Proceedings from the First Global Artificial Intelligence in Gastroenterology and Endoscopy Summit.

BACKGROUND AND AIMS: Artificial intelligence (AI), specifically deep learning, offers the potential to enhance the field of GI endoscopy in areas ranging from lesion detection and classification to quality metrics and documentation. Progress in this field will be measured by whether AI implementation can lead to improved patient outcomes and more efficient clinical workflow for GI endoscopists. The aims of this article are to report the findings of a multidisciplinary group of experts focusing on issues in AI research and applications related to gastroenterology and endoscopy, to review the current status of the field, and to produce recommendations for investigators developing and studying new AI technologies for gastroenterology. METHODS: A multidisciplinary meeting was held on September 28, 2019, bringing together academic, industry, and regulatory experts in diverse fields including gastroenterology, computer and imaging sciences, machine learning, computer vision, U.S. Food and Drug Administration, and the National Institutes of Health. Recent and ongoing studies in gastroenterology and current technology in AI were presented and discussed, key gaps in knowledge were identified, and recommendations were made for research that would have the highest impact in making advances and implementation in the field of AI to gastroenterology. RESULTS: There was a consensus that AI will transform the field of gastroenterology, particularly endoscopy and image interpretation. Powered by advanced machine learning algorithms, the use of computer vision in endoscopy has the potential to result in better prediction and treatment outcomes for patients with gastroenterology disorders and cancer. Large libraries of endoscopic images, "EndoNet," will be important to facilitate development and application of AI systems. The regulatory environment for implementation of AI systems is evolving, but common outcomes such as colon polyp detection have been highlighted as potential clinical trial endpoints. Other threshold outcomes will be important, as well as clarity on iterative improvement of clinical systems. CONCLUSIONS: Gastroenterology is a prime candidate for early adoption of AI. AI is rapidly moving from an experimental phase to a clinical implementation phase in gastroenterology. It is anticipated that the implementation of AI in gastroenterology over the next decade will have a significant and positive impact on patient care and clinical workflows. Ongoing collaboration among gastroenterologists, industry experts, and regulatory agencies will be important to ensure that progress is rapid and clinically meaningful. However, several constraints and areas will benefit from further exploration, including potential clinical applications, implementation, structure and governance, role of gastroenterologists, and potential impact of AI in gastroenterology.

Are Current Technical Exclusion Criteria for Clinical Trials of Magnetic Resonance-Guided High-Intensity Focused Ultrasound Too Restrictive?: Early Experiences at a Pediatric Hospital.

Certain technical criteria must be met to ensure the treatment safety of magnetic resonance-guided high-intensity focused ultrasound. We retrospectively reviewed how our enrollment criteria were applied from 2014 to 2017 in a clinical trial of magnetic resonance-guided high-intensity focused ultrasound ablation of recurrent malignant and locally aggressive benign solid tumors. Among the 36 screened patients between 2014 and 2017, more than one-third were excluded for technical exclusion criteria such as the anatomic location and proximity to prosthetics. Overall, patients were difficult to accrue for this trial, given the incidence of these tumors. To increase potential accrual, screening exclusion criteria could be more generalized and centered on the ability to achieve an acceptable treatment safety margin, rather than specifically excluding on the basis of general anatomic areas.

Radiofrequency Ablation Duration per Tumor Volume May Correlate with Overall Survival in Solitary Hepatocellular Carcinoma Patients Treated with Radiofrequency Ablation Plus Lyso-Thermosensitive Liposomal Doxorubicin.

PURPOSE: To determine whether burn time per tumor volume (BPV) (min/mL), where burn time is the total time during which radiofrequency (RF) energy is being applied, is correlated with hepatocellular carcinoma (HCC) treatment outcomes using RF ablation and lyso-thermosensitive liposomal doxorubicin (LTLD). MATERIALS AND METHODS: The HEAT study was a double-blind, randomized controlled phase III trial of RF ablation only versus RF ablation + LTLD in patients with HCCs 3-7 cm in diameter. Effect of BPV on progression-free survival and overall survival (OS) was analyzed. RESULTS: BPV demonstrated statistically significant differences between study groups for OS (P = .038, hazard ratio [HR] = 0.85), but not for progression-free survival (P = .389, HR = 1.059). In a separate analysis, treatment groups were independently analyzed to determine the effect of BPV within each individual group. OS improved as BPV increased for patients receiving RF ablation + LTLD (P = .017, HR = 0.836, confidence interval [0.722, 0.968]). This same association was not observed in patients receiving RF ablation only (P = .57, HR = 0.99). CONCLUSIONS: BPV may be a useful metric for RF ablation + LTLD combination therapy for solitary HCC. The analysis suggested that the burn time for the tumor needs to be adjusted depending on the tumor volume. Because this is a post hoc study, the results are only suggestive and need to be confirmed with prospective studies.

Technical aspects of osteoid osteoma ablation in children using MR-guided high intensity focussed ultrasound.

BACKGROUND: Osteoid osteoma (OO) is a painful bone tumour occurring in children and young adults. Magnetic resonance imaging-guided high intensity focussed ultrasound (MR-HIFU) allows non-invasive treatment without ionising radiation exposure, in contrast to the current standard of care treatment with radiofrequency ablation (RFA). This report describes technical aspects of MR-HIFU ablation in the first 8 paediatric OO patients treated in a safety and feasibility clinical trial (total enrolment of up to 12 patients). MATERIALS AND METHODS: OO lesions and adjacent periosteum were treated with MR-HIFU ablation in 5-20 sonications (sonication duration = 16-48 s, frequency = 1.2 MHz, acoustic power = 20-160 W). Detailed treatment workflow, patient positioning and coupling strategies, as well as temperature and tissue perfusion changes were summarised and correlated. RESULTS: MR-HIFU ablation was feasible in all eight cases. Ultrasound standoff pads were shaped to conform to extremity contours providing acoustic coupling and aided patient positioning. The energy delivered was 10 ± 7 kJ per treatment, raising maximum temperature to 83 ± 3 °C. Post ablation contrast-enhanced MRI showed ablated volumes ranging 0.46-19.4 cm3 extending further into bone (7 ± 4 mm) than into soft tissue (4 ± 6 mm, p = 0.01, Mann-Whitney). Treatment time ranged 30-86 min for sonication and 160 ± 40 min for anaesthesia. No serious treatment-related adverse events were observed. Complete pain relief with no medication occurred in 7/8 patients within 28 days following treatment. CONCLUSIONS: MR-HIFU ablation of painful OO appears technically feasible in children and it may become a non-invasive and radiation-free alternative for painful OO. Therapy success, efficiency, and applicability may be improved through specialised equipment designed more specifically for extremity bone ablation.

Mechanical fractionation of tissues using microsecond-long HIFU pulses on a clinical MR-HIFU system.

PURPOSE: High intensity focussed ultrasound (HIFU) can non-invasively treat tumours with minimal or no damage to intervening tissues. While continuous-wave HIFU thermally ablates target tissue, the effect of hundreds of microsecond-long pulsed sonications is examined in this work. The objective of this study was to characterise sonication parameter-dependent thermomechanical bioeffects to provide the foundation for future preclinical studies and facilitate clinical translation. METHODS AND MATERIALS: Acoustic power, number of cycles/pulse, sonication time and pulse repetition frequency (PRF) were varied on a clinical magnetic resonance imaging (MRI)-guided HIFU (MR-HIFU) system. Ex vivo porcine liver, kidney and cardiac muscle tissue samples were sonicated (3 × 3 grid pattern, 1 mm spacing). Temperature, thermal dose and T2 relaxation times were quantified using MRI. Lesions were histologically analysed using H&E and vimentin stains for lesion structure and viability. RESULTS: Thermomechanical HIFU bioeffects produced distinct types of fractionated tissue lesions: solid/thermal, paste-like and vacuolated. Sonications at 20 or 60 Hz PRF generated substantial tissue damage beyond the focal region, with reduced viability on vimentin staining, whereas H&E staining indicated intact tissue. Same sonication parameters produced dissimilar lesions in different tissue types, while significant differences in temperature, thermal dose and T2 were observed between the parameter sets. CONCLUSION: Clinical MR-HIFU system was utilised to generate distinct types of lesions and to produce targeted thermomechanical bioeffects in ex vivo tissues. The results guide HIFU research on thermomechanical tissue bioeffects, inform future studies and advice sonication parameter selection for direct tumour ablation or immunomodulation using a clinical MR-HIFU system.

Ezrin Inhibition Up-regulates Stress Response Gene Expression.

Ezrin is a member of the ERM (ezrin/radixin/moesin) family of proteins that links cortical cytoskeleton to the plasma membrane. High expression of ezrin correlates with poor prognosis and metastasis in osteosarcoma. In this study, to uncover specific cellular responses evoked by ezrin inhibition that can be used as a specific pharmacodynamic marker(s), we profiled global gene expression in osteosarcoma cells after treatment with small molecule ezrin inhibitors, NSC305787 and NSC668394. We identified and validated several up-regulated integrated stress response genes including PTGS2, ATF3, DDIT3, DDIT4, TRIB3, and ATF4 as novel ezrin-regulated transcripts. Analysis of transcriptional response in skin and peripheral blood mononuclear cells from NSC305787-treated mice compared with a control group revealed that, among those genes, the stress gene DDIT4/REDD1 may be used as a surrogate pharmacodynamic marker of ezrin inhibitor compound activity. In addition, we validated the anti-metastatic effects of NSC305787 in reducing the incidence of lung metastasis in a genetically engineered mouse model of osteosarcoma and evaluated the pharmacokinetics of NSC305787 and NSC668394 in mice. In conclusion, our findings suggest that cytoplasmic ezrin, previously considered a dormant and inactive protein, has important functions in regulating gene expression that may result in down-regulation of stress response genes.

Comparison of Noninvasive High-Intensity Focused Ultrasound with Radiofrequency Ablation of Osteoid Osteoma.

OBJECTIVE: To evaluate clinical feasibility and safety of magnetic resonance imaging-guided high-intensity focused ultrasound (MR-HIFU) treatment of symptomatic osteoid osteoma and to compare clinical response with standard of care treatment. STUDY DESIGN: Nine subjects with radiologically confirmed, symptomatic osteoid osteoma were treated with MR-HIFU in an institutional review board-approved clinical trial. Treatment feasibility and safety were assessed. Clinical response was evaluated in terms of analgesic requirement, visual analog scale pain score, and sleep quality. Anesthesia, procedure, and recovery times were recorded. This MR-HIFU group was compared with a historical control group of 9 consecutive patients treated with radiofrequency ablation. RESULTS: Nine subjects (7 male, 2 female; 16 ± 6 years) were treated with MR-HIFU without technical difficulties or any serious adverse events. There was significant decrease in their median pain scores 4 weeks within treatment (6 vs 0, P < .01). Total pain resolution and cessation of analgesics were achieved in 8 of 9 patients after 4 weeks. In the radiofrequency ablation group, 9 patients (8 male, 1 female; 10 ± 6 years) were treated in routine clinical practice. All 9 demonstrated complete pain resolution and cessation of medications by 4 weeks with a significant decrease in median pain scores (9 vs 0, P < .001). One developed a second-degree skin burn, but there were no other adverse events. Procedure times and treatment charges were comparable between the 2 groups. CONCLUSION: This pilot study shows that MR-HIFU treatment of osteoid osteoma refractory to medical therapy is feasible and can be performed safely in pediatric patients. Clinical response is comparable with standard of care treatment but without any incisions or exposure to ionizing radiation. TRIAL REGISTRATION: ClinicalTrials.govNCT02349971.

Safely assessing radiofrequency heating potential of conductive devices using image-based current measurements.

PURPOSE: Many procedures involving catheters and implanted medical devices could benefit from MRI guidance but are currently contraindicated due to risk of significant heating near linear conductive structures. A priori safety prediction is impossible in vivo and thus, safety is typically investigated in vitro by directly measuring temperature rise. Existing methods of investigating safety are inflexible and provide few data. Furthermore, they are fundamentally limited because dangerous temperatures rises can only be investigated if induced. A method of remotely predicting safety is necessary for ensuring safety in patients. THEORY AND METHODS: Electric current induced on the metallic object causes any dangerous heating; thus a remote method of safely characterizing the induced radiofrequency (RF) current distribution would suffice to evaluate safety assuming conservative estimates for local tissue properties. Here we propose a method of analyzing induced phase artifacts seen in low-specific absorption rate characterization images, to determine induced current on an interventional device. This induced current distribution can then be used to predict RF heating behavior under application of any other imaging sequence. RESULTS: This method has been successfully used to reproduce numerical simulations in a phantom. Furthermore, the heating behavior around a conductive wire produced by a scan other than that used to characterize current was successfully predicted. CONCLUSION: It has been shown in phantom experiments that remote current characterization can safely prevent dangerous scans as well as enable safe scans that previously would not have been attempted.

Human papillomavirus type 16 E7 oncoprotein upregulates the retinoic acid receptor-beta expression in cervical cancer cell lines and K14E7 transgenic mice.

Persistent infection with high-risk human papillomaviruses is the main etiological factor in cervical cancer (CC). The human papillomavirus type 16 (HPV16) E7 oncoprotein alters several cellular processes, regulating the expression of many genes in order to avoid cell cycle control. Retinoic acid receptor beta (RARB) blocks cell growth, inducing differentiation and apoptosis. This tumor suppressor gene is gradually silenced in late passages of foreskin keratinocytes immortalized with HPV16 and in various tumors, including CC, mainly by epigenetic modifications. We investigated the effect of E7 oncoprotein on RARB gene expression. We found that HPV16 E7 increases RARB mRNA and RAR-beta protein expression both in vitro and in the cervix of young K14E7 transgenic mice. In E7-expressing cells, RARB overexpression is further increased in the presence of the tumor suppressor p53 (TP53) R273C mutant. This effect does not change when either C33-A or E7-expressing C33-A cell line is treated with Trichostatin A, suggesting that E7 enhances RARB expression independently of histone deacetylases inhibition. These findings indicate that RARB overexpression is part of the early molecular events induced by the E7 oncoprotein.

COVID-19 Detection From Respiratory Sounds With Hierarchical Spectrogram Transformers.

Monitoring of prevalent airborne diseases such as COVID-19 characteristically involves respiratory assessments. While auscultation is a mainstream method for preliminary screening of disease symptoms, its utility is hampered by the need for dedicated hospital visits. Remote monitoring based on recordings of respiratory sounds on portable devices is a promising alternative, which can assist in early assessment of COVID-19 that primarily affects the lower respiratory tract. In this study, we introduce a novel deep learning approach to distinguish patients with COVID-19 from healthy controls given audio recordings of cough or breathing sounds. The proposed approach leverages a novel hierarchical spectrogram transformer (HST) on spectrogram representations of respiratory sounds. HST embodies self-attention mechanisms over local windows in spectrograms, and window size is progressively grown over model stages to capture local to global context. HST is compared against state-of-the-art conventional and deep-learning baselines. Demonstrations on crowd-sourced multi-national datasets indicate that HST outperforms competing methods, achieving over 90% area under the receiver operating characteristic curve (AUC) in detecting COVID-19 cases.

Effects of Transcranial Direct Current Stimulation on Motor and Cognitive Dysfunction in an Experimental Traumatic Brain Injury Model.

AIM: To investigate the therapeutic and neuroprotective effects of transcranial direct current stimulation (tDCS) application on the traumatic brain injury (TBI)-induced glutamate and calcium excitotoxicity and loss of motor and cognitive functions. MATERIAL AND METHODS: Forty rats were equally divided in the sham, TBI, tDCS + TBI + tDCS, and TBI + tDCS groups. Mild TBI was induced by dropping a 450-g iron weight from a height of 1 m onto the skull of the rats. The tDCS + TBI + tDCS group was prophylactically administered 1 mA stimulation for 30 min for 7 days starting 5 days before inducing TBI. In the TBI + tDCS group, tDCS (1 mA for 30 min) was administered 2 h after TBI, on days 1 and 2. Cognitive and locomotor functions were assessed using the novel object recognition and open field tests. The calcium, glutamate, and N-methyl-D-aspartate receptor 1 (NMDAR1) levels in the hippocampus were measured using enzyme-linked immunosorbent assay. RESULTS: Although the motor and cognitive functions were substantially reduced in the TBI group when compared with the sham, they improved in the treatment groups (p < 0.05). The calcium, glutamate, and NMDAR1 levels were considerably higher in the TBI group than in the sham (p < 0.001). However, they were considerably lower in the tDCS + TBI + tDCS and TBI + tDCS groups than in the TBI groups (p < 0.05). In particular, the change in the tDCS + TBI + tDCS group was higher than that in the TBI + tDCS group. CONCLUSION: Application of tDCS before the development of TBI improved motor and cognitive dysfunction. It demonstrated a neuroprotective and therapeutic effect by reducing the excitotoxicity via the regulation of calcium and glutamate levels.

Retrospective Evaluation of Patients with Spontaneous Intracerebral Hematomas

AIM: To investigate the relationship among the modified Rankin scores of patients who had intracerebral hematomas at discharge, demographic characteristics of the patients, and the characteristics of the hematoma. MATERIAL AND METHODS: In this study, patients diagnosed with intracerebral hematoma and treated at the Ministry of Health Ankara Training and Research Hospital Neurosurgery Clinic between January 2010 and December 2020 were examined retrospectively. The age, gender, comorbidity, anticoagulant?antiaggregant use, and Glasgow Coma Scale score of the patients were obtained from hospital records. The modified Rankin scale (mRS) was used to assess patients at discharge. RESULTS: Herein, a total of 114 patients with supratentorial intracerebral hematoma were evaluated. The modified Rankin score ranged from 0 to 6, with a mean score of 3.47 ± 2.26. When the patients were evaluated based on their discharge status, the mortality rate was 33.3% (n=38). Fifty percent of the patients who used anticoagulant?antiaggregant died. High mRS scores were seen more frequently in advanced age. Among the other diseases of the patients, hypertension and the use of anticoagulant? antiaggregant were found to be statistically significant with high mRS scores (p < 0.001). Patients with low Glasgow Coma Scale score at the time of admission had significantly higher mRS scores (p < 0.001). CONCLUSION: Patients with advanced age, hypertension, and anticoagulant?antiaggregant use had a higher mRS score after hematoma formation. Preventable risk factors for spontaneous intraparenchymal hematomas are among the leading causes of disability, and early detection and treatment of underlying diseases are critical for hematoma prevention. Awareness about risk factors should be the priority to improve early diagnosis and reduce treatment disability rates.

Factors Affecting Resorption Following Cranioplasty with an Autologous Bone Graft.

AIM: To evaluate the relationship between the surgical techniques, the waiting time for surgery, postoperative distance between the graft-bone margin and the percentage of bone resorption, we analyzed patients who underwent cranioplasty. Cranioplasty is a necessary surgery to preserve brain tissue and provide an appropriate microenvironment. MATERIAL AND METHODS: In this study, patients who underwent autologous bone grafting after decompressive craniectomy by the Neurosurgery Clinic of University of Health Sciences Ankara Training and Research Hospital between 2018 and 2021 were examined. RESULTS: Thirty-nine patients who underwent autologous cranioplasty following decompressive craniectomy were included in the study. The average expected time for cranioplasty surgery following decompressive craniectomy was 16.97±13.478 weeks (min:2 max:62 weeks). The expected time between decompressive craniectomy and cranioplasty surgeries and resorption rates were compared. The resorption rate was above 30% in 7 of 10 patients with 24 weeks or more between craniectomy and cranioplasty, and less than 30% in 17 of 25 patients in surgeries less than 24 weeks (p=0.04). Following cranioplasty surgery, the distance between the graft-bone margin and the resorption rates were also compared. In this analysis, statistically significant differences were detected between the distance between the graft-bone border and the resorption rates. Resorption rates increased in 15 of 19 patients with a postcranioplasty distance of 1 mm or more (p < 0.00001). CONCLUSION: Early cranioplasty surgery is important in order to reduce complications that may occur after craniectomy. In addition, it is important to keep the defect area small in size during craniectomy surgery and to keep the cutting edge thinner when the bone graft is taken, in order to reduce the development of bone graft resorption.

Evaluation of bioreductive activation of anticancer drugs idarubicin and mitomycin C by NADH-cytochrome b5 reductase and cytochrome P450 2B4.

This study attempted to investigate the ability of microsomal NADH-cytochrome b5 reductase and cytochrome P450 2B4 to reductively activate idarubicin and mitomycin C. In vitro plasmid DNA damage experiments and assays using purified hepatic enzymes were employed to examine their respective roles in the metabolic activation of anticancer drugs. Mitomycin C was found to be not a good substrate for microsomal b5 reductase unlike P450 reductase. It produced low amounts of strand breaks in DNA when incubated with b5 reductase and its one-electron reduction by purified enzyme was found as negligible. Our findings revealed that P450 reductase-mediated metabolism of idarubicin resulted in a large increase in single-strand DNA breaks, whereas, b5 reductase neither catalyzed the reduction of idarubicin nor mediated the formation of DNA damage in the presence of idarubicin. The reconstitution studies, on the other hand, have identified rabbit liver CYP2B4 isozyme as being a potential candidate enzyme for reductive bioactivation of idarubicin and mitomycin C. Thus, the present novel findings strongly suggest that while b5 reductase could not play a key role in the cytotoxic and/or antitumor effects of idarubicin and mitomycin C, CYP2B4 could potentiate their activity in combination with P450 reductase.

Mucosa-Associated Lymphoid Tissue Lymphoma With Lymphomeningothelial Lesion of the Dura.

Mucosa-associated lymphoid tissue (MALT) was first described as low-grade lymphoma associated with the stomach mucosa. Although the stomach and ocular adnexa are the most common localizations of MALT lymphoma, it has also been described in many other organs, including the head and neck, lungs, thyroid, breast, bladder, saliva glands, conjunctiva, and tear glands. MALT lymphoma originating from the dura is rare. The case is here presented of an 83-year-old female operated on with an initial diagnosis of acute subdural hematoma. In the histopathological examination, there was seen to be lymphoplasmacytic infiltration of the dura and a lymphomeningothelial lesion. Immunohistochemically, low-grade MALT lymphoma showing B-cell phenotype was considered. This is the first reported case of lymphomeningothelial lesion in MALT lymphoma originating from the dura.

Reverse polarized inductive coupling to transmit and receive radiofrequency coil arrays.

In this study, the reverse polarization method is implemented using transmit and receive arrays to improve the visibility of the interventional devices. Linearly polarized signal sources--inductively and receptively coupled radiofrequency coils--are used in the experimental setups to demonstrate the ability of the method to separate these sources from a forward polarized anatomy signal. Two different applications of the reverse polarization method are presented here: (a) catheter tracking and (b) fiducial marker visualization, in both of which transmit and receive arrays are used. The performance of the reverse polarization method was further tested with phantom and volunteer studies, and the results proved the feasibility of this method with transmit and receive arrays.

The Comparison of Autologous Bone, Methyl-Methacrylate, Porous Polyethylene, and Titanium Mesh in Cranioplasty.

AIM: To discuss four different materials that are frequently used in cranioplasty, and to reveal their advantages and disadvantages. MATERIAL AND METHODS: We retrospectively reviewed 85 of our cranioplasty surgeries between 2016 and 2019. Reconstruction surgeries were excluded from our study due to craniofacial trauma. RESULTS: Of the materials used in cranioplasty, 33 are autologous bone, 32 are methyl-methacrylate, 12 are porous polyethylene, and 8 are titanium mesh. Complications developed in 16 patients. Of these, 10 are infection, 3 are flap collapse, 2 are wound healing disorders, and 1 is reactive effusion complications due to the used material. The highest complication rate was 21.9% in cranioplasty with methyl-methacrylate. No major complications were observed in cranioplasty with titanium mesh. CONCLUSION: Cranioplasty, which are among the surgeries with high complications in neurosurgery, maintain their importance today. As technology is developed and cost problems are resolved, cranioplasty takes its place among the safer and standard neurosurgical operations.

Integrating Eye Tracking and Speech Recognition Accurately Annotates MR Brain Images for Deep Learning: Proof of Principle.

PURPOSE: To generate and assess an algorithm combining eye tracking and speech recognition to extract brain lesion location labels automatically for deep learning (DL). MATERIALS AND METHODS: In this retrospective study, 700 two-dimensional brain tumor MRI scans from the Brain Tumor Segmentation database were clinically interpreted. For each image, a single radiologist dictated a standard phrase describing the lesion into a microphone, simulating clinical interpretation. Eye-tracking data were recorded simultaneously. Using speech recognition, gaze points corresponding to each lesion were obtained. Lesion locations were used to train a keypoint detection convolutional neural network to find new lesions. A network was trained to localize lesions for an independent test set of 85 images. The statistical measure to evaluate our method was percent accuracy. RESULTS: Eye tracking with speech recognition was 92% accurate in labeling lesion locations from the training dataset, thereby demonstrating that fully simulated interpretation can yield reliable tumor location labels. These labels became those that were used to train the DL network. The detection network trained on these labels predicted lesion location of a separate testing set with 85% accuracy. CONCLUSION: The DL network was able to locate brain tumors on the basis of training data that were labeled automatically from simulated clinical image interpretation.© RSNA, 2020.

Clofarabine induces ERK/MSK/CREB activation through inhibiting CD99 on Ewing sarcoma cells.

Clofarabine, an FDA approved purine analog, is used in the treatment of relapsed or refractory acute lymphoblastic leukemia. Clofarabine acts by inhibiting DNA synthesis. We demonstrated that clofarabine may have a novel function though inhibiting CD99, a transmembrane protein highly expressed on Ewing Sarcoma (ES) cells. CD99 is a validated target in ES whose inhibition may lead to a high therapeutic index for patients. Here we present additional data to support the hypothesis that clofarabine acts on CD99 and regulates key signaling pathways in ES. Cellular thermal shift assay indicated a direct interaction between clofarabine and CD99 in ES cell lysates. Clofarabine induced ES cell death does not require clofarabine's conversion to its active form by deoxycytidine kinase. A phosphokinase array screen with clofarabine and a CD99 blocking antibody identified alterations in signaling pathways. CD99 inhibition with clofarabine in ES cells caused rapid and sustained phosphorylation of ERK, MSK, and CREB. However, activation of this pathway did not correlate with clofarabine induced ES cell death. In summary, we demonstrated that clofarabine may activate ERK, MSK, and CREB phosphorylation through CD99 within minutes, however this paradoxical activation and subsequent ES cell death requires additional investigation.

Evaluation of the protective effects of quercetin, rutin, naringenin, resveratrol and trolox against idarubicin-induced DNA damage.

PURPOSE: Idarubicin is a synthetic anthracycline anticancer drug widely used in the treatment of some hematological malignancies. The studies in our laboratory have clearly demonstrated that idarubicin can undergo reductive bioactivation by NADPH-cytochrome P450 reductase to free radicals with resulting formation of DNA strand breaks, which can potentially contribute to its genotoxic effects [Celik, H., Arinç, E., Bioreduction of idarubicin and formation of ROS responsible for DNA cleavage by NADPH-cytochrome P450 reductase and its potential role in the antitumor effect. J Pharm Pharm Sci, 11(4):68-82, 2008]. In the current study, our aim was to investigate the possible protective effects of several phenolic antioxidants, quercetin, rutin, naringenin, resveratrol and trolox, against the DNA-damaging effect of idarubicin originating from its P450 reductase-catalyzed bioactivation. METHODS: DNA damage was measured by detecting single-strand breaks in plasmid pBR322 DNA using a cell-free agarose gel method. RESULTS: Our results indicated that, among the compounds tested, quercetin was the most potent antioxidant in preventing DNA damage. Quercetin significantly decreased the extent of DNA strand breaks in a dose-dependent manner; 100 microM of quercetin almost completely inhibited the DNA strand breakage. Unlike quercetin, its glycosidated conjugate rutin, failed to provide any significant protection against idarubicin-induced DNA strand breaks except at the highest concentration tested (2 mM). The protective effects of other antioxidants were significantly less than that of quercetin even at high concentrations. Quercetin was found to be also an effective protector against DNA damage induced by mitomycin C. CONCLUSION: We conclude that quercetin, one of the most abundant flavonoids in the human diet, is highly effective in reducing the DNA damage caused by the antitumor agents, idarubicin and mitomycin C, following bioactivation by P450 reductase.