodsForty-two cervical cancer patients treated with combined external beam radiotherapy (EBRT) and brachytherapy (BT) were retrospectively studied, including 12 with Grade ≥ 2 rectum toxicity and 30 patients with Grade 0–1 toxicity (non-toxicity patients). The cumulative equivalent 2-Gy rectal surface dose was deformably summed using the deformation vector fields obtained through a recent developed local topology preserved non-rigid point matching algorithm. The cumulative three-dimensional (3D) dose was flattened and mapped to a two-dimensional (2D) plane to obtain the rectum surface dose map (RSDM). The dose volume parameters (DVPs) were calculated from the 3D rectum surface, while the texture features and the dose geometric parameters (DGPs) were extracted from the 2D RSDM. Representative features further computed from DVPs, textures and DGPs by principle component analysis (PCA) and statistical analysis were respectively fed into a support vector machine equipped with a sequential feature selection procedure. The predictive powers of the representative features were compared with the GEC-ESTRO dosimetric parameters D0.1/1/2cm3.ResultsSatisfactory predictive accuracy of sensitivity 74.75 and 84.75%, specificity 72.67 and 79.87%, and area under the receiver operating characteristic curve (AUC) 0.82 and 0.91 were respectively achieved by the PCA features and statistical significant features, which were superior to the D0.1/1/2cm3 (AUC 0.71). The relative area in dose levels of 64Gy, 67Gy, 68Gy, 87Gy, 88Gy and 89Gy, perimeters in dose levels of 89Gy, as well as two texture features were ranked as the important factors that were closely correlated with rectal toxicity.ConclusionsOur extensive experimental results have demonstrated the feasibility of the proposed scheme. A future large patient cohort study is still needed for model validation.

TH-CD-206-08: An Anthropopathic Deformable Phantom for Geometric and Dose Accumulation Accuracy Validation of Deformable Image Registration

PURPOSE To design and construct a three-dimensional (3D) anthropopathic abdominal phantom for evaluating deformable image registration (DIR) accuracy on images and dose deformation in adaptive radiation therapy (ART). METHOD Organ moulds, including liver, kidney, spleen, stomach, vertebra and two metastasis tumors, are 3D printed using the contours from an ovarian cancer patient. The organ moulds are molded with deformable gels that made of different mixtures of polyvinyl chloride (PVC) and the softener dioctyl terephthalate. Gels with different densities are obtained by a polynomial fitting curve which describes the relation between the CT number and PVC-softener blending ratio. The rigid vertebras are constructed by moulding with white cement. The final abdominal phantom is assembled by arranging all the fabricated organs inside a hollow dummy according to their anatomies and sealed with deformable gel with averaged CT number of muscle and fat. Geometric and dosimetric landmarks are embedded inside the phantom for spatial accuracy and dose accumulation accuracy studies. Three DIR algorithms available in the open source DIR toolkit-DIRART, including the Demons, the Horn-Schunck and Lucas-Kanade method and the Level-Set Motion method, are tested using the constructed phantom. RESULTS Viscoelastic behavior is observed in the constructed deformable gel, which serves as an ideal material for the deformable phantom. The constructed abdominal phantom consists of highly realistic anatomy and the fabricated organs inside have close CT number to its reference patient. DIR accuracy studies conducted on the constructed phantom using three DIR approaches indicate that geometric accuracy of a DIR algorithm has achieved does not guarantee accuracy in dose accumulation. CONCLUSIONS We have designed and constructed an anthropopathic abdominal deformable phantom with satisfactory elastic property, realistic organ density and anatomy. This physical phantom is recyclable and can be used for routine validations of DIR geometric accuracy and dose accumulation accuracy in ART. This work is supported in part by grant from VARIAN MEDICAL SYSTEMS INC, the National Natural Science Foundation of China (no 81428019 and no 81301940), the Guangdong Natural Science Foundation (2015A030313302) and the 2015 Pearl River S&T Nova Program of Guangzhou (201506010096).