Mutational landscape of nasopharyngeal carcinoma based on targeted next-generation sequencing: implications for predicting clinical outcomes.

BACKGROUND: The aim of this study was to draw a comprehensive mutational landscape of nasopharyngeal carcinoma (NPC) tumors and identify the prognostic factors for distant metastasis-free survival (DMFS). METHODS: A total of forty primary nonkeratinizing NPC patients underwent targeted next-generation sequencing of 450 cancer-relevant genes. Analysis of these sequencing and clinical data was performed comprehensively. Univariate Cox regression analysis and multivariate Lasso-Cox regression analyses were performed to identify factors that predict distant metastasis and construct a risk score model, and seventy percent of patients were randomly selected from among the samples as a validation cohort. A receiver operating characteristic (ROC) curve and Harrell's concordance index (C-index) were used to investigate whether the risk score was superior to the TNM stage in predicting the survival of patients. The survival of patients was determined by Kaplan-Meier curves and log-rank tests. RESULTS: The twenty most frequently mutated genes were identified, such as KMT2D, CYLD, and TP53 et al. Their mutation frequencies of them were compared with those of the COSMIC database and cBioPortal database. N stage, tumor mutational burden (TMB), PIK3CA, and SF3B1 were identified as predictors to build the risk score model. The risk score model showed a higher AUC and C-index than the TNM stage model, regardless of the training cohort or validation cohort. Moreover, this study found that patients with tumors harboring PI3K/AKT or RAS pathway mutations have worse DMFS than their wild-type counterparts. CONCLUSIONS: In this study, we drew a mutational landscape of NPC tumors and established a novel four predictor-based prognostic model, which had much better predictive capacity than TNM stage.

Diffusion-weighted imaging in assessing pathological response of tumor in breast cancer subtype to neoadjuvant chemotherapy.

PURPOSE: To investigate the efficacy of diffusion-weighted imaging (DWI) for reflecting and predicting pathological tumor response in breast cancer subtype to neoadjuvant chemotherapy (NAC). MATERIALS AND METHODS: The retrospective study included 176 patients with breast cancer who underwent magnetic resonance imaging (MRI) examinations before and after NAC prior to surgery. The pre- and post-NAC apparent diffusion coefficient (ADC) values of tumor were measured respectively on DWI. The pathological response was classified into either a complete response (pCR) or as a noncomplete response (pNCR) to NAC with the Miller & Payne system. The relationship between the ADC value and the pathological response was assessed according to intrinsic subtypes (Luminal A, Luminal B, HER2-enriched, and triple negative) defined by immunohistochemical features. RESULTS: Multiple comparisons respectively showed that pre-NAC and post-NAC ADC were significantly different among four subtypes (P < 0.001). After the comparison between two different subtypes, the pre-NAC ADC value of the triple-negative and HER2-enriched subtypes were significantly higher than Luminal A (P < 0.001 and P < 0.001) and Luminal B subtype (P < 0.001 and P = 0.009), and the post-NAC ADC of triple-negative subtype was significantly higher than the others (P < 0.001). The pre-NAC ADC of pCRs was significantly lower than that of pNCRs only in the triple-negative subtype among four subtypes (P < 0.001), and the post-NAC ADC of pCRs was significantly higher than that of pNCRs in each subtype (P < 0.001). CONCLUSION: DWI appears to be a promising tool to determine the association of pathological response to NAC in breast cancer subtypes.

[Influence of registration based on different reference markers on the displacement of the geometry consisted of all clips in the cavity for external-beam partial breast irradiation at moderate deep inspiration breath holding].

OBJECTIVE: To investigate the influence of registration based on different reference markers on the displacement of the geometry consisted of all clips in the cavity for external-beam partial breast irradiation at moderate deep inspiration breath holding assisted by active breathing control device. METHODS: Twenty-seven early stage breast cancer patients feasible for external beam partial breast irradiation (EB-PBI) were selected. The patients undertaken three-dimensional computed tomography (3DCT) simulation scan at moderate deep inspiration breath holding (mDIBH) assisted by active breathing control device, and two sets of mDIBH CT images were got and transferred to the Pinnacle 3 planning system. All of the silver clips were delineated and a geometry consisted of all clips were generated. On the account of automatic registration of mDIBH CT images, manual registration was carried out based separately on the topside clip in the cavity, the labeled skin at anterior surface of the cavity at central level and the metal mark on the body surface near the cavity, then the displacements of center of the geometry in left-right (LR), anterior-posterior (AP) and superior-inferior (SI) directions based separately on the three registrations were measured. RESULTS: The displacements of center of the geometry in LR, AP and SI directions based on registration of the clips, the labeled skin and the metal mark were (0.61 ± 0.62)mm vs. (1.11 ± 1.21)mm vs. (1.31 ± 1.55)mm, (0.63 ± 0.59)mm vs. (0.92 ± 0.93)mm vs. (1.19 ± 1.24)mm and (0.91 ± 0.96)mm vs. (2.13 ± 2.12)mm vs. (1.93 ± 1.55)mm, respectively. Compared the displacements of center of the geometry in the same direction between the three registrations, significant differences were found only in SI direction between clip registration and skin registration, clip registration and mark registration (t = 5.045, 7.210 and P = 0.025, 0.007) . Compared the displacements of center of the geometry between three dimensional directions for each reference registration, there was no significant difference (all P > 0.05). CONCLUSIONS: When EB-PBI is carried out in state of mDIBH, measurement of the intrafraction displacement based on registration of the clip in the cavity is a reasonable selection. Otherwise, excessive margin enlargement of PTV in SI direction will be generated if the regional skin or metal mark is selected as registration reference.

Analysis of the advantage of individual PTVs defined on axial 3D CT and 4D CT images for liver cancer.

The purpose of this study was to compare positional and volumetric differences of planning target volumes (PTVs) defined on axial three dimensional CT (3D CT) and four dimensional CT (4D CT) for liver cancer. Fourteen patients with liver cancer underwent 3D CT and 4D CT simulation scans during free breathing. The tumor motion was measured by 4D CT. Three internal target volumes (ITVs) were produced based on the clinical target volume from 3DCT (CTV3D): i) A conventional ITV (ITVconv) was produced by adding 10 mm in CC direction and 5 mm in LR and and AP directions to CTV3D; ii) A specific ITV (ITVspec) was created using a specific margin in transaxial direction; iii) ITVvector was produced by adding an isotropic margin derived from the individual tumor motion vector. ITV4D was defined on the fusion of CTVs on all phases of 4D CT. PTVs were generated by adding a 5 mm setup margin to ITVs. The average centroid shifts between PTVs derived from 3DCT and PTV4D in left-right (LR), anterior-posterior (AP), and cranial-caudal (CC) directions were close to zero. Comparing PTV4D to PTVconv, PTVspec, and PTVvector resulted in a decrease in volume size by 33.18% ± 12.39%, 24.95% ± 13.01%, 48.08% ± 15.32%, respectively. The mean degree of inclusions (DI) of PTV4D in PTVconv, and PTV4D in PTVspec, and PTV4D in PTVvector was 0.98, 0.97, and 0.99, which showed no significant correlation to tumor motion vector (r = -0.470, 0.259, and 0.244; p = 0.090, 0.371, and 0.401). The mean DIs of PTVconv in PTV4D, PTVspec in PTV4D, and PTVvector in PTV4D was 0.66, 0.73, and 0.52. The size of individual PTV from 4D CT is significantly less than that of PTVs from 3DCT. The position of targets derived from axial 3DCT images scatters around the center of 4D targets randomly. Compared to conventional PTV, the use of 3D CT-based PTVs with individual margins cannot significantly reduce normal tissues being unnecessarily irradiated, but may contribute to reducing the risk of missing targets for tumors with large motion.

[Evaluation of dosimetric variance in forward intensity modulated radiotherapy of the breast based on 4D CT and 3D CT during free breathing].

OBJECTIVE: To explore the dosimetric variance in forward intensity modulated radiotherapy (IMRT) based on 4D CT and 3D CT after breast conserving surgery. METHODS: Seventeen patients after breast conserving surgery underwent 3D CT simulation scans followed by respiration-synchronized 4D CT simulation scans at free breathing state. The treatment plan constructed using the end inspiration (EI) scan was then copied and applied to the end expiration (EE), and 3D scans and dose distribution were calculated separately. Dose-volume histograms (DVHs) parameters for the CTV, PTV, ipsilateral lung and heart were evaluated and compared. RESULTS: The CTV volume difference was biggest between T0 and 3D CT, and the volume difference was 4.10 cm(3). Mean dose of PTV at EE was lower than that at EI (P = 0.019), but there were no statistically significant difference between 3D and EI, EE (all P > 0.05). The homogeneity index (HI) at EI, EE, 3D plans were 0.149, 0.159 and 0.164, respectively, and a significant difference was only between EI and EE (P = 0.039). The highest conformal index (CI) was at EI phase (P < 0.05), and there was no significant difference between EE and 3D (P = 0.758). The V(40) and V(50) of ipsilateral lung at EE phase were lower than that at EI (P < 0.05). There were no significant differences in all the indexes for heart (P > 0.05). CONCLUSIONS: The breast deformation during respiration may be disregarded in whole breast IMRT. PTV dose distribution is significantly changed between EI and EE phases, and the differentiation of the lung high dose area between EI and EE phases may be induced by thorax expansion. 3D treatment planning is sufficient for whole breast forward IMRT, but 4D CT scans assisted by respiratory gating ensures more precise delivery of radiation dose.

[Comparison of three methods to delineate internal gross target volume of the primary hepatocarcinoma based on four-dimensional CT simulation images].

OBJECTIVE: To compare the position and magnitude of internal target gross volume (IGTV) of primary hepatocarcinoma delineated by three methods based on four-dimensional computed tomography (4D-CT) and to investigate the relevant factors affecting the position and magnitude. METHODS: Twenty patients with primary hepatocarcinoma after transcatheter arterial chemoembolization (TACE) underwent big bore 4D-CT simulation scan of the thorax and abdomen using a real-time position management (RPM) system for simultaneous record of the respiratory signals. The CT images with respiratory signal data were reconstructed and sorted into 10 phase groups in a respiratory cycle, with 0% phase corresponding to end-inhale and 50% corresponding to end-exhale. The maximum intensity projection (MIP) image was generated. IGTVs of the tumor were delineated using the following three methods: (1) The gross tumor volume (GTV) on each of the ten respiratory phases of the 4D-CT image set was delineated and fused ten GTV to produce IGTV10; (2) The GTVs delineated separately based on 0% and 50% phase were fused to produce IGTV(IN+EX); (3) The visible tumor on the MIP image was delineated to produce IGTV(MIP). Twenty patients were divided into groups A and B based on the location of the target center,and were divided into groups C and D based on the tumor maximum diameter. The patients were divided into groups E and F based on the three-dimensional (3D) motion vector of the target center. The position of the target center, the volume of target, the degree of inclusion (DI) and the matching index (MI) were compared reciprocally between IGTV10, IGTV(IN+EX) and IGTV(MIP), and the influence of the tumor position and 3D motion vector on the related parameters were compared based on the grouping. RESULTS: The average differences between the position of the center of IGTVs on direction of X, Y and Z axes were less than 1.5 mm, and the difference was statistically not significant. The volume of IGTV10 was larger than that of IGTV(IN+EX), but the difference was not significant (t = 0.354, P = 0.725). The volume of IGTV10 was larger than that of IGTV(MIP) but the difference was not significant (t = -0.392, P = 0.697). The ratio of IGTV(IN+EX) to IGTV10 was 0.75 +/- 0.15 and the ratio of IGTV(MIP) to IGTV10 was 0.78 +/- 0.14. The DI of IGTV(IN+EX) in IGTV10 was (74.85 +/- 15.09)% and that of IGTV(MIP) in IGTV10 was (68.87 +/- 13.69)%. The MI between IGTV10 and IGTV(IN+EX), IGTV10 and IGTV(MIP) were 0.75 +/- 0.15 and 0.67 +/- 0.13, respectively. The median of ratio of IGTV(IN+EX)/ IGTV10 was 0.57 in group A versus 0.87 in group B, statistically with a significant difference between the groups A and B (Z = -3.300,P = 0.001). The median of ratio of IGTV(MIP)/IGTV10 was 0.51 in the group A and 0.72 in group B, with a significant difference between the groups A and B (Z = -3.413, P = 0.001). The median of ratio of IGTV(IN+EX)/IGTV10 was 0.79 in group C versus 0.74 in group D, with a difference not significant (Z = -0.920, P = 0.358). The median of ratio of IGTV(MIP)/IGTV10 was 0.85 in group C versus 0.80 in group D, with a non-significant difference (Z = -0.568, P = 0.570). The median of ratio of IGTV(IN+EX)/IGTV10 was 0.87 in group E versus 0.68 in group F, with a significant difference between the two groups (Z = -2.897, P = 0.004). The median of ratio of IGTV(MIP)/IGTV10 was 0.85 in the group E versus 0.81 in the group F, with a non-significant difference (Z = -0.568, P = 0.570). CONCLUSIONS: The center displacement of the IGTVs delineated separately by the three techniques based on 4D-CT images is not obvious. IGTV(IN+EX) and IGTV(MIP) can not replace IGTV10, however, IGTV(IN+EX) is more close to IGTV10 comparing with IGTV(MIP). The ratio of IGTV10 and IGTV(MIP) is correlated to the 3D motion vector of the tumor. When the tumor is situated in the upper part of the liver and with a 3D motion vector less than 9 mm, IGTV10 should be the best IGTV.

[Displacement of the silver clips in surgical cavity based on four-dimensional CT images for patients undertaking external-beam partial breast irradiation after breast-conserving surgery].

OBJECTIVE: To explore the displacement of the selected clips and the center of the geometry consisted of all the clips in the surgical cavity measured on the basis of four-dimensional computed tomography (4D-CT) simulation images. METHODS: Fourteen breast cancer patients after breast-conserving surgery were recruited for external beam partial-breast irradiation (EB-PBI), and received large aperture CT simulation. The 4D-CT image data sets were collected when the patient was in the free breathing state. Using the Varian Eclipse treatment planning system, the selected four clips in the cavity were separately delineated on the CT images from 10 phases of the breath cycle, and all of the clips in the cavity were marked to obtain the geometry. Then the displacement of the four selected clips and the center of the geometry in the left-right (LR), anterior-posterior (AP), and superior-inferior (SI) directions were measured. The differences of the displacement were compared. RESULTS: The displacements in the AP and SI directions were always greater than the displacement in LR direction for the same selected clip. The difference of the displacements in the same direction of the different selected clips was not statistically significant (P>0.05). The displacements of the geometry center consisted of all of the clips in the LR, AP, SI directions were (1.34±0.39) mm, (2.01±1.02) mm and (1.89±1.03) mm, respectively, and the difference of the displacements between LR and AP, LR and SI were all statistically significant (P<0.05). In the same directions (LR, AP and SI), the displacement of geometry center was always greater than the displacement of the selected clips, and the difference except SI direction was all statistically significant (P<0.05). In the SI direction, the association between the displacement of geometry center and the upper clip, geometry center and the lower clip was statistically significant (P<0.05). CONCLUSION: When the target for EB-PBI is defined on the basis of 4D-CT simulation images, the displacement of the selected clips at the border of the surgical cavity is not qualified to substitute the displacement of the target defined basing on all of the clips in the surgical cavity.

Demethylation of miR-34a upregulates expression of membrane palmitoylated proteins and promotes the apoptosis of liver cancer cells.

BACKGROUND: Liver cancer is a common cancer and the main cause of cancer-related deaths worldwide. Liver cancer is the sixth most common cancer in the world. Although miR-34a and palmitoyl membrane palmitoylated protein (MPP2) are reportedly involved in various cell processes, their precise roles in liver cancer are still unclear. AIM: To investigate the expression of micro RNA 34a (miR-34a), methylation of the miR-34a promoter and the expression of MPP2 in liver cancer cells and their related mechanisms. METHODS: Together, 78 cases of liver cancer tissues and 78 cases of adjacent tissues were collected. The methylation degree of miR-34a promoter in liver cancer/ paracancerous tissue and liver cancer cells/normal liver cells, and the expression levels of miR-34a and MPP2 in the above samples were detected. Demethylation of liver cancer cells or transfection of liver cancer cells with miR-34a mimetic was performed. The MPP2 overexpression vector was used to transfect liver cancer cells, and the changes in proliferation, invasion, apoptosis, migration, and other biological functions of liver cancer cells after the above interventions were observed. Double luciferase reporter genes were used to detect the targeting relationship between miR-34a and MPP2. RESULTS: Clinical samples showed that the expression levels of miR-34a and MPP2 in liver cancer tissues were lower than those in the normal tissues. The methylation degree of miR-34a promoter region in liver cancer cells was higher than that in normal liver cells. After miR-34a demethylation/mimetic transfection/MPP2 overexpression, the apoptosis of liver cancer cells was increased; the proliferation, invasion and migration capabilities were decreased; the expression levels of caspase 3, caspase 9, E-cadherin, and B-cell lymphoma 2 (Bcl-2)-associated X protein were increased; and the expression levels of Bcl-2, N-cadherin, and ß-catenin were decreased. Double luciferase reporter genes confirmed that MPP2 is targeted by miR-34a. Rescue experiments showed that small interfering MPP2 could counteract the promoting effect of miR-34a demethylation on apoptosis and the inhibitory effect on cell proliferation, invasion, and migration. CONCLUSION: miR-34a demethylation upregulates the expression level of MPP2 in liver cancer cells and promotes the apoptosis of liver cancer cells. miR-34a demethylation is a potential method for liver cancer treatment.

[Comparison of overlap ratios of the target volume in different respiratory states with active breathing control for external-beam partial breast irradiation].

OBJECTIVE: To explore the overlap ratio of the target volume in different respiratory statuses of active breath control (ABC) and their differences during external-beam partial breast irradiation (EB-PBI), and from the perspective of target volume overlap to determine the influence of the ABC-assisted breathing condition on intra-fractional target movement of EB-PBI. METHODS: The patients, who received breast-conserving surgery with silver clips marked at the margins of the cavity and were suitable for EB-PBI, were immobilized on the breast bracket to undertake CT simulation assisted by ABC device, six sets of CT simulation images including two sets of image in state of moderate deep inspiration breathing control (mDIBH), two sets of images in state of free breath (FB) and two sets of images in state of deep expiration breathing control (DEBH) were obtained. The six sets of images were transferred to Pinnacle(3) treatment planning system (TPS), then automatic fusion and registration between two sets of mDIBH images, two sets of FB images, two sets of DEBH images and mDIBH image and DEBH image were achieved separately. Thereafter, the overlap ratios of GTV with GTV, CTV with CTV, PTV with PTV were calculated by the Pinnacle(3) TPS. The differences between the overlap ratios of the three kinds of targets in the same registered image and the difference between the overlap ratios of the same kind of target in the different registered images were statistically analyzed using statistical package of SPSS 11.5. RESULTS: Based on mDIBH/mDIBH registration, the overlap ratios of GTV/GTV, CTV/CTV and PTV/PTV were (83.54 ± 11.41)%, (93.00 ± 6.49)%, and (95.26 ± 4.90)%, respectively, and the differences of the overlap ratios between GTV/GTV and CTV/CTV, GTV/GTV and PTV/PTV were all statistically significant (P < 0.05), but statistically not significant between CTV/CTV and PTV/PTV (P > 0.05). Based on FB/FB registration, the overlap ratios of GTV/GTV, CTV/CTV and PTV/PTV were (72.55 ± 29.10)%, (89.36 ± 9.53)% and (92.47 ± 7.25)%, respectively, and the differences of the overlap ratios between GTV/GTV and CTV/CTV, CTV/CTV and PTV/PTV were all not statistically significant (P > 0.05), but statistically significant between GTV/GTV and PTV/PTV (P < 0.05). Based on DEBH/DEBH registration, the overlap ratios of GTV/GTV, CTV/CTV and PTV/PTV were (79.48 ± 22.31)%, (92.83 ± 6.77)% and (95.05 ± 4.81)%, respectively, and the differences of the overlap ratios between GTV/GTV and CTV/CTV (P = 0.000), CTV/CTV and PTV/PTV (P = 0.037), GTV/GTV and PTV/PTV (P = 0.000) were statistically all significant (P = 0.000). The differences of the overlap ratios of GTV/GTV, CTV/CTV, and PTV/PTV (P = 0.000) between mDIBH/mDIBH and DEBH/DEBH, mDIBH/mDIBH and FB/FB, FB/FB and DEBH/DEBH were all statistically significant (P = 0.000), and not statistically significant between mDIBH/mDIBH and mDIBH/DEBH, FB/FB and mDIBH/DEBH. CONCLUSIONS: During the delivering of EB-PBI assisted by ABC, the intra-fractional overlap ratios of the target volume between the same breathing state is increasing in the order of GTV/GTV → CTV/CTV → PTV/PTV. The difference of the overlap ratios of the target volumes between mDIBH and mDIBH, FB and FB, DEBH and DEBH is not significant, and the overlap ratios of PTV/PTV in the three breathing statuses of mDIBH, FB and DEBH reaches a higher level. Therefore, from the perspective of target volume overlap, if the setup error is corrected online before delivering, the necessity of breathing control during delivering of EB-PBI is worthy discussing.

[Influence of active breathing control on the dose distribution in the target of forward whole-breast intensity-modulated radiotherapy after breast conserving surgery].

OBJECTIVE: To explore the influence of intrafraction and interfraction target displacement on the dose distribution in the target of forward whole-breast intensity-modulated radiotherapy (IMRT) assisted by active breathing control (ABC). METHODS: Each of the selected patient who had received breast conserving surgery was immobilized and received the primary CT simulation assisted by ABC device to get five sets of CT images in three different breathing status, including free breathing (FB) (one set), moderate deep inspiration breathing hold (mDIBH)(two sets) and deep expiration breathing hold (DEBH) (2 sets). After 10 to 15 fractions of radiation, the repeated CT simulation was completed and the same five sets of CT images were obtained at FB, mDIBH, and DEBH, respectively. In the Pinnacle3 treatment planning system, the forward IMRT planning was completed on the first set of mDIBH CT images from the primary CT simulation, and the planning was separately copied by the special system order to the second set of CT images from the primary CT simulation and to the first set of CT images from the repeated CT simulation, keeping the primary angle, direction, size and shape of the MLC field and prescribed dose un-changed. the volumes covered by selected high dose area in the selected segment were compared. RESULTS: In the planning based on the first set of mDIBH CT images from the primary CT simulation, the volume irradiated by equal and more than 103% of prescribed dose in the segment was (1.16 +/- 0.39) cm3, and the volumes were (3.88 +/- 1.07) cm3 and (51.66 +/- 8.68) cm3 in the plannings copied from the first set of mDIBH CT images from the primary CT simulation respectively to the second set of CT images from the primary CT simulation and first set of CT images from the repeat CT simulation, the difference of the volume in the two plannings based on the two set mDIBH CT image from the primary CT simulation was not statistically significant (t = -1.672, P = 0.103). The difference of the volume in the two plannings based on the two sets of mDIBH CT images respectively from the primary and repeat CT simulations had a significant difference (t = -5.728, P < 0.01). CONCLUSION: If the same threshold of mDIBH is maintained during IMRT after breast conserving surgery, the influence of the intrafraction target displacement on the dose distribution is not significant. However, if set-up error is not adjusted, the interfraction change of position of the segment given to cover the high dose area in the IMRT planning will be significant, resulting in a significant change of dose distribution in the breast.

[Relationship of dose-volume histogram parameters and computed tomography grading of radiation-induced lung injury in patients with non-small cell lung cancer treated by three-dimensional conformal radiotherapy].

OBJECTIVE: To explore the relationship of dose-volume histogram (DVH) parameters and computed tomography grading of radiation-induced lung injury in patients with non-small cell lung cancer (NSCLC) treated by three-dimensional conformal radiotherapy (3D-CRT). METHODS: One hundred sixty-nine patients with stage I approximately III NSCLC, treated by 3D-CRT and followed by CT scan for more than six months after 3D-CRT, were divided into grade 0 to grade 4 based on the appearance of radiation-induced lung injury on CT image defined jointly by radiotherapist and radiologist. The patients were divided into CT positive group (grade 2 to grade 4) and CT negative group (grade 0 to grade 1), then the treatment planning shown to the patients were reviewed to compare and analyze the relationship of CT grading of radiation-induced lung injury and the DVH parameter selected. RESULTS: Regardless of whole lung or tumor-bearing lung, there was a statistically significant difference in normal tissue complication probability (NTCP) between the patients grouped with different CT grading of radiation-induced lung injury, and the mean of NTCP increased along with upgrade of CT grading. There was a statistically significant difference of mean lung dose (MLD) regardless of whole lung or tumor-bearing lung between the patients grouped with different CT grading of radiation-induced lung injury, and MLD increased along with upgrade of CT grading. There was a statistically significant difference of the volume received equal or more than 20 Gy (V(20)), 30 Gy (V(30)), 40 Gy (V(40)) of whole lung and tumor-bearing lung between the patients grouped with different CT grading of radiation-induced lung injury, and V(20), V(30), V(40) increased along with upgrade of CT grading. There were not statistically significant differences of the DVH parameters of the contralateral lung in the patients of different groups based on the CT grading. On statistical analysis, the DVH parameters of whole lung and tumor-bearing lung closely correlated with CT grading of radiation-induced injury of the tumor-bearing lung, and there was a relatively strongest relationship between NTCP and CT grading of the tumor-bearing lung (eta = 0.522). CONCLUSION: DVH parameters such NTCP, MLD, V(20), V(30), and V(40) are statistically correlated closely with CT grading of radiation-induced lung injury after radiotherapy for the patients with NSCLC treated by 3D-CRT. Therefore the parameters can be selected as the reference for evaluation after 3D-CRT for patients with NSCLC.

A case report of targeted therapy with apatinib in a patient with recurrent high grade glioma.

RATIONALE: Despite the approval of antiangiogenic therapy for high grade glioma (HGG) patients, survival benefits are still limited. New treatment plans have always been developed to improve the survival. PATIENT CONCERNS: A 26-year-old woman was admitted to our hospital for distending pain of head and eye. DIAGNOSES: Resonance imaging (MRI) revealed a large spherical heterogeneously enhancing, mixed cystic and solid mass in the right frontal region, and the midline shifted. INTERVENTION: The patient received apatinib therapy for positive vascular endothelial growth factor. OUTCOMES: A partial response was observed after 4 weeks and remains sustained until now. LESSONS: It suggests that apatinib might be a feasible option for the treatment in advanced HGG patients or patients with poor physical condition.

Which is the optimal threshold for defining functional lung in single-photon emission computed tomography lung perfusion imaging of lung cancer patients?

PURPOSE: The aim of this study was to investigate the optimal threshold for the functional lung (FL) definition of single-photon emission computed tomography (SPECT) lung perfusion imaging. PATIENTS AND METHODS: Forty consecutive stage III non-small-cell lung cancer patients underwent SPECT lung perfusion scans and PET/CT scans for treatment planning, and the images were coregistered. Total lung and perfusion lung volumes corresponding to 10, 20, …, 60% of the maximum SPECT count were segmented automatically. The SPECT-weighted mean lung dose (SWMDx%) and the percentage of FL volume receiving more than 20 Gy (Fx%V20) of different thresholds were investigated using SPECT-weighted dose-volume histograms. Receiver-operator characteristic curves were used to identify SWMD and FV20 of different thresholds in predicting the incidence of radiation pneumonitis (RP). RESULTS: Eleven (27.5%) patients developed RP (grades 1, 2, 3, and 4 were 10.0, 7.5, 7.5, and 2.5%, respectively) after treatment. The largest area under the receiver-operator characteristic curve was 0.881 for the ability of SWMD to predict RP with 20% as the threshold and 0.928 for the ability of FV20 with 20% as the threshold. CONCLUSION: The SWMD20% and FV20 of FL using 20% of the maximum SPECT count as the threshold may be better predictors for the risk of RP.

Clinical significance of serum dynamics of HSP90a level in esophageal squamous cell carcinoma patients treated with definitive chemoradiotherapy.

PURPOSE: We evaluate whether the change of heat shock protein 90a (HSP90a) level before and after definitive chemoradiotherapy (CRT) in esophageal squamous cell carcinoma (ESCC) affects tumor response and overall survival (OS). This study aimed to investigate the role of HSP90a reduction ratio after CRT. METHODS: Correlations between pre-CRT HSP90a levels and the tumor response to CRT were analysed. Patients were divided into three groups (Group 1: Serum HSP90a levels pretreatment CRT less than 124 ng/mL; Group 2: pre-CRT HSP90a of 124 ng/mL or more with HSP90a reduction ratio of 65% or more; Group 3: pre-CRT HSP90a of 124 ng/mL or more with HSP90a reduction ratio less than 65%), and their oncologic outcomes were compared. RESULTS: The rates of good response in HSP90a low (pre-CRT HSP90a ≤ 124 ng/mL) and high groups (pre-CRT HSP90a ≤ 124 ng/mL) were 67.3% (68/101) and 37.78% (20/79), respectively (P= 0.004). The rates of good response were significantly higher in Group 1 than in Groups 2 and 3 (58.5% vs. 46.0% and 27.8%, respectively; P= 0.013). The results from statistical analysis indicated that the tumor response was significantly associated with the serum levels of pre-CRT HSP90a and HSP90a Group (P< 0.05). The OS rate was not different between Groups 1 and 2 but was significantly lower in Group 3. HSP90a Group were independent prognostic factors for OS. CONCLUSIONS: HSP90a levels could be of clinical value as a predictor of response to CRT HSP90a reduction ratio might be an independent prognostic factor for in ESCC patients treated with definitive CRT.

Management of salivary gland carcinomas - a review.

Salivary gland carcinomas are a heterogeneous group of tumors with many histological subtypes which occur in both major and minor salivary glands. However, they have a relatively low of incidence. Their rarity limits study size and the ability to perform phase III trials. Therefore, to date, the entire management is usually varied. Certain published studies have paid more attention to the systemic therapy in the management of metastatic or locally recurrent salivary gland cancer, while little effort has been made to study the entire management for this lesions. Although results of treatment for patients with salivary gland carcinoma have improved in recent years, the treatment of salivary gland cancers is still not standardized. And some patients who haven't received optimal treatment strategies had a reduced survival. In this review, the topics covered include surgery and radiotherapy, selective neck dissection, chemotherapy, and targeted therapy, which aimed to summarize the optimal management approaches and to develop recommendations for managing this lesions. For these rare cancers, there is also a need for a determined, coordinated effort to conduct high-quality clinical trials.

Low-grade nasopharyngeal papillary adenocarcinoma: a case report and review of the literature.

Low-grade nasopharyngeal papillary adenocarcinoma is an extremely rare tumor, with only a limited number of cases reported in the literature. Some published studies have paid more attention to the clinicopathological features of nasopharyngeal adenocarcinoma, while little effort has been made to study the optimal therapeutic strategies. We report about a woman diagnosed with low-grade nasopharyngeal papillary adenocarcinoma. She received the treatment approach that combined transnasal endoscopic surgery to remove the lesion with postoperative radiotherapy for nasal cavity. There was no evidence of recurrence after 4 months of surgery, and further follow-up is being continued. Through this example, we wanted to explore the optimal therapeutic strategies for primary nasopharyngeal adenocarcinomas.

Recurrence pattern of squamous cell carcinoma in the midthoracic esophagus: implications for the clinical target volume design of postoperative radiotherapy.

BACKGROUND: Postoperative radiotherapy has shown positive efficacy in lowering the recurrence rate and improving the survival rate for patients with esophageal squamous cell carcinoma (ESCC). However, controversies still exist about the postoperative prophylactic radiation target volume. This study was designed to analyze the patterns of recurrence and to provide a reference for determination of the postoperative radiotherapy target volume for patients with midthoracic ESCC. PATIENTS AND METHODS: A total of 338 patients with recurrent or metastatic midthoracic ESCC after radical surgery were retrospectively examined. The patterns of recurrence including locoregional and distant metastasis were analyzed for these patients. RESULTS: The rates of lymph node (LN) metastasis were 28.4% supraclavicular, 77.2% upper mediastinal, 32.0% middle mediastinal, 50.0% lower mediastinal, and 19.5% abdominal LNs. In subgroup analyses, the rate of abdominal LN metastasis was significantly higher in patients with histological node-positive than that in patients with histological node-negative (P=0.033). Further analysis in patients with histological node-positive demonstrated that patients with three or more positive nodes are more prone to abdominal LN metastasis, compared with patients with one or two positive nodes (χ2=4.367, P=0.037). The length of tumor and histological differentiation were also the high-risk factors for abdominal LN metastasis. CONCLUSION: For midthoracic ESCC with histological node-negative, or one or two positive nodes, the supraclavicular and stations 2, 4, 5, and 7 LNs should be delineated as clinical target volume of postoperative prophylactic irradiation, and upper abdominal LNs should be excluded. While for midthoracic ESCC with three or more positive nodes, upper abdominal LNs should also be included. The length of tumor and histological differentiation should be considered comprehensively to design the clinical target volume for radiotherapy.

Anatomic distribution of supraclavicular lymph node in patients with esophageal cancer.

PURPOSE: Definitive chemoradiation therapy remains the standard of care for patients with localized esophageal carcinoma who choose nonsurgical management. However, there is no consensus regarding delineation of the nodal clinical target volume (CTVn), especially for lower cervical lymph nodes. This study aimed to map the location of metastatic supraclavicular lymph nodes in thoracic esophageal carcinoma patients with supraclavicular node involvement and generate an atlas to delineate the CTVn for elective nodal radiation of esophageal squamous cell carcinoma. PATIENTS AND METHODS: In this study, the supraclavicular regional lymph node was further divided into four subgroups. The locations of the involved supraclavicular nodes for all patients were then transferred onto a template computed tomography (CT) image. A volume probability map was then generated with nodal volumes, and was displayed on the template CT to provide a visual impression of nodal frequencies and anatomic distribution. RESULTS: We identified 154 supraclavicular nodal metastases based on CT image in 96 patients. Of these, 29.2% were located in group I region, 59.7% in group II region, 10.4% in group III region, and 0.7% in group IV region. CONCLUSION: On the basis of our study, we suggest that the appropriate radiation field of CTVn should include the group I and II regions and the CTVn exterior margin along the lateral side of the internal jugular vein may be suitable.

Analysis of the variability among radiation oncologists in delineation of the postsurgical tumor bed based on 4D-CT.

OBJECTIVE: This study investigated interobserver and intraobserver variability in radiation oncologists' definition of the tumor bed (TB) after breast-conserving surgery (BCS). RESULTS: The TB volume, CVS and number of surgical clips were not significantly related to intraobserver variability. Moreover, no correlation was noted between CT slice thickness and interobserver variability (Δinter, DSCinter) in TB delineation, and no significant difference was noted among the three groups. The TB volume was negatively correlated with Δinter. DSCinter improved significantly with increased TB volume and decreased Δinter. DSCinter also increased significantly in patients with a CVS of 3 to 5 compared with patients with a CVS of 1 to 2. DSCinter was thus positively correlated with the CVS, with a correlation coefficient of 0.451. The use of 7 to 9 surgical clips neither decreased Δinter nor increased DSCinter. MATERIALS AND METHODS: Five or more surgical clips were placed at the TB during lumpectomy. The TB was delineated on the end expiration scan. The data were stratified based on the cavity visualization score (CVS), CT slice thickness and surgical clip number. The Dice similarity coefficient (DSC) and inter(intra)observer variability (Δinter and Δintra) in different groups were evaluated and compared. CONCLUSIONS: Inter(intra)observer variability in TB delineation was decreased for breast cancer patients implanted with 5 or more surgical clips in the cohort with a higher CVS and a larger TB. The use of more than 6 surgical clips did not significantly improve TB delineation, so 5 to 6 surgical clips are likely adequate to delineate the TB.

Comparison of planning target volumes based on three-dimensional and four-dimensional CT imaging of thoracic esophageal cancer.

BACKGROUND AND PURPOSE: To investigate the definition of planning target volumes (PTVs) based on four-dimensional computed tomography (4DCT) compared with conventional PTV definition and PTV definition using asymmetrical margins for thoracic primary esophageal cancer. MATERIALS AND METHODS: Forty-three patients with esophageal cancer underwent 3DCT and 4DCT simulation scans during free breathing. The motions of primary tumors located in the proximal (group A), middle (group B), and distal (group C) thoracic esophagus were obtained from the 4DCT scans. PTV3D was defined on 3DCT using the tumor motion measured based on 4DCT, PTV conventional (PTVconv) was defined on 3DCT by adding a 1.0 cm margin to the clinical target volume, and PTV4D was defined as the union of the target volumes contoured on the ten phases of the 4DCT images. The centroid positions, volumetric differences, and dice similarity coefficients were evaluated for all PTVs. RESULTS: The median centroid shifts between PTV3D and PTV4D and between PTVconv and PTV4D in all three dimensions were <0.3 cm for the three groups. The median size ratios of PTV4D to PTV3D were 0.80, 0.88, and 0.71, and PTV4D to PTVconv were 0.67, 0.73, and 0.76 (χ (2)=-3.18, -2.98, and -3.06; P=0.001, 0.003, and 0.002) for groups A, B, and C, respectively. The dice similarity coefficients were 0.87, 0.90, and 0.81 between PTV4D and PTV3D and 0.80, 0.84, and 0.83 between PTV4D and PTVconv (χ (2) =-3.18, -2.98, and -3.06; P=0.001, 0.003, and 0.002) for groups A, B, and C, respectively. The difference between the degree of inclusion of PTV4D in PTV3D and that of PTV4D in PTVconv was <2% for all groups. Compared with PTVconv, the amount of irradiated normal tissue for PTV3D was decreased by 11.81% and 11.86% in groups A and B, respectively, but was increased by 2.93% in group C. CONCLUSION: For proximal and middle esophageal cancer, 3DCT-based PTV using asymmetrical margins provides good coverage of PTV4D; however, for distal esophageal cancer, 3DCT-based PTV using conventional margins provides ideal conformity with PTV4D.