Autophagy Governs Protumorigenic Effects of Mitotic Slippage-induced Senescence.

The most commonly utilized class of chemotherapeutic agents administered as a first-line therapy are antimitotic drugs; however, their clinical success is often impeded by chemoresistance and disease relapse. Hence, a better understanding of the cellular pathways underlying escape from cell death is critical. Mitotic slippage describes the cellular process where cells exit antimitotic drug-enforced mitotic arrest and "slip" into interphase without proper chromosome segregation and cytokinesis. The current report explores the cell fate consequence following mitotic slippage and assesses a major outcome following treatment with many chemotherapies, therapy-induced senescence. It was found that cells postslippage entered senescence and could impart the senescence-associated secretory phenotype (SASP). SASP factor production elicited paracrine protumorigenic effects, such as migration, invasion, and vascularization. Both senescence and SASP factor development were found to be dependent on autophagy. Autophagy induction during mitotic slippage involved the autophagy activator AMPK and endoplasmic reticulum stress response protein PERK. Pharmacologic inhibition of autophagy or silencing of autophagy-related ATG5 led to a bypass of G1 arrest senescence, reduced SASP-associated paracrine tumorigenic effects, and increased DNA damage after S-phase entry with a concomitant increase in apoptosis. Consistent with this, the autophagy inhibitor chloroquine and microtubule-stabilizing drug paclitaxel synergistically inhibited tumor growth in mice. Sensitivity to this combinatorial treatment was dependent on p53 status, an important factor to consider before treatment.Implications: Clinical regimens targeting senescence and SASP could provide a potential effective combinatorial strategy with antimitotic drugs. Mol Cancer Res; 16(11); 1625-40. ©2018 AACR.

Indication of lower neck irradiation in nasopharyngeal carcinoma without nodal metastasis: the potential impact of tumor volume.

BACKGROUND: Elective radiation of lower neck is controversial for nasopharyngeal carcinoma (NPC) without lymph node metastasis (N0 disease). Tumor volume is an important prognostic indicator. The objective of this study is to explore the potential impact of tumor volume on the indication of the lower neck irradiation for N0-NPC, by a qualitative evaluation of the relationship between tumor volume and nodal metastasis. METHODS: Magnetic resonance (MR) images of 99 consecutive patients with NPC who underwent treatment were retrospectively reviewed. Primary tumor volumes of NPC were semi-automatically measured, nodal metastases were N-classified and neck level involvements were examined. Distributions of tumor volumes among N-category-based groups and distributions of N-categories among tumor volume-based groups were analyzed, respectively. RESULTS: The numbers of patients with N0 to N3 disease were 12, 39, 32, and 16, respectively. The volumes of primary tumor were from 3.3 to 89.6 ml, with a median of 17.1 ml. For patients with nodal metastasis, tumor volume did not increase significantly with the advancing of N-category (P > 0.05). No significant difference was found for the distribution of N1, N2, and N3 categories among tumor volume-based groups (P > 0.05). Nevertheless patients with nodal metastasis had significantly larger tumor volumes than those without metastasis (P < 0.05). Patients with larger tumor volumes were associated with an increased incidence of nodal metastasis. CONCLUSIONS: Certain positive correlations existed between tumor volume and the presence of nodal metastasis. The tumor volume (>10 ml) is a potential indicator for the lower neck irradiation for N0-NPC.

Deconvolution assessment of splenic and splanchnic contributions to portal venous blood flow in liver cirrhosis.

PURPOSE: To devise a noninvasive imaging method for resolving the relative contribution of splenic and splanchnic blood flow to portal venous flow and derive quantitative estimates for parameters pertaining to splenic and portal hemodynamics. METHODS: Tracer concentration-time curves of the aorta, portal vein, and spleen can be extracted from dynamic contrast-enhanced (DCE) CT or MR images. A combination of two tracer analysis approaches, namely arterial-venous sampling and residual tracer deconvolution, is proposed to model these concentration-time curves and derive hemodynamic parameters pertaining to splenic and portal circulation. Clinical feasibility of the proposed method was explored using DCE CT datasets of eight cirrhotic patients. Monte Carlo simulations were performed to evaluate the confidence of the parameter estimates. RESULTS: Portal blood flow was estimated to be 763.8 +/- 438.1 ml/min in cirrhotic patients and the splenic contribution was found to be elevated (0.75 +/- 0.22). Estimates of splenic blood flow (582 +/- 420 ml/min) and transit time (15.3 +/- 10.1 s) in cirrhotic patients were consistent with reported values obtained using duplex Doppler ultrasound and dynamic scintigraphy, respectively. CONCLUSIONS: This study shows the feasibility of noninvasive assessment of splenic and portal hemodynamic parameters by DCE imaging using a combination of tracer kinetics modeling techniques.

Independent component analysis of dynamic contrast-enhanced magnetic resonance images of breast carcinoma: a feasibility study.

PURPOSE: To study the possibility of using independent component analysis (ICA) to identify breast lesions as separate hemodynamic sources on dynamic contrast-enhanced (DCE) MR images, as depicted by the passage of contrast medium. MATERIALS AND METHODS: Six patients who were histopathologically confirmed with breast carcinoma underwent DCE MRI with 5 precontrast and 60 postcontrast scans at a time-resolution of 8 s. A spatial ICA algorithm was applied on the DCE MRI data set to extract spatial component maps corresponding to source locations with different signal time-intensity patterns. To verify the present hypothesis of the ability of ICA to reveal tumor voxels as a separate hemodynamic phase, tumor margins were outlined by an experienced radiologist who was blinded from the ICA results, and the manual outlines were compared with the ICA maps. RESULTS: Consistently for each of the six patient study cases, it was found that ICA yields a tumor component map associated with typical tumor enhancement patterns of rapid enhancement with washout or plateau. Tumor outlines manually drawn by the radiologist were in good agreement with the tumor locations depicted in the tumor component maps. CONCLUSION: ICA may provide an objective method for identifying the outlines of enhancing breast tumors on DCE MR images and to automatically extract the tumor signal intensity-time curve for subsequent tracer kinetics analysis.

Significance of tumour volume measurements in tongue cancer: a novel role in staging.

BACKGROUND: Tongue cancers are staged by the American Joint Committee on Cancer and the Union Internationale Contre le Cancer TNM staging systems. Cancer, however, evolves in a 3-D plane. Hence, using the largest tumour diameter will not reflect total cancer volume. We aim to evaluate the use of tongue cancer tumour volume (Tv) as a prognostic predictor of disease recurrence and survival. METHODS: The study is a retrospective analysis of patients in Singapore General Hospital who underwent complete resection for histologically proven tongue carcinoma from 2000 to 2002. The Tv was measured on staging T(2)-weighted magnetic resonance imaging datasets by semiautomated methods. RESULTS: Seventeen patients with a median follow-up duration of 57.9 months were studied. A wide range of volumes was noted in each T stage. The median time to relapse was 8.6 months for those with Tv > or = 13 cc but was not achieved for those with Tv < 13 cc. The hazard ratio comparing Tv > or = 13 cc versus <13 cc is 9.02 (95% confidence interval (CI) 1.70-47.94, P = 0.014). Of the seven deaths reported, five patients had Tv > or = 13 cc. The median overall survival was 15.8 months for those with Tv > or = 13 cc but was not achieved for those with Tv < 13 cc. The hazards of death for Tv > or = 13 cc was 3.91 times that of Tv < 13 cc (95% CI 0.86-17.86, P = 0.078). CONCLUSION: Tongue cancer Tv measurement allows a more refined and accurate assessment of tumour status. This can be a possible prognostic indicator and be used in a novel staging method for the future.

Extraction of metastatic lymph nodes from MR images using two deformable model-based approaches.

We presented and evaluated two deformable model-based approaches, region plus contour deformation (RPCD), and level sets to extract metastatic cervical nodal lesions from pretreatment T2-weighted magnetic resonance images. The RPCD method first uses a region deformation to achieve a rough boundary of the target node from a manually drawn initial contour, based on signal statistics. After that, an active contour deformation is employed to drive the rough boundary to the real node-normal tissue interface. Differently, the level sets move a manually drawn initial contour toward the desired nodal boundary under the control of the evolvement speed function, which is influenced by image gradient force. The two methods were tested by extracting 33 metastatic cervical nodes from 18 nasopharyngeal carcinoma patients. Experiments on a basis of pixel matching to reference standard showed that RPCD and level sets achieved averaged percentage matching at 82-84% and 87-88%, respectively. In addition, both methods had significantly lower interoperator variances than the manual tracing method. It was suggested these two methods could be useful tools for the evaluation of metastatic nodal volume as an indicator of classification and treatment response, or be alternatives for the delineation of metastatic nodal lesions in radiation treatment planning.

The relationship between nasopharyngeal carcinoma tumor volume and TNM T-classification: a quantitative analysis.

Recent findings show that tumor volume is a significant prognostic factor for the treatment of nasopharyngeal carcinoma (NPC). The inclusion of tumor volume as an additional prognostic factor in the UICC TNM classification system was suggested; however, how tumor volume could possibly be incorporated is still unexplored. In this paper, we report a quantitative analysis on the relationship between NPC tumor volume and T-classification, using the data from 206 NPC patients. By T-classification and semi-automatic tumor volume measurement, the difference in tumor volumes among the various TNM T-classification groups was examined. In addition, a statistics-based analysis scheme, which used the T-classification as the "gold standard", was proposed to classify NPC tumors into volume-based groups to explore the possible links. The results show that NPC tumor volume has positive correlation with advancing T-classification groups and significant difference existed in the distribution of T-classification among various volume-based groups (P < 0.001). By the proposed statistical scheme, tumor volume could be included as an additional prognostic factor in the TNM framework, following validation studies.

Correlation between MR imaging-derived nasopharyngeal carcinoma tumor volume and TNM system.

PURPOSE: To measure nasopharyngeal carcinoma tumor volume based on magnetic resonance images using a validated semiautomated measurement methodology and correlate tumor volume with TNM T classification. METHODS AND MATERIALS: The study population consisted of 206 consecutive nasopharyngeal carcinoma patients who had magnetic resonance imaging staging scans. Tumor volume was measured using a semisupervised knowledge-based fuzzy clustering algorithm. Patients were divided into 4 groups according to TNM T classification. The difference in tumor volumes among the various TNM T-classification groups was examined. RESULTS: The mean tumor volume in each T-classification group is as follows: T1, 8.6 mL +/- 5.0 (standard deviation [SD]); T2, 18.1 mL +/- 8.1 (SD); T3, 25.8 mL +/- 14.1 (SD); and T4, 36.2 mL +/- 18.9 (SD). The mean tumor volume increased significantly with advancing T classification (p < 0.0001). Tumor volume in a more advanced T group was significantly larger than that in an adjacent early T group (p < 0.01). CONCLUSION: Validated magnetic resonance imaging-based tumor volume shows positive correlation between tumor volume and advancing T-classification groups. It may be possible to incorporate tumor volume as an additional prognostic factor into the existing TNM system.

Imaging of the nasopharynx and skull base.

The prerequisite for the correct diagnosis and accurate delineation of skull base lesions is familiarity with the complex anatomy of the skull base. Imaging plays a central role in the management of skull base disease because this region is often difficult to evaluate clinically. CT and MR imaging are complementary; they are often used together to demonstrate the full disease extent. This article focuses on the critical anatomy of the skull base and how this knowledge contributes to accurate disease assessment.

Nasopharyngeal carcinoma tumor volume measurement..

Tumor volume was measured in 69 patients with nasopharyngeal carcinoma. On transverse nonenhanced T1-weighted and gadolinium-enhanced T1-weighted magnetic resonance (MR) images, segmentation was performed by means of seed growing and knowledge-based fuzzy clustering methods. Data were compared with those collected with the manual tracing method and analyzed for interoperator variance and interobserver reliability. There was no significant difference between the volumes determined with manual tracing or semiautomated segmentation (P >.05). On the volume level, Pearson correction coefficients were close for both the manual tracing and semiautomated methods. Significant differences in interoperator variance existed between the two methods on the pixel level (P <.05). Compared with manual tracing, the semiautomated method helped reduce interoperator variance and obtain higher interobserver reliability. Findings in the current study validate the use of semiautomated volume measurement methods for nasopharyngeal carcinoma.

Tongue carcinoma: tumor volume measurement.

PURPOSE: To validate the semiautomated methods of tongue carcinoma tumor volume measurement by comparing the conventional manual trace method with 2 semiautomated computer methods: seed growing and region deformation. MATERIALS AND METHODS: The study population consisted of 16 patients with histology-proven tongue carcinoma. Two head-and-neck radiologists independently measured the tumor volume demonstrated on pretreatment T2-weighted magnetic resonance data sets. The tumor volumes were measured using manual tracing and semiautomated seed growing and region deformation algorithm. Data were recorded for analysis of interoperator variance and interobserver reliability at volume and pixel levels. RESULTS: There was no significant difference between the manually traced volume and semiautomated segmentation volumes for both operators. No significant difference was found in interobserver variance among the 3 methods at volume level. However, there was significant difference between manual tracing and semiautomated segmentation methods in interobserver reliability at pixel level. CONCLUSION: The semiautomated methods could achieve satisfactory segmentation results. They could also reduce interoperator variance and obtain a higher interobserver reliability. This study validates the use of semiautomated volume measurement methods for tongue carcinoma.

Imaging of the nasopharynx and skull base.

The prerequisite for the correct diagnosis and accurate delineation of skull base lesions is familiarity with the complex anatomy of the skull base. Imaging plays a central role in the management of skull base disease because this region is often difficult to evaluate clinically. CT and MR imaging are complementary; they are often used together to demonstrate the full disease extent. This article focuses on the critical anatomy of theskull base and how this knowledge contributes to accurate disease assessment.