Automatic planning for functional lung avoidance radiotherapy based on function-guided beam angle selection and plan optimization.

OBJECTIVE: This study aims to develop a fully Automatic Planning framework for Functional Lung Avoidance Radiotherapy (AP-FLART). Approach: The AP-FLART integrates a dosimetric score-based beam angle selection method and a meta-optimization-based plan optimization method, both of which incorporate lung function information to guide dose redirection from high-functional lung (HFL) to low-functional lung (LFL). It is applicable to both contour-based FLART (cFLART) and voxel-based FLART (vFLART) optimization options. A cohort of 18 lung cancer patient cases underwent planning-CT and SPECT perfusion scans were collected. AP-FLART was applied to generate conventional RT (ConvRT), cFLART, and vFLART plans for all cases. We compared automatic against manual ConvRT plans as well as automatic ConvRT against FLART plans, to evaluate the effectiveness of AP-FLART. Ablation studies were performed to evaluate the contribution of function-guided beam angle selection and plan optimization to dose redirection. Main results: Automatic ConvRT plans generated by AP-FALRT exhibited similar quality compared to manual counterparts. Furthermore, compared to automatic ConvRT plans, HFL mean dose, V20, and V5 were significantly reduced by 1.13 Gy (p<.001), 2.01% (p<.001), and 6.66% (p<.001) respectively for cFLART plans. Besides, vFLART plans showed a decrease in lung functionally weighted mean dose by 0.64 Gy (p<.01), fV20 by 0.90% (p=0.099), and fV5 by 5.07% (p<.01) respectively. Though inferior conformity was observed, all dose constraints were well satisfied. The ablation study results indicated that both function-guided beam angle selection and plan optimization significantly contributed to dose redirection. Significance: AP-FLART can effectively redirect doses from HFL to LFL without severely degrading conventional dose metrics, producing high-quality FLART plans. It has the potential to advance the research and clinical application of FLART by providing labor-free, consistent, and high-quality plans. Keywords: Functional lung avoidance radiotherapy; Automatic planning; Beam angle selection; Plan optimization.

Establishment and validation of a risk score model based on EUS: assessment of lymph node metastasis in early gastric cancer.

BACKGROUND AND AIMS: Lymph node metastasis significantly affects the prognosis of early gastric cancer patients. EUS plays a crucial role in the preoperative assessment of early gastric cancer. This study evaluated the efficacy of EUS in identifying lymph node metastasis in early gastric cancer patients and developed a risk score model to aid in choosing the best treatment options. METHODS: We retrospectively analyzed the effectiveness of EUS for detecting lymph node metastasis in early gastric cancer patients. A risk score model for predicting lymph node metastasis preoperatively was created using independent risk factors identified through binary logistic regression analysis and subsequently validated. Receiver operating characteristic curves were generated for both the development and validation cohorts. RESULTS: The overall accuracy of EUS in identifying lymph node metastasis was 85.3%, although its sensitivity (29.2%) and positive predictive value (38.7%) were relatively low. Patients were categorized based on preoperative risk factors for lymph node metastasis, including tumor size of ≥20 mm, lymph nodes of ≥10 mm, body mass index of ≥24 kg/m2, and lymph node metastasis on CT scans. A 7-point risk score model was developed to assess the likelihood of lymph node metastasis. The areas under the receiver operating characteristic curve for the development and validation sets were 0.842 and 0.837, respectively, with sensitivities of 64% and 79%, respectively. CONCLUSIONS: We developed a practical risk score model based on preoperative factors to help EUS predict lymph node metastasis in early gastric cancer patients, guiding the selection of optimal treatment approaches for these patients.

Allogeneic Hematopoietic Stem Cell Transplantation Can Improve Prognosis of Extramedullary Infiltration Positive t(8;21) Acute Myeloid Leukemia.

BACKGROUND In t(8;21) acute myeloid leukemia (AML), patients with extramedullary infiltration (EMI) tend to have worse survival outcomes than those without EMI. However, it is still unclear whether allogeneic hematopoietic stem cell transplantation (allo-HSCT) benefits EMI-positive t(8;21) AML patients. MATERIAL AND METHODS This study retrospectively enrolled 651 t(8;21) AML patients, and analyzed 51 patients with EMI at diagnosis. Among the 51 patients, 15 patients received allo-HSCT. RESULTS The incidence of EMI in t(8;21) AML was 10.0%, and the first complete remission rate was 78.5% in EMI-positive t(8;21) AML patients. The central nervous system was the most frequently involved site (29.4%), followed by bones (15.7%), and skin (9.8%). In terms of karyotype, 19 (37.3%) patients were t(8;21) alone, 12 (23.5%) had additional loss of a sex chromosome, and 5 (9.8%) had complex karyotype. Significantly better overall survival was observed in patients with allo-HSCT compared to patients without allo-HSCT in both multivariable models (HR=0.32; P=0.0122) and the Kaplan-Meier curves (P=0.0157). CONCLUSIONS Allo-HSCT improved the survival of EMI-positive t(8;21) AML.

Autophagy Inhibition Contributes to Apoptosis of PLK4 Downregulation-induced Dormant Cells in Colorectal Cancer.

Dormant cancer cells account for cancer recurrence, distant metastasis and drug resistance which lead to poor prognosis in colorectal cancer (CRC). However, little is known about the molecular mechanisms regulating tumor cell dormancy and how to eliminate dormant cancer cells. Recent studies indicate autophagy affects dormant tumor cell survival. Here, we found that polo-like kinases 4 (PLK4), a central regulator of the cell cycle and proliferation, plays a crucial role in regulating CRC cells dormancy both in vitro and in vivo. Downregulation of PLK4 induced dormancy and inhibited migration and invasion in different CRC cell lines. Clinically, PLK4 expression was correlated with the dormancy markers (Ki67, p-ERK, p-p38) and late recurrence in CRC tissues. Mechanistically, downregulation of PLK4 induced autophagy contributed to restoring phenotypically aggressive tumor cells to a dormant state through the MAPK signaling pathway, and inhibition of autophagy would trigger apoptosis of dormant cells. Our findings reveal that downregulation of PLK4-induced autophagy contributes to tumor dormancy and autophagy inhibition leads to apoptosis of CRC dormant cells. Our study is the first to report that downregulation PLK4 induced autophagy is an early event in CRC dormancy and highlights autophagy inhibitor as a potential therapeutic target for dormant cell elimination.

A virtual audit system for intensity-modulated radiation therapy credentialing in Japan Clinical Oncology Group clinical trials: A pilot study.

PURPOSE: The Medical Physics Working Group of the Radiation Therapy Study Group at the Japan Clinical Oncology Group is currently developing a virtual audit system for intensity-modulated radiation therapy dosimetry credentialing. The target dosimeters include films and array detectors, such as ArcCHECK (Sun Nuclear Corporation, Melbourne, Florida, USA) and Delta4 (ScandiDos, Uppsala, Sweden). This pilot study investigated the feasibility of our virtual audit system using previously acquired data. METHODS: We analyzed 46 films (32 and 14 in the axial and coronal planes, respectively) from 29 institutions. Global gamma analysis between measured and planned dose distributions used the following settings: 3%/3 mm criteria (the dose denominator was 2 Gy), 30% threshold dose, no scaling of the datasets, and 90% tolerance level. In addition, 21 datasets from nine institutions were obtained for array evaluation. Five institutions used ArcCHECK, while the others used Delta4. Global gamma analysis was performed with 3%/2 mm criteria (the dose denominator was the maximum calculated dose), 10% threshold dose, and 95% tolerance level. The film calibration and gamma analysis were conducted with in-house software developed using Python (version 3.9.2). RESULTS: The means ± standard deviations of the gamma passing rates were 99.4 ± 1.5% (range, 92.8%-100%) and 99.2 ± 1.0% (range, 97.0%-100%) in the film and array evaluations, respectively. CONCLUSION: This pilot study demonstrated the feasibility of virtual audits. The proposed virtual audit system will contribute to more efficient, cheaper, and more rapid trial credentialing than on-site and postal audits; however, the limitations should be considered when operating our virtual audit system.

Integrating Bulk-seq and Single-cell-seq Reveals Estrogen and MAPK Pathways Associating with Neuroblastoma Outcome.

INTRODUCTION: Neuroblastoma is the most common extracranial solid tumor in children. Patients with high-risk neuroblastoma have a 5-year survival rate less than 50% after extensive treatment. Signaling pathways control cell fate decisions that dictate the behavior of tumor cells. The deregulation of signaling pathways is etiological in cancer cells. Thus, we speculated that the pathway activity of neuroblastoma contains more prognostic information and therapeutic targets. METHODS: Using a footprint-based method, we calculated the activity of fourteen pathways in neuroblastoma. Through stepwise Cox regression analyses, we established a three-gene prognostic signature whose predictive performance was evaluated by external validation. Combining a single-cell sequencing dataset, the most active pathways in high-risk neuroblastoma were found. RESULTS: We found that several pathway activities were correlated with neuroblastoma outcomes. We built a three-gene model comprising DLK1, FLT3, and NTRK1, which exhibited superior internal and external performances. We created a nomogram that combines clinical characteristics to aid in the selection and visualization of high-risk neuroblastoma patients. Furthermore, by integrating a single-cell sequencing dataset, we found that estrogen and MAPK were the most active pathways in high-risk neuroblastoma. CONCLUSION: Our findings suggest that pathway-related therapies may hold promise for the treatment of high-risk neuroblastoma.

Feasibility study of deep learning-based markerless real-time lung tumor tracking with orthogonal X-ray projection images.

PURPOSE: The feasibility of a deep learning-based markerless real-time tumor tracking (RTTT) method was retrospectively studied with orthogonal kV X-ray images and clinical tracking records acquired during lung cancer treatment. METHODS: Ten patients with lung cancer treated with marker-implanted RTTT were included. The prescription dose was 50 Gy in four fractions, using seven- to nine-port non-coplanar static beams. This corresponds to 14-18 X-ray tube angles for an orthogonal X-ray imaging system rotating with the gantry. All patients underwent 10 respiratory phases four-dimensional computed tomography. After a data augmentation approach, for each X-ray tube angle of a patient, 2250 digitally reconstructed radiograph (DRR) images with gross tumor volume (GTV) contour labeled were obtained. These images were adopted to train the patient and X-ray tube angle-specific GTV contour prediction model. During the testing, the model trained with DRR images predicted GTV contour on X-ray projection images acquired during treatment. The predicted three-dimensional (3D) positions of the GTV were calculated based on the centroids of the contours in the orthogonal images. The 3D positions of GTV determined by the marker-implanted RTTT during the treatment were considered as the ground truth. The 3D deviations between the prediction and the ground truth were calculated to evaluate the performance of the model. RESULTS: The median GTV volume and motion range were 7.42 (range, 1.18-25.74) cm3 and 22 (range, 11-28) mm, respectively. In total, 8993 3D position comparisons were included. The mean calculation time was 85 ms per image. The overall median value of the 3D deviation was 2.27 (interquartile range: 1.66-2.95) mm. The probability of the 3D deviation smaller than 5 mm was 93.6%. CONCLUSIONS: The evaluation results and calculation efficiency show the proposed deep learning-based markerless RTTT method may be feasible for patients with lung cancer.

Development of independent dose verification plugin using Eclipse scripting API for brachytherapy.

In this study, an independent dose verification plugin (DVP) using the Eclipse Scripting Application Programming Interface (ESAPI) for brachytherapy was developed. The DVP was based on the general 2D formalism reported in AAPM-TG43U1. The coordinate and orientation of each source position were extracted from the translation matrix acquired from the treatment planning system (TPS), and the distance between the source and verification point (r) was calculated. Moreover, the angles subtended by the center-tip and tip-tip of the hypothetical line source with respect to the verification point (θ and ß) were calculated. With r, θ, ß and the active length of the source acquired from the TPS, the geometry function was calculated. As the TPS calculated the radial dose function, g(r), and 2D anisotropy function, F(r,θ), by interpolating and extrapolating the corresponding table stored in the TPS, the DVP calculated g(r) and F(r,θ) independently from equations fitted with the Monte Carlo data. The relative deviation of the fitted g(r) and F(r,θ) for the GammaMed Plus HDR 192Ir source was 0.5% and 0.9%, respectively. The acceptance range of the relative dose difference was set to ±1.03% based on the relative deviation between the fitted functions and Monte Carlo data, and the linear error propagation law. For 64 verification points from sixteen plans, the mean of absolute values of the relative dose difference was 0.19%. The standard deviation (SD) of the relative dose difference was 0.17%. The DVP maximizes efficiency and minimizes human error for the brachytherapy plan check.

Diagnosis of mediastinal cysts: the role and safety of EUS-FNA with 19-gauge needle: a retrospective cohort study.

Background: Mediastinal cysts are uncommon, and their diagnosis remains a clinical challenge, especially for patients with a solid mass on computed tomography (CT). Endoscopic ultrasound (EUS) is considered a valuable method to differentiate mediastinal cysts and EUS-fine needle aspiration (FNA) is a strategy for obtaining specimens from the cysts for cytological diagnosis. This study aims to evaluate the safety and utility of EUS-FNA for diagnosis of mediastinal cysts. Methods: This was a retrospective analysis of patients who underwent EUS-FNA with 19-gauge needle at Tianjin Medical University Cancer Institute and Hospital and were further diagnosed with mediastinal cysts confirmed by cytological and surgical pathological results between January 2016 and December 2020. Safety was estimated by the incidence of reported adverse events (AEs). Patients were followed for 48 hours and 1 week after the EUS-FNA procedure to evaluate AEs. Results: A total of 20 patients were diagnosed with mediastinal cysts using EUS-FNA, yet only 5 were diagnosed by CT. There were 15 patients diagnosed with bronchogenic cyst, 4 with enteric cyst, and 1 with pericardial cyst. The EUS appearance of cyst content varied, ranging from anechoic (4 cases) to hypoechoic (16 cases). AEs occurred in 2/20 (10%) patients after the EUS-FNA indicating an acceptable low rate of AEs. For all anechoic cysts that underwent complete FNA drainage, 3 patients had good prognosis, whereas 1 experienced recurrence. For 16 patients with hypoechoic cysts, adequate tissue was obtained for cytological examination. No patient developed an infection-related complication. Conclusions: For the diagnosis of mediastinal cysts, EUS-FNA was more accurate than CT. The EUS-FNA of mediastinal cysts is safe with an acceptable low rate of AEs when antibiotic prophylaxis is used postoperatively. Cysts containing free-flowing fluid can be achieved with complete needle drainage by a single pass with a 19-gauge needle.

The prognostic benefit from intermediate-dose cytarabine as consolidation therapy varies by cytogenetic subtype in t(8;21) acute myeloid leukemia: a retrospective cohort study.

Background: Patients with different karyotypes had different prognosis in t(8;21) acute myeloid leukemia (AML). Cytarabine (Ara-C) plays an important role as consolidation therapy in t(8;21) AML. T(8;21) AML patients with different karyotypes responded differently to post-remission therapy with Ara-C. However, the optimum dose of Ara-C in patients with different karyotypes remains unclear. Methods: From January 2002 to September 2018, a total of 188 younger adult (14-60 years) patients with t(8;21) AML were enrolled in this retrospective study. Cytogenetic analysis and aberration descriptions followed the International System for Human Cytogenetic Nomenclature. All the patients achieved first complete remission (CR1) after induction chemotherapy. Patients received low-dose Ara-C [LDAC (<1 g/m2)], intermediate-dose Ara-C [IDAC (1-1.5 g/m2)], or high-dose Ara-c [HiDAC (2-3 g/m2)] regimens as consolidation therapy after CR1. All patients were followed for survival or relapse until death, or study completion. We analyzed the prognosis of LDAC, IDAC, and HiDAC regimens as consolidation therapy in patients with different karyotypes. The primary endpoint was overall survival (OS) and the secondary endpoint was relapse-free survival (RFS). Results: The results showed IDAC significantly improved OS compared with LDAC [hazard rate (HR) =0.55, P=0.0375] when the clinical factors were adjusted. However, no significant difference between HiDAC and IDAC was found. Subgroup analysis further showed that the OS advantage of IDAC was focused on patients with additional cytogenetic abnormalities, including loss of X chromosome (-X), del(9q), or complex karyotype (group B, HR =0.21, P=0.0125), but not on patients with t(8;21)-only or additional loss of Y chromosome (-Y) cytogenetics (group A, HR =0.77, P=0.4804) in multivariate analysis. Similarly, better OS was shown after IDAC than LDAC consolidation in patients in group B, whether they received allogeneic hematopoietic stem cell transplantation (allo-HSCT) or not, but not in group A. Conclusions: IDAC was suitable for patients with additional -X, del(9q), or complex karyotype, while LDAC might be sufficient for patients with t(8;21)-only or additional -Y cytogenetics. It suggested that t(8;21) AML patients with different karyotypes should use different consolidation regimens.

Endoscopic ultrasound-guided fine needle aspiration for smooth benign appearing malignant esophageal stricture: a cross-sectional study.

Background: Endoscopic biopsy is standard for the diagnosis of esophageal malignancy. However, few cases are difficult to diagnose as they present with smooth esophageal stricture with negative biopsy results. We aimed to evaluate the effectiveness and safety of endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) in the diagnosis of biopsy-negative suspected malignant esophageal strictures. Methods: We retrospectively analyzed cases of esophageal stricture with negative biopsies. From September 2016 to November 2021, 50 patients were enrolled. All the patients accepted the EUS-FNA examination. And histological and cytological specimens were obtained from all patients. Clinical, endoscopic, imaging, cytological, and histopathological results were noted and analyzed. Results: A total of 50 patients (40 male and 10 female) were enrolled in this study. The 19G puncture needle was used in 6 cases and the 22G puncture needle was used in 44 cases; an average of 2.7 needles were used per case. Satisfactory specimens were obtained by EUS-FNA for all subjects. All patients were diagnosed as malignant tumor. The diagnosis was confirmed by EUS-FNA biopsies in 98% of patients. Based on the surgical pathology results, there were 16 cases of esophageal squamous cell carcinoma, 2 cases of esophageal metastatic carcinoma, 1 case of esophageal sarcoma, 22 cases of lung cancer, 6 cases of mediastinal lymph node metastasis, and 3 cases of mediastinal tumor. No obvious complications were observed. A total of 5 cases were treated with surgery, 28 with chemotherapy, 3 with chemotherapy + surgery, and 12 with radiotherapy; 2 patients ceased treatment. No obvious complications, such as bleeding and mediastinal infection, were observed. Conclusions: EUS-FNA is effective and safe for the diagnosis of malignant esophageal strictures with smooth overlying esophageal mucosa. EUS-FNA is effective and safe for patients with smooth esophagus stenosis for whom satisfactory cytological and histological specimens can be obtained, and the diagnosis can be confirmed by cytological, histological, and immunohistochemical examinations. It can be used as the first choice for diagnosis and treatment.

Definitive chemoradiotherapy versus neoadjuvant chemoradiotherapy followed by surgery in patients with locally advanced esophageal squamous cell carcinoma who achieved clinical complete response when induction chemoradiation finished: A phase II random.

BACKGROUND AND PURPOSE: More than 40% of patients with esophageal squamous cell carcinoma (ESCC) exhibit pathological complete responses (pCR) after neoadjuvant chemoradiotherapy (nCRT), and theoretically, these patients may be cured by CRT and omit surgery. This prospectively randomized pilot study compared definitive chemoradiotherapy (dCRT) with nCRT in patients with locally advanced ESCC who achieved clinical complete responses (cCRs) to nCRT. MATERIALS AND METHODS: Single center, randomized, open phase 2 study of 256 patients with locally advanced ESCC enrolled between April 2016 and November 2018. Immediately when nCRT finished, patients enrolled underwent response evaluations within 1 week. Patients with cCR were randomly allocated to undergo surgery (arm A) or complete CRT up to the definitive radiation dose (arm B). The primary end point was 3-year disease-free survival (DFS). RESULTS: Finally, 71 patients were randomly assigned to the nCRT (n = 36) and dCRT (n = 35) arms. The median observation time was 35.7 months. The 3-year DFS rate was 56.43 % in arm A versus 54.73 % in arm B (hazard ratio [HR] = 0.862, 95 % confidence interval [CI] = 0.452 to 1.645, P = 0.652). The 3-year overall survival (OS) rates in arms A and B were 69.5 % and 62.3 % (HR = 0.824, 95 % CI = 403-1.688, P = 0.597), respectively. CONCLUSIONS: According to our treatment response evaluation criteria, survival of the patients with cCR after nCRT was not significant different between nCRT group and dCRT group. An optimized response evaluation strategy soon after nCRT may guide next therapy decisions for patients with locally advanced ESCC.

Evaluation of correlation between intrafractional residual setup errors and accumulation of delivered dose distributions in single isocenter volumetric modulated arc therapy for multiple brain metastases.

PURPOSE: To evaluate the displacement of gross tumor volume (GTV) positions caused by intrafractional residual setup errors (RSEs) and to accumulate delivered dose distributions considering intrafraction RSEs in fractionated-stereotactic radiotherapy (f-SRT) with single isocenter volumetric modulated arc therapy (SI-VMAT) for multiple brain metastases. METHODS: Overall, 72 consecutive patients who underwent f-SRT with SI-VMAT for multiple brain metastases were included. For all patients, 6D correction was performed using the ExacTrac X-ray (ETX) system. GTV displacement (ΔD) was calculated considering the intrafractional RSEs measured by the ETX system during irradiation. The correlation between ΔD and the distance from the isocenter to each GTV (d) was analyzed. Computed tomography (CT) images considering the intrafractional RSEs were generated for five patients with ΔD > 1 mm. The delivered dose distributions for all fractions were reconstructed on the corresponding CT, followed by their accumulation. RESULTS: The 95th percentile of ΔD from 7,270 resultant center positions of 417 GTVs was 0.92 mm. No correlation was observed between ΔD and d. For 53 GTVs from five patients with ΔD > 1 mm, the difference of GTV D99.5% and D0.5% between the planned and accumulated values was -0.4 ± 2.5% and -1.0 ± 0.8%, respectively. There was no correlation between d and the difference of GTV D99.5% and D0.5%. CONCLUSIONS: We found no significant difference in GTV D99.5% and D0.5%, despite the location of GTVs far from the isocenter. However, it should be noted that this result was because the intrafractional RSEs were reduced to a clinically acceptable level.

Development of AI-driven prediction models to realize real-time tumor tracking during radiotherapy.

BACKGROUND: In infrared reflective (IR) marker-based hybrid real-time tumor tracking (RTTT), the internal target position is predicted with the positions of IR markers attached on the patient's body surface using a prediction model. In this work, we developed two artificial intelligence (AI)-driven prediction models to improve RTTT radiotherapy, namely, a convolutional neural network (CNN) and an adaptive neuro-fuzzy inference system (ANFIS) model. The models aim to improve the accuracy in predicting three-dimensional tumor motion. METHODS: From patients whose respiration-induced motion of the tumor, indicated by the fiducial markers, exceeded 8 mm, 1079 logfiles of IR marker-based hybrid RTTT (IR Tracking) with the gimbal-head radiotherapy system were acquired and randomly divided into two datasets. All the included patients were breathing freely with more than four external IR markers. The historical dataset for the CNN model contained 1003 logfiles, while the remaining 76 logfiles complemented the evaluation dataset. The logfiles recorded the external IR marker positions at a frequency of 60 Hz and fiducial markers as surrogates for the detected target positions every 80-640 ms for 20-40 s. For each logfile in the evaluation dataset, the prediction models were trained based on the data in the first three quarters of the recording period. In the last quarter, the performance of the patient-specific prediction models was tested and evaluated. The overall performance of the AI-driven prediction models was ranked by the percentage of predicted target position within 2 mm of the detected target position. Moreover, the performance of the AI-driven models was compared to a regression prediction model currently implemented in gimbal-head radiotherapy systems. RESULTS: The percentage of the predicted target position within 2 mm of the detected target position was 95.1%, 92.6% and 85.6% for the CNN, ANFIS, and regression model, respectively. In the evaluation dataset, the CNN, ANFIS, and regression model performed best in 43, 28 and 5 logfiles, respectively. CONCLUSIONS: The proposed AI-driven prediction models outperformed the regression prediction model, and the overall performance of the CNN model was slightly better than that of the ANFIS model on the evaluation dataset.

Development of a deep learning-based patient-specific target contour prediction model for markerless tumor positioning.

PURPOSE: For pancreatic cancer patients, image guided radiation therapy and real-time tumor tracking (RTTT) techniques can deliver radiation to the target accurately. Currently, for the radiation therapy machine with kV X-ray imaging systems, internal markers must be implemented to facilitate tumor tracking. The purpose of this study was to develop a markerless deep learning-based pancreatic tumor positioning procedure for real-time tumor tracking with a kV X-ray imaging system. METHODS AND MATERIALS: Fourteen pancreatic cancer patients treated with intensity-modulated radiation therapy from six fixed gantry angles with a gimbal-head radiotherapy system were included in this study. For a gimbal-head radiotherapy system, the three-dimensional (3D) intrafraction target position can be determined using an orthogonal kV X-ray imaging system. All patients underwent four-dimensional computed tomography (4DCT) simulations for treatment planning, which were divided into 10 respiratory phases. After a patient's 4DCT was acquired, for each X-ray tube angle, 10 digitally reconstructed radiograph (DRR) images were obtained. Then, a data augmentation procedure was conducted. The data augmentation procedure first rotated the CT volume around the superior-inferior and anterior-posterior directions from -3° to 3° in 1.5° intervals. Then, the Super-SloMo model was adapted to interpolate 10 frames between respiratory phases. In total, the data augmentation procedure expanded the data scale 250-fold. In this study, for each patient, 12 datasets containing the DRR images from each specific X-ray tube angle based on the radiation therapy plan were obtained. The augmented dataset was randomly divided into training and testing datasets. The training dataset contained 2000 DRR images with clinical target volume (CTV) contours labeled for fine-tuning the pre-trained target contour prediction model. After the fine-tuning, the patient and X-ray tube angle-specific CTV contour prediction model was acquired. The testing dataset contained the remaining 500 images to evaluate the performance of the CTV contour prediction model. The dice similarity coefficient (DSC) between the area enclosed by the CTV contour and predicted contour was calculated to evaluate the model's contour prediction performance. The 3D position of the CTV was calculated based on the centroid of the contour in the orthogonal DRR images, and the 3D error of the prediction position was calculated to evaluate the CTV positioning performance. For each patient, the DSC results from 12 X-ray tube angles and 3D error from 6 gantry angles were calculated, representing the novelty of this study. RESULTS: The mean and standard deviation (SD) of all patients' DSCs were 0.98 and 0.015, respectively. The mean and SD of the 3D error were 0.29 mm and 0.14 mm, respectively. The global maximum 3D error was 1.66 mm, and the global minimum DSC was 0.81. The mean calculation time for CTV contour prediction was 55 ms per image. This fulfills the requirement of RTTT. CONCLUSIONS: Regarding the positioning accuracy and calculation efficiency, the presented procedure can provide a solution for markerless real-time tumor tracking for pancreatic cancer patients.

Addition of camrelizumab to docetaxel, cisplatin, and radiation therapy in patients with locally advanced esophageal squamous cell carcinoma: a phase 1b study.

Patients with locally advanced esophageal squamous cell carcinoma (ESCC) show poor survival after concurrent chemoradiotherapy. This study investigated the safety and feasibility of combining concurrent chemoradiotherapy with the anti-PD-1 antibody camrelizumab as first-line treatment for these patients. In this phase 1b study (ClinicalTrials.gov NCT03671265), patients received concurrent chemotherapy (cisplatin [25 mg/m2] plus docetaxel [25 mg/m2] for 4 weeks) and radiotherapy (2.0 Gy/fraction, total 60 Gy) with camrelizumab (200 mg every 2 weeks for 32 weeks). Primary endpoints were safety and tolerability, and health-related quality of life. Secondary endpoints were radiological and pathological response rates, overall survival (OS), and progression-free survival (PFS). Candidate biomarkers in tumor and peripheral blood were monitored at baseline and after 40 Gy radiation. Twenty patients were enrolled. The most common treatment-related grade 3 adverse events included radiation esophagitis (20%) and esophageal fistula (10%). Serious treatment-related adverse events occurred in eight (40%) patients. No treatment-related deaths were reported. Health-related quality of life did not deteriorate. Thirteen (65%) patients had an objective response after 40 Gy radiation. At a median follow-up of 23.7 months (95% CI 21.9-24.5), OS and PFS time ranged from 8.2-28.5 and 4.0-28.5 months, respectively. The 12-month and 24-month OS rate was 85.0% and 69.6%; PFS rate was 80.0% and 65.0%. Tumor PD-L1 expression and CD11c+ dendritic cells and peripheral-blood IL-27, IL-15, Eotaxin-3, and IL-22 were associated with OS. First-line concurrent chemoradiotherapy plus camrelizumab had a manageable safety profile and promising antitumour efficacy for ESCC, and deserves further study.

Safety and Feasibility of Radiotherapy Plus Camrelizumab for Locally Advanced Esophageal Squamous Cell Carcinoma.

LESSONS LEARNED: Radiotherapy plus anti-PD-1 antibody as first-line therapy is safe and feasible in locally advanced esophageal squamous cell carcinoma (ESCC). Tumor-infiltrating and peripheral lymphocytes were associated with patient survival. Further studies combining chemoradiotherapy with immunotherapy in locally advanced ESCC and exploration of predictive biomarkers are warranted. BACKGROUND: We conducted a phase Ib study of radiotherapy plus programmed cell death protein 1 (PD-1) monoclonal antibody camrelizumab as first-line treatment for locally advanced esophageal squamous cell carcinoma (ESCC). METHODS: We planned to enroll 20 patients with newly diagnosed locally advanced ESCC. Patients received 60 Gy radiation (2.0 Gy/fraction, 5 fractions/week), with camrelizumab (200 mg every 2 weeks) starting with radiotherapy and continuing for 32 weeks (i.e., for 16 cycles). The primary endpoints were safety and feasibility. Secondary endpoints were rates of radiologic and pathologic response, overall survival (OS), and progression-free survival (PFS). Study data were collected by the week during radiotherapy (RT), every month during the maintenance camrelizumab treatment, and every 3 months after treatment. Tumor microenvironment and peripheral blood were monitored at baseline and after 40 Gy radiation for association with efficacy. RESULTS: Twenty patients were enrolled and received treatment. One patient (patient 10) was excluded upon discovery of a second tumor in the bladder during treatment, leaving 19 patients for analysis. Toxicity was deemed tolerable. Fourteen (74%) patients had assessed objective response. At a median follow-up time of 31.0 months (95% confidence interval [CI], 27.0-35.1), median OS and PFS times were 16.7 months (95% CI, 5.9-27.9) and 11.7 months (95% CI, 0-30.3), respectively. OS and PFS rates at 24 months were 31.6% and 35.5%, respectively. Kaplan-Meier analysis revealed associations between the following factors and OS/PFS: tumor programmed cell death ligand 1 (PD-L1) expression, PD-1+ CD8+ , PD-1+ CD4+ T cells, and PD-L1+ CD4+ T cells; peripheral blood CD4+ , CD8+ , CD4+ regulatory T cells, and their subsets. CONCLUSION: Radiotherapy plus camrelizumab had manageable toxicity and antitumor efficacy for locally advanced ESCC. Several biomarkers were associated with clinical benefit and deserve further study.

The molecular mechanism of a novel derivative of BTO-956 induced apoptosis in human myelomonocytic lymphoma cells.

Acute myeloid leukemia (AML) is a malignant cancer of the hematopoietic system. Although the effectiveness of arsenic compounds has been recognized and applied clinically, some patients are still found resistant to this chemotherapy. In this study, we investigated that a synthetic thyroid hormone analog (TA), 2-iodo-4-nitro-1-(o-tolyloxy) benzene, had a strong apoptosis effect on U937 cells. U937 cells were treated with TA, and examinted the generation of reactive oxygen species (ROS), dysfunction of mitochondria, expression of pro-apoptosis and anti-apoptosis, and cleavage of caspase-3 and Poly (ADP-ribose) polymerase (PARP). Further, it is also evaluated that insight molecular mechanism and signaling pathways involved in the study. It is found that TA significantly induced apoptosis in U937 cells through production of ROS, dysfunction of mitochondria, and activation of caspase cascade. It was also observed that MAPK signaling pathway including ERK, JNK, and P38 signals are involved in the induction of apoptosis. Moreover, marked activation of autophagy and ER stress markers such as LC3, P62, Beclin1 and GRP78, CHOP were observed, respectively. Pretreatment with ER stress inhibitor tauroursodeoxycholic acid (TUDCA) and autophagy inhibitor 3-Methyladenine (3-MA) have successfully attenuated and aggravated TA-induced apoptosis, respectively. We further confirmed the active involvement of ER stress and autophagy signals. In conclusion, TA induced apoptosis through ER stress and activation of autophagy, and the latter is not conducive to TA-induced cell death. Our results may provide a new insight into the strategic development of novel therapy for the treatment of AML.

Accuracy of endoscopic ultrasound-guided needle aspiration specimens for molecular diagnosis of non-small-cell lung carcinoma.

BACKGROUND: Endoscopic ultrasonography-guided fine-needle aspiration (EUS-FNA) and endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) are highly sensitive for diagnosing and staging lung cancer. In recent years, targeted therapy has shown great significance in the treatment of non-small cell lung carcinoma (NSCLC). Using these minimally invasive techniques to obtain specimens for molecular testing will provide patients with a more convenient diagnostic approach. AIM: To evaluate the feasibility and accuracy of tissue samples obtained using EUS-FNA and EBUS-TBNA for molecular diagnosis of NSCLC. METHODS: A total of 83 patients with NSCLC underwent molecular testing using tissues obtained from EUS-FNA or EBUS-TBNA at the Tianjin Medical University Cancer Hospital from January 2017 to June 2019. All enrolled patients underwent chest computed tomography or positron emission tomography/computed tomography prior to puncture. We detected abnormal expression of EGFR, KRAS, MET, HER2, ROS1 and anaplastic lymphoma kinase protein. Two patients failed to complete molecular testing due to insufficient tumor tissue. The clinical features, puncture records, molecular testing results and targeted treatment in the remaining 81 patients were summarized. RESULTS: In a total of 99 tissue samples obtained from 83 patients, molecular testing was successfully completed in 93 samples with a sample adequacy ratio of 93.9% (93/99). Biopsy samples from two patients failed to provide test results due to insufficient tumor tissue. In the remaining 81 patients, 62 cases (76.5%) were found to have adenocarcinoma, 11 cases (13.6%) had squamous cell carcinoma, 3 cases (3.7%) had adenosquamous carcinoma and 5 cases (6.2%) had NSCLC-not otherwise specified. The results of molecular testing showed EGFR mutations in 21 cases (25.9%), KRAS mutations in 9 cases (11.1%), ROS-1 rearrangement in 1 case (1.2%) and anaplastic lymphoma kinase-positive in 5 cases (6.2%). Twenty-four patients with positive results received targeted therapy. The total effectiveness rate of targeted therapy was 66.7% (16/24), and the disease control rate was 83.3% (20/24). CONCLUSION: Tissue samples obtained by EUS-FNA or EBUS-TBNA are feasible for the molecular diagnosis of NSCLC and can provide reliable evidence for clinical diagnosis and treatment.