Potentialities of multi-b-values diffusion-weighted imaging for predicting efficacy of concurrent chemoradiotherapy in cervical cancer patients.

BACKGROUND: To testify whether multi-b-values diffusion-weighted imaging (DWI) can be used to ultra-early predict treatment response of concurrent chemoradiotherapy (CCRT) in cervical cancer patients and to assess the predictive ability of concerning parameters. METHODS: Fifty-three patients with biopsy proved cervical cancer were retrospectively recruited in this study. All patients underwent pelvic multi-b-values DWI before and at the 3rd day during treatment. The apparent diffusion coefficient (ADC), true diffusion coefficient (Dslow), perfusion-related pseudo-diffusion coefficient (Dfast), perfusion fraction (f), distributed diffusion coefficient (DDC) and intravoxel diffusion heterogeneity index(α) were generated by mono-exponential, bi-exponential and stretched exponential models. Treatment response was assessed based on Response Evaluation Criteria in Solid Tumors (RECIST v1.1) at 1 month after the completion of whole CCRT. Parameters were compared using independent t test or Mann-Whitney U test as appropriate. Receiver operating characteristic (ROC) curves was used for statistical evaluations. RESULTS: ADC-T0 (p = 0.02), Dslow-T0 (p <  0.01), DDC-T0 (p = 0.03), ADC-T1 (p <  0.01), Dslow-T1 (p <  0.01), ΔADC (p = 0.04) and Δα (p <  0.01) were significant lower in non-CR group patients. ROC analyses showed that ADC-T1 and Δα exhibited high prediction value, with area under the curves of 0.880 and 0.869, respectively. CONCLUSIONS: Multi-b-values DWI can be used as a noninvasive technique to assess and predict treatment response in cervical cancer patients at the 3rd day of CCRT. ADC-T1 and Δα can be used to differentiate good responders from poor responders.

Role and mechanism of miR-4778-3p and its targets NR2C2 and Med19 in cervical cancer radioresistance.

The aim of this study was to investigate the effect of miR-4778-3p on the radiosensitivity of cervical cancer cells and to elucidate the underlying mechanism. Tissue samples were collected from eight patients with cervical cancer prior to chemoradiotherapy. MicroRNA chip analyses, RT-PCR, gene transfection, CCK8, wound healing and Transwell assays, colony-forming assay, western blot, and the Dual-Luciferase Reporter Assay System were used to evaluate the role of miR-4778-3p in cervical cancer radiosensitivity and its relationships with target molecules NR2C2 and Med19. Thirty-two differentially expressed miRNA molecules (fold-change > 2; p < 0.05) associated with cervical cancer radioresistance were identified. The expression of miR-4778-3p was significantly lower in recurrent or metastatic patients than in control subjects. In vitro studies using radioresistant HeLa and SiHa cervical cancer cell lines showed that miR-4778-3p upregulation significantly inhibited cell proliferation, invasiveness, and migration after irradiation. There was also a significant increase in apoptosis and a significant decrease in the proportion of cells at the G2/M phase. Further, miR-4778-3p upregulation led to increased expression of apoptosis-related molecules, such as Bax, Caspase-3, Caspase-8, and Caspase-9. Reporter gene assays showed that miR-4778-3p bound specifically to NR2C2 and Med19 and negatively regulated their expression. Thus, miR-4778-3p reduces the vitality, proliferation, and migration of radioresistant cervical cancer cells and may regulate the radiosensitivity of cervical cancer by targeting and regulating NR2C2 and Med19 expression.

Vaginal dose of radical radiotherapy for cervical cancer in China: a multicenter study.

BACKGROUND: The posterior-inferior border of symphysis (PIBS) point system is a novel vaginal dose-reporting method and is a simple and reliable method proposed by the Medical University of Vienna proposed for both external-beam radiotherapy (EBRT) and brachytherapy (BT). In this multicenter study, we sought to first evaluate the vaginal radiation dose in Chinese cervical cancer patients according to the PIBS point system and then to analyze the factors influencing the dose distribution. METHODS: We collected data from the medical records of 936 cervical cancer patients who underwent concurrent radiochemotherapy at 13 different institutions in China. Radiation doses at points A, PIBS+ 2 cm, PIBS and PIBS-2 cm, International Commission on Radiation Units (ICRU)-R and ICRU-B were measured. RESULTS: The median total doses in EQD2α/ß = 3 at points PIBS+ 2 cm, PIBS and PIBS-2 cm were 82.5 (52.7-392.1) Gy, 56.2 (51.4-82.1) Gy and 2.6 (0.9-7.4) Gy, respectively. The median total doses in EQD2α/ß = 3 at ICRU-R and ICRU-B were 77.5 (54.8-132.4) Gy and 79.9 (60.7-133.7) Gy, respectively. The mean vaginal reference length (VRL) was 4.6 ± 1.0 cm (median, 4.5 cm). In patients with VRL ≤4.5 cm, the mean total doses in EQD2α/ß = 3 at points PIBS+ 2 cm, PIBS and PIBS-2 cm were 128.5, 60.7 and 0.8 Gy, respectively. In patients with VRL > 4.5 cm, the mean total doses at these three points were 68.9, 0.5 and 54.5 Gy, respectively. Classification of patients revealed significant differences (P < 0.05) between these two groups. CONCLUSIONS: With the PIBS point system, Chinese patients with a shorter VRL of < 4.5 cm received higher radiation doses at the PIBS+ 2 cm, PIBS and PIBS-2 cm points than European and American patients. Further studies are required to establish the dose-effect relationships with these points as references. The study was registered as a clinical trial (NCT03257475) on August 22, 2017.

The Prognosis and Risk Stratification Based on Pelvic Lymph Node Characteristics in Patients With Locally Advanced Cervical Squamous Cell Carcinoma Treated With Concurrent Chemoradiotherapy.

BACKGROUND: The purpose of this study is to determine the prognostic significance of pelvic lymph node (PLN) characteristics and perform risk stratification in patients undergoing concurrent chemoradiotherapy for locally advanced cervical squamous cell carcinoma. METHODS: We retrospectively reviewed the records of 609 patients with Federation Internationale de Gynecologie et d'Obstetrique (FIGO) stage II to IVa who underwent concurrent chemoradiotherapy, compared overall survival (OS), distant metastasis-free survival (DMFS), and pelvic recurrence-free survival between patients with or without PLN involvement. We further analyzed prognostic factors for OS and DMFS including FIGO stage, tumor volume, and lymph node (LN) characteristics in 300 patients with PLN involvement. RESULTS: The 3-year OS rate was 81.7% versus 92.8% (P = 0.002) and the 3-year DMFS rate was 79.3% versus 92.7% (P = 0.006) in patients with or without PLN involvement, respectively. With univariable analysis, FIGO stage, LN-volume, LN-number, LN-diameter, and matted/necrotic LN affected both OS and DMFS. Based on multivariable analysis, we created a risk stratification model. For OS, the independent risk factors were FIGO stage III or IVa, LN-volume of 3 cm or more, LN-diameter of 1.5 cm or more, and matted/necrotic LN. The low-risk group (no risk factors), mid-risk group (1 or 2 risk factors), and high-risk group (3 or 4 risk factors) had a 3-year OS of 96.6%, 84.9%, and 64.7%, respectively (P = 0.005). For DMFS, LN-diameter of 1.5 cm or more, LN-number of 3 or more, and matted/necrotic LN were the independent risk factors. The subgroups for DMFS were the low-risk group (no risk factors), the mid-risk group (1 risk factor), and the high-risk group (2 or 3 risk factors), and the 3-year DMFS was 92.4%, 76.2%, and 64.6%, respectively (P = 0.001). CONCLUSIONS: The prognosis was significantly poorer for patients with high-risk lymph node characteristics. Using this risk stratification, we should select the most appropriate and individualized treatment modality to improve outcomes in those patients with a poorer prognosis.

Bilateral visual loss after selective artery embolization in the neck for hemorrhage of malignant tumor.

INTRODUCTION AND IMPORTANCE: Currently, selective arterial embolization (SAE) has been widely applied for the treatment of many diseases due to its minimal invasiveness. But the complications caused by SAE can be serious. CASE PRESENTATION: Here, we report a case of a patient who experienced bilateral blindness 4 h after selective arterial embolization (SAE). A 67-year-old man, with a 13-year history of nasopharyngeal carcinoma, was admitted to our hospital for nasopharyngeal carcinoma hemorrhage and was scheduled for SAE. The patient did not have any thromboembolic complications. His had a platelet count of 43 × 109/L (range 150-400 × 109/L) and a prothrombin time (PT) of 9.3 s. The surgery was completed under local anesthesia. However, 4 h after the surgery, the patient complained of visual loss. We performed a fundoscopy examination, which showed bilateral ophthalmic artery embolism. CLINICAL DISCUSSION: Bilateral ophthalmic artery embolism is fatal to vision. When this occurs, it would be difficult to save the eyes. So, the relevant selection of the optimal properties of the used PVA and coil embolization materials is important during SAE. CONCLUSION: It is important to improve the existing understanding of the involvement various vessels during embolization of head and neck tumors. Furthermore, special and paramount attention is to be paid to the specific pre-operative angio-architecture, particular patient condition, and the prudent choice of embolic material to prevent the occurrence of ectopic embolization.

Using New Vaginal Doses Evaluation System to Assess the Dose-Effect Relationship for Vaginal Stenosis After Definitive Radio(Chemo)Therapy for Cervical Cancer.

Objective: The study aims to investigate if a relationship exists between vaginal doses and vaginal stenosis (VS) using posterior-inferior border of symphysis (PIBS) points and the International Commission on Radiation Units-Rectum (ICRU-R) point evaluation system for definitive radio(chemo)therapy in locally advanced cervical cancer. Methods and Materials: From a vaginal dose study in China, 351 patients were prospectively assessed. For every reference point of the PIBS system and ICRU-R point was calculated for all BT and summed with EBRT. Pearson's chi-square test and Student's unpaired t-test compared variables with and without vaginal stenosis (VS) G ≥2. The risk factors were assessed for VS G ≥2 in multi- and univariate analyses through Cox proportional hazards model followed by a dose-effect curve construction. The VS morbidity rate was compared via the log-rank test using the median vaginal reference length (VRL). Results: The patients (38-month median follow-up) had 21.3% three-year actuarial estimate for VS G ≥2. Compared to G <2 patients, VS G ≥2 patients received higher doses to PIBS points except for PIBS - 2 and had significantly shorter VRL. VRL (HR = 1.765, P = 0.038), total EBRT and BT ICRU-R point dose (HR = 1.017, p = 0.003) were risk factors for VS. With VRL >4.6 cm, the 3-year actuarial estimate was 12.8% vs. 29.6% for VRL ≤4.6 cm. According to the model curve, the risks were 21, 30, and 39% at 75, 85, and 95 Gy, respectively (ICRU-R point dose). Conclusions: PIBS system point doses correlated with late vaginal toxicity. VRL combined with both EBRT and BT dose to the ICRU-R point contribute to VS risk.

Multicenter, Randomized, Phase III Trial of Short-Term Radiotherapy Plus Chemotherapy Versus Long-Term Chemoradiotherapy in Locally Advanced Rectal Cancer (STELLAR).

PURPOSE: To ascertain if preoperative short-term radiotherapy followed by chemotherapy is not inferior to a standard schedule of long-term chemoradiotherapy in patients with locally advanced rectal cancer. MATERIALS AND METHODS: Patients with distal or middle-third, clinical primary tumor stage 3-4 and/or regional lymph node-positive rectal cancer were randomly assigned (1:1) to short-term radiotherapy (25 Gy in five fractions over 1 week) followed by four cycles of chemotherapy (total neoadjuvant therapy [TNT]) or chemoradiotherapy (50 Gy in 25 fractions over 5 weeks, concurrently with capecitabine [chemoradiotherapy; CRT]). Total mesorectal excision was undertaken 6-8 weeks after preoperative treatment, with two additional cycles of CAPOX (intravenous oxaliplatin [130 mg/m2, once a day] on day 1 and capecitabine [1,000 mg/m2, twice a day] from days 1 to 14) in the TNT group and six cycles of CAPOX in the CRT group. The primary end point was 3-year disease-free survival (DFS). RESULTS: Between August 2015 and August 2018, a total of 599 patients were randomly assigned to receive TNT (n = 302) or CRT (n = 297). At a median follow-up of 35.0 months, 3-year DFS was 64.5% and 62.3% in TNT and CRT groups, respectively (hazard ratio, 0.883; one-sided 95% CI, not applicable to 1.11; P < .001 for noninferiority). There was no significant difference in metastasis-free survival or locoregional recurrence, but the TNT group had better 3-year overall survival than the CRT group (86.5% v 75.1%; P = .033). Treatment effects on DFS and overall survival were similar regardless of prognostic factors. The prevalence of acute grade III-V toxicities during preoperative treatment was 26.5% in the TNT group versus 12.6% in the CRT group (P < .001). CONCLUSION: Short-term radiotherapy with preoperative chemotherapy followed by surgery was efficacious with acceptable toxicity and could be used as an alternative to CRT for locally advanced rectal cancer.

Predicting Disease-Free Survival With Multiparametric MRI-Derived Radiomic Signature in Cervical Cancer Patients Underwent CCRT.

Prognostic biomarkers that can reliably predict the disease-free survival (DFS) of locally advanced cervical cancer (LACC) are needed for identifying those patients at high risk for progression, who may benefit from a more aggressive treatment. In the present study, we aimed to construct a multiparametric MRI-derived radiomic signature for predicting DFS of LACC patients who underwent concurrent chemoradiotherapy (CCRT). METHODS: This multicenter retrospective study recruited 263 patients with International Federation of Gynecology and Obetrics (FIGO) stage IB-IVA treated with CCRT for whom pretreatment MRI scans were performed. They were randomly divided into two groups: primary cohort (n = 178) and validation cohort (n = 85). The LASSO regression and Cox proportional hazard regression were conducted to construct the radiomic signature (RS). According to the cutoff of the RS value, patients were dichotomized into low- and high-risk groups. Pearson's correlation and Kaplan-Meier analysis were conducted to evaluate the association between the RS and DFS. The RS, the clinical model incorporating FIGO stage and lymph node metastasis by the multivariate Cox proportional hazard model, and a combined model incorporating RS and clinical model were constructed to estimate DFS individually. RESULTS: The final radiomic signature consisted of four radiomic features: T2W_wavelet-LH_ glszm_Size Zone NonUniformity, ADC_wavelet-HL-first order_ Median, ADC_wavelet-HH-glrlm_Long Run Low Gray Level Emphasis, and ADC_wavelet _LL_gldm_Large Dependence High Gray Emphasis. Higher RS was significantly associated with worse DFS in the primary and validation cohorts (both p<0.001). The RS demonstrated better prognostic performance in predicting DFS than the clinical model in both cohorts (C-index, 0.736-0.758 for RS, and 0.603-0.649 for clinical model). However, the combined model showed no significant improvement (C-index, 0.648, 95% CI, 0.571-0.685). CONCLUSIONS: The present study indicated that the multiparametric MRI-derived radiomic signature could be used as a non-invasive prognostic tool for predicting DFS in LACC patients.

DCE-MRI Quantitative Parameters as Predictors of Treatment Response in Patients With Locally Advanced Cervical Squamous Cell Carcinoma Underwent CCRT.

PURPOSE: To evaluate the predictive value of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) quantitative parameters in treatment response to concurrent chemoradiotherapy (CCRT) for locally advanced cervical squamous cell carcinoma (LACSC). METHODS AND MATERIALS: LACSC patients underwent CCRT had DCE-MRI before (e0) and after 3 days of treatment (e3). Extended Tofts Linear model with a user arterial input function was adopted to generate quantitative measurements. Endothelial transfer constant (Ktrans), reflux rate (Kep), fractional extravascular extracellular space volume (Ve), and fractional plasma volume (Vp) were calculated, and percentage changes ΔKtrans, ΔKep, ΔVe, and ΔVp were computed. The correlations of these measurements with the tumor regression rate were analyzed. The predictive value of these parameters on treatment outcome was generated by the receiver operating characteristic (ROC) curve. Univariate and multivariate logistic regression analyses were conducted to find the independent variables. RESULTS: Ktrans-e0, Kep -e0, ΔKtrans, and ΔVe were positively correlated with the tumor regression rate. Mean values of Ktrans-e0, Ktrans-e3, ΔKtrans, and ΔVe were higher in the non-residual tumor group than residual tumor group and were independent prognostic factors for predicting residual tumor occurrence. Ktrans-e3 showed the highest area under the curve (AUC) for treatment response prediction. CONCLUSIONS: Quantitative parameters at e0 and e3 from DCE-MRI could be used as potential indicators for predicting treatment response of LACSC.

Up-regulation of D-serine might induce GABAergic neuronal degeneration in the cerebral cortex and hippocampus in the mouse pilocarpine model of epilepsy.

Epilepsy is a serious neurological disorder with neuronal loss and spontaneous recurrent seizures, but the neurochemical basis remains largely unclear. We hypothesize that D-serine, a newly identified endogenous co-agonist of N-methyl-D-aspartate (NMDA) receptor, may trigger excitotoxicity and neuronal damage in epileptogenesis. By using a mouse pilocarpine model, immunohistochemistry, Fluoro-Jade staining and double-labeling, the present study revealed up-regulation of D-serine expression in a proportion (41%) of neurons in the cerebral cortex and hippocampus. The D-serine-positive neurons occurred at 4 h, reached peak levels at 12-24 h, and gradually went down at 3-14 days. Moreover, most of D-serine-positive neurons were GABAergic (98%), underwent degenerating death (93%), and were accompanied enhancing phosphorylation of NMDA receptor subunit 1. This study has provided new evidence that up-regulation of D-serine production might induce GABAergic neuronal degeneration through excitotoxic mechanism in the pilocarpine model and may be involved in early pathogenesis and recurrent seizure of chronic epilepsy.

Efficacy and Toxicity of IMRT-Based Simultaneous Integrated Boost for the Definitive Management of Positive Lymph Nodes in Patients with Cervical Cancer.

Background: The optimal radiotherapy regimen for treating metastatic lymphadenopathy in patients with locally advanced cervical cancer remains controversial. This study aimed to investigate the clinical outcomes, as well as associated toxicities, of intensity-modulated radiotherapy (IMRT) with a simultaneous integrated boost (SIB) for pelvic and para-aortic lymph nodes (LNs). Methods: Between 2011 and 2015, 74 patients with 2014 International Federation of Gynecology and Obstetrics stage IIB-IVB cervical cancer exhibiting pelvic or para-aortic LN involvement were examined. The pelvic field planning dose was 45-50 Gy in 25 fractions, and an SIB of 62.5 Gy in 25 fractions was delivered to positive LNs. Next, CT-guided brachytherapy was performed 24 Gy in 3 fractions to 42 Gy in 6 fractions once or twice weekly. Results: The median follow-up duration was 36 (range: 3-62) months. The 3-year local control, distant metastasis-free survival, and overall survival rates were 91.7%, 75.7%, and 71.4%, respectively. No residual or recurrent LNs were detected. Six patients developed grade 3 acute gastrointestinal (GI) toxicity. Twenty-nine (39.2%) and 3 (4.1%) patients developed grade 3 and 4 hematological toxicities, respectively. Twenty patients (28.5%) developed grade ≥2 chronic GI toxicity. Only 1 patient (1.4%) experienced a grade 4 rectovaginal fistula, and 3 patients (4.2%) developed grade 2 genitourinary toxicities. SIB to the LNs did not influence acute or chronic toxicity rates. Conclusions: Our findings demonstrate that a dose of 62.5 Gy to positive LNs using the IMRT with SIB method can achieve excellent clinical outcomes with acceptable toxicity.

Changes in magnetic resonance T2-weighted imaging signal intensity correlate with concurrent chemoradiotherapy response in cervical cancer.

PURPOSE: This study is aimed to compare magnetic resonance imaging (MRI) parameters and clinical pathological factors (CPF) of residual tumor group with non-residual tumor group in cervical cancer (CC) patients during concurrent chemoradiotherapy (CCRT), and thus to establish a biomarker for individualized treatment strategy. MATERIAL AND METHODS: From May 2014 to November 2015, 164 CC patients were included in this retrospective study. T2-weighted MRI was performed at pre-treatment (week-0), the completion of external radiotherapy (RT) (week-4), and one month after the completion of CCRT, using 3.0T MR scanner with regular pelvic coil. Mean signal intensity and tumor size on T2WI images were measured and calculated for each tumor, and lumbar 4-5 intervertebral disc at week-0 and week-4. All patients subsequently underwent routine follow-up, including periodic clinical and imaging examinations when necessary. Receiver operator characteristics (ROC) analysis were conducted to determine cut-off values. RESULTS: The residual tumor group showed a higher Δ tumor-to-disc signal intensity ratio (ΔTDR) than non-residual tumor group (0.78 ± 0.30 vs. 0.48 ± 0.19, t = 3.42, p < 0.05). The biomarker of combined MRI parameter and CPF showed the highest diagnostic performance than single MRI parameter or CPF alone. CONCLUSIONS: MRI parameter ΔTDR may be an independent prognostic factor for predicting residual tumor occurrence in CC after CCRT treatment. The combination of MRI parameter and CPF can serve as a valuable biomarker to distinguish CC with higher possibility of residual tumor occurrence.

Neurokinin-3 peptide instead of neurokinin-1 synergistically exacerbates kainic acid-inducing degeneration of neurons in the substantia nigra of mice.

Neurokinin peptides neurokinin-1 (NK1), neurokinin-3 (NK3), and related receptors are abundantly distributed in the substantia nigra (SN) and evidenced by their possible roles in the Parkinson's disease. Differential intervention roles of NK3 on kainic acid (KA)-induced neuronal injury in the SN of mice were thus in vitro and in vivo studied by Fluoro-Jade C (FJC) staining, immunohistochemistry to tyrosine hydroxylase (TH) or phospho-NMDA receptor, and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. It revealed that (i) in contrast to protective effect of NK1 agonist septide that reduced FJC-positive degenerative neurons and lesion volume insulted by KA, NK3 agonist senktide significantly increased FJC-positive ones and lesion volume, and this effect was sufficiently reversed by NK3 antagonist SB218795; (ii) similarly, senktide reduced TH-positive neurons and this effect was antagonized by SB218795, but septide increased TH-positive ones; (iii) mechanistic observation showed differential influences of NK1 and NK3 agonists on phosphorylated-NMDA receptor subunit 1 (phospho-NMDAR1) and glial fibrillary acidic protein-expressing astrocytes, i.e. senktide enhanced of NMDA receptor phosphorylation and astrocyte activity, while septide reduced NMDA receptor phosphorylation and astrocytic response; (iv) cell culture further confirmed the exacerbating effect of NK3 agonist on KA-induced lesion of nigral cells or dopaminergic neurons, in which administration of senktide alone did not show significant cell toxicity. This study presents new evidence that neurokinin NK3 instead of NK1 synergistically exacerbate excitotoxic neuronal degeneration in the SN in a dose-dependent manner and possibly through modulation of NMDA receptor phosphorylation and astrocyte activity, suggesting their potential significance in novel pharmaceutical therapy against Parkinson's disease.

Nestin small interfering RNA (siRNA) reduces cell growth in cultured astrocytoma cells.

Nestin is an embryonic intermediate filament that transiently expressed in the neural stem/progenitor cells in the developing central nervous system (CNS). Growing evidence has shown that abundant expression of nestin also occurs in both pathological glial-derived tumor cells and reactive astrocytes in various CNS injuries, implying that nestin may play a crucial role in cell growth or proliferation of astrocyte-derived tumor cells. In the present study, we have investigated the possible role of nestin expression in cell growth or survival of CNS tumor cells by using novel small interfering RNA (siRNA) method in cell culture of rat astrocytoma C6 cell line. The nestin expression and cell growth of the cultured astrocytoma cells were examined after nestin siRNA duplex was delivered by cell transfection for 6 h and cell culture was maintained for 48 h. It revealed an effective suppression influence of nestin siRNA on cell growth of cultured astrocytoma cells in a dose-dependent manner. Quantitative data analysis showed that the doses of nestin siRNA at 30-120 nM significantly decreased both cell numbers and expression levels of nestin mRNA and protein. The nestin siRNA also suppressed expression of cellular glial fibrillary acid protein but showed no obvious influence on expression level of Ki-67 protein (a cell proliferation marker). This study has provided in vitro evidence that nestin siRNA can effectively block nestin expression and reduce cell growth of the cultured C6 astrocytoma cells, strongly suggesting that nestin siRNA-induced suppression of tumor cell growth may provide a potential novel clinical therapy against CNS astroglioma events.

The Efficacy and Late Toxicities of Computed Tomography-based Brachytherapy with Intracavitary and Interstitial Technique in Advanced Cervical Cancer.

Purpose: To report the efficacy and late side effects(LSEs) of CT-based image-guided brachytherapy for the treatment of cervical cancer. Materials: Between 2008 and 2014, 100 patients with FIGO stage IIB-IVA cervical carcinoma were analyzed. The patients received pelvic irradiation (45-50 Gy in 25 fractions) with concurrent chemotherapy, whereas the mean prescribed EBRT dose, including initial and boost doses to positive lymph nodes, ranged from 54 to 64 Gy. Afterwards, intracavitary(IC) or combined intracavitary/interstitial(IC/IS) brachytherapy was performed using a CT-based procedure with prescribed doses of 6 or 8 Gy in 3-7 fractions. Results: The median follow-up time was 46 months. The 5-year local control, distant metastasis-free survival, and overall survival rates were 88.9%, 81.8%, 77.9%, respectively. IC/IS brachytherapy improved the HR-CTV D90 compared with IC (p<0.01). Seven patients (7.0%) had grade 2 bladder LSEs and none had grade 3/4 bladder LSEs. There was no significant relationship between bladder LSEs and the dose-volume histogram (p>0.05 for all). Thirty-seven patients (37%) had grade 2 rectal LSEs, 3(3%) had grade 3 rectal LSE. The rectum D1cc, D2cc, and D5cc values were significantly higher in patients with grades 2/3 rectal toxicity than in those with grades 0/1 (p<0.05 for all). There was no grade 2 and above small bowel LSEs. Conclusions: CT-based brachytherapy planning can achieve excellent local control with acceptable morbidity. HR-CTV D90 can increase in the IC/IS group compared with the IC group. The D1cc, D2cc, and D5cc all showed excellent predictive values for rectal LSEs.

Individualized pelvic lymphadenectomy should follow neoadjuvant concurrent chemoradiotherapy for locally advanced cervical cancer.

To study the outcomes following concurrent chemoradiotherapy (CCRT) and subsequent radical surgery for locally advanced cervical cancer (LACC), analyze the relationship between imaging-diagnosed and postoperative-diagnosed lymph node (LN) involvement, and identify patients who would benefit from individualized pelvic lymphadenectomy.We retrospectively reviewed records of 410 patients who underwent CCRT followed by radical surgery for International Federation of Gynecology and Obstetrics Stage Ib2-IIIb disease. Correlations of LN size on imaging before CCRT with pathological responses after CCRT, overall survival (OS), distant metastasis-free survival (DMFS), and complications were analyzed.During a median follow-up of 51.3 months, the respective 5-year OS and DMFS were 86.7% and 88.6%, respectively. Pathological primary tumor type, LN size on imaging before CCRT, and pathologic response after CCRT were independent prognostic factors for OS. Patients with a LN ≥0.8 cm had a significantly higher residual carcinoma rate versus those with LN <0.8 cm (33% vs 22.6%, P = .032). Postoperative pathological positive LN frequencies differed significantly by LN size on imaging (LN <0.8 cm vs LN ≥0.8 cm, 3% vs 19.3%, P < .0001). Grade 1-3 lower extremity edema occurred in 23.9% of cases; no grade 3-4 gastrointestinal and genitourinary toxicities were observed.CCRT followed by radical surgery for LACC yielded encouraging outcomes without unacceptable complications. Additionally, patients with a LN <0.8 cm on imaging before CCRT had a very low risk of postoperative pathological positive LN identification. Individualized pelvic lymphadenectomy (e.g., omitting or limiting the extent of LN dissection) might be an alternative option for some patients with a low risk of LN metastasis.

Fluoro-Jade C can specifically stain the degenerative neurons in the substantia nigra of the 1-methyl-4-phenyl-1,2,3,6-tetrahydro pyridine-treated C57BL/6 mice.

Fluoro-Jade C, a new-developed fluorescent dye, has been successfully applied for identification of neuronal degeneration in the substantia nigra of 1-methyl-4-phenyl-1,2,3,6-tetrahydro pyridine (MPTP)-treated mice in the present study. The animal model was first prepared by intraperitoneal injection of neurotoxicant MPTP that can specifically induce degeneration of dopamine neurons in the substantia nigra of C57BL/6 mice. Fluoro-Jade C was then utilized to stain the midbrain sections and semiquantitation analysis was carried out in comparison with controls. It revealed that Fluoro-Jade C-positive cells showed strong green color in neuronal profile and were observed in the substantia nigra of MPTP-treated mice whereas they were not detected in that of controls. The Fluoro-Jade C-positive cells were mostly shrunken or smaller-sized in their cell bodies in comparing with that of normal dopamine neurons of controls. In the midbrain of MPTP-treated mice, Fluoro-Jade C-positive neuronal cells were exclusively distributed in the substantia nigra pars compacta, but rarely seen in the ventral tegemental area where dopamine neurons were numerously distributed. Double-labeling experiments indicated that a population of Fluoro-Jade C-positive cells (23%) exhibited neuron-specific nuclear protein-immunoreactivity and none of them showed immunoreactivity to glial cell marker glial fibrillary acid protein. However, most of Fluoro-Jade C-positive degenerative neurons (98%) lost their immunoreactivity to dopaminergic marker tyrosine hydroxylase in the substantia nigra of MPTP-treated mice. Taken together with previous observations, this study has presented that Fluoro-Jade C can be sensitively and specifically utilized to identify the neuronal degeneration in the substantia nigra of rodent animals receiving MPTP insult.

High VEGFR1/2 expression levels are predictors of poor survival in patients with cervical cancer.

The aim of the study to evaluate the prognostic significance of vascular endothelial growth factor receptor 1 and 2 (VEGFR1/2) expression levels and to correlate these levels with clinicopathological parameters in patients with cervical cancer.Forty-two patients with International Federation of Gynecology and Obstetrics Stage IIB-IVB cervical cancer were analyzed between January 2011 and December 2012. RNA expression levels of VEGFR1/2 were assessed by branched DNA-liquidchip technology and immunohistochemistry. Associations between RNA expression levels, important clinicopathological parameters, and patient survival were statistically evaluated.Higher VEGFR1/2 expression levels were predictive of poor overall survival (P = 0.009 and P = 0.024, respectively). Patients with higher VEGFR1 expression levels were associated with poorer progression-free survival than those with lower VEGFR1 expression levels (P = 0.043). In addition, patients with higher VEGFR1 expression levels were more likely to develop distant metastases than those with lower VEGFR1 expression levels (P = 0.049). Higher VEGFR2 expression levels were associated with larger tumor size (P = 0.037).VEGFR1/2 expression levels were prognostic factors for patients with cervical cancer. Higher VEGFR1/2 expression levels were also predictive of poor overall survival.

Differential co-expression of AMPA receptor subunits in substance P receptor-containing neurons of basal forebrain regions of C57/BL mice.

We are interested in cellular co-expression patterns of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionate (AMPA) receptor subunits 1-4 (GluR1-4) in substance P receptor (SPR)-containing neurons of the basal forebrain, which may act as a morphological basis for interaction between neurokinins and glutamate-driven neuronal signaling and excitotoxicity. Immunohistochemistry and laser scanning confocal microscopy in adult C57/BL mice revealed that distribution of SPR-positive neurons overlapped with that of GluR1-4-containing ones in most basal forebrain regions, i.e. the medial septal nucleus, nucleus of diagonal band of Broca, magnocellular preoptic nucleus and substantia innominata. Neurons showing both SPR and GluR1-4-immunoreactivities were found in above cholinergic neurons-rich containing basal forebrain regions. Semi-quantification analysis indicated that about 57-95% of SPR-positive neurons displayed GluR1-4-immunoreactivity. The percentages of AMPA receptor subunits co-localizing in SPR-positive neurons were GluR4 (48%), GluR1 (47%), GluR2 (26%) and GluR3 (20%), respectively. However, the neurons co-expressing SPR and GluR1-4 were hardly detected in the basal nucleus of Meynert of the basal forebrain. The co-localization of SPR and AMPA receptors has provided a molecular basis for functional interaction between neurokinins and AMPA receptors-mediated signaling in basal forebrain neurons. This study has also implied that glutamate-driven neuronal transmission and excitotoxicity can be modulated by neurokinin peptides in most basal forebrain regions but not in the basal nucleus of Meynert, suggesting that neurokinins or SP may play certain roles in determining neuronal functional properties or excitotoxic susceptibility in the various basal forebrain regions of mammals.

Late rectal toxicity determined by dose-volume parameters in computed tomography-based brachytherapy for locally advanced cervical cancer.

The aim of this study was to observe the relationship between dose-volume histogram (DVH) parameters and rectal late side effects (LSE) in computed tomography (CT)-based brachytherapy (BT) for patients with locally advanced cervical cancer. In total, 144 cervical cancer patients received external beam radiotherapy and CT-based BT. The data from 111 survival cases with pelvic local control (LC) were used to analyze the relationship between DVH parameters and rectal LSE. The total doses, manifesting 2, 1, and 0.1 cm(3) (D2cc , D1cc , and D0.1cc ) of the rectum, and D90 for high-risk clinical target volume (HR CTV) were computed and normalized to 2 Gy fractions (EQD2) using a linear-quadratic model. The rectal LSE were evaluated by the late effects in normal tissues-subjective, objective, management, and analytic (LENT-SOMA) scale. A dose-response relationship was evaluated by probit analyses. For all patients, the total rate of rectal LSE was 56%, and the rate of ≥Grade 2 LSE was 27.4%. For the 111 survival cases with pelvic LC, the total mean for D2cc was 71.23 ± 5.54 Gy for the rectum, and the D2cc , D1cc , and D0.1cc values for Grades 2 and 3 were higher than those for Grades 0 and 1. In addition, the number of complications increased, and the complications became more severe as the dose increased, with a dose of 73.5 Gy resulting in a 10% probability of ≥Grade 3 LSE. In conclusion, DVH parameters could predict the incidence and grades of rectal LSE in CT-based BT. D2cc showed an excellent predictive value, and 73.5 Gy for D2cc of the rectum might be considered as an alternative dose limit.