A Randomized Trial Comparing Quality of Life After Low-Dose Rate or High-Dose Rate Prostate Brachytherapy Boost With Pelvic External Beam Radiation Therapy.

PURPOSE: To compare health-related quality of life (QoL) in urinary, bowel, and sexual domains after combined external beam radiation therapy (EBRT) and either low-dose rate (LDR) or high-dose rate (HDR) prostate brachytherapy (BT). METHODS AND MATERIALS: Eligible men with intermediate or high-risk prostate cancer treated with combined pelvic EBRT and BT were randomly assigned to either HDR (15 Gy) or LDR (110 Gy) boost. International Prostate Symptom Score, Index of Erectile Function, and Expanded Prostate Cancer Composite were collected at baseline, 1, 3, 6, and 12 months, every 6 months to 3 years and then annually along with prostate-specific antigen/testosterone. Fisher's exact test compared categorical variables and the Mann-Whitney U test Expanded Prostate Cancer Index Composite (EPIC) domain scores. RESULTS: From January 2014 to December 2019, a random number generator assigned 195 men: 108 to HDR and 87 to LDR. Median age was 71 years. Risk group was high in 57% and unfavorable intermediate in 43%. Androgen deprivation (used in 74%) began with 3 months neoadjuvant and continued for median 12 months. Baseline EPIC scores were similar for the LDR/HDR cohorts: 89 and 88 respectively for Genito-urinary; 92 and 93 for Gastro-intestinal. EPIC urinary scores decreased at 1 month for HDR but recovered promptly to a steady state by 6 months. LDR scores reached a nadir at 3 months with slow recovery to 18 months, after which urinary QoL was similar for HDR and LDR. Bowel QOL scores fell in both cohorts reaching respective nadirs at 12 months. HDR patients recovered close to baseline and maintained higher scores than LDR patients to 5 years. The decline for LDR patients remained more than the minimum clinically important difference out to 5 years. CONCLUSIONS: The patient experience for combined EBRT and prostate BT is improved with HDR BT. Urinary QoL improves over time to be equivalent between the 2 modalities after 18 months, but LDR patients report lasting bowel symptoms.

Semi-automatic method for pre-surgery scoliosis classification on X-ray images using Bending Asymmetry Index.

PURPOSE: Bending Asymmetry Index (BAI) has been proposed to characterize the types of scoliotic curve in three-dimensional ultrasound imaging. Scolioscan has demonstrated its validity and reliability in scoliosis assessment with manual assessment-based X-ray imaging. The objective of this study is to investigate the ultrasound-derived BAI method to X-ray imaging of scoliosis, with supplementary information provided for the pre-surgery planning. METHODS: About 30 pre-surgery scoliosis subjects (9 males and 21 females; Cobb: 50.9 ± 19.7°, range 18°-115°) were investigated retrospectively. Each subject underwent three-posture X-ray scanning supine on a plain mattress on the same day. BAI is an indicator to distinguish structural or non-structural curves through the spine flexibility information obtained from lateral bending spinal profiles. BAI was calculated semi-automatically with manual annotation of vertebral centroids and pelvis level inclination adjustment. BAI classification was validated with the scoliotic curve type and traditional Lenke classification using side-bending Cobb angle measurement (S-Cobb). RESULTS: 82 curves from 30 pre-surgery scoliosis patients were included. The correlation coefficient was R2 = 0.730 (p < 0.05) between BAI and S-Cobb. In terms of scoliotic curve type classification, all curves were correctly classified; out of 30 subjects, 1 case was confirmed as misclassified when applying to Lenke classification earlier, thus has been adjusted. CONCLUSION: BAI method has demonstrated its inter-modality versatility in X-ray imaging application. The curve type classification and the pre-surgery Lenke classification both indicated promising performances upon the exploratory dataset. A fully-automated of BAI measurement is surely an interesting direction to continue our endeavor. Deep learning on the vertebral-level segmentation should be involved in further study.

Biological Aging and Periodontal Disease: Analysis of NHANES (2001-2002).

INTRODUCTION: Periodontitis is a chronic inflammatory disease caused by multiple potential contributing factors such as bacterial biofilm infection of the tissues surrounding the teeth and environmental determinants and a dysregulated host response for modifying and resolving the inflammation. Because periodontal disease is a major public health concern with substantial increases in the prevalence and severity in aging populations, previous studies of periodontitis tended to approach the disease as an age-associated outcome across the life span. However, few investigations have considered that, as a chronic noncommunicable disease, periodontitis may not simply be a disease that increases with age but may contribute to more rapid biologic aging. OBJECTIVES: Increasing population data supports the potential disconnect between chronological aging and biologic aging, which would contribute to the heterogeneity of aging phenotypes within chronologic ages across populations. Thus, our aim was to test whether periodontal disease affects biological aging across the life span. METHODS: The prevalence of periodontitis in the adult US population is a portion of the assessment of the National Health and Nutrition Examination Survey (NHANES), which has been ongoing since 1971 through 2-y cycles sampling populations across the country. We used NHANES 2001-2002 to test the hypothesis that the presence/severity of periodontal disease as an exposure variable would negatively affect telomere length, a measure of biological aging, and that this relationship is modified by factors that also affect the progression of periodontitis, such as sex, race/ethnicity, and smoking. RESULTS: The data demonstrated a significant impact of periodontitis on decreasing telomere lengths across the life span. These differences were modulated by age, sex, race/ethnicity, and smoking within the population. CONCLUSION: The findings lay the groundwork for future studies documenting broader effects on biological aging parameters as well as potential intervention strategies for periodontitis in driving unhealthy aging processes. KNOWLEDGE TRANSFER STATEMENT: Periodontitis is a chronic inflammatory disease and dysregulated host response. Shortening of telomeres is a reflection of biologic aging. Decreased telomere lengths with periodontitis are seemingly related to chronic infection and persistent local and systemic inflammation. These findings suggest that periodontitis is not simply a disease of aging but may also transmit chronic systemic signals that could affect more rapid biological aging. Clinicians can use this outcome to recognize the role of periodontitis in driving unhealthy aging processes in patients.

Pan-Asian adapted ESMO Clinical Practice Guidelines for the management of patients with locally-advanced unresectable non-small-cell lung cancer: a KSMO-ESMO initiative endorsed by CSCO, ISMPO, JSMO, MOS, SSO and TOS.

The most recent version of the European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for the diagnosis, treatment and follow-up of early and locally-advanced non-small-cell lung cancer (NSCLC) was published in 2017, and covered the diagnosis, staging, management and treatment of both early stage I and II disease and locally-advanced stage III disease. At the ESMO Asia Meeting in November 2018, it was decided by both the ESMO and the Korean Society of Medical Oncology (KSMO) to convene a special face-to-face guidelines meeting in 2019 in Seoul. The aim was to adapt the ESMO 2017 guidelines to take into account potential differences related to ethnicity, cancer biology and standard practices associated with the treatment of locally-advanced, unresectable NSCLC in Asian patients. These guidelines represent the consensus opinions reached by those experts in the treatment of patients with lung cancer who represented the oncology societies of Korea (KSMO), China (CSCO), India (ISMPO), Japan (JSMO), Malaysia (MOS), Singapore (SSO) and Taiwan (TOS). The voting was based on scientific evidence, and it was independent of both local current treatment practices and the treatment availability and reimbursement situations in the individual participating Asian countries.

Sequential spine-hand radiography for assessing skeletal maturity with low radiation EOS imaging system for bracing treatment recommendation in adolescent idiopathic scoliosis: a feasibility and validity study.

PURPOSE: The EOS-imaging system is increasingly adopted for clinical follow-up in scoliosis with the advantages of simultaneous biplanar imaging of the spine in an erect position. Skeletal maturity assessment using a hand radiograph is an essential adjunct to spinal radiography in scoliosis follow-up. This study aims at testing the feasibility and validity of a newly proposed EOS workflow with sequential spine-hand radiography for skeletal maturity assessment and bracing recommendation. METHODS: EOS spine-hand radiographs from patients with diagnosis of idiopathic scoliosis, including both sexes and an age range of ten to 14 years, were scored using the Thumb Ossification Composite Index (TOCI), Sanders and Risser methods. Intraclass correlation coefficients (ICCs) were calculated for inter/intraobserver agreement and were tested with Cronbach's alpha values. RESULTS: In all, 60 EOS-spine hand radiographs selected from subjects with diagnosis of adolescent idiopathic scoliosis (AIS), including 32 male patients (mean age 11.53 years; 10 to 14) and 28 female patients (mean age 11.50 years; 10 to 13) who underwent sequential spine-hand low dose EOS imaging were generated for analysis. The overall interobserver (ICC = 0.997) and intraobserver agreement (α > 0.9) demonstrated excellent agreement for TOCI staging; ICC > 0.994 for both TOCI and Sanders staging comparing traditional digital versus EOS hand radiography; ICC ≥ 0.841 for agreement on bracing recommendation among TOCI versus the Risser and Sanders system. CONCLUSION: With the proposed new EOS workflow it was feasible to produce high image quality for skeletal maturity assessment with excellent reliability and validity to inform consistent bracing recommendation in AIS. The workflow is applicable for busy daily clinic settings in tertiary scoliosis centres with reduced time cost, improved efficiency and throughput of the radiology department. LEVEL OF EVIDENCE: III.

Gonadal shield: is it the Albatross hanging around the neck of developmental dysplasia of the hip research?

PURPOSE: Prospective randomized controlled trials and long-term studies are essential future directions for building -evidence-based practices in developmental dysplasia of the hip (DDH), however, sufficient attrition in data (> 20%) can introduce bias deteriorating research quality. Pelvic radiography is synonymous with DDH assessment and so are -Gonadal Shield (GS) recommendations with pelvic radiography. -Nonetheless, losses to diagnostic information and inadequate protection have been increasingly implicated to GS usage, with significantly worse implications in female patients. Understandably for DDH, a disease with 80% female prevalence, the impact of GS usage on quality of radiographs and readability of radiological data may be drastic. This study aims to objectively define the implications of GS recommendations in DDH patients. METHODS: Pelvis radiographs of all DDH patients under the hip surveillance programme at a tertiary care hospital with a written protocol for GS usage were evaluated. Images were reviewed for gender, GS presence, adequate gonadal protection and obstruction of essential anatomical landmarks for pelvic indices. RESULTS: In all, 131 pelvis radiographs with DDH diagnoses (age: 1.25 to 6 years; 107 female, 24 male pelvises) were reviewed. Only 42.67% (56) of pelvis radiographs used GS despite the presence of a clear protocol. Useful anatomical landmarks were obstructed in 58.9% of radiographs with GS present. Lost diagnostic information was more common in female patients than male patients (68.1% versus 11.1%, p < 0.01). GS was ineffective at gonadal protection in 73.2% (41) of the pelvises with worse protection in female patients (78.7% vs 44.4%; p = 0.03). CONCLUSIONS: Ironically, essential anatomy was obstructed in all the adequately protected female pelvises. Routine GS usage results in substantial attrition of radiographic data in DDH patients. LEVEL OF EVIDENCE: III.

Functional links between Disabled-2 Ser723 phosphorylation and thrombin signaling in human platelets.

Essentials Disabled-2 (Dab2) phosphorylation status in thrombin signaling of human platelet was investigated. Ser723 was the major Dab2 phosphorylation site in human platelets stimulated by thrombin. Dab2 S723 phosphorylation (pS723) caused the dissociation of Dab2-CIN85 protein complex. Dab2-pS723 regulated ADP release and integrin αIIbß3 activation in thrombin-treated platelets. SUMMARY: Background Disabled-2 (Dab2) is a platelet protein that is functionally involved in thrombin signaling in mice. It is unknown whether or not Dab2 undergoes phosphorylation during human platelet activation. Objectives To investigate the phosphorylation status of Dab2 and its functional consequences in thrombin-stimulated human platelets. Methods Dab2 was immunoprecipitated from resting and thrombin-stimulated platelet lysates for differential isotopic labeling. After enrichment of the phosphopeptides, the phosphorylation sites were analyzed by mass spectrometry. The corresponding phospho-specific antibody was generated. The protein kinases responsible for and the functional significance of Dab2 phosphorylation were defined by the use of signaling pathway inhibitors/activators, protein kinase assays, and various molecular approaches. Results Dab2 was phosphorylated at Ser227, Ser394, Ser401 and Ser723 in thrombin-stimulated platelets, with Ser723 phosphorylation being the most significantly increased by thrombin. Dab2 was phosphorylated by protein kinase C at Ser723 in a Gαq -dependent manner. ADP released from the stimulated platelets further activated the Gßγ -dependent pathway to sustain Ser723 phosphorylation. The Cbl-interacting protein of 85 kDa (CIN85) bound to Dab2 at a motif adjacent to Ser723 in resting platelets. The consequence of Ser723 phosphorylation was the dissociation of CIN85 from the Dab2-CIN85 complex. These molecular events led to increases in fibrinogen binding and platelet aggregation in thrombin-stimulated platelets by regulating αIIb ß3 activation and ADP release. Conclusions Dab2 Ser723 phosphorylation is a key molecular event in thrombin-stimulated inside-out signaling and platelet activation, contributing to a new function of Dab2 in thrombin signaling.

Multi-disciplinary Orthopaedics Rehabilitation Empowerment (MORE) program: A new standard of care for injured workers in Hong Kong.

BACKGROUND: The objective of this study is to evaluate the effects of the Multi-disciplinary Orthopaedics Rehabilitation Empowerment (MORE) Program on reducing chronic disability among injured workers and improving efficiency of work rehabilitation process. METHODS: A cohort of patients with workplace injuries in the lower back were recruited from orthopaedics clinics and assigned to either MORE group (n= 139) or control group (n= 106). Patients in MORE group received an early MRI screening and a coordinated multi-disciplinary management, while patients in the control group received conventional care. Outcome variables are time to return-to-work (RTW) from date of injury, waiting time for MRI screening and time to medical assessment board (MAB). RESULTS: Patients in the MORE Program had significantly shorter duration for RTW (MORE: 6.1 months, CONTROL: 12.8 months, p< 0.01), and more RTW cases (n= 64, 46.0%) compared to CONTROL group (n= 29, 27.4%). The MORE group also had much shorter waiting time for MRI scans (91.85 vs. 309.2 days, p< 0.001) and MAB referral after MRI scans (97.2 vs. 178.9 days, p= 0.001) compared to CONTROL group. CONCLUSIONS: The MORE Program which emphasizes early intervention and early MRI screening, is shown to be effective in shortening sick leave and improving RTW outcomes of injured workers.

γ-Synuclein Expression Is a Malignant Index in Oral Squamous Cell Carcinoma.

Dysregulation of γ-synuclein (SNCG) has been reported in many cancers; however, its role in cancer development is still controversial. Here, we examined the potential involvement of DNA methylation in regulating SNCG and its role in oral squamous cell carcinoma (OSCC). We used 8 OSCC cell lines to investigate SNCG methylation and expression. SNCG methylation was examination by methylation-specific polymerase chain reaction and bisulfate sequencing. Cells showing a high degree of SNCG methylation were treated with 5-aza (methylation inhibitor), and changes in their methylation and expression profiles were analyzed. Functional effects of SNCG in OSCC were examined by its overexpression and knockdown. Additionally, methylation and expression of SNCG in OSCC tissues were investigated and correlated with clinicopathologic features. All OSCC cells showed detectable SNCG expression at the mRNA and protein levels. Methylation-specific polymerase chain reaction and bisulfate sequencing revealed high SNCG expression in SCC25 cells with the unmethylated allele, and their 15 CpG islands were unmethylated. The methylated allele was detected only in OEC-M1 cells exhibiting low SNCG expression, and their CpG islands were partially methylated. 5-aza treatment in OEC-M1 cells attenuated methylation and restored SNCG expression. SNCG overexpression increased colony forming, migration, and invasion abilities in OEC-M1 cells. Silencing SNCG in SCC25 cells suppressed these behaviors. All 25 tumor-adjacent normal tissues were negative for SNCG immunostaining. SNCG upregulation was frequently observed in dysplastic and OSCC tissues. Positive SNCG expression was found in 45% (37 of 82) OSCC tissues. Positive SNCG expression in OSCC significantly correlated with cancer staging and lymph node metastasis. However, SNCG methylation did not correlate with its expression and clinicopathologic variables in OSCC tissues. DNA methylation may participate in regulating SNCG expression in some OSCC cells. SNCG upregulation could be involved in OSCC progression.

Interaction between hepatic membrane type 1 matrix metalloproteinase and acireductone dioxygenase 1 regulates hepatitis C virus infection.

Membrane type 1 matrix metalloproteinase (MT1-MMP) binds to and regulates the function of tetraspanin-enriched microdomains. It also physically interacts with claudin-1 and acireductone dioxygenase 1 (ADI1), both associated with hepatitis C virus (HCV) cell entry. Here, we examined hepatic expression of MT1-MMP, ADI1 and claudin-1 as well as their physical interaction in relation to serum or intrahepatic HCV-RNA levels. A total of 104 liver biopsies obtained from chronic hepatitis C patients and 84 liver tissues obtained from noncancerous parts of surgically removed HCV-related hepatocellular carcinoma were analysed. Positive cytoplasmic ADI1 in liver biopsies was associated with higher serum HCV-RNA levels (P = 0.009). Positive MT1-MMP and ADI1 interaction assessed by co-immunoprecipitation was associated with lower tissue HCV-RNA levels (P = 0.009). Hepatic HCV-RNA levels were positively associated with ADI1 levels in the MT1-MMP and ADI1 co-immunoprecipitates (P = 0.030). Overexpression of MT1-MMP in Huh7.5 cells suppressed cell entry of HCV pseudoparticles as well as HCVcc infection. The suppression effect could be reversed by co-expression of ADI1 in a dose-dependent manner. In summary, clinical and cell-based experiments suggested that physical interaction between MT1-MMP and ADI1 led to suppression of HCV infection. This inhibitory effect could be reversed by ADI1 overexpression.

CD40 ligand induces RIP1-dependent, necroptosis-like cell death in low-grade serous but not serous borderline ovarian tumor cells.

Ovarian high-grade serous carcinomas (HGSCs) and invasive low-grade serous carcinomas (LGSCs) are considered to be distinct entities. In particular, LGSCs are thought to arise from non-invasive serous borderline ovarian tumors (SBOTs) and show poor responsiveness to conventional chemotherapy. The pro-apoptotic effects of CD40 ligand (CD40L) have been demonstrated in HGSC, though the underlying mechanisms are not fully understood. Conversely, the therapeutic potential of the CD40L-CD40 system has yet to be evaluated in LGSC. We now show that CD40 protein is focally expressed on tumor cells in two of five primary LGSCs compared with no expression in eight primary SBOTs. Treatment with CD40L or agonistic CD40 antibody decreased the viability of LGSC-derived MPSC1 and VOA1312 cells, but not SBOT3.1 cells. Small interfering RNA (siRNA) targeting CD40 was used to show that it is required for these reductions in cell viability. CD40L treatment increased cleaved caspase-3 levels in MPSC1 cells though, surprisingly, neither pan-caspase inhibitor nor caspase-3 siRNA reversed or even attenuated CD40L-induced cell death. In addition, CD40-induced cell death was not affected by knockdown of the mitochondrial proteins apoptosis-inducing factor (AIF) and endonuclease G (EndoG). Interestingly, CD40L-induced cell death was blocked by necrostatin-1, an inhibitor of receptor-interacting protein 1 (RIP1), and attenuated by inhibitors of RIP3 (GSK'872) or MLKL (mixed lineage kinase domain-like; necrosulfonamide). Our results indicate that the upregulation of CD40 may be relatively common in LGSC and that CD40 activation induces RIP1-dependent, necroptosis-like cell death in LGSC cells.

Lifelong bound feet in China: a quantitative ultrasound and lifestyle questionnaire study in postmenopausal women.

OBJECTIVE: The phenomenon of foot binding, also known as 'lotus feet', has an enduring and influential history in China. To achieve a man-made smaller foot size, lifelong foot binding may have had adverse effects on the skeleton. We investigated bone properties in postmenopausal women with bound feet, which may provide new information for developing countermeasures for prevention of fragility fractures. DESIGN: Population-based cohort study. PARTICIPANTS: This study involved 254 postmenopausal women aged 65-80, including 172 with bound feet and 82 age- and gender-matched control subjects, living in a remote region of China. OUTCOMES: Anthropometric, SF-36 Lifestyle Questionnaire and heel quantitative ultrasound (QUS) data were collected for the whole study population. A small subset of two cases was also invited for assessment of bone mineral density and microarchitecture at the distal tibia using high-resolution peripheral quantitative CT (HR-pQCT) and gait and balance tests. RESULTS: Women with bound feet had significantly lower QUS values than age-matched women with normal feet; this was supported by HR-pQCT data. However, SF-36 Questionnaire results did not reveal any statistically significant differences in any categorical responses, including physical functioning, general health vitality and physical component summary score, and number of previous fractures. No impairment of body balance was found in the small subset. CONCLUSIONS: The man-made changes caused by foot binding led to reduced physical activity, making the subjects prone to osteoporosis. Women with bound feet and osteoporosis did not have a higher incidence of fragility fractures than controls. This might be explained by compensation in physical activity to improve body balance, implying the importance of improving or maintaining body balance in overall prevention strategies against fragility fractures.

Acid ceramidase induces sphingosine kinase 1/S1P receptor 2-mediated activation of oncogenic Akt signaling.

Acid ceramidase (AC) is overexpressed in most prostate tumors and confers oncogenic phenotypes to prostate cancer cells. AC modulates the cellular balance between ceramide, sphingosine and sphingosine 1-phosphate (S1P). These bioactive sphingolipids have diverse, powerful and often oppositional impacts on cell signaling, including the activation status of the oncogenic kinase Akt. Our studies show that AC expression correlates with phosphorylation of Akt in human prostate tumors, and elevation of phosphorylated Akt in tumor versus patient-matched benign tissue is contingent upon AC elevation. Investigation of the mechanism for AC-induced Akt activation revealed that AC activates Akt through sphingosine kinase 1 (SphK1)-derived generation of S1P. This signaling pathway proceeds through S1P receptor 2 (S1PR2)-dependent stimulation of PI3K. Functionally, AC-overexpressing cells are insensitive to cytotoxic chemotherapy, however, these cells are more susceptible to targeted inhibition of Akt. AC-overexpressing cells proliferate more rapidly than control cells and form more colonies in soft agar; however, these effects are profoundly sensitive to Akt inhibition, demonstrating increased dependence on Akt signaling for the oncogenic phenotypes of AC-overexpressing cells. These observations may have clinical implications for targeted therapy as PI3K and Akt inhibitors emerge from clinical trials.

Egr-1 mediates epidermal growth factor-induced downregulation of E-cadherin expression via Slug in human ovarian cancer cells.

Loss of the cell adhesion protein E-cadherin increases the invasive capability of ovarian cancer cells. We have previously shown that epidermal growth factor (EGF) downregulates E-cadherin and induces ovarian cancer cell invasion through the H(2)O(2)/p38 MAPK-mediated upregulation of the E-cadherin transcriptional repressor Snail. However, the molecular mechanisms underlying the EGF-induced downregulation of E-cadherin are not fully understood. In the current study, we demonstrated that treatment of two ovarian cancer cell lines, SKOV3 and OVCAR5, with EGF induced the expression of the transcription factor Egr-1, and this induction was abolished by small interfering RNA (siRNA)-mediated depletion of the EGF receptor. EGF-induced Egr-1 expression required the activation of the ERK1/2 and PI3K/Akt signaling pathways and was unrelated to EGF-induced H(2)O(2) production and activation of the p38 MAPK pathway. Moreover, depletion of Egr-1 with siRNA abolished the EGF-induced downregulation of E-cadherin and increased cell invasion. Interestingly, siRNA depletion of Egr-1 attenuated the EGF-induced expression of Slug, but not that of Snail. Moreover, chromatin immunoprecipitation (ChIP) analysis showed that Slug is a target gene of Egr-1. These results provide evidence that Egr-1 is a mediator that is involved in the EGF-induced downregulation of E-cadherin and increased cell invasion. Our results also demonstrate that EGF activates two independent signaling pathways, which are the H(2)O(2)/p38 MAPK-mediated upregulation of Snail expression and the Egr-1-mediated upregulation of Slug expression. These two signaling pathways contribute to the EGF-induced downregulation of E-cadherin, which subsequently increases the invasive capability of ovarian cancer cells.

Medulloblastoma in adults. Treatment outcome, relapse patterns, and prognostic factors.

BACKGROUND AND PURPOSE: In this study, the clinical outcome and prognostic factors of adult medulloblastoma patients receiving multimodal treatment were investigated. PATIENTS AND METHODS: The clinical manifestations, treatment variables, and outcome of adult patients with medulloblastoma at our institution between 1983 and 2009 were retrospectively reviewed. RESULTS: A total of 20 adult patients were included (median age 22 years). Craniospinal irradiation (CSI) was given postoperatively. The craniospinal axis received a median of 30 Gy (range 23.4-39.6 Gy) in fractions of 1.6-2 Gy/day, and the tumor was boosted to a total median dose of 50 Gy (range 50-55.25 Gy). The 3-year disease-free survival (DFS) and overall survival (OS) rates for all patients were 45% and 50%, respectively. In univariate analysis, Karnofsky Performance Scale (KPS) > 70, neurologic symptoms duration > 30 days, lateral tumor location, standard risk patients, no hydrocephalus, radiotherapy (RT) treatment field (CSI + brain boost), and CSI dose ≥ 30 Gy were associated with better DFS. Standard-risk patients, RT treatment field (CSI + brain boost), and CSI dose ≥ 30 Gy were also significantly associated with better OS. CONCLUSION: The combined modality treatment results in a favorable outcome for adult medulloblastoma patients. Further investigation of the prognostic factors, radiation-related factors, and systemic chemotherapy is needed.

Hepatic expression of MxA and OAS1 in an ex vivo liver slice assay independently predicts treatment outcomes in chronic hepatitis C.

Antiviral effect of interferon is mediated by the expression of interferon-stimulated genes (ISGs). However, because of the difficulty in obtaining paired liver biopsies before and after interferon treatment, the key ISGs expressed in human hepatocytes and responsible for interferon-based antiviral activities in chronic hepatitis C remain illusive. Prior to a standard course of peginterferon plus ribavirin therapy, 104 patients underwent a liver biopsy. A small piece of the liver biopsy sample from each patient was submitted for ex vivo tissue culture in the presence or absence of interferon. Hepatic expression of 8 ISGs was detected by RT-PCR. The ISG expression patterns and clinicopathological variables were correlated with subsequent treatment outcomes. Multivariate logistic regression analysis showed that hepatic MxA expression (P = 0.008) and leucocyte count (P = 0.040) independently predicted the end of therapeutic virological response, while hepatic OAS1 expression (P = 0.003), genotype 1 (P = 0.002), HCV-RNA level (P = 0.007), AST/ALT ratio (P = 0.004) and leucocyte count (P = 0.034) independently predicted the sustained virological response. Immunohistochemistry analysis showed that interferon-induced OAS1 expression localized to the hepatocytes. In conclusion, hepatic MxA and OAS1 expression predicted, respectively, the end of therapeutic and sustained virological responses in interferon-based treatment of chronic hepatitis C.

MMP-9 from sublethally irradiated tumor promotes Lewis lung carcinoma cell invasiveness and pulmonary metastasis.

Matrix metalloproteinases (MMPs) associate with tumor progression and metastasis. We sought to investigate the role of MMP-9 from sublethally irradiated tumor in accelerated pulmonary metastasis of Lewis lung carcinoma (LLC-LM) and the corresponding anti-metastasis strategies in C57BL/6 mice. We used Matrigel-coated Boyden chamber assays and chicken chorioallantoic membrane assays to evaluate the invasion capability of irradiated LLC-LM cells (7.5 Gy), reverse transcription-polymerase chain reaction and the western blot assay to investigate the expression of MMPs by irradiated cells, and small interfering RNA duplexes to inhibit MMP-9 expression. LLC-LM cells differing in MMP-2 or -9 expression were subcutaneously injected into right thighs and the resulting tumors were irradiated (10 Gy × 5) to induce pulmonary metastasis. Radiation significantly enhanced MMP-9 at both the transcriptional and translational levels. MMP-9 siRNA significantly inhibited in vitro radiation-enhanced invasiveness. The number of radiation-accelerated pulmonary metastases was significantly reduced by MMP-9 knockdown and MMP-2/9 knockdown. Reverse transcription-polymerase chain reaction of LLC-LM cells in the blood and lung tissue revealed MMP-9 involvement in radiation-enhanced intravasation. Either higher-dose irradiation (30 Gy × 2) or pretreatment with prototypical MMP-9 inhibitor, zoledronic acid, significantly reduced the number of pulmonary metastases. The viability of irradiated tumor was seen on both positron emission tomography and magnetic resonance imaging, and tumor/serum MMP-9 levels suggested the association of local control of primary tumor and inhibition of time-dependent MMP-9 activities. Our results demonstrate that MMP-9 is crucially involved in radiation-enhanced LLC-LM cell invasiveness in vitro and in pulmonary metastasis from inadequately irradiated primary tumor in vivo.

Phase-specific cone beam computed tomography reduces reconstructed volume loss of moving phantom.

PURPOSE: The accurate volumetric calculation of moving targets/organs is required to use cone-beam computed tomography (CBCT) for replanning purposes. This study was aimed to correct the reconstructed volume losses of moving phantoms by phase-specific CBCT. MATERIALS AND METHODS: Planning fan-beam CT (FBCT) of five hepatobiliary/gastrointestinal/pancreatic cancer patients were acquired under active breathing control and compared with free-breathing CBCT for kidney volumes. Three different-sized ball phantoms were scanned by FBCT and CBCT. Images were imported to a planning system to compare the reconstructed volumes. The phantoms were moved longitudinally on an oscillator with different amplitudes/frequencies. The phase-specific projections of CBCT for moving phantoms were selected for volume reconstruction. RESULTS: The differences in reconstructed volumes of static small, medium, large phantoms between FBCT and CBCT were - 6.7%, - 2.3%, and - 2.0%, respectively. With amplitudes of 7.5-20 mm and frequencies of 8-16 oscillations/min, volume losses on CBCT were comparable with FBCT in large moving phantoms (range 9.1-27.2%). Amplitudes were more subject to volume losses than frequencies. On phase-specific CBCT, volume losses were reduced to 2.3-6.5% by reconstruction using 2-3 projections at end/midoscillation phase. CONCLUSION: Amplitude had more impact than frequency on volume losses of moving phantoms on CBCT. Phase-specific CBCT reduced volume losses.

Inhibition of p53 represses E-cadherin expression by increasing DNA methyltransferase-1 and promoter methylation in serous borderline ovarian tumor cells.

The mechanisms underlying the progression of noninvasive serous borderline ovarian tumors (SBOT) to low-grade invasive carcinomas are poorly understood. We recently showed that inhibition of p53 induces SBOT invasion by activating the PI3K/Akt pathway and transcriptionally repressing E-cadherin. In human cancers, aberrant DNA methylation is a common phenomenon, and it is thought to be involved in the progression from noninvasive to invasive ovarian carcinomas. In this study, we tested the hypothesis that inhibition of p53 downregulates E-cadherin by regulating the methylation of its promoter in SBOT cells. Here, we show that DNA methyltransferase-1 (DNMT1), but not DNMT3a or DNMT3b, was increased in SV40 LT-infected SBOT4 cells, SBOT4-LT and the low-grade invasive serous ovarian carcinoma-derived cell line MPSC1. Treatment with 5-Aza-dC, a DNMT1 inhibitor, restored E-cadherin promoter methylation and expression, and inhibited cell invasion in both invasive SBOT4-LT and MPSC1 cells. Moreover, knockdown of endogenous p53 using siRNA in SBOT3.1 cells induced DNMT1 expression and led to an increase in E-cadherin promoter methylation. Additionally, activation of the PI3K/Akt pathway is required for p53 inhibition-induced DNMT1 expression. The increase in DNMT1 was associated with the inhibition of p53-induced downregulation of E-cadherin and cell invasion. Our findings show an important role for p53 in the progression of SBOT to an invasive carcinoma, and suggest that downregulation of E-cadherin by DNMT1-mediated promoter methylation contributes to this process.

Inhibition of p53 induces invasion of serous borderline ovarian tumor cells by accentuating PI3K/Akt-mediated suppression of E-cadherin.

Serous borderline ovarian tumors (SBOTs) are slow-growing, non-invasive ovarian epithelial neoplasms. SBOTs are considered to be distinct entities that give rise to invasive low-grade serous carcinomas (LGCs), which have a relatively poor prognosis and are unrelated to high-grade serous carcinomas (HGCs). The mechanisms underlying the progression of non-invasive SBOTs to invasive epithelial ovarian carcinomas are not understood. We recently established short-term cultures of SBOT cells from tumor biopsies and showed that inactivation of p53, retinoblastoma (Rb) and/or PP2A by the simian virus 40 (SV40) large (LT) and small T antigens extends the life span of the cells and endows them with the ability to invade Matrigel-coated transwells. In this study, we show that concurrent inhibition of p53 and Rb by the SV40 LT produces cells (referred to as SBOT4-LT) with increased life span and cell invasion. To distinguish the roles of p53 and Rb in the progression from SBOTs to invasive ovarian carcinomas, we performed small interfering RNA-mediated knockdown of endogenous p53 in a spontaneously immortalized SBOT cell line, SBOT3.1, which increased cell invasion. This increased invasive activity was associated with the transcriptional downregulation of E-cadherin, correlated with an increase in PIK3CA levels and the increased activation of Akt. Conversely, in invasive LGC-derived MPSC1 cells, enhancing the levels of p53 decreased cell invasion and diminished the phosphatidylinositol 3-kinase (PI3K)/Akt-mediated downregulation of E-cadherin. Inhibition of Rb also enhanced invasiveness, but did not affect the levels of PIK3CA and E-cadherin in SBOT3.1 cells, suggesting that it functions by a different pathway. To our knowledge, this study is the first to show that p53 has an important role in the progression from SBOTs to invasive carcinomas. In addition, our findings suggest that downregulation of E-cadherin by the PI3K/Akt pathway contributes to this progression.