Citations

Abstract FAM46C is one of the most recurrently mutated genes in multiple myeloma; however its role in disease pathogenesis has not been determined. Here we demonstrate that wild-type (WT) FAM46C overexpression induces substantial cytotoxicity in multiple myeloma cells. In contrast, FAM46C mutations found in multiple myeloma patients abrogate this cytotoxicity, indicating a survival advantage conferred by the FAM46C mutant phenotype. WT FAM46C overexpression downregulated IRF4, CEBPB, and MYC and upregulated immunoglobulin (Ig) light chain and HSPA5/BIP. Furthermore, pathway analysis suggests that enforced FAM46C expression activated the unfolded protein response pathway and induced mitochondrial dysfunction. CRISPR-mediated depletion of endogenous FAM46C enhanced multiple myeloma cell growth, decreased Ig light chain and HSPA5/BIP expression, activated ERK and antiapoptotic signaling, and conferred relative resistance to dexamethasone and lenalidomide treatments. Genes altered in FAM46C-depleted cells were enriched for signaling pathways regulating estrogen, glucocorticoid, B-cell receptor signaling, and ATM signaling. Together these results implicate FAM46C in myeloma cell growth and survival and identify FAM46C mutation as a contributor to myeloma pathogenesis and disease progression via perturbation in plasma cell differentiation and endoplasmic reticulum homeostasis. Cancer Res; 77(16); 4317–27. ©2017 AACR.

ObjectivesTo develop and validate a nomogram to estimate the pretest probability of malignancy in Chinese patients with solid solitary pulmonary nodule (SPN).Materials and MethodsA primary cohort of 1798 patients with pathologically confirmed solid SPNs after surgery was retrospectively studied at five institutions from January 2014 to December 2015. A nomogram based on independent prediction factors of malignant solid SPN was developed. Predictive performance also was evaluated using the calibration curve and the area under the receiver operating characteristic curve (AUC).ResultsThe mean age of the cohort was 58.9 ± 10.7 years. In univariate and multivariate analysis, age; history of cancer; the log base 10 transformations of serum carcinoembryonic antigen value; nodule diameter; the presence of spiculation, pleural indentation, and calcification remained the predictive factors of malignancy. A nomogram was developed, and the AUC value (0.85; 95%CI, 0.83‐0.88) was significantly higher than other three models. The calibration cure showed optimal agreement between the malignant probability as predicted by nomogram and the actual probability.ConclusionsWe developed and validated a nomogram that can estimate the pretest probability of malignant solid SPNs, which can assist clinical physicians to select and interpret the results of subsequent diagnostic tests.

Respiratory motion is traditionally assessed using tumor motion magnitude. In proton therapy, respiratory motion causes density variations along the beam path that result in uncertainties of proton range. This work has investigated the use of water‐equivalent thickness (WET) to quantitatively assess the effects of respiratory motion on calculated dose in passively scattered proton therapy (PSPT). A cohort of 29 locally advanced non‐small cell lung cancer patients treated with 87 PSPT treatment fields were selected for analysis. The variation in WET (ΔWET) along each field was calculated between exhale and inhale phases of the simulation four‐dimensional computed tomography. The change in calculated dose (ΔDose) between full‐inhale and full‐exhale phase was quantified for each field using dose differences, 3D gamma analysis, and differential area under the curve (ΔAUC) analysis. Pearson correlation coefficients were calculated between ΔDose and ΔWET. Three PSPT plans were redesigned using field angles to minimize variations in ΔWET and compared to the original plans. The median ΔWET over 87 treatment fields ranged from 1‐9 mm, while the ΔWET 95th percentile value ranged up to 42 mm. The ΔWET was significantly correlated to the ΔDose for all metrics analyzed. The patient plans that were redesigned using ΔWET analysis to select field angles were more robust to the effects of respiratory motion, as ΔAUC values were reduced by more than 60% in all three cases. The tumor motion magnitude alone does not capture the potential dosimetric error due to respiratory motion because the proton range is sensitive to the motion of all patient anatomy. The use of ΔWET has been demonstrated to identify situations where respiratory motion can impact the calculated dose. Angular analysis of ΔWET may be capable of designing radiotherapy plans that are more robust to the effects of respiratory motion.PACS number(s): 87.55.‐x

The objective of this study was to evaluate and understand the systematic error between the planned three‐dimensional (3D) dose and the delivered dose to patient in scanning beam proton therapy for lung tumors. Single‐field and multifield optimized scanning beam proton therapy plans were generated for ten patients with stage II‐III lung cancer with a mix of tumor motion and size. 3D doses in CT datasets for different respiratory phases and the time‐weighted average CT, as well as the four‐dimensional (4D) doses were computed for both plans. The 3D and 4D dose differences for the targets and different organs at risk were compared using dose‐volume histogram (DVH) and voxel‐based techniques, and correlated with the extent of tumor motion. The gross tumor volume (GTV) dose was maintained in all 3D and 4D doses, using the internal GTV override technique. The DVH and voxel‐based techniques are highly correlated. The mean dose error and the standard deviation of dose error for all target volumes were both less than 1.5% for all but one patient. However, the point dose difference between the 3D and 4D doses was up to 6% for the GTV and greater than 10% for the clinical and planning target volumes. Changes in the 4D and 3D doses were not correlated with tumor motion. The planning technique (single‐field or multifield optimized) did not affect the observed systematic error. In conclusion, the dose error in 3D dose calculation varies from patient to patient and does not correlate with lung tumor motion. Therefore, patient‐specific evaluation of the 4D dose is important for scanning beam proton therapy for lung tumors.PACS number: 87.55.D