Reliability of histologic assessment in patients with eosinophilic oesophagitis.

BACKGROUND: The validity of the eosinophilic oesophagitis (EoE) histologic scoring system (EoEHSS) has been demonstrated, but only preliminary reliability data exist. AIM: Formally assess the reliability of the EoEHSS and additional histologic features. METHODS: Four expert gastrointestinal pathologists independently reviewed slides from adult patients with EoE (N = 45) twice, in random order, using standardised training materials and scoring conventions for the EoEHSS and additional histologic features agreed upon during a modified Delphi process. Intra- and inter-rater reliability for scoring the EoEHSS, a visual analogue scale (VAS) of overall histopathologic disease severity, and additional histologic features were assessed using intra-class correlation coefficients (ICCs). RESULTS: Almost perfect intra-rater reliability was observed for the composite EoEHSS scores and the VAS. Inter-rater reliability was also almost perfect for the composite EoEHSS scores and substantial for the VAS. Of the EoEHSS items, eosinophilic inflammation was associated with the highest ICC estimates and consistent with almost perfect intra- and inter-rater reliability. With the exception of dyskeratotic epithelial cells and surface epithelial alteration, ICC estimates for the remaining EoEHSS items were above the benchmarks for substantial intra-rater, and moderate inter-rater reliability. Estimation of peak eosinophil count and number of lamina propria eosinophils were associated with the highest ICC estimates among the exploratory items. CONCLUSION: The composite EoEHSS and most component items are associated with substantial reliability when assessed by central pathologists. Future studies should assess responsiveness of the score to change after a therapeutic intervention to facilitate its use in clinical trials.

Phase I/II trial of dose-reduced capecitabine in elderly patients with advanced colorectal cancer.

BACKGROUND: Combination chemotherapy is associated with improved outcomes in trials of selected fit patients with advanced colorectal cancer (acrc). For older or less-fit patients, combination chemotherapy is associated with greater toxicity and less benefit. Capecitabine monotherapy is a reasonable option for those patients, but the optimal dose remains controversial. METHODS: A multicentre phase i/ii trial of reduced-dose capecitabine (2000 mg/m2, days 1-14 every 21 days) was conducted in 221 patients representing one or more of the following subsets: age greater than 65 years (n = 167), Eastern Cooperative Oncology Group (ecog) performance status of 1 or greater (n = 139), elevated lactate dehydrogenase (ldh) (n = 105), or prior pelvic radiation (n = 54). Based on phase i results, patients with prior pelvic radiation received capecitabine 750 mg/m2 twice daily. The goal was to ascertain efficacy in a design that was unlikely to cause high levels of toxicity. RESULTS: Median age in the patient cohort was 72 years. A median of 5 and a mean of 8 capecitabine cycles were given (range: 0-50 cycles). Grade 3 or 4 toxicity occurred in 25% of patients during the first 3 cycles (8.1% hand-foot syndrome, 7.7% diarrhea). The response rate was 13.6%, with a 69.7% disease control rate. Median progression-free survival (pfs) was 5.6 months. Post progression, 56 patients received further capecitabine monotherapy (median of 4 additional cycles). Median overall survival duration for the patients was 14.3 months. Median survival was significantly higher for those who, at baseline, had an ecog performance status of 0 (compared with 1 or more) and normal ldh (compared with elevated ldh). CONCLUSIONS: Toxicity is less with dose-reduced capecitabine than with historical full-dose capecitabine, with only a small trade-off in efficacy, seen as a lower objective response rate. The improved tolerability could lead to an increased number of cycles of therapy, and pfs appears to be consistently higher at the lower dose. Those observations should, in the absence of a head-to-head clinical trial, be viewed as compelling evidence that 1000 mg/m2, or even 750 mg/m2, twice daily is an appropriate dose in elderly or frail patients with acrc.

Randomised non-inferiority trial: 1600 mg versus 400 mg tablets of mesalazine for the treatment of mild-to-moderate ulcerative colitis.

BACKGROUND: High concentration mesalazine formulations are more convenient than conventional low concentration formulations for the treatment of ulcerative colitis (UC). AIM: To compare the efficacy and safety of 1600 mg and 400 mg tablet mesalazine formulations. METHODS: Patients with mild-to-moderate active UC (Mayo Clinic Score >5; N=817) were randomised to 3.2 g of oral mesalazine, administered as two 1600 mg tablets once, or four 400 mg tablets twice daily. We hypothesised that treatment with the 1600 mg tablet was non-inferior (within a 10% margin) to the 400 mg tablet for induction of clinical and endoscopic remission at week 8. Open-label treatment with the 1600 mg tablet continued for 26-30 weeks based on induction response. Predictors of treatment response were also explored. RESULTS: At week 8, remission occurred in 22.4% and 24.6% of patients receiving the 1600 mg and 400 mg tablets, respectively (absolute difference -2.2%, 95% CI: -8.1% to 3.8%, non-inferiority P=.005). Endoscopic and histopathologic disease activity, leucocyte concentration and age were significantly associated with clinical remission (P=.022, .042, .014 and .023, respectively). At week 38, 43.9% (296/675) of patients who continued treatment with the 1600 mg formulation were in remission, including 70.3% (142/202) of patients who received a reduced dose of mesalazine (1.6 g/d). The overall incidence of serious adverse events was low. CONCLUSIONS: Induction therapy with 3.2 mg mesalazine using two 1600 mg tablets once-daily was statistically and clinically non-inferior to a twice-daily regimen using four 400 mg tablets (NCT01903252).

The development of a magnetic resonance imaging index for fistulising Crohn's disease.

BACKGROUND: Magnetic resonance imaging (MRI) is the gold standard for assessment of perianal fistulising Crohn's disease (CD). The Van Assche index is the most commonly used MRI fistula index. AIMS: To assess the reliability of the Van Assche index, and to modify the instrument to improve reliability and create a novel index for fistulising CD. METHODS: A consensus process developed scoring conventions for existing Van Assche index component items and new items. Four experienced radiologists evaluated 50 MRI images in random order on three occasions. Reliability was assessed by estimates of intraclass correlation coefficients (ICCs). Common sources of disagreement were identified and recommendations made to minimise disagreement. A mixed effects model used a 100 mm visual anologue scale (VAS) for global severity as outcome and component items as predictors to create a modified Van Assche index. RESULTS: Intraclass correlation coefficients (95% confidence intervals) for intra-rater reliability of the original and modified Van Assche indices and the VAS were 0.86 (0.81-0.90), 0.90 (0.86-0.93) and 0.86 (0.82-0.89). Corresponding ICCs for inter-rater reliability were 0.66 (0.52-0.76), 0.67 (0.55-0.75) and 0.58 (0.47-0.66). Sources of disagreement included number, location, and extension of fistula tracts, and rectal wall involvement. A modified Van Assche index (range 0-24) was created that included seven component items. CONCLUSIONS: Although "almost perfect" intra-rater reliability was observed for the assessment of MRI images for fistulising CD using the Van Assche index, inter-rater reliability was considerably lower. Our modification of this index should result in a more optimal instrument.

Pain expectations in neuropathic pain: Is it best to be optimistic?

BACKGROUND: Pain expectancy may be an important variable that has been found to influence the effectiveness of treatments for pain. Much of the literature supports a self-fulfilment perspective where expectations for pain relief predict the actual pain experienced. However, in conditions such as neuropathic pain (NeP) where pain relief is difficult to attain, expectations for pain relief could be unrealistic. The objective of this study was to investigate the relationship between realistic/unrealistic expectations and 6-month, post-treatment outcomes. METHODS: We performed a retrospective analysis of a large cohort of patients with NeP (n = 789) attending tertiary care centres to determine the association between unrealistic (both positive and negative) and realistic expectations with outcomes after multidisciplinary treatment. An expectation variable with three categories was calculated: realistic expectations were those whose expected reduction in pain was similar to the observed mean group reduction in pain, while optimistic and pessimistic expectations were those who over- or under-estimated the expected response to treatment, respectively. The association between baseline realistic/unrealistic expectations and 6-month pain-related disability, catastrophizing and psychological distress was assessed. RESULTS: Univariable analyses suggested that realistic expectations were associated with lower levels of disability, catastrophizing and psychological distress, compared to unrealistic expectations. However, after adjustment for baseline symptom severity, multivariable analysis revealed that patients with optimistic expectations had lower levels of disability, than those with realistic expectations. Those with pessimistic expectations had higher levels of catastrophizing and psychological distress at follow-up. CONCLUSIONS: These findings are largely congruent with the self-fulfilment perspective to expectations. SIGNIFICANCE: This study defined realistic pain expectations with patient data. Examining the relationship between expectations between pain and disability in a large cohort of patients with neuropathic pain.

Impact on health-related quality of life and costs of managing chronic neuropathic pain in academic pain centres: Results from a one-year prospective observational Canadian study.

BACKGROUND: The management of chronic pain, including neuropathic pain (NeP), is a major public health issue. However, there is a paucity of data evaluating pain management strategies in real-life settings. OBJECTIVE: To inform policy makers about the economic value of managing chronic NeP in academic centres by conducting a subeconomic assessment of a Canadian multicentre cohort study aimed at determining the long-term outcomes of the management of chronic NeP in academic pain centres. Specific questions regarding the economic value of this type of program were answered by a subset of patients to provide further information to policy makers. METHODS: Baseline demographic information and several pain-related measurements were collected at baseline, three, six and 12 months in the main study. A resource use questionnaire aimed at determining NeP-related costs and the EuroQoL-5 Dimension were collected in the subset study from consenting patients. Statistical analyses were conducted to compare outcomes over time and according to responder status. RESULTS: A total of 298 patients were evaluated in the present economic evaluation. The mean (± SD) age of the participants was 53.7±14.0 years, and 56% were female. At intake, the mean duration of NeP was >5 years. Statistically significant improvements in all pain and health-related quality of life outcomes were observed between the baseline and one-year visits. Use decreased over time for many health care resources (eg, visits to the emergency room decreased by one-half), which resulted in overall cost savings. CONCLUSION: The results suggest that increased access to academic pain centres should be facilitated in Canada.

Development of interim patient-reported outcome measures for the assessment of ulcerative colitis disease activity in clinical trials.

BACKGROUND: Patient-reported outcomes (PROs) have an increasingly important role in the evaluation of new therapies for inflammatory bowel disease. The US Food and Drug Administration has issued formal guidance to describe the role of PRO instruments in evaluation of claims for product labelling. However, no validated PRO exists for ulcerative colitis. AIM: To investigate whether the PROs from the Mayo Clinic Score (MCS) for UC can be modified, to develop an interim PRO for use in clinical trials, alone or in combination with endoscopy. METHODS: Data from an induction trial of a mesalazine (mesalamine) formulation were used to compare effect sizes between mesalazine and placebo for PRO items (stool frequency and rectal bleeding) alone and in combination with endoscopy. The operating properties of the PRO were validated using data from a phase 2 trial of MLN02, a humanised antibody to the α4ß7 integrin in patients with UC. RESULTS: A two-item PRO (PRO2) consisting of rectal bleeding = 0 and stool frequency ≤1 or ≤2, combined with an endoscopy subscore ≤1 yielded statistically significant differences between active drug and placebo. This combination yielded the most similar effect sizes and placebo rates for remission, compared to the primary trials. Use of PRO items alone yielded high placebo remission rates in both data sets, although rates were lower when the items were combined and remission defined as PRO2 = 0. CONCLUSION: Patient-reported outcomes items derived from the Mayo Clinic Score combined with endoscopy as a co-primary endpoint may be an appropriate interim outcome measure for ulcerative colitis trials.

Usefulness of Ki-67, Mitoses, and Tumor Size for Predicting Metastasis in Carcinoid Tumors of the Lung: A Study of 48 Cases at a Tertiary Care Centre in Canada.

Background. Evaluation of Ki-67 index in lung carcinoid tumors (LCTs) has been of interest in order to identify high risk subsets. Our objectives are (1) to evaluate the usefulness of Ki-67 index, mitoses, and tumor size in predicting metastasis and (2) to compare the Manual Conventional Method (MCM) and the Computer Assisted Image Analysis Method (CIAM) for Ki-67 calculation. Methods. We studied 48 patients with LCTs from two academic centres in Canada. For Ki-67 calculation, digital images of 5000 cells were counted using an image processing software and 2000 cells by MCM. Mitoses/10 HPF was counted. Results. We had 37 typical carcinoids (TCs) and 11 atypical carcinoids (ACs). 7/48 patients developed metastasis. There was a positive relationship between metastasis and carcinoid type (P = 0.039) and metastasis and mitoses (≥2) (P = 0.017). Although not statistically significant, the mean Ki-67 index for ACs was higher than for TCs (0.95% versus 0.72%, CIAM, P = 0.299). Similarly, although not statistically significant, the mean Ki-67 index for metastatic group (MG) was higher than for nonmetastatic group (NMG) (1.01% versus 0.71% by CIAM, P = 0.281). However when Ki-67 index data was categorized at various levels, there is suggestion of a useful cutoff (≥0.50%) to predict metastasis (P = 0.106, CIAM). A significantly higher proportion of patients with mitosis ≥2 and Ki-67 index ≥0.50% had metastasis (P = 0.033) compared to other patients. Similarly patients with tumor size ≥3 cm and Ki-67 ≥0.50% had a greater percentage of metastases than others (P = 0.039). Although there was a strong correlation between two (MCM versus CIAM) counting methods (r = 0.929, P = 0.001), overall the calculated Ki-67 index was slightly higher by MCM (range 0 to 6.4, mean 1.5) compared to CIAM (range 0 to 2.9, mean 0.75). Conclusion. This study confirms that mitoses ≥2 is a powerful predictor of metastasis in LCTs. Although this is a small sample size, there is suggestion that analysis of Ki-67 index along with mitoses and tumor size may be a useful adjunct for predicting metastasis in LCTs.

A prospective cohort study to determine the relationship between serum infliximab concentration and efficacy in patients with luminal Crohn's disease.

BACKGROUND: Patients with Crohn's disease (CD) may experience disease relapse on maintenance infliximab. Anti-drug antibodies likely contribute to loss of response, and serum infliximab levels likely correlate with efficacy. AIM: To prospectively evaluate the relationship between trough serum infliximab concentration and disease activity. METHODS: Adult patients (N = 327) with a diagnosis of CD who had received at least five consecutive infliximab infusions and who planned to receive at least two additional infusions were enrolled. The Crohn's Disease Activity Index (CDAI), serum infliximab, C-reactive protein (CRP) and antibodies-to-infliximab (ATI) were assessed at baseline, week 4 and week 8. Receiver operating characteristic (ROC) analysis examined the relationship between infliximab concentrations and disease activity. RESULTS: The mean CDAI score, which decreased 1.05 points between infusions, did not correlate with the mean change in trough infliximab concentration (+0.39 µg/mL; r = 0.099, P = 0.083), but was associated with the mean change in CRP concentration (r = 0.19, P < 0.001). Trough infliximab concentrations below 2.8-4.6 µg/mL best predicted a ≥ 70 point increase in the CDAI between infusions, and those below 2.7-2.8 µg/mL best predicted CRP >5 mg/mL at the second infusion. ATI at either visit decreased the proportion of patients with therapeutic infliximab trough levels compared with patients who were ATI negative (17.5% vs. 77.3% at visit 1 and 13.8% vs. 75.6% at visit 3; P < 0.001 for both comparisons). CONCLUSIONS: This prospective study confirms the relationship between trough infliximab concentrations, inflammation and antibodies-to-infliximab. Infliximab trough concentrations below 3 µg/mL may increase the likelihood of symptoms and inflammation (ClinicalTrials.gov identifier: NCT00676988).

Sci-Fri AM: Imaging - 04: SPECT-based functional lung imaging in the prediction of radiation pneumonitis: A retrospective clinical and dosimetric correlation.

PURPOSE: To investigate whether functionally-weighted dose-volume histogram (DVH) parameters are more predictive of radiation-induced pneumonitis (RP) than standard parameters such as V20 and mean lung dose (MLD). MATERIALS AND METHODS: A retrospective chart review identified 26 patients who received curative-intent radiation therapy for primary carcinoma of the lung. Prior to treatment, all patients received single photon emission computed tomography (SPECT) to assess both lung ventilation and lung perfusion. Patients were assessed for clinical RP using standard criteria and were separated into a non-RP group (RP grade < 2) and an RP-group (RP grade ≥ 2). Standard DVH parameters (V10, V20, V30, MLD) and their function-weighted counterparts (for perfusion: pF10, pF20, pF30, pMLD; for ventilation: vF10, vF20, vF30, vMLD) were evaluated for each group. Receiver operating characteristics (ROC) curves were created and the area under the curve (AUC) computed. RESULTS: 7 of 26 patients had grade ≥ 2 pneumonitis. Both pF20 (p=0.022) and vF20 (p=0.036) were significantly different between the 2 groups; V20 was not (p=0.06). Both pF30 (p=0.008) and vF30 (p=0.025) were significantly different between groups while V30 failed to reach significance (p=0.072). Standard MLD (p=0.011), pMLD (p=0.001), and vMLD (p=0.011) were all significantly different. The ROC curves indicated that both the perfusion-weighted parameters and the ventilation-weighted parameters outperformed the standard DVH parameters as predictors of RP grade ≥2. CONCLUSIONS: SPECT-based, function-weighted DVH parameters appear to be useful as predictors of RP.

ABC transporters influence sensitivity of Brugia malayi to moxidectin and have potential roles in drug resistance.

Some ABC transporters play a significant role in human health and illness because they confer multidrug resistance (MDR) through their overexpression. Compounds that inhibit the drug efflux mechanism can improve efficacy or reverse resistance. Of the eight described ABC transporter subfamilies, those proteins conferring MDR in humans are in subfamilies A, B, C, and G. In nematodes, transporters in subfamilies B and C are suggested to confer resistance to ivermectin. The Brugia malayi ABC transporter superfamily was examined to assess their potential to influence sensitivity to moxidectin. There was an increase in expression of ABC transporters in subfamilies A, B, C, and G following treatment. Co-administration of moxidectin with inhibitors of ABC transporter function did not enhance sensitivity to moxidectin in males; however, sensitivity was significantly enhanced in females and microfilariae. The work suggests that ABC transporters influence sensitivity to moxidectin and have a potential role in drug resistance.

What are the factors that predict outcome at relapse after previous esophagectomy and adjuvant therapy in high-risk esophageal cancer?

OBJECTIVES: The present study investigated factors affecting outcome at relapse after previous surgery and adjuvant chemoradiation (crt) in high-risk esophageal cancer patients. PATIENTS AND METHODS: From 1989 to 1999, we followed high-risk resected esophageal cancer patients who had completed postoperative crt therapy. Patients who relapsed with a disease-free interval of less than 3 months were treated with palliative crt when appropriate. Patients with a disease-free interval of 3 months or more were treated with best supportive care. Post-recurrence survival was estimated using the Kaplan-Meier technique, and statistical comparisons were made using log-rank chi-square tests and Cox regression. RESULTS: Of the 69 patients treated with adjuvant crt after esophagectomy, 46 experienced recurrence. Median time to relapse was 28 months (range: 0.1-40 months). Among the 46 relapsed patients, median age was 61 years (range: 37-82 years), and 42 were men. At the initial staging, 44 of 46 were node-positive; 31 of 46 had adenocarcinoma. In 33 of 46, post-esophagectomy resection margins were clear. Median follow-up after recurrence was 30.5 months (range: 1.3-100 months). Median overall survival after recurrence was 5.8 months, and the 12-month, 24-month, and 36-month survival rates were 20%, 10%, and 5% respectively. Of the prognostic factors analyzed, only resection margin status and interval to recurrence were statistically significant for patient outcome in univariate and multivariate analysis. Patients who had positive resection margins and who relapsed 12 or fewer months after surgery and adjuvant crt had a median post-recurrence overall survival of 0.85 months as compared with 6.0 months in other patients (more than 12 months to relapse, or negative resection margins, or both; log-rank p = 0.003). CONCLUSIONS: Resection margin status and interval to disease relapse are significant independent prognostic factors for patient outcome after adjuvant crt therapy.

Inventory and analysis of ATP-binding cassette (ABC) systems in Brugia malayi.

ABC systems are one of the largest described protein superfamilies. These systems have a domain organization that may contain 1 or more transmembrane domains (ABC_TM1F) and 1 or 2 ATP-binding domains (ABC_2). The functions (e.g., import, export and DNA repair) of these proteins distinguish the 3 classes of ABC systems. Mining and PCR-based cloning were used to identify 33 putative ABC systems from the Brugia malayi genome. There were 31 class 2 genes, commonly called ABC transporters, and 2 class 3 genes. The ABC transporters were divided into subfamilies. Three belonged to subfamily A, 16 to subfamily B, 5 to subfamily C, 1 to subfamily E and 3 to subfamilies F and G, respectively. None were placed in subfamilies D and H. Similar to other ABC systems, the ABC_2 domain of B. malayi genes was conserved and contained the Walker A and B motifs, the signature sequence/linker region and the switch region with the conserved histidine. The ABC_TM1F domain was less conserved. The relative abundance of ABC systems was quantified using real-time reverse transcription PCR and was significantly higher in female adults of B. malayi than in males and microfilaria, particularly those in subfamilies B and C, which are associated with drug resistance.

Brugia malayi: in vitro effects of ivermectin and moxidectin on adults and microfilariae.

The effect of ivermectin and moxidectin on the motility of Brugia malayi adults and microfilariae and on the fertility of B. malayi females was examined. Motility was reduced in adults after exposure to both drugs and worms were non-motile and dead within eight days. The motility of microfilariae was significantly reduced at all drug concentrations and ceased at concentrations of 2500 and 5000mug/mL. The motility of microfilariae released by females was reduced after exposure to both drugs, however ivermectin had a greater effect at concentrations between 170 and 5000mug/mL. Both drugs reduced the number of microfilariae released by females and within four days their release was inhibited. The presence of the bacterial endosymbiont Wolbachia was examined in adults and microfilariae after exposure to increasing concentrations of ivermectin and moxidectin. A decrease in wsp expression was correlated with increasing drug concentration.

Postoperative extended-volume external-beam radiation therapy in high-risk esophageal cancer patients: a prospective experience.

BACKGROUND AND PURPOSE: Extended-volume external-beam radiation therapy (RT) following esophagectomy is controversial. The present prospective study evaluates the feasibility of extended-volume RT treatment in high-risk esophagectomy patients with a cervical anastomosis receiving postoperative combined chemoradiation therapy. PATIENTS AND METHODS: From 2001 to 2006, 15 patients with resected esophageal cancer were prospectively accrued to this pilot study to evaluate the adverse effects of extended-volume RT. Postoperative management was carried out at London Regional Cancer Program. Eligibility criteria were pathology-proven esophageal malignancy (T3-4, N0-1), disease amenable to surgical resection, and esophagectomy with or without resection margin involvement. Patients with distant metastases (M1) and patients treated with previous RT were excluded. All 15 study patients received 4 cycles of 5-fluorouracil-based chemotherapy. External-beam RT was conducted using conformal computed tomography planning, with multi-field arrangement tailored to the pathology findings, with coverage of a clinical target volume encompassing the primary tumour bed and the anastomotic site in the neck. The radiation therapy dose was 50.40 Gy at 1.8 Gy per fraction. The RT was delivered concurrently with the third cycle of chemotherapy. The study outcomes-disease-free survival (DFS) and overall survival (OS)-were calculated by the Kaplan-Meier method. Treatment-related toxicities were assessed using the U.S. National Cancer Institute's Common Toxicity Criteria. RESULTS: The study accrued 10 men and 5 women of median age 64 years (range: 48-80 years) and TNM stages T3N0 (n = 1), T2N1 (n = 2), T3N1 (n = 11), and T4N1 (n = 1). Histopathology included 5 adenocarcinomas and 10 squamous-cell carcinomas. Resection margins were clear in 10 patients. The median follow-up time was 19 months (range: 3.5-53.4 months). Before radiation therapy commenced, delay in chemotherapy occurred in 20% of patients, and dose reduction was required in 13.3%. During the concurrent chemoradiation therapy phase, 20% of the patients experienced chemotherapy delay, and 6.6% experienced dose reduction. No patient experienced treatment-related acute and chronic esophagitis above grade 2. Disease recurred in 40% of the patients (6/15), and median time to relapse was 24 months. No tumour recurred at the anastomotic site. The median DFS was 23 months, and the median OS was 21 months. CONCLUSIONS: Extended-volume external-beam RT encompassing the tumour bed and the anastomotic site is feasible and safe for high-risk T3-4, N0-1 esophageal cancer patients after esophagectomy.

The dose-volume interaction in adult supratentorial low-grade glioma: higher radiation dose is beneficial among patients with partial resection.

PURPOSE: To evaluate the hypothesis that adults with partially resected (PR<50% resection) supratentorial low-grade glioma (LGG) benefit from higher doses of radiation. METHODS: Patients receiving post-operative radiation for WHO grade I-II LGG at the University of Western Ontario between 1979 and 2001 were studied. Patient characteristics evaluated included: age, gender, symptom duration>30 days, seizures at presentation, Karnofsky performance status (KPS)<70, astrocytoma pathology (AS), and radiation dose. A Cox proportional hazard regression model was constructed to test the influence of radiation dose. RESULTS: One hundred and seven patients were analyzed. Patients who had PR were not significantly different from those with STR (subtotal/total resection) in terms of patient characteristics. Median survival (MST) of PR patients who received50 Gy had a MST of 109.2 months. The interaction of radiation dose and extent of resection was tested after controlling for other patient factors by Cox regression model. The interaction was highly significant for both OS and PFS (P=0.013 and P=0.003, respectively). This model remained significant after excluding six patients receiving doses<42 Gy (OS, P=0.024, and PFS, P=0.001). CONCLUSIONS: The outcome for patients with LGG is dependent on extent of tumor resection and radiation dose. Patients with PR should be considered for higher radiation dose schedules (>50 Gy). Future trials on therapeutic strategies for LGG should consider stratification of patients by extent of tumor resection. Our data suggests that one dose does not fit all.

Early outcomes of coronary artery bypass with and without cardiopulmonary bypass in octogenarians.

BACKGROUND: Off-pump coronary artery bypass (OPCAB) surgery has been successfully used in diverse patient populations and has been postulated to be safer than conventional coronary artery bypass (CCAB) surgery in some high-risk patients, including the elderly. OBJECTIVE: To compare the safety of OPCAB surgery versus CCAB surgery in the octogenarian population of two large southwestern Ontario cardiac surgical units. RESULTS: Two hundred thirty-six consecutive octogenarians underwent primary isolated coronary artery bypass surgery from November 2000 to March 2005. Patients undergoing OPCAB surgery tended to have higher Parsonnet scores, while patients undergoing CCAB surgery had a greater number of emergent operations. The Canadian Cardiovascular Network predicted that mortality risk was similar in both groups. In-hospital mortality was similar between groups, as was postoperative myocardial infarction and new onset of renal dysfunction. However, in the OPCAB group, there was a decreased incidence of postoperative neurological dysfunction (2.3% in the OPCAB group versus 10.5% in the CCAB group, P=0.01), in particular cerebrovascular accidents (1.5% in the OPCAB group versus 7.6% in the CCAB group, P=0.05), and a decreased incidence of prolonged intubation (5.3% in the OPCAB group versus 13.3% in the CCAB group, P=0.04). Multivariable analysis found that cardiopulmonary bypass had no significant impact on mortality or length of stay. CONCLUSIONS: In octogenarian patients, OPCAB surgery is as safe as CCAB surgery in terms of mortality and major morbidity. Furthermore, a significant reduction in neurological dysfunction and prolonged intubation was seen in the OPCAB group compared with the CCAB group.

Assessing the prognostic significance of transrectal ultrasound extracapsular extension in prostate cancer.

AIMS: To determine the prognostic value of transrectal ultrasound (TRUS)-detected extraprostatic disease for prostate cancer in patients receiving radical external-beam radiation therapy (EBRT). MATERIALS AND METHODS: A chart review of 181 patients treated with radical EBRT for prostate cancer was conducted. All patients underwent TRUS assessment by one radiologist. The median radiation dose delivered to the prostate was 66 Gy (range 53-70 Gy) in 33 fractions (range 20-39 fractions). Median follow-up time for all patients was 6.5 years. Sixty-four (35%) out of 181 patients were found to have extracapsular disease on TRUS. Clinical relapse was defined as the first occurrence of either salvage hormonal therapy administration by the treating oncologist or clinical, radiological, and/or pathologic evidence of recurrent or progressive disease. In terms of biochemical failure, two prognostic variable analyses were carried out using both the American Society for Therapeutic Radiology and Oncology (ASTRO) consensus guidelines and the Houston definition of biochemical failure. The primary end point for the prognostic variable analyses was time to first clinical or biochemical failure (CBF). RESULTS: For time to CBF using the ASTRO consensus guidelines for biochemical failure, univariable analysis revealed that the prostate-specific antigen (PSA) (P = 0.018), clinical T stage (P = 0.002), Gleason score (P = 0.021), adjuvant hormonal therapy (P = 0.032) and TRUS T staging (P = 0.0001) were statistically significant prognostic factors. On multivariable analysis, clinical T stage (P = 0.051) was of borderline statistical significance, whereas PSA (P = 0.036), TRUS T stage (P = 0.0002) and adjuvant hormonal therapy (P = 0.015) were found to be independent prognostic factors. For time to CBF using the Houston definition of biochemical failure, univariable analysis revealed that PSA (P = 0.001), Gleason score (P = 0.026) and prostate volume (P = 0.013) were statistically significant prognostic factors. On multivariable analysis, PSA (P = 0.002), Gleason score (P = 0.012), and adjuvant hormonal therapy (P = 0.041) were found to be independent prognostic factors. TRUS T staging was not found to be independently significant. CONCLUSIONS: A clear role for TRUS staging as an independent prognostic factor, in the setting of other more established variables, such as Gleason grade, PSA, and digital rectal examination (DRE) T stage, was not confirmed in this study, population.

Timing of ball release in overarm throws affects ball speed in unskilled but not skilled individuals.

We tested the hypothesis that variability in the timing of ball release in overarm throws affects ball speed. Nine unskilled and six skilled throwers made 30 throws fast and accurately from a sitting and standing position. Angular positions of finger and arm segments were recorded with search-coils at 1000 Hz; ball speed was measured with a radar gun. The time of ball release from the fingertips was measured with respect to seven arm kinematic reference points. Mean timing windows for ball release were 28 ms for unskilled throwers and 7 ms for skilled throwers. Mixed-model analyses of variance showed that a there was a statistically significant relationship between ball speed and the timing of ball release in unskilled throwers, but not in skilled throwers. This was presumably due to the difference in variability of the timing of ball release between the two groups. In contrast, skilled throwers showed a relationship between ball speed and peak forearm angular velocity (one measure of arm speed). We conclude that although variability in the timing of ball release can affect ball speed, this is only a major factor in unskilled throwers. When skilled throwers throw fast, variability in ball speed is due to variability in arm speed.

The stability of utility scores: test-retest reliability and the interpretation of utility scores in elective total hip arthroplasty.

PURPOSES: Are utility scores for hypothetical health states stable over time even when the health of the patient changes dramatically? Can investigators who use scores for hypothetical states be confident about the stability of those scores? The first purpose is to assess the stability of standard gamble utility scores for three hypothetical health states describing mild, moderate, and severe osteoarthritis (OA) (test-retest reliability). How should investigators interpret utility scores? The second purpose is to provide evidence on the marker-state approach to assist in interpreting utility scores. BACKGROUND: SG scores for three hypothetical marker states and the patient's current state were obtained at multiple times in a longitudinal study of elective total hip arthroplasty (THA). SG scores for current health increased from a mean of 0.59 pre-surgery to 0.76 post-surgery. METHODS: Test-retest reliability was assessed using the intra-class correlation coefficient (ICC). The effects of time on scores were analysed using an analysis of covariance. RESULTS: At the group level the marker-state scores were stable. Mean scores for mild, moderate, and severe OA were 0.69, 0.61, and 0.41. With respect to test-retest reliability, ICCs varied from 0.49 to 0.62. In general, time did not affect the scores for the three marker states. CONCLUSIONS: Group-level standard gamble scores are stable. At the individual level scores for hypothetical health states are somewhat stable over time. The marker states assist in interpretation indicating that, on average, THA converted moderate OA to better than mild.