Pancreatic cancer prognosis is predicted by an ATAC-array technology for assessing chromatin accessibility.

Unlike other malignancies, therapeutic options in pancreatic ductal adenocarcinoma (PDAC) are largely limited to cytotoxic chemotherapy without the benefit of molecular markers predicting response. Here we report tumor-cell-intrinsic chromatin accessibility patterns of treatment-naïve surgically resected PDAC tumors that were subsequently treated with (Gem)/Abraxane adjuvant chemotherapy. By ATAC-seq analyses of EpCAM+ PDAC malignant epithelial cells sorted from 54 freshly resected human tumors, we show here the discovery of a signature of 1092 chromatin loci displaying differential accessibility between patients with disease free survival (DFS) < 1 year and patients with DFS > 1 year. Analyzing transcription factor (TF) binding motifs within these loci, we identify two TFs (ZKSCAN1 and HNF1b) displaying differential nuclear localization between patients with short vs. long DFS. We further develop a chromatin accessibility microarray methodology termed "ATAC-array", an easy-to-use platform obviating the time and cost of next generation sequencing. Applying this methodology to the original ATAC-seq libraries as well as independent libraries generated from patient-derived organoids, we validate ATAC-array technology in both the original ATAC-seq cohort as well as in an independent validation cohort. We conclude that PDAC prognosis can be predicted by ATAC-array, which represents a low-cost, clinically feasible technology for assessing chromatin accessibility profiles.

Risk of cancer in patients with ankylosing spondylitis: a nationwide cohort study in Taiwan.

Objective: To estimate the incidence of cancer among patients with ankylosing spondylitis (AS) and compare this risk with that of the general population.Method: We obtained data from Taiwan's National Health Insurance database on 19 289 patients with a first diagnosis of AS registered between 2000 and 2012 with no history of cancer before the diagnosis of AS. Standardized incidence ratios (SIRs) for all cancers and for site-specific cancers were used to assess whether AS was associated with an increased risk of cancer.Results: During the follow-up period, 485 patients developed cancer. The incidence rate was therefore 256.3 per 100 000 person-years. Compared with the general population, patients with AS had an increased risk of cancer [SIR 1.33, 95% confidence interval (CI) 1.20-1.47]. The SIR of cancer was higher in older patients; the risk increased from 8 years after initial diagnosis. Among solid tumours, the risk of melanoma was the highest (SIR 4.64, 95% CI 1.93-11.15), followed by prostate (SIR 2.53, 95% CI 2.01-3.19), thyroid (SIR 2.09, 95% CI 1.45-3.00), and bone cancer (SIR 2.00, 95% CI 1.01-3.99). Among haematological cancers, the risk of leukaemia was the highest (SIR 1.94, 95% CI 1.21-3.12). By contrast, the risks of oesophageal and oral cancers decreased in patients with AS.Conclusion: This nationwide population-based cohort study demonstrated that patients with AS in Taiwan are at an increased risk of cancer, particularly melanoma; prostate, thyroid, and bone cancers; and haematological malignancies.

Deep Transfer Learning and Radiomics Feature Prediction of Survival of Patients with High-Grade Gliomas.

BACKGROUND AND PURPOSE: Patient survival in high-grade glioma remains poor, despite the recent developments in cancer treatment. As new chemo-, targeted molecular, and immune therapies emerge and show promising results in clinical trials, image-based methods for early prediction of treatment response are needed. Deep learning models that incorporate radiomics features promise to extract information from brain MR imaging that correlates with response and prognosis. We report initial production of a combined deep learning and radiomics model to predict overall survival in a clinically heterogeneous cohort of patients with high-grade gliomas. MATERIALS AND METHODS: Fifty patients with high-grade gliomas from our hospital and 128 patients with high-grade glioma from The Cancer Genome Atlas were included. For each patient, we calculated 348 hand-crafted radiomics features and 8192 deep features generated by a pretrained convolutional neural network. We then applied feature selection and Elastic Net-Cox modeling to differentiate patients into long- and short-term survivors. RESULTS: In the 50 patients with high-grade gliomas from our institution, the combined feature analysis framework classified the patients into long- and short-term survivor groups with a log-rank test P value < .001. In the 128 patients from The Cancer Genome Atlas, the framework classified patients into long- and short-term survivors with a log-rank test P value of .014. For the mixed cohort of 50 patients from our institution and 58 patients from The Cancer Genome Atlas, it yielded a log-rank test P value of .035. CONCLUSIONS: A deep learning model combining deep and radiomics features can dichotomize patients with high-grade gliomas into long- and short-term survivors.

MiR-93 blocks STAT3 to alleviate hepatic injury after ischemia-reperfusion.

OBJECTIVE: Signal transducer and activator of transcription 3 (STAT3) is correlated with ischemia-reperfusion (I-R) injury. The previous studies showed a decreased miR-93 expression after I-R injury of heart or brain organs, but without knowledge in liver tissues. This study aims to investigate effects of MiR-93 on the hepatic injury after ischemia/reperfusion. MATERIALS AND METHODS: Rat liver I-R model was generated. Liver function indexes including alanine transaminase (ALT) and aspartate aminotransferase (AST) were quantified, and serum tumor necrosis factor α (TNF-α), interleukin-1ß (IL-1ß), and interleukin-6 (IL-6) levels were quantified. Hepatic tissue apoptosis was measured by transferase-mediated deoxyuridine triphosphate-biotin nick end labeling (TUNEL), and expression of microRNA-93 (miR-93), STAT3, and phosphorylated STAT3 (p-STAT3) were measured. Dual luciferase reporter gene assay confirmed targeted relationship between miR-93 and STAT3. Agomir or miR-93 agomir was injected into the peritoneal cavity of I-R model, followed by ALT and AST assays. Serum levels of TNF-α, IL-1ß, and IL-6 were measured, followed by TUNEL assay for comparing STAT3 and p-STAT3 expression. RESULTS: Comparing to sham group, I-R group rat showed significantly elevated serum ALT, AST, TNF-α, IL-1ß, and IL-6 contents, along with significantly elevated hepatic cell apoptosis, plus decreased miR-93 expression, whilst STAT3 and p-STAT3 expression was enhanced. Intraperitoneal injection of miR-93 agomir significantly decreased STAT3 or p-STAT3 expression, and decreased cell apoptotic rate. Serum levels of ALT, AST, TNF-α, IL-1ß, and IL-6 were significantly decreased, accompanied by improved liver function. CONCLUSIONS: Hepatic I-R injury is accompanied by miR-93 down-regulation, plus STAT3 up-regulation. Overexpression of miR-93 significantly depressed STAT3 expression in liver I-R injury, alleviated hepatic injury or apoptosis, decreased inflammatory response, and improved liver function.

Roxadustat (FG-4592) Versus Epoetin Alfa for Anemia in Patients Receiving Maintenance Hemodialysis: A Phase 2, Randomized, 6- to 19-Week, Open-Label, Active-Comparator, Dose-Ranging, Safety and Exploratory Efficacy Study.

BACKGROUND: Roxadustat (FG-4592) is an oral hypoxia-inducible factor prolyl-hydroxylase inhibitor that promotes erythropoiesis through increasing endogenous erythropoietin, improving iron regulation, and reducing hepcidin. STUDY DESIGN: Phase 2, randomized (3:1), open-label, active-comparator, safety and efficacy study. SETTING & PARTICIPANTS: Patients with stable end-stage renal disease treated with hemodialysis who previously had hemoglobin (Hb) levels maintained with epoetin alfa. INTERVENTION: Part 1: 6-week dose-ranging study in 54 individuals of thrice-weekly oral roxadustat doses versus continuation of intravenous epoetin alfa. Part 2: 19-week treatment in 90 individuals in 6 cohorts with various starting doses and adjustment rules (1.0-2.0mg/kg or tiered weight based) in individuals with a range of epoetin alfa responsiveness. Intravenous iron was prohibited. OUTCOMES: Primary end point was Hb level response, defined as end-of-treatment Hb level change (ΔHb) of -0.5g/dL or greater from baseline (part 1) and as mean Hb level ≥ 11.0g/dL during the last 4 treatment weeks (part 2). MEASUREMENTS: Hepcidin, iron parameters, cholesterol, and plasma erythropoietin (the latter in a subset). RESULTS: Baseline epoetin alfa doses were 138.3±51.3 (SD) and 136.3±47.7U/kg/wk in part 1 and 152.8±80.6 and 173.4±83.7U/kg/wk in part 2, in individuals randomly assigned to roxadustat and epoetin alfa, respectively. Hb level responder rates in part 1 were 79% in pooled roxadustat 1.5 to 2.0mg/kg compared to 33% in the epoetin alfa control arm (P=0.03). Hepcidin level reduction was greater at roxadustat 2.0mg/kg versus epoetin alfa (P<0.05). In part 2, the average roxadustat dose requirement for Hb level maintenance was ∼1.7mg/kg. The least-squares-mean ΔHb in roxadustat-treated individuals was comparable to that in epoetin alfa-treated individuals (about -0.5g/dL) and the least-squares-mean difference in ΔHb between both treatment arms was -0.03 (95% CI, -0.39 to 0.33) g/dL (mixed effect model-repeated measure). Roxadustat significantly reduced mean total cholesterol levels, not observed with epoetin alfa. No safety concerns were raised. LIMITATIONS: Short treatment duration and small sample size. CONCLUSIONS: In this phase 2 study of anemia therapy in patients with end-stage renal disease on maintenance hemodialysis therapy, roxadustat was well tolerated and effectively maintained Hb levels.

Safety and efficacy of oral febuxostat for treatment of HLA-B*5801-negative gout: a randomized, open-label, multicentre, allopurinol-controlled study.

OBJECTIVES: This phase IIIB study compared the efficacy and safety of febuxostat and allopurinol in gout patients with or without tophi who were HLA-B*5801 negative. METHOD: Eligible patients were randomized to a febuxostat group (80 mg QD) or an allopurinol group (300 mg QD). Following an initial 2-week washout period, over the next 12 weeks we made five measurements of serum urate levels along with assessments of adverse events (AEs). RESULTS: Forty-three out of 152 screened subjects (28.3%) were ineligible either because of the presence of the HLA-B*5801 allele or for various other reasons. The febuxostat group (n = 54) and the allopurinol group (n = 55) had no significant differences in demographic or baseline characteristics. From week 2 to week 12, the febuxostat group had a significantly lower serum urate level than the allopurinol group (p ≤ 0.001 for all comparisons) and significantly more patients with serum urate levels less than 6.0 mg/dL. The serum urate levels of the febuxostat group declined by more than 40% from week 2 to week 12 and this decrease was greater than that in the allopurinol group (~30%). The two groups were similar in terms of AEs. CONCLUSIONS: Febuxostat was more effective than allopurinol in reducing the serum urate levels of Han Chinese patients with gout or tophaceous gout who were HLA-B*5801 negative, without causing any serious skin reactions. Febuxostat should be considered for treatment of Han Chinese patients with gout who are HLA-B*5801 negative.

Role of hydrogen sulfide within the dorsal motor nucleus of the vagus in the control of gastric function in rats.

BACKGROUND: Hydrogen sulfide (H2 S) is a gaseous messenger and serves as an important neuromodulator in the central nervous system. This study aimed to clarify the role of H2 S within the dorsal motor nucleus of the vagus (DMV) in the control of gastric function in rats. METHODS: Cystathionine ß-synthetase (CBS) is an important generator of endogenous H2 S in the brain. We investigated the distribution of CBS in the DMV using immunohistochemical method, and the effects of H2 S on gastric motility and on gastric acid secretion. KEY RESULTS: CBS-immunoreactive (IR) neurons were detected in the rostral, intermediate and caudal DMV, with the highest number of CBS-IR neurons in the caudal DMV, and the lowest in the intermediate DMV. We also found that microinjection of the exogenous H2 S donor NaHS (0.04 and 0.08 mol/L; 0.1 µL; n = 6; p < 0.05) into the DMV significantly inhibited gastric motility with a dose-dependent trend, and promoted gastric acid secretion in Wistar rats. Microinjection of the same volume of physiological saline (PS; 0.1 µL, n = 6, p > 0.05) at the same location did not noticeably change gastric motility and acid secretion. CONCLUSIONS & INFERENCES: The data from these experiments suggest that the CBS that produces H2 S is present in the DMV, and microinjection of NaHS into the DMV inhibited gastric motility and enhanced gastric acid secretion in rats.

A phase II, open-label, multicenter study to evaluate the antitumor efficacy of CO-1.01 as second-line therapy for gemcitabine-refractory patients with stage IV pancreatic adenocarcinoma and negative tumor hENT1 expression.

BACKGROUND: Nucleotide transporters such as human equilibrative nucleoside transporter-1 (hENT1) play a major role in transporting gemcitabine into cells. CO-1.01 (gemcitabine-5'-elaidate) is a novel cytotoxic agent consisting of a fatty acid derivative of gemcitabine, which is transported intracellularly independent of hENT1. CO-1.01 was postulated to have efficacy as a second-line treatment in gemcitabine-refractory pancreatic adenocarcinoma in patients with negative tumor hENT1 expression. METHODS: Eligibility criteria included patients with either a newly procured or archival biopsy tumor confirming the absence of hENT1 and either gemcitabine-refractory metastatic pancreas adenocarcinoma or with progression of disease following resection during or within 3 months of adjuvant gemcitabine therapy. Patients were treated with intravenous infusion of CO-1.01 dosed at 1250 mg/m(2) on Days 1, 8, and 15 of a 4-week cycle. The primary end point was disease control rate (DCR). RESULTS: Nineteen patients were enrolled of which 18 patients were evaluable for efficacy assessment. Thirteen patients (68%) had liver metastases, 6 (32%) had lymph node metastases, and 10 (53%) had lung metastases. Two of 18 patients (11%) achieved disease control. The median survival time was 4.3 (95% CI 2.1-8.1) months. All patients experienced at least one treatment-related adverse event with the majority of events being mild or moderate. CONCLUSION: This study did not meet its primary endpoint and no efficacy signal was identified for CO-1.01 in treating progressive metastatic pancreas adenocarcinoma.

A phase II study of gemcitabine and cisplatin plus sorafenib in patients with advanced biliary adenocarcinomas.

BACKGROUND: This study evaluated the addition of sorafenib to gemcitabine and cisplatin in biliary adenocarcinoma first-line therapy. METHODS: Patients with advanced biliary adenocarcinomas received gemcitabine 1000 mg m(-2) and cisplatin 25 mg m(-2) on a 2 weeks on/1 week off cycle and sorafenib 400 mg twice daily. After the initial 16 patients were enrolled, the chemotherapy doses were amended in view of grade 3 and 4 hand-foot skin reaction and haematologic toxicity. Subsequently, 21 patients received gemcitabine 800 mg m(-2), cisplatin 20 mg m(-2) and sorafenib 400 mg. The primary end point was an improvement in 6-month progression-free survival (PFS6) from historical 57-77% (90% power, type I error of 10%). Pretreatment pERK, evaluated by immunostaining, was correlated with clinical outcome. RESULTS: A total of 39 patients were accrued. The most common grade 3-4 toxicities noted in >10% of patients were fatigue, elevated liver function tests and haematologic toxicities including thromboemboli, hyponatraemia and hypophosphataemia. Six-month progression-free survival was 51% (95% confidence interval (CI) 34-66%). Median PFS and overall survival were 6.5 (95% CI: 3.5-8.3) and 14.4 months (95% CI: 11.6-19.2 months), respectively. No correlation was observed between pERK and outcomes. CONCLUSION: The addition of sorafenib to gemcitabine and cisplatin in biliary adenocarcinomas did not improve efficacy over historical data, and toxicity was increased.

The association between low-dose aspirin use and the incidence of colorectal cancer: a nationwide cohort study.

BACKGROUND: Considerable evidence suggests that aspirin has a chemopreventive effect on colorectal cancer (CRC). However, optimal dose and treatment duration have not been defined, and data on the effects of low-dose aspirin are contradictory. AIM: To determine if the incidence of CRC in patients with low-dose aspirin use was lower than in those without aspirin use. METHOD: From Taiwan's National Health Insurance research database, aspirin users (n = 1985) were defined as adults (age ≥20 years) with at least 3.5 years of regular low-dose aspirin use (50-150 mg per day) between 1998 and 2002. Non-users (n = 7940) were those who did not use aspirin and were matched 4:1 with the user group by age, gender, date of ambulatory care (index date), and presence of known risk factors for cardiovascular disease (including hypertension, diabetes mellitus and hyperlipidaemia). Follow-up of the two study groups was made until the end of 2010, and incidences and hazard ratios of colorectal cancer were determined. RESULTS: During a median follow-up period of 8.9 years, 129 non-users and 14 users developed CRC, corresponding to incidence rates of 180.43 and 79.42 per 100,000 person-years respectively. Duration of aspirin use among users ranged from 3.5 to 12.6 years (mean 8.7 years). The multivariate-adjusted hazard ratio for CRC was 0.5 (95% confidence interval 0.28-0.87) among users as compared with non-users. CONCLUSIONS: Long-term use of low-dose aspirin appears to be associated with a lower incidence of CRC in patients with high cardiovascular risk. Further randomised clinical trials are necessary to confirm these findings.

T2-weighted MR imaging early after chemoradiotherapy to evaluate treatment response in head and neck squamous cell carcinoma.

BACKGROUND AND PURPOSE: T2-weighted MRI shows potential in early posttreatment assessment of the primary tumor. Residual masses composed entirely of low T2-signal scar tissue suggest local control and those ≥1 cm of similar signal to untreated tumor suggest local failure. The purpose of this study was to investigate the diagnostic accuracy of T2-weighted MR imaging early after chemoradiotherapy for identifying primary tumor treatment failure in squamous cell carcinoma of the head and neck. MATERIALS AND METHODS: At 6 weeks after treatment, T2-weighted MR images of 37 primary tumors in 37 patients were assessed. Residual masses were divided into 3 patterns: pattern 1 = scar tissue only (flat-edged/retracted mass of low T2 signal intensity); pattern 2 = mass without features described in pattern 1 or 3; and pattern 3 = any pattern that included an expansile mass ≥1 cm of intermediate T2 signal intensity (similar grade of signal intensity to the untreated tumor). T2 patterns were analyzed for local outcome (Fisher exact test) and time to local failure (univariate and multivariate analysis of T2 pattern, age, T stage, and tumor size by use of the Cox regression model). RESULTS: Residual masses after treatment were present in 34 (92%) of 37 patients. Local failures occurred in residual masses with pattern 1 in 0 (0%) of 14 patients; pattern 2 in 6 (55%) of 11 patients; and pattern 3 in 9 (100%) of 9 patients. Significant associations were found between local control and pattern 1 (P = <.0001; sensitivity, 74%; specificity, 100%; PPV, 100%; NPV, 75%; accuracy, 85%), and between local failure and pattern 3 (P = <.0001; sensitivity, 60%; specificity, 100%; PPV, 100%; NPV, 76%; accuracy, 82%). Pattern 2 showed no significant associations with local outcome. Univariate analysis of time to local failure showed that the T2 pattern was significant (P < .0001) and remained significant on multivariate analysis. CONCLUSIONS: T2-weighted MR imaging is a potential tool for early posttreatment assessment of primary HNSCC treatment response. Awareness of correlation of the T2 pattern of any residual mass with treatment outcome at the primary site may contribute to patient treatment.

Cancer risk among patients with systemic sclerosis: a nationwide population study in Taiwan.

OBJECTIVES: Systemic sclerosis (SSc) has been associated with high cancer risk. We compared the cancer risk among SSc patients with that among the general Taiwanese population. METHODS: The catastrophic illness registry of the Taiwan National Health Insurance Research Dataset (NHIRD) was used to identify patients diagnosed with SSc and cancer in Taiwan during 1996-2008. The standardized incidence ratio (SIR) for cancer was calculated, and mortality was ascertained using the data from the National Death Registry. RESULTS: Data analysis revealed that 2053 (472 men, 1581 women) Taiwanese individuals were diagnosed with SSc during the study period and 83 (30 men, 53 women) had cancer. The incidence of cancer was 6.9/1000 person-years. The most common cancer sites in male SSc patients were the lung (n = 10), oral cavity and pharynx (n = 8), and gastrointestinal tract (n = 4), and those in female patients were the breast (n = 11), lungs (n = 11), and blood (n = 6). Compared to the Taiwanese population of 1996, the all-cancer SIR for SSc was 1.63 [95% confidence interval (CI) 1.31-2.01]. Cancer risk was elevated for cancers of the lung (SIR 4.20), oral cavity and pharynx (SIR 3.67), and blood (SIR 3.50). A cancer diagnosis in SSc patients was associated with a hazard ratio (HR) of 2.15 (95% CI 1.30-3.53). Among cancer patients, a diagnosis of SSc was not associated with increased mortality. CONCLUSIONS: SSc patients are at high risk of developing cancer, especially of the lung, oral cavity and pharynx, and blood.

Incidence, cancer risk and mortality of dermatomyositis and polymyositis in Taiwan: a nationwide population study.

BACKGROUND: Nationwide data on the epidemiology of dermatomyositis (DM) and polymyositis (PM) were limited. OBJECTIVES: This study was to estimate the incidence, occurrence of cancer and mortality of DM and PM in Taiwan. METHODS: Both the register of critical illness of the Taiwan National Health Insurance Research Dataset and the National Death Registry of Taiwan were used to calculate estimates of the incidence, cancer association, and mortality of DM and PM between 2003 and 2007. RESULTS: A total of 803 DM and 500 PM cases were identified between 2003 and 2007. Mean age at diagnosis was 44·0 ± 18·3 years for DM and 49·2 ± 15·9 years for PM. The overall annual incidences of DM and PM were 7·1 (95% CI 6·6-7·6) and 4·4 (95% CI 4·0-4·8) cases per million population. The incidence of both DM and PM increased with age and reached a peak at age 50-59 years. One hundred and eleven (13·8%) patients with DM and 31 (6·2%) patients with PM had cancers. The diagnosis of most cancers was made after the diagnoses of DM (n = 71; 64·0%) and PM (n = 21; 67·7%). Overall, the standardized incidence ratios (SIR) for cancer were 5·36 (4·12-6·87) and 1·80 (1·10-2·79) among patients with DM and PM; however, during the first year, SIRs for cancer were 24·55 (95% CI 18·62-31·79) and 9·17 (95% CI 14·82-15·93) in patients with DM and PM, respectively. The most common types of cancer were nasopharyngeal cancer for men and breast cancer for women. Patients with DM and PM had standardized mortality ratios of 7·68 (6·41-9·01) and 5·29 (4·28-6·48). CONCLUSION: This study reports robust estimates of important aspects of the epidemiology of both DM and PM in Taiwan. This highlights the rarity of these diseases, and their associated cancer risks and increased mortality.

Epidemiology and mortality of systemic sclerosis: a nationwide population study in Taiwan.

OBJECTIVES: There have been few nationwide population studies of systemic sclerosis (SSc). We describe the epidemiological features of SSc in Taiwan. METHODS: The catastrophic illness registry of the Taiwan National Health Insurance Research Dataset (NHIRD) and the National Death Registry of Taiwan were used to calculate estimates of the incidence, prevalence, and mortality of SSc. RESULTS: A total of 1479 persons (325 males, 1154 females) with incident SSc were enrolled in the study. The annual incidence of SSc in Taiwan was found to be 10.9 cases (4.7 males, 17.4 females) per million population. During 2002-2007, the mean prevalence was 56.3 cases per million population. There were 204 deaths (70 males, 134 females) during the study period; 1-, 2-, and 5-year survival rates were 94.9, 92.0, and 83.2%, respectively. SSc patients had a standardized mortality ratio (SMR) of 3.24 [95% confidence interval (CI) 2.82-3.71] for all-cause mortality, as compared with the national population in 2002. There was excess mortality from neoplasms (SMR 1.50, 95% CI 1.03-2.11), cardiovascular diseases (2.23, 1.52-3.16), kidney disease (4.67, 2.66-7.64), gastrointestinal diseases (2.50, 1.27-4.46), and pulmonary diseases (3.20, 1.89-5.09). In addition to male sex and older age, cancer and end-stage renal disease (ESRD) diagnosis were risk factors for death, with hazard ratios (HRs) of 2.71 (95% CI 1.27-5.76) and 2.59 (1.14-5.90), respectively. CONCLUSION: SSc patients had a threefold greater risk of all-cause mortality than the general population of Taiwan. Male sex, older age, diagnosis of cancer, and ESRD were risk factors for death.

Does primary tumour volumetry performed early in the course of definitive concomitant chemoradiotherapy for head and neck squamous cell carcinoma improve prediction of primary site outcome?

Although previous studies have documented correlations between pre-treatment or post-treatment primary tumour volumes and local outcome following definitive concomitant chemoradiotherapy (CCRT) in head and neck squamous cell carcinoma (HNSCC), no study has included and compared tumour volumes during CCRT. We reviewed the MRIs of 69 HNSCC patients treated with a 6 weeks course of CCRT and who underwent successful MRI pre-treatment (n = 69), 2 weeks intra-treatment (n = 48) and 6 weeks post-treatment (n = 61). Primary tumour volumes on MRI at the three time points were calculated and compared for their predictive value for primary site outcome. Volume thresholds optimised to predict failure with the highest accuracy and positive predictive value (PPV) were calculated. The mean pre-treatment volume was 24.6 cm³ (range, 1.1-187.9 cm³) and the mean follow-up interval was 41 months (range, 12-100 months). 23 primary tumours failed treatment (33%). Volumes before, during and after CCRT were positively associated with local failure (p = 0.015, p = 0.009, p<0.0001). Volume reductions during and after CCRT were negatively associated with local failure (p = 0.021, p = 0.001). Pre-treatment and intra-treatment volume thresholds achieved the highest accuracy and produced intermediate PPVs (51-64%) for predicting local failure. Optimised intra-treatment thresholds did not identify any more treatment failures than the pre-treatment thresholds. By comparison, a 6 weeks post-treatment volume reduction (<35%) achieved 100% PPV for failure, albeit with 26% sensitivity. In conclusion, primary tumour volumetry performed early in CCRT provides minimal additional information compared with pre-treatment volumetry, with respect to predicting post-treatment local failures. Therefore, volumetry during CCRT is unlikely to be useful for guiding individual response-based therapeutic modifications.

Can diffusion-weighted imaging distinguish between normal and squamous cell carcinoma of the palatine tonsil?

The utility of diffusion-weighted imaging (DWI) in the detection of squamous cell carcinoma (SCC) of the tonsils has not been previously investigated. This preliminary study compared DWI of apparent SCC tonsillar tumours with normal tonsils. DWI of the tonsils was performed in 10 patients with newly diagnosed tonsil SCC that was evident on conventional MRI and in 17 patients undergoing cranial MRI for other indications. Regions of interest (ROI) were drawn around each identifiable tonsil on the apparent diffusion coefficient (ADC) map and the mean ADC value for each tonsil was calculated. ADC values for normal and SCC tonsils were compared using the Mann-Whitney U-test. The median ADC and range (x10(-3) mm(2) s(-1)) were found to be 0.814 and 0.548-1.312, respectively, for normal tonsils compared with 0.933 and 0.789-1.175, respectively, for SCC tonsils. ADC values were significantly higher for SCC tonsils than for normal tonsils (p = 0.009). No SCC tonsil had an ADC less than 0.82 x 10(-3) mm(2) s(-1) compared with 58% of normal tonsils. We conclude that there is a difference in the ADC between normal tonsils and SCC tonsils where the cancer is apparent on conventional MRI. These results are promising, although further studies are now required to determine whether DWI can be used to identify or exclude smaller foci of SCC within tonsils where the cancer is not evident on conventional MRI.

Impact of neurological and medical complications on 3-month outcomes in acute ischaemic stroke.

OBJECTIVE: To evaluate the impact of neurological and medical complications on 3-month outcomes in acute ischaemic stroke patients. METHODS: We prospectively investigated complications for all the consecutive acute ischaemic stroke patients admitted within 7 days from onset in four university hospitals during a 1-year period. Baseline data and 3-month outcomes were collected. Poor outcome was defined as a modified Rankin Scale score 3-6. RESULTS: A total of 1 254 patients were recruited: 264 (21.1%) and 303 (24.2%) patients experienced one or more neurological and medical complications, respectively. The most common complications were ischaemic stroke progression (17.1%) and pneumonia (12.0%). Of 1 233 patients with available 3-month outcomes, 34.9% had a poor outcome. Multivariate analysis revealed that neurological (odds ratio, 95% confidence interval; 5.47, 3.63-8.24) and medical (3.47, 2.30-5.23) complications were independent predictors of the poor outcome. For the individual complications, ischaemic stroke progression (7.48, 4.73-11.84), symptomatic hemorrhagic transformation (3.57, 1.33-9.54), pneumonia (4.44, 2.20-8.99), extracranial bleeding (4.45, 1.88-10.53), and urinary tract infection (2.72, 1.32-5.60) were independently associated with the poor outcome. CONCLUSION: Outcome after ischaemic stroke is adversely influenced by complications, especially ischaemic stroke progression, symptomatic hemorrhagic transformation, pneumonia, extracranial bleeding, and urinary tract infection. Interventions to prevent those complications might improve ischaemic stroke outcome.

A split-organ delineation approach for dose optimisation for intensity-modulated radiotherapy for advanced T-stage nasopharyngeal carcinoma.

AIMS: To assess the dosimetric effect of using a split-organ delineation approach during intensity-modulated radiotherapy (IMRT) treatment planning for advanced T-stage nasopharyngeal carcinoma (NPC). MATERIALS AND METHODS: Twenty NPC patients with T3-4 tumours were studied. A reference (REF) IMRT plan was generated based on a standard treatment planning protocol, with a set of user-defined dose constraints for optimisation. An investigative (INV) IMRT plan was then generated based on the same protocol, but treating several organs at risk (OARs; parotid glands, temporal lobes, cochlea, auditory nerves and planning organ at risk volume [PRV] of the brainstem) as split organs consisting of target-overlapping and non-target-overlapping sub-segments. These sub-segments were assigned independent dose constraints. The REF and INV plans were compared with respect to target coverage and OAR sparing. Target coverage was evaluated by the Dmin (minimum dose), V66/V60 (percentage volume of gross target volume [GTV]/planning target volume [PTV] receiving 66 Gy/60 Gy), target conformity index (CI), and tumour control probability (TCP). The sparing of OARs was evaluated by the commonly used dose end points for the respective OAR, and normal tissue complication probability (NTCP). RESULTS: For PTV coverage, the INV plan was superior to the REF plan in terms of Dmin (P=0.000), CI (P=0.005) and TCP (P=0.002). This is attributed to an increase in dose to the PTV-OAR overlapping sub-segments. Regarding the sparing of OARs, there was a significant reduction in the mean dose of the parotid glands (P=0.002), and a slight, but non-significant, increase in NTCP of the temporal lobes, cochlea and brainstem. CONCLUSIONS: Using a split-organ delineation approach in IMRT treatment planning for advanced T-stage NPC, a significant improvement in the target coverage and TCP could be achieved, whereas the mean dose of the parotid was reduced significantly. There was insignificant change in the NTCP of the temporal lobe, parotid gland, cochlea and brainstem, but a significant change in the NTCP of the auditory nerve. The approach provides the planner extra room to manipulate the dose constraints during optimisation, and to obtain the desired result in less attempts. This approach also has the potential to be used in a broader context for IMRT planning for other tumour sites.

Feasibility of using interpolated contours of targets and organs at risk in intensity-modulated radiation therapy treatment planning for advanced-stage nasopharyngeal carcinoma.

To assess the dosimetric effect of using interpolated contours in planning intensity-modulated radiation therapy (IMRT) for advanced T-stage nasopharyngeal carcinoma. The present study focused on T3-T4 tumours where the proximity of targets to neurological organs poses a stringent test on the feasibility of such an approach. Contours of targets and organs were delineated on CT images of 2.5-mm interval and a reference IMRT plan was generated. An investigative (INV) IMRT plan was then generated with the same planning protocol, but based on interpolated contours that replaced deleted contours on alternate slices. The reference and INV plans were compared. Regarding target coverage, all targets in the INV plans met the acceptance criteria except for the PTV in one case. Regarding organs, the mean dose to 1% volume of the brainstem and spinal cord in the INV plans were kept below their dose limits. No significant differences in the mean doses to others organs were found. Satisfactory target coverage and protection of critical organs to a degree similar to full-scale contouring could be achieved with use of interpolated contours. The saving in manpower time for contouring is expected to significantly improve the throughput of the IMRT planning process.

Overall survival after concurrent cisplatin-radiotherapy compared with radiotherapy alone in locoregionally advanced nasopharyngeal carcinoma.

This phase III randomized study compared concurrent cisplatin-radiotherapy (CRT) versus radiotherapy (RT) alone in patients with locoregionally advanced nasopharyngeal carcinoma. A total of 350 patients were randomly assigned to receive external RT alone or concurrently with cisplatin at a dosage of 40 mg/m(2) weekly. The primary endpoint was overall survival, and the median follow-up was 5.5 years. The 5-year overall survival was 58.6% (95% confidence interval [CI] = 50.9% to 66.2%) for the RT arm and 70.3% (95% CI = 63.4% to 77.3%) for the CRT arm. In Cox regression analysis adjusted for T stage, age, and overall stage, the difference in overall survival was statistically significantly in favor of concurrent CRT (P = .049, hazard ratio [HR] = 0.71 [95% CI = 0.5 to 1.0]). Subgroup analysis demonstrated that there was no difference between overall survival in the arms for T1/T2 stage (P = .74, HR = 0.93 [95% CI = 0.59 to 1.4]), whereas there was a difference between the arms for T3/T4 stage (P = .013, HR = 0.51 [95% CI = 0.3 to 0.88]), favoring the CRT arm. The regimen of weekly concurrent CRT is a promising standard treatment strategy for locoregionally advanced nasopharyngeal carcinoma patients.