Error detection using a multi-channel hybrid network with a low-resolution detector in patient-specific quality assurance.

PURPOSE: This study aimed to develop a hybrid multi-channel network to detect multileaf collimator (MLC) positional errors using dose difference (DD) maps and gamma maps generated from low-resolution detectors in patient-specific quality assurance (QA) for Intensity Modulated Radiation Therapy (IMRT). METHODS: A total of 68 plans with 358 beams of IMRT were included in this study. The MLC leaf positions of all control points in the original IMRT plans were modified to simulate four types of errors: shift error, opening error, closing error, and random error. These modified plans were imported into the treatment planning system (TPS) to calculate the predicted dose, while the PTW seven29 phantom was utilized to obtain the measured dose distributions. Based on the measured and predicted dose, DD maps and gamma maps, both with and without errors, were generated, resulting in a dataset with 3222 samples. The network's performance was evaluated using various metrics, including accuracy, sensitivity, specificity, precision, F1-score, ROC curves, and normalized confusion matrix. Besides, other baseline methods, such as single-channel hybrid network, ResNet-18, and Swin-Transformer, were also evaluated as a comparison. RESULTS: The experimental results showed that the multi-channel hybrid network outperformed other methods, demonstrating higher average precision, accuracy, sensitivity, specificity, and F1-scores, with values of 0.87, 0.89, 0.85, 0.97, and 0.85, respectively. The multi-channel hybrid network also achieved higher AUC values in the random errors (0.964) and the error-free (0.946) categories. Although the average accuracy of the multi-channel hybrid network was only marginally better than that of ResNet-18 and Swin Transformer, it significantly outperformed them regarding precision in the error-free category. CONCLUSION: The proposed multi-channel hybrid network exhibits a high level of accuracy in identifying MLC errors using low-resolution detectors. The method offers an effective and reliable solution for promoting quality and safety of IMRT QA.

Development and validation of a scatter-corrected CBCT image-guided method for cervical cancer brachytherapy.

Background and purpose: Multiple patient transfers have a nonnegligible impact on the accuracy of dose delivery for cervical cancer brachytherapy. We consider using on-site cone-beam CT (CBCT) to resolve this problem. However, CBCT clinical applications are limited due to inadequate image quality. This paper implements a scatter correction method using planning CT (pCT) prior to obtaining high-quality CBCT images and evaluates the dose calculation accuracy of CBCT-guided brachytherapy for cervical cancer. Materials and methods: The CBCT of a self-developed female pelvis phantom and five patients was first corrected using empirical uniform scatter correction in the projection domain and further corrected in the image domain. In both phantom and patient studies, the CBCT image quality before and after scatter correction was evaluated with registered pCT (rCT). Model-based dose calculation was performed using the commercial package Acuros®BV. The dose distributions of rCT-based plans and corrected CBCT-based plans in the phantom and patients were compared using 3D local gamma analysis. A statistical analysis of the differences in dosimetric parameters of five patients was also performed. Results: In both phantom and patient studies, the HU error of selected ROIs was reduced to less than 15 HU. Using the dose distribution of the rCT-based plan as the baseline, the γ pass rate (2%, 2 mm) of the corrected CBCT-based plan in phantom and patients all exceeded 98% and 93%, respectively, with the threshold dose set to 3, 6, 9, and 12 Gy. The average percentage deviation (APD) of D90 of HRCTV and D2cc of OARs was less than 1% between rCT-based and corrected CBCT-based plans. Conclusion: Scatter correction using a pCT prior can effectively improve the CBCT image quality and CBCT-based cervical brachytherapy dose calculation accuracy, indicating promising prospects in both simplified brachytherapy processes and accurate brachytherapy dose delivery.

Comparison of the Dosimetric Influence of Applicator Displacement on 2D and 3D Brachytherapy for Cervical Cancer Treatment.

To compare the dosimetric influence of applicator displacement on two-dimensional brachytherapy (2D-BT) and three-dimensional brachytherapy (3D-BT) for cervical cancer. Nineteen patients who received computed tomography-guided tandem-and-ovoid (T&O) brachytherapy were retrospectively selected. Both 2D (point-based) and 3D (volume-based) plans with and without virtual applicator displacement in the 3 axes were created for each patient. Dose changes at point A, D90 of the high-risk clinical target volume (HR-CTV) and intermediate-risk CTV (IR-CTV), and the D0.1cc, D1cc, D2cc, and D5cc of organs-at-risk (OARs) caused by applicator displacement were evaluated. Both 2D-BT and 3D-BT plans were sensitive to T&O applicator displacement. The D90 of the CTV and the dose at point A were very sensitive to applicator displacement in the right-left direction (X-axis). An applicator shift of >2 mm in the X-axis resulted in a change of >5% in the dose at point A and D90 of HR-CTV and IR-CTV. In addition, the doses to the OARs were mostly affected by applicator displacement in the anterior-posterior direction (Z-axis). A displacement of <1.5 mm in the Z-axis was required to avoid a dose change of >10% for OARs. For both 2D-BT and 3D-BT plans, T&O displacement greater than ± 2 mm in the X-axis or T&O applicator displacement ± 1.5 mm in the Z-axis resulted in significant dose changes to the tumor and OARs. In comparison with 3D-BT plans, 2D-BT plans delivered a higher dose to the tumor, and the OARs received more undesirable doses when applicator displacement occurred. The influence of applicator displacement on the doses to the tumor and OARs differed between 2D-BT and 3D-BT. Physicians should take individual patient differences into account when selecting a brachytherapy plan to mitigate the influence of applicator displacement.

Sequential and Iterative Auto-Segmentation of High-Risk Clinical Target Volume for Radiotherapy of Nasopharyngeal Carcinoma in Planning CT Images.

Background: Accurate segmentation of tumor targets is critical for maximizing tumor control and minimizing normal tissue toxicity. We proposed a sequential and iterative U-Net (SI-Net) deep learning method to auto-segment the high-risk primary tumor clinical target volume (CTVp1) for treatment planning of nasopharyngeal carcinoma (NPC) radiotherapy. Methods: The SI-Net is a variant of the U-Net architecture. The input of SI-Net includes one CT image, the CTVp1 contour on this image, and the next CT image. The output is the predicted CTVp1 contour on the next CT image. We designed the SI-Net, using the left side to learn the volumetric features and the right to localize the contour on the next image. Two prediction directions, one from inferior to superior (forward direction) and the other from superior to inferior (backward direction), were tested. The performance was compared between the SI-Net and the U-Net using Dice similarity coefficient (DSC), Jaccard index (JI), average surface distance (ASD), and Hausdorff distance (HD) metrics. Results: The DSC and JI values from the forward direction SI-Net model were 5 and 6% higher than those from the U-Net model (0.84 ± 0.04 vs. 0.80 ± 0.05 and 0.74 ± 0.05 vs. 0.69 ± 0.05, p < 0.001). The smaller ASD and HD values also indicated a better performance (2.8 ± 1.0 vs. 3.3 ± 1.0 mm and 8.7 ± 2.5 vs. 9.7 ± 2.7 mm, p < 0.01) for the SI-Net model. For the backward direction SI-Net model, the DSC and JI values were still better than those from the U-Net model (p < 0.01), although there were no significant differences in ASD and HD. Conclusions: The SI-Net model preserved the continuity between adjacent images and thus improved the segmentation accuracy compared with the conventional U-Net model. This model has potential of improving the efficiency and consistence of CTVp1 contouring for NPC patients.

Development of an In Vivo Retrodialysis Calibration Method Using Stable Isotope Labeling to Monitor Metabolic Pathways in the Tumor Microenvironment via Microdialysis.

Microdialysis is a technique that utilizes a semipermeable membrane to sample analytes present within tissue interstitial fluid. Analyte-specific calibration is required for quantitative microdialysis, but these calibration methods are tedious, require significant technical skill, and often cannot be performed jointly with the experimental measurements. Here, we describe a method using retrodialysis with stable-isotope-labeled analytes that enables simultaneous calibration and quantification for in vivo tumor microdialysis. Isotope-labeled amino acids relevant to immuno-metabolism in the tumor microenvironment (tryptophan, kynurenine, glutamine, and glutamate) were added to the microdialysis perfusate, and microdialysis probes were inserted in subcutaneous CT26 and MC38 tumors in mice. The levels of both the endogenous and isotope-labeled amino acids in the perfusate outlet were quantified using LC-MS/MS. Plasma and tumor tissue samples were also collected from the same mice and amino acid levels quantified using LC-MS/MS. Amino acids which showed statistically significant differences between the CT26-bearing and MC38-bearing mice in tumor lysate (tryptophan, kynurenine, and glutamine) and plasma (glutamate) were not the same as those identified as significantly different in tumor interstitial fluid (kynurenine and glutamate), underscoring how microdialysis can provide unique and complementary insights into tumor and immune metabolism within the tumor microenvironment.

RN927C, a Site-Specific Trop-2 Antibody-Drug Conjugate (ADC) with Enhanced Stability, Is Highly Efficacious in Preclinical Solid Tumor Models.

Trop-2, also known as TACSTD2, EGP-1, GA733-1, and M1S1, is frequently expressed on a variety of human carcinomas, and its expression is often associated with poor prognosis of the diseases. However, it is also present on the epithelium of several normal tissues. A comprehensively designed Trop-2-targeting antibody-drug conjugate (ADC), balancing both efficacy and toxicity, is therefore necessary to achieve clinical utility. To this end, we developed a cleavable Trop-2 ADC (RN927C) using a site-specific transglutaminase-mediated conjugation method and a proprietary microtubule inhibitor (MTI) linker-payload, PF-06380101. Robust in vitro cytotoxicity of RN927C was observed on a panel of Trop-2-expressing tumor cell lines, with IC50 generally in the subnanomolar range. As expected for an MTI-containing ADC, RN927C readily induced mitotic arrest of treated cells in vitro and in vivo, followed by subsequent cell death. The in vivo efficacy of RN927C was tested in multiple cell line and patient-derived xenograft tumor models, including pancreatic, lung, ovarian, and triple-negative breast tumor types. Single-dose administration of RN927C at 0.75 to 3 mg/kg was generally sufficient to induce sustained regression of Trop-2-expressing tumors and showed superior efficacy over standard treatment with paclitaxel or gemcitabine. Administration of RN927C in nonhuman primate toxicity studies resulted in target-mediated effects in skin and oral mucosa, consistent with Trop-2 expression in these epithelial tissues with minimal, non-dose limiting off-target toxicities. On the basis of the combined efficacy and safety results, RN927C is postulated to have a favorable therapeutic index for treatment of solid tumors. Mol Cancer Ther; 15(11); 2698-708. ©2016 AACR.

Feasibility of Singlet Analysis for Ligand Binding Assays: a Retrospective Examination of Data Generated Using the Gyrolab Platform.

There are many sources of analytical variability in ligand binding assays (LBA). One strategy to reduce variability has been duplicate analyses. With recent advances in LBA technologies, it is conceivable that singlet analysis is possible. We retrospectively evaluated singlet analysis using Gyrolab data. Relative precision of duplicates compared to singlets was evaluated using 60 datasets from toxicokinetic (TK) or pharmacokinetic (PK) studies which contained over 23,000 replicate pairs composed of standards, quality control (QC), and animal samples measured with 23 different bioanalytical assays. The comparison was first done with standard curve and QCs followed by PK parameters (i.e., Cmax and AUC). Statistical analyses were performed on combined duplicate versus singlets using a concordance correlation coefficient (CCC), a measurement used to assess agreement. Variance component analyses were conducted on PK estimates to assess the relative analytical and biological variability. Overall, 97.5% of replicate pairs had a %CV of <11% and 50% of the results had a %CV of ≤1.38%. There was no observable bias in concentration comparing the first replicate with the second (CCC of 0.99746 and accuracy value of 1). The comparison of AUC and Cmax showed no observable difference between singlet and duplicate (CCC for AUC and Cmax >0.99999). Analysis of variance indicated an AUC inter-subject variability 35.3-fold greater than replicate variability and 8.5-fold greater for Cmax. Running replicates from the same sample will not significantly reduce variation or change PK parameters. These analyses indicated the majority of variance was inter-subject and supported the use of a singlet strategy.

A retrospective study on intensity-modulated radiation therapy combined with chemotherapy after D2 radical surgery for gastric carcinoma.

In order to investigate the clinical value of different chemotherapies, the efficacy of intensity-modulated radiation therapy with concurrent chemotherapy following D2 radical surgery for gastric carcinoma was evaluated in this study. A total of 102 patients who underwent D2 radical surgery for gastric carcinoma followed by concurrent chemoradiotherapy (CRT) between January, 2008 and March, 2012, were selected. The 5/7 field intensity-modulated radiation therapy was used, with a planning target volume dose of 45 Gy in 25 fractions over 5 weeks. Among these patients, 45 were administered 400 mg/m2/day fluorouracil and 20 mg/m2/day tetrahydrofurfuryl alcohol through intravenous infusion 4 days before and 3 days after the radiotherapy (F-CRT group), while 57 patients received 825 mg/m2 capecitabine orally twice a day (C-CRT group). The 3-year overall and the disease-free survival rates were 75.5 and 70.5%, respectively. The overall 3-year survival rates of the F-CRT and C-CRT groups were 72.2 and 78.5% (P>0.05), respectively, and the 3-year disease-free survival rates were 67.7 and 72.8% (P>0.05), respectively. No significant differences were observed between the two groups. However, during the concurrent CRT, significant differences were found in the incidence of grade 1-2 haematological toxicity between the F-CRT and C-CRT groups (73.3 vs. 50.9%, respectively; χ2 =5.320, P=0.021). Significant differences were also found in the incidence of grade 1-2 gastrointestinal reactions between the two groups (77.8 vs. 57.9%, respectively; χ2=4.474, P=0.034). Therefore, intensity-modulated radiation therapy combined with concurrent chemotherapy following D2 radical surgery for gastric cancer was found to be safe and effective. In addition, radiotherapy was better tolerated and more likely to be completed using C-CRT rather than F-CRT.

Osteopontin induces growth of metastatic tumors in a preclinical model of non-small lung cancer.

Osteopontin (OPN), also known as SPP1 (secreted phosphoprotein), is an integrin binding glyco-phosphoprotein produced by a variety of tissues. In cancer patients expression of OPN has been associated with poor prognosis in several tumor types including breast, lung, and colorectal cancers. Despite wide expression in tumor cells and stroma, there is limited evidence supporting role of OPN in tumor progression and metastasis. Using phage display technology we identified a high affinity anti-OPN monoclonal antibody (hereafter AOM1). The binding site for AOM1 was identified as SVVYGLRSKS sequence which is immediately adjacent to the RGD motif and also spans the thrombin cleavage site of the human OPN. AOM1 efficiently inhibited OPNa binding to recombinant integrin αvß3 with an IC50 of 65 nM. Due to its unique binding site, AOM1 is capable of inhibiting OPN cleavage by thrombin which has been shown to produce an OPN fragment that is biologically more active than the full length OPN. Screening of human cell lines identified tumor cells with increased expression of OPN receptors (αvß3 and CD44v6) such as mesothelioma, hepatocellular carcinoma, breast, and non-small cell lung adenocarcinoma (NSCLC). CD44v6 and αvß3 were also found to be highly enriched in the monocyte, but not lymphocyte, subset of human peripheral blood mononuclear cells (hPBMCs). In vitro, OPNa induced migration of both tumor and hPBMCs in a transwell migration assay. AOM1 significantly blocked cell migration further validating its specificity for the ligand. OPN was found to be enriched in mouse plasma in a number of pre-clinical tumor model of non-small cell lung cancers. To assess the role of OPN in tumor growth and metastasis and to evaluate a potential therapeutic indication for AOM1, we employed a Kras(G12D-LSL)p53(fl/fl) subcutaneously implanted in vivo model of NSCLC which possesses a high capacity to metastasize into the lung. Our data indicated that treatment of tumor bearing mice with AOM1 as a single agent or in combination with Carboplatin significantly inhibited growth of large metastatic tumors in the lung further supporting a role for OPN in tumor metastasis and progression.

Treatment outcome of radiotherapy alone versus radiochemotherapy in early stage nasal natural killer/T-cell lymphoma.

This study aims to investigate the prognostic factors and long-term treatment outcome in patients with early stage nasal natural killer (NK)/T-cell lymphoma. Sixty-four patients were recruited in this study, whose clinical and laboratory data were collected from hospital records. Early stage (stage IE: 51, stage IIE: 13) nasal NK/T-cell lymphoma (NNTCL) was established according to Ann Arbor staging classification. Among these patients, 23 received radiotherapy (RT) alone, the remaining 41 cases were treated with radiochemotherapy (RCT) comprised of 1-6 cycles of anthracycline-based chemotherapeutic regimens. Results show that the median overall survival (OS) time was 41 months. The 5-year OS and progression-free survival rates were 59.2 and 52.3%, respectively. The 5-year OS rate for patients who received RT alone was 57.9%, whereas that for patients who received RCT was 61.5% (P = 0.47). There is no significant difference between two treatment modalities. Multivariate analysis showed that Eastern Cooperative Oncology Group performance status (PS) score > or = 2, local tumor invasion out of nasal cavity, and lower complete remission (CR) rates in the initial treatment were significant unfavorable independent prognostic factors. Taken together, our study suggests that RCT did not improve the survival rate of patients with early stage NNTCL. PS score before treatment, local tumor invasion out of nasal cavity, and CR rate of the primary treatment may be independent prognostic factors among the subtype lymphoma entity.

[Effect of natural killer cell line NK-92 against human ovarian carcinoma cells in vitro and in vivo].

OBJECTIVE: To study the cytotoxic activity of NK-92 cells irradiated against human ovarian cancer. METHODS: NK-92 cells were exposed to different doses of radiation and assayed for proliferation by a standard (3)H-thymidine incorporation assay and cell count by using trypan blue exclusion. The cytotoxic activity of NK-92 cells against targets was measured in a standard (51)Cr-release assay in vitro. The effectiveness of irradiated NK-92 cells on ovarian cancer was compared with the control group of cancers (without injection of irradiated NK-92 cells). RESULTS: (1) In vitro:The proliferation of NK-92 cells was inhibited by radiation of 4, 8 and 16 Gy, respectively. From the (3)H-thymidine incorporation data, irradiation by 4 Gy reduced cell proliferation to 29% of control, while 8 Gy reduced proliferation to 6%. The cytotoxicity of NK-92 cells at 4 Gy 2 days following irradiation was approximately 42%-62% for ovarian cancer cell HO-8910, while it was 33%-58% at 8 Gy. (2) In vivo: Tumor size in treatment group was (0.047 +/- 0.019) cm(3) on day 30 after inoculation, and (0.167 +/- 0.021) cm(3) on day 40 and (0.343 +/- 0.022) cm(3) on day 50, while the sizes were smaller in treatment group (P < 0.01). In addition, the tumor group animals died between 74-82 days after injection of HO-8910 cells, while the treatment group animals were alive over 120 days (P < 0.01). CONCLUSION: Our study indicates that injection of irradiated NK-92 cells may be a potentially effective treatment for human ovarian carcinoma.