Development and evaluation of ultrasound image tracking technology based on Mask R-CNN applied to respiratory motion compensation system.

Background: For respiration induced tumor displacement during a radiation therapy, a common method to prevent the extra radiation is image-guided radiation therapy. Moreover, mask region-based convolutional neural networks (Mask R-CNN) is one of the state-of-the-art (SOTA) object detection frameworks capable of conducting object classification, localization, and pixel-level instance segmentation. Methods: We developed a novel ultrasound image tracking technology based on Mask R-CNN for stable tracking of the detected diaphragm motion and applied to the respiratory motion compensation system (RMCS). For training Mask R-CNN, 1800 ultrasonic images of the human diaphragm are collected. Subsequently, an ultrasonic image tracking algorithm was developed to compute the mean pixel coordinates of the diaphragm detected by Mask R-CNN. These calculated coordinates are then utilized by the RMCS for compensation purposes. The tracking similarity verification experiment of mask ultrasonic imaging tracking algorithm (M-UITA) is performed. Results: The correlation between the input signal and the signal tracked by M-UITA was evaluated during the experiment. The average discrete Fréchet distance was less than 4 mm. Subsequently, a respiratory displacement compensation experiment was conducted. The proposed method was compared to UITA, and the compensation rates of three different respiratory signals were calculated and compared. The experimental results showed that the proposed method achieved a 6.22% improvement in compensation rate compared to UITA. Conclusions: This study introduces a novel method called M-UITA, which offers high tracking precision and excellent stability for monitoring diaphragm movement. Additionally, it eliminates the need for manual parameter adjustments during operation, which is an added advantage.

Effectiveness of Stereotactic Ablative Radiotherapy for Systemic Therapy Respondents with Inoperable Pulmonary Oligometastases and Oligoprogression.

Stereotactic ablative radiotherapy (SABR) may improve survival in patients with inoperable pulmonary oligometastases. However, the impact of pulmonary oligometastatic status after systemic therapy on SABR outcomes remains unclear. Hence, we investigated the outcomes of SABR in 45 patients with 77 lung tumors and the prognostic value of pulmonary oligoprogression. Eligibility criteria were pulmonary oligometastases (defined as ≤5 metastatic lung tumors), controlled extrapulmonary disease (EPD) after front-line systemic therapy, SABR as primary local treatment for inoperable pulmonary metastases, and consecutive imaging follow-up. Oligometastatic lung tumor was classified into controlled or oligoprogressive status. Overall survival (OS), in-field progression-free survival (IFPFS), out-field progression-free survival (OFPFS), and prognostic variables were evaluated. With 21.8 months median follow-up, the median OS, IFPFS, and OFPFS were 28.3, not reached, and 6.5 months, respectively. Two-year OS, IFPFS, and OFPFS rates were 56.0%, 74.2%, and 17.3%, respectively. Oligoprogressive status (p = 0.003), disease-free interval < 24 months (p = 0.041), and biologically effective dose (BED10) < 100 Gy (p = 0.006) were independently associated with inferior OS. BED10 ≥ 100 Gy (p = 0.029) was independently correlated with longer IFPFS. Oligoprogressive status (p = 0.017) and EPD (p = 0.019) were significantly associated with inferior OFPFS. Grade ≥ 2 radiation pneumonitis occurred in four (8.9%) patients. Conclusively, SABR with BED10 ≥ 100 Gy could provide substantial in-field tumor control and longer OS for systemic therapy respondents with inoperable pulmonary oligometastases. Oligoprogressive lung tumors exhibited a higher risk of out-field treatment failure and shorter OS. Hence, systemic therapy should be tailored for patients with oligoprogression to reduce the risk of out-field treatment failure. However, in the absence of effective systemic therapy, SABR is a reasonable alternative to reduce resistant tumor burden.

Normoxically overexpressed hypoxia inducible factor 1-alpha is involved in arsenic trioxide resistance acquisition in hepatocellular carcinoma.

BACKGROUND: The aim of this study was to examine the underlying signaling mechanisms of arsenic trioxide (ATO)-mediated anticancer effects and the responsible biomarker(s) for the acquired resistance in human heptatocellular carcinoma (HCC). MATERIALS AND METHODS: The therapeutic effects of ATO were examined using 2 characteristically distinct HCC cell lines, Hep-J5 (overexpressing HIF-1α/GRP78) and SK-Hep-1 (the matched control). ATO-mediated proliferation inhibition, oxidative stress, and apoptosis were analyzed using flowcytometric analysis and western blotting. The role of HIF-1α and GRP78 in HCC resistance to ATO treatment was determined using RNA silencing and inhibitor approaches. RESULTS: SK-Hep-1 cells, lacking both HIF-1α and GRP78 expressions were responsive to ATO-induced apoptosis via an oxidative-nitrosative mechanism. Intracellular glutathione depletion and lipid peroxidation have been identified as the early cascade of events preceding apoptosis via cytochrome c release and the severe drop of mitochondrial membrane potential (MMP). Conversely, Hep-J5 cells, with normoxic coexpression of HIF-1α and GRP78, were resistant to ATO-induced apoptosis. GRP78-silenced Hep-J5 cells remained resistant to ATO treatment. In contrast, ATO resistance in Hep-J5 cells was overcome by the addition of YC-1, a HIF-1α inhibitor. CONCLUSIONS: HIF-1α was identified as the major positive modifier for ATO resistance acquisition in HCC, and it represents a prime molecular target for overcoming ATO resistance.

Effects of functional electrical stimulation on dysphagia caused by radiation therapy in patients with nasopharyngeal carcinoma.

PURPOSE: This study aimed to assess the effectiveness of functional electrical stimulation on the swallowing function of irradiated nasopharyngeal carcinoma patients with dysphagia. MATERIALS AND METHODS: Twenty nasopharyngeal carcinoma subjects with dysphagia were divided into a functional electrical stimulation (FES) and a home rehabilitation program (HRP) group. Each subject completed a quality of life questionnaire on swallowing and a videofluoroscopic study at the commencement and the end of the procedures. The FES group received functional electrical stimulation of the supra-hyoid muscles over 15 sessions. The HRP group performed self-swallowing exercises at home. The evaluation parameters included the quality of life questionnaire scores, the penetration-aspiration scale (PAS), the movement of the hyoid bone, and the amount of pyriform sinuses stasis. RESULTS: Most swallowing outcomes of the FES group improved after FES. The quality of life score (p=0.003), the duration of the movement of thin barium through the hyoid (p=0.001), the moving speed of paste barium through the hyoid (p=0.028), and the pyriform sinus stasis area of the paste barium (p=0.026) reached significant difference in the FES group. Most swallowing outcomes did not improve in the HRP group. The degree of improvement in the movement speed of the hyoid bone in the thin barium (p=0.018) and the PAS of the paste barium (p=0.016) were statistically significantly greater in the FES group than in the HRP group. CONCLUSION: FES will improve the swallowing function of NPC patients with dysphagia and bring about better quality of life.

A 2-year follow-up of swallowing function after radiation therapy in patients with nasopharyngeal carcinoma.

OBJECTIVE: To evaluate over a 2-year period the serial swallowing function of patients with nasopharyngeal carcinoma (NPC) after completing radiotherapy (RT). DESIGN: Prospective longitudinal follow-up. SETTING: University hospital. PARTICIPANTS: Patients with NPC (N=76) referred for RT: 53 of them at 1 year after RT, and 23 at 2 years after RT. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Participants completed a questionnaire and had a video-recorded fluoroscopic swallowing study before RT and 1 month, 1 year, and 2 years after RT. RESULTS: The highest incidence of dysphagia symptoms and retropharyngeal soft tissue swelling occurred in the first month after RT and decreased over time. Pharyngeal transit time was prolonged continuously up to 1 year after RT. Epiglottic vallecular stasis and pharyngeal mucosal coating were worst in the first month after RT and stable afterwards. Aspiration was uncommon during the first 2 years after RT. CONCLUSIONS: At a 2-year follow-up after RT, patients with NPC had a progressively increasing pharyngeal transit time, although the subjectively identified symptoms of dysphagia decreased after the first month after RT.

The feasibility of an approximate irregular field dose distribution simulation program applied to a respiratory motion compensation system.

PURPOSE: This study optimized our previously proposed simulation program for the approximate irregular field dose distribution (SPAD) and applied it to a respiratory motion compensation system (RMCS) and respiratory motion simulation system (RMSS). The main purpose was to rapidly analyze the two-dimensional dose distribution and evaluate the compensation effect of the RMCS during radiotherapy. METHODS: This study modified the SPAD to improve the rapid analysis of the dose distribution. In the experimental setup, four different respiratory signal patterns were input to the RMSS for actuation, and an ultrasound image tracking algorithm was used to capture the real-time respiratory displacement, which was input to the RMCS for actuation. A linear accelerator simultaneously irradiated the EBT3 film. The gamma passing rate was used to verify the dose similarity between the EBT3 film and the SPAD, and conformity index (CI) and compensation rate (CR) were used to quantify the compensation effect. RESULTS: The Gamma passing rates were 70.48-81.39% (2%/2mm) and 88.23-96.23% (5%/3mm) for various collimator opening patterns. However, the passing rates of the SPAD and EBT3 film ranged from 61.85% to 99.85% at each treatment time point. Under the four different respiratory signal patterns, CR ranged between 21% and 75%. After compensation, the CI for 85%, 90%, and 95% isodose constraints were 0.78, 0.57, and 0.12, respectively. CONCLUSIONS: This study has demonstrated that the dose change during each stage of the treatment process can be analyzed rapidly using the improved SPAD. After compensation, applying the RMCS can reduce the treatment errors caused by respiratory movements.

Ex Vivo Expanded Circulating Tumor Cells for Clinical Anti-Cancer Drug Prediction in Patients with Head and Neck Cancer.

The advanced-stage head and neck cancer (HNC) patients respond poorly to platinum-based treatments. Thus, a reliable pretreatment method for evaluating platinum treatment response would improve therapeutic efficiency and outcomes. This study describes a novel strategy to predict clinical drug responses in HNC patients by using eSelect, a lab-developed biomimetic cell culture system, which enables us to perform ex vivo expansion and drug sensitivity profiling of circulating tumor cells (CTCs). Forty liquid biopsies were collected from HNC patients, and the CTCs were expanded ex vivo using the eSelect system within four weeks. Immunofluorescence staining confirmed that the CTC-derived organoids were positive for EpCAM and negative for CD45. Two illustrative cases present the potential of this strategy for evaluating treatment response. The statistical analysis confirmed that drug sensitivity in CTC-derived organoids was associated with a clinical response. The multivariant logistic regression model predicted that the treatment accuracy of chemotherapy responses achieved 93.75%, and the area under the curves (AUCs) of prediction models was 0.8841 in the whole dataset and 0.9167 in cisplatin specific dataset. In summary, cisplatin sensitivity profiles of patient-derived CTCs expanded ex vivo correlate with a clinical response to cisplatin treatment, and this can potentially underpin predictive assays to guide HNC treatments.

Tumor motion tracking based on a four-dimensional computed tomography respiratory motion model driven by an ultrasound tracking technique.

BACKGROUND: An ultrasound image tracking algorithm (UITA) was combined with four-dimensional computed tomography (4DCT) to create a real-time tumor motion-conversion model. The real-time position of a lung tumor phantom based on the real-time diaphragm motion trajectories detected by ultrasound imaging in the superior-inferior (SI) and medial-lateral (ML) directions were obtained. METHODS: Three different tumor motion-conversion models were created using a respiratory motion simulation system (RMSS) combined with 4DCT. The tumor tracking error was verified using cone-beam computed tomography (CBCT). The tumor motion-conversion model was produced by using the UITA to monitor the motion trajectories of the diaphragm phantom in the SI direction, and using 4DCT to monitor the motion trajectories of the tumor phantom in the SI and ML directions over the same time period, to obtain parameters for the motion-conversion model such as the tumor center position and the amplitude and phase ratios. RESULTS: The tumor movement was monitored for 90 s using CBCT to determine the real motion trajectories of the tumor phantom and using ultrasound imaging to simultaneously record the diaphragm movement. The absolute error of the motion trajectories of the real and estimated tumor varied between 0.5 and 2.1 mm in the two directions. CONCLUSIONS: This study has demonstrated the feasibility of using ultrasound imaging to track diaphragmatic motion combined with a 4DCT tumor motion-conversion model to track tumor motion in the SI and ML directions. The proposed method makes tracking a lung tumor feasible in real time, including under different breathing conditions.

Simulating the approximate irregular field dose distribution in radiotherapy using an ultrasound tracking technique.

PURPOSE: This study used an ultrasound image tracking algorithm (UITA) in combination with a proposed simulation program for the approximate irregular field dose distribution (SPAD) to assess the feasibility of performing dose distribution simulations for two-dimensional radiotherapy. METHODS: This study created five different types of multileaf collimator openings, and applied a SPAD to analyze the matrix position parameters for each regular field to generate a static program-simulation dose distribution map (PDDM), whose similarity was then compared with a static radiochromic film experimental-measurement dose distribution map (EDDM). A two-dimensional respiration motion simulation system (RMSS) was used to reproduce the respiration motion, and the UITA was used to capture the respiration signals. Respiration signals were input to the SPAD to generate two dynamic PDDMs, which were compared for similarity with the dynamic EDDM. RESULTS: In order to verify the dose distribution between different dose measurement techniques, the gamma passing rate with 2%/2 mm criterion was used for the EDDM and PDDM, the passing rates were between 94.31% and 99.71% in the static field analyses, and between 84.45% and 96.09% for simulations with the UITA signal input and between 89.35% and 97.78% for simulations with the original signal input in the dynamic field analyses. CONCLUSIONS: Static and dynamic dose distribution maps can be simulated based on the proposed matrix position parameters of various fields and by using the UITA to track respiration signals during radiation therapy. The present findings indicate that it is possible to develop a reusable and time-saving dose distribution measurement tool.

Chemoradiotherapy for Inoperable Carotid Body Leiomyosarcoma: A Case Report and Review of Literature.

Vascular leiomyosarcoma is an extremely rare tumor and is associated with poor prognosis among leiomyosarcoma. Surgical resection remains the main treatment option. But outcome of definitive treatment with chemoradiotherapy in inoperable patients is not clear. Here, we report treatment and outcome of definitive chemoradiotherapy in a case of vascular leiomyosarcoma. A 64-year-old man with the initial presentation of pulsatile right neck mass was diagnosed with right carotid body leiomyosarcoma. He refused surgical intervention due to risk of carotid body injury and ischemic stroke. Successful tumor control was achieved with carboplatin-based concurrent chemoradiotherapy. Investigational liquid biopsy for circulating sarcoma cells was also performed to analyze drug sensitivity profile of this rare tumor. One year after treatment, the disease remained well controlled and there was no evidence of baroreflex failure or treatment-related late toxicities. To our best knowledge, this is the first case report of right carotid body leiomyosarcoma controlled with definitive concurrent chemoradiotherapy. The approach of personalized multi-modality treatment will be a focus of our future investigation.

A Combined Systemic Strategy for Overcoming Cisplatin Resistance in Head and Neck Cancer: From Target Identification to Drug Discovery.

Cisplatin is the first-line chemotherapy agent for head and neck cancer (HNC), but its therapeutic effects are hampered by its resistance. In this study, we employed systemic strategies to overcome cisplatin resistance (CR) in HNC. CR cells derived from isogenic HNC cell lines were generated. The CR related hub genes, functional mechanisms, and the sensitizing candidates were globally investigated by transcriptomic and bioinformatic analyses. Clinically, the prognostic significance was assessed by the Kaplan-Meier method. Cellular and molecular techniques, including cell viability assay, tumorsphere formation assay, RT-qPCR, and immunoblot, were used. Results showed that these CR cells possessed highly invasive and stem-like properties. A total of 647 molecules was identified, and the mitotic division exhibited a novel functional mechanism significantly related to CR. A panel of signature molecules, MSRB3, RHEB, ULBP1, and spindle pole body component 25 (SPC25), was found to correlate with poor prognosis in HNC patients. SPC25 was further shown as a prominent molecule, which markedly suppressed cancer stemness and attenuated CR after silencing. Celastrol, a nature extract compound, was demonstrated to effectively inhibit SPC25 expression and reverse CR phenotype. In conclusion, the development of SPC25 inhibitors, such as the application of celastrol, maybe a novel strategy to sensitize cisplatin for the treatment of refractory HNC.

Ex Vivo Expansion and Drug Sensitivity Profiling of Circulating Tumor Cells from Patients with Small Cell Lung Cancer.

Small cell lung cancer (SCLC) represents one of the most aggressive malignancies among cancer types. Not only tumor sample availability is limited, but also the ability for tumor cells to rapidly acquire drug resistance are the rate-limiting bottlenecks for overall survival in current clinical settings. A liquid biopsy capable of capturing and enriching circulating tumor cells (CTCs), together with the possibility of drug screening, is a promising solution. Here, we illustrate the development of a highly efficient ex vivo CTC expansion system based on binary colloidal crystals substrate. Clinical samples were enrolled from 22 patients with SCLC in the study. The CTCs were enriched and expanded from the collected peripheral blood samples. Expanded cells were analyzed for protein expression and observed for drug sensitivity with the use of immunofluorescence and ATP titer evaluation, respectively. Successful CTC spheroid proliferation was established after 4 weeks within 82% of all the collected peripheral blood samples from enrolled patients. Upon immunofluorescence analysis, the enriched cells showed positive markers for EpCAM, TTF-1, synaptophysin and negative for CD45. Additionally, the expanded CTCs demonstrated marked heterogeneity in the expression of E-cadherin and N-cadherin. In a preliminary case series, the drug sensitivity of patient-derived CTC to cisplatin and etoposide was studied to see the correlation with the corresponding therapeutic outcome. In conclusion, our study demonstrates that it is possible to efficiently expand CTCs from SCLC within a clinically relevant time frame; the biomarker information generated from enriched CTCs can assist the selection of effective drugs and improve disease outcome.

Comparison of surgery or radiotherapy on complications and quality of life in patients with the stage IB and IIA uterine cervical cancer.

OBJECTIVES: To compare the long-term complications and quality of life of patients with stage IB and stage IIA uterine cervical carcinoma treated by surgery or radiotherapy. METHODS: From August 2003 to May 2004, 202 patients with uterine cervical carcinoma were treated with surgery or radiotherapy at two institutions and were enrolled in this study upon follow-up at least 2 years post treatment. All patients completed the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire and complications Questionnaire. RESULTS: Constipation (p<0.001), flushing (p<0.001), dysuria (p<0.001), urinary incontinence (p<0.01), dysparia (p<0.05) and vaginal dryness (p<0.05) were statistically higher in the surgery treated group, while diarrhea (p<0.001), bloody stools (p<0.001) and abdominal pain (p<0.01) were higher in the radiotherapy group. Using factor analysis and introducing personal conditioned variables, pelvic neural dysfunction was significantly higher in surgery group and intestinal dysfunction was higher in radiotherapy group. There was no difference in sexual dysfunction between these two modalities. Comparison of EORTC QLQ-C30 showed that the majority of issues had minimal differences between these two treatment modalities, except social functioning (p<0.05; higher in radiotherapy group), constipation (p<0.001; higher in surgery group) and diarrhea (p<0.01; higher in radiotherapy group). CONCLUSIONS: In early stage uterine cervical cancer patients, surgery or radiotherapy resulted in different complications, whereas long-term quality of life showed few differences between these two different modalities. These data were helpful for physicians in regards to the changes of patients, and moreover, for rehabilitation and supportive care of the patients after treatment.

Expression of AHI1 Rescues Amyloidogenic Pathology in Alzheimer's Disease Model Cells.

A hallmark of Alzheimer's disease (AD) pathogenesis is the accumulation of extracellular plaques mainly composed of amyloid-ß (Aß) derived from amyloid precursor protein (APP) cleavage. Recent reports suggest that transport of APP in vesicles with huntingtin-associated protein-1 (HAP1) negatively regulates Aß production. In neurons, HAP1 forms a stable complex with Abelson helper integration site-1 (AHI1), in which mutations cause neurodevelopmental and psychiatric disorders. HAP1 and AHI1 interact with tropomyosin receptor kinases (Trks), which are also associated with APP and mediate neurotrophic signaling. In this study, we hypothesize that AHI1 participates in APP trafficking and processing to rescue AD pathology. Indeed, AHI1 was significantly reduced in mouse neuroblastoma N2a cells expressing human Swedish and Indiana APP (designed as AD model cells) and in 3xTg-AD mouse brain. The AD model cells as well as Ahi1-knockdown cells expressing wild-type APP-695 exhibited a significant reduction in viability. In addition, the AD model cells were reduced in neurite outgrowth. APP C-terminal fragment-ß (CTFß) and Aß42 were increased in the AD cell lysates and the culture media, respectively. To investigate the mechanism how AHI1 alters APP activities, we overexpressed human AHI1 in the AD model cells. The results showed that AHI1 interacted with APP physically in mouse brain and transfected N2a cells despite APP genotypes. AHI1 expression facilitated intracellular translocation of APP and inhibited APP amyloidogenic process to reduce the level of APP-CTFß in the total lysates of AD model cells as well as Aß in the culture media. Consequently, AHI1-APP interactions enhanced neurotrophic signaling through Erk activation and led to restored cell survival and differentiation.

Effectiveness of stereotactic ablative radiotherapy in patients with advanced hepatocellular carcinoma unsuitable for transarterial chemoembolization.

BACKGROUND: Stereotactic ablative radiotherapy (SABR) can deliver tumoricidal doses and achieve long-term control in early hepatocellular carcinoma (HCC). However, limited studies have investigated the safety and effectiveness of SABR in patients with advanced diseases that is unsuitable for transarterial chemoembolization (TACE). METHODS: In this observational study, we reviewed the medical records of patients with Barcelona Clinic Liver Cancer (BCLC) stage C disease treated with linear accelerator-based SABR between 2008 and 2016. Their tumors were either refractory to TACE or TACE was contraindicated. Overall survival (OS), in-field progression-free survival (IFPFS), and out-field progression-free survival were calculated using Kaplan-Meier analysis. The Cox regression model was used to examine the effects of variables. Treatment-related toxicities were scored according to the Common Terminology Criteria for Adverse Events (version 4.03) and whether patients developed radiation-induced liver disease (RILD) after SABR. RESULTS: This study included 32 patients. The mean maximal tumor diameter and tumor volumes were 4.7 cm and 135.9 ml, respectively. Patients received linear accelerator-based SABR with a median prescribed dose of 48 Gy (30-60 Gy) in three to six fractions. Based on the assessment of treatment response by using the Response Evaluation Criteria in Solid Tumors (version 1.1), 19% of patients achieved a complete response and 53% achieved a partial response. After a median follow-up of 18.1 months (4.0-65.9 months), 10, 19, and 9 patients experienced in-field failure, out-field hepatic recurrence, and extrahepatic metastases, respectively. The estimated 2-year OS and IFPFS rates were 54.4% and 62.7%, respectively. In a multivariate analysis, a pretreatment Cancer of the Liver Italian Program (CLIP) score of ⩾2 (p = 0.01) was a prognostic factor for shorter OS, and a biologically effective dose (BED) of < 85 Gy10 (p = 0.011) and a Child-Pugh score of ⩾6 (p = 0.014) were prognostic factors for inferior IFPFS. In this study five and eight patients developed classic and nonclassic RILD, respectively. CONCLUSIONS: SABR can serve as a salvage treatment for patients with HCC with BCLC stage C disease unsuitable for TACE, in particular, in those with a baseline CLIP score of ⩽1. A BED10 of ⩾85 Gy is an appropriate prescribed dose for tumor control. Because out-field relapse is the major cause of treatment failure, SABR in combination with novel systemic modalities should be investigated in future studies.

Postirradiated neuroendocrine carcinoma of the sinonasal tract.

OBJECTIVES/HYPOTHESIS: Neuroendocrine carcinoma (NEC) of the sinonasal tract is rare. In this present study, we report our treatment experience with sinonasal NEC. STUDY DESIGN: Retrospective case series. METHODS: A retrospective review of the clinical outcomes and pathology of 18 patients with NEC arising from the sinonasal region. RESULTS: Ten tumors were primary NEC without previous radiation, and eight tumors were postirradiated NEC occurring within the radiation field for previous nasopharyngeal carcinoma in six patients and tonsillar lymphoma in one and neck metastasis of unknown primary origin in one, with an interval between previous radiotherapy and diagnosis of NEC from 82 to 385 months, with a mean of 197 months. Fifteen tumors were small cell carcinoma, two were atypical carcinoid, and one was typical carcinoid tumor. Fifteen patients underwent surgery with/without postoperative adjuvant chemoradiotherapy. Three patients received induction chemotherapy or primary radiotherapy with further definitive treatment. The 5-year disease-free and overall survival rates of all 18 patients were 56.1% and 62.2%, respectively. In comparing primary NEC with postirradiated NEC, they were similar in age, sex distribution, stage, pathology, and treatment, and the 5-year overall survival rates were 70% and 62.5%, respectively. CONCLUSIONS: In this series, postirradiated NEC is common, which may be the result of there being a large number of long-term nasopharyngeal carcinoma survivors. The prognoses of postirradiated NEC and primary NEC appear to be similar despite the relatively short follow-up period in the postirradiated NEC group.

Comparison of Thoracic Radiotherapy Efficacy Between Patients With and Without EGFR-mutated Lung Adenocarcinoma.

To investigate the association between tumor response to thoracic radiotherapy and epidermal growth factor receptor (EGFR) mutation status in patients with lung adenocarcinoma, we collected 48 patients treated between January 2010 and December 2013. Of the 18 patients with EGFR mutation, 15 (83.3%) had a single mutation, and three (16.7%) had double mutation. Different EGFR mutation subtypes exhibited different responses to radiotherapy. The identified double EGFR mutations were associated with reduction of residual tumor burden (RTB) after radiotherapy. In univariate analysis, EGFR mutations in exon 18, 20, and 21 and double EGFR mutation were significant factors predicting RTB. In multivariate analysis, exon 20 mutation was the only significant factor. Patients with EGFR mutation seemed to have longer mean overall survival (OS) compared to the group with wild-type EGFR (31.1 vs. 26.6 months, p=0.49). The median and mean OS in patients with double EGFR mutation vs. wild-type EGFR were 20.1 vs. 16.9 months and 28.9 vs. 26.6 months, respectively. Further studies with larger sample size are warranted to clarify the association of EGFR mutation status with the lung tumor response after radiotherapy.

Piperlongumine inhibits cancer stem cell properties and regulates multiple malignant phenotypes in oral cancer.

Piperlongumine (PL), a natural product of Piper longum, inhibits multiple malignant phenotypes. Therefore, the present study examined whether PL suppresses cancer stemness in oral cancer. The cellular effects of PL were determined by examining alterations in tumor sphere formation, cell migration, invasion, proliferation ability, chemosensitivity and radiosensitivity. Reverse transcription-quantitative polymerase chain reaction analysis and western blotting were performed in order to determine molecular expression levels. The present study revealed that PL inhibited cancer stem cell-forming ability and suppressed the expression of the stemness-related transcription factors SRY-Box 2, POU class 5 homeobox 1, and Nanog homeobox. However, it increased the expression of the differentiation marker cytokeratin 18. PL also suppressed cell migration and invasion, resulting in the elimination of the epithelial-mesenchymal transition. Furthermore, PL increased chemo- and radiosensitivity and suppressed tumor growth in vitro and in vivo. The results of the present study suggested that PL inhibits malignant phenotypes via the suppression of cancer stemness in oral cancer. Thus, PL may serve as an effective therapeutic agent for oral cancer.

Experimental verification of a two-dimensional respiratory motion compensation system with ultrasound tracking technique in radiation therapy.

This study proposed respiratory motion compensation system (RMCS) combined with an ultrasound image tracking algorithm (UITA) to compensate for respiration-induced tumor motion during radiotherapy, and to address the problem of inaccurate radiation dose delivery caused by respiratory movement. This study used an ultrasound imaging system to monitor respiratory movements combined with the proposed UITA and RMCS for tracking and compensation of the respiratory motion. Respiratory motion compensation was performed using prerecorded human respiratory motion signals and also sinusoidal signals. A linear accelerator was used to deliver radiation doses to GAFchromic EBT3 dosimetry film, and the conformity index (CI), root-mean-square error, compensation rate (CR), and planning target volume (PTV) were used to evaluate the tracking and compensation performance of the proposed system. Human respiratory pattern signals were captured using the UITA and compensated by the RMCS, which yielded CR values of 34-78%. In addition, the maximum coronal area of the PTV ranged from 85.53 mm2 to 351.11 mm2 (uncompensated), which reduced to from 17.72 mm2 to 66.17 mm2 after compensation, with an area reduction ratio of up to 90%. In real-time monitoring of the respiration compensation state, the CI values for 85% and 90% isodose areas increased to 0.7 and 0.68, respectively. The proposed UITA and RMCS can reduce the movement of the tracked target relative to the LINAC in radiation therapy, thereby reducing the required size of the PTV margin and increasing the effect of the radiation dose received by the treatment target.

Tracking and compensation of respiration pattern by an automatic compensation system.

PURPOSE: This study aimed to determine the feasibility of using an ultrasound image tracking algorithm (UITA) combined with a respiration compensating system (RCS) to track and compensate the respiration pattern of the diaphragm in real time. METHODS: Diaphragm motions and various respiration patterns were tracked and captured in volunteers using our previously developed UITA (Kuo et al., J Xray Sci Technol, 2016:875). A diaphragm phantom was placed on a respiration simulation system (RSS) that received signals with different respiration patterns to simulate actual human respiration signals. The RSS was mounted on the RCS, which is 180 cm long and driven by inputting a compensating signal to a linear actuator underneath with and without using a phase-lead compensator (PLC) (Chuang et al., J Xray Sci Technol, 2015:503). The target displacement was calculated automatically by the UITA and compensated by the RCS. The phantom displacements were observed using a fluoroscopic imaging system on the linear accelerator at the Department of Radiation Oncology, Taipei Medical University Hospital, and the results were also compared with the displacements measured by the UITA and the RSS for correlation verification. In addition, the compensating effect was analyzed after activating the RCS. RESULTS: The experimental results indicate a significant correlation between the UITA-calculated and actual displacements, with a correlation coefficient of up to 91% for the simulated respiration patterns. After activating the RCS, the obtained compensating effect was more than 65%, and even up to 85% if a PLC was used. Moreover, the compensation of 10 extreme respiration patterns of diaphragm was improved significantly through the use of a PLC, with a peak compensating rate of 88.92% being achieved. Finally, compensation effects ranging from 52% to 74% were obtained in 10 human volunteers. CONCLUSIONS: This study combined ultrasound imaging tracking technology with the RCS to offset the respiration-induced diaphragm displacement and compensate the various respiration patterns, even including those with baseline-shift phenomenon in real time with the aid of a noninvasive ultrasound imaging system.