TSG-6 - a double-edged sword for osteoarthritis (OA).

PURPOSE: To explore mechanisms underlying the association of TSG-6 with osteoarthritis (OA) progression. METHODS: TSG-6-mediated heavy chain (HC) transfer (TSG-6 activity) and its association with inflammatory mediators were quantified in knee OA (n=25) synovial fluids (SFs). Paired intact and damaged cartilages from the same individuals (20 tibial and 12 meniscal) were analyzed by qRT-PCR and immunohistochemistry (IHC) for gene and protein expression of TSG-6 and components of Inter-alpha-Inhibitor (IαI) and TSG-6 activity ± spiked in IαI. Primary chondrocyte cultures (n=5) ± IL1ß or TNFα were evaluated for gene expression. The effects of TSG-6 activity on cartilage extracellular matrix (ECM) assembly were explored using quantitative hyaluronan (HA)-aggrecan binding assays. RESULTS: TSG-6 activity was significantly associated (R > 0.683, P < 0.0002) with inflammatory mediators including TIMP-1, A2M, MMP3, VEGF, VCAM-1, ICAM-1 and IL-6. Although TSG-6 protein and mRNA were highly expressed in damaged articular and meniscal cartilage and cytokine-treated chondrocytes, there was little or no cartilage expression of components of the IαI complex (containing HC1). By IHC, TSG-6 was present throughout lesioned cartilage but HC1 only at lesioned surfaces. TSG-6 impaired HA-aggrecan assembly, but TSG-6 mediated HA-HC formation reduced this negative effect. CONCLUSIONS: TSG-6 activity is a global inflammatory biomarker in knee OA SF. IαI, supplied from outside cartilage, only penetrates the cartilage surface, restricting TSG-6 activity (HC transfer) to this region. Therefore, unopposed TSG-6 in intermediate and deep regions of OA cartilage could possibly block matrix assembly, leading to futile synthesis and account for increased risk of OA progression.

The association of pre-operative body pain diagram scores with pain outcomes following total knee arthroplasty.

OBJECTIVE: Approximately 20% of total knee arthroplasty (TKA) recipients have suboptimal pain relief. We evaluated the association between pre-surgical widespread body pain and incomplete pain relief following TKA. METHOD: This prospective analysis included 241 patients with knee osteoarthritis (OA) undergoing unilateral TKA who completed questionnaires preoperatively and up to 12 months post-operatively. Questionnaires included the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain scale and a body pain diagram. We derived the number of non-index painful body regions from the diagram. We used Poisson regression to determine the association between painful body regions identified preoperatively and both WOMAC pain at follow-up and improvement in pain as defined by the minimal clinically important difference (MCID). RESULTS: Mean subject age was 66 years (SD 9), and 61% were females. Adjusting for age, sex, co-morbid conditions, baseline pain, pain catastrophizing, and mental health, we found that more widespread body pain was associated with a higher likelihood of reporting 12-month WOMAC pain score >15 (relative risk [RR] per painful body region 1.39, 95% CI 1.18-1.63) and a greater likelihood of failing to achieve the MCID (RR 1.47, 95% CI 1.16-1.86).). Pain catastrophizing was an independent predictor of persistent pain and failure to improve by the MCID (RR 3.57, 95% CI 1.73-7.31). CONCLUSIONS: Pre-operative widespread pain was associated with greater pain at 12-months and failure to reach the MCID. Widespread pain as captured by the pain diagram, along with the pain catastrophizing score, may help identify persons with suboptimal TKA outcome.

Hyaluronan molecular weight distribution is associated with the risk of knee osteoarthritis progression.

OBJECTIVE: We investigated the relationship between the molecular weight (MW) distribution of hyaluronan (HA) in synovial fluid (SF) and risk of knee osteoarthritis (OA) progression. METHODS: HA MW was analyzed for 65 baseline knee SFs. At 3-year follow-up, knees were scored for change in joint space narrowing (JSN), osteophyte (OST) progression, or occurrence of total knee arthroplasty (TKA). HA MW distribution was analyzed using agarose gel electrophoresis (AGE), and its relationship to OA progression was evaluated using logistic regression. The association between HA MW and self-reported baseline knee pain was analyzed using Pearson's correlation coefficients. RESULTS: Knee OA was categorized as non-progressing (OST-/JSN-, 26 knees, 40%), or progressing based on OST (OST+/JSN-, 24 knees, 37%), OST and JSN (OST+/JSN+, 7 knees, 11%) or total knee arthroplasty (TKA, 8 knees, 12%). The MW distribution of HA in baseline SFs was significantly associated with the odds of OA progression, particularly for index knees. After adjusting for age, gender, BMI, baseline X-ray grade and pain, each increase of one percentage point in %HA below 1 million significantly increased the odds of JSN (odds ratios (OR) = 1.45, 95% CI 1.02-2.07), TKA or JSN (OR = 1.24, 95%CI 1.01-1.53) and the odds of any progression (OR = 1.16, 95% CI 1.01-1.32). HA MW distribution significantly correlated with pain. CONCLUSION: These data suggest that the odds of knee OA progression increases as HA MW distribution shifts lower and highlight the value of reporting MW distribution rather than just average MW values for HA.

TSG-6 activity as a novel biomarker of progression in knee osteoarthritis.

OBJECTIVE: To establish whether there is an association between TSG-6 activity and osteoarthritis progression. DESIGN: TSG-6 activity was determined in 132 synovial fluids from patients with OA of the knee, using a novel quantitative TSG-6 activity assay. The association between TSG-6 activities at baseline and four distinct disease progression states, determined at 3-year follow-up, was analyzed using logistic regression. RESULTS: There was a statistically significant relationship between TSG-6 activity at baseline and all OA progression states over a 3-year period. Patient knees with TSG-6 activities in the top tenth percentile, compared to the median activity, had an odds ratio (OR) of at least 7.86 (confidence interval (CI) [3.2, 20.5]) for total knee arthroplasty (TKA) within 3 years, and of at least 5.20 (CI [1.8, 13.9]) after adjustment for confounding factors. Receiver operating characteristic (ROC) analysis for knee arthroplasty yielded a cut-off point of 13.3 TSG-6 activity units/ml with the following parameters: area under the curve 0.90 (CI [0.804, 0.996]), sensitivity 0.91 (CI [0.59, 0.99]), specificity 0.82 (CI [0.74, 0.88]) and a negative predictive value (NPV) of 0.99 (CI [0.934, 0.994]). CONCLUSION: The TSG-6 activity is a promising independent biomarker for OA progression. Given the high NPV, this assay may be particularly suitable for identifying patients at low risk of rapid disease progression and to assist in the timing of arthroplasty.

Does ultrasound guidance improve the outcomes of arthrocentesis and corticosteroid injection of the knee?

OBJECTIVE: The present randomized controlled trial compared arthrocentesis of the effusive knee followed by corticosteroid injection performed by the conventional anatomic landmark palpation-guided technique to the same procedure performed with ultrasound (US) needle guidance. METHODS: Sixty-four palpably effusive knees were randomized to (i) palpation-guided arthrocentesis with a conventional 20-mL syringe (22 knees), (ii) US-guided arthrocentesis with a 25-mL reciprocating procedure device (RPD) mechanical aspirating syringe (22 knees), or (iii) US-guided arthrocentesis with a 60-mL automatic aspirating syringe (20 knees). The one-needle two-syringe technique was used. Outcome measures included patient pain by the Visual Analogue Scale (VAS) for pain (0-10 cm), the proportion of diagnostic samples, synovial fluid volume yield, complications, and therapeutic outcome at 2 weeks. RESULTS: Sonographic guidance resulted in 48% less procedural pan (VAS; palpation-guided: 5.8 ± 3.0 cm, US-guided: 3.0 ± 2.8 cm, p < 0.001), 183% increased aspirated synovial fluid volumes (palpation-guided: 12 ± 10 mL, US-guided: 34 ± 25 mL, p < 0.0001), and improved outcomes at 2 weeks (VAS; palpation-guided: 2.8 ± 2.4 cm, US-guided: 1.5 ± 1.9 cm, p = 0.034). Outcomes of sonographic guidance with the mechanical syringe and automatic syringe were comparable in all outcome measures. CONCLUSIONS: US-guided arthrocentesis and injection of the knee are superior to anatomic landmark palpation-guided arthrocentesis, resulting in significantly less procedural pain, improved arthrocentesis success, greater synovial fluid yield, more complete joint decompression, and improved clinical outcomes.

An integrated analysis of five double-blind, randomized controlled trials evaluating the safety and efficacy of a hyaluronan product for intra-articular injection in osteoarthritis of the knee.

OBJECTIVE: Five double-blind, randomized, saline-controlled trials (RCTs) were included in the United States marketing application for an intra-articular hyaluronan (IA-HA) product for the treatment of osteoarthritis (OA) of the knee. We report an integrated analysis of the primary Case Report Form (CRF) data from these trials. METHOD: Trials were similar in design, patient population and outcome measures - all included the Lequèsne Algofunctional Index (LI), a validated composite index of pain and function, evaluating treatment over 3 months. Individual patient data were pooled; a repeated measures analysis of covariance was performed in the intent-to-treat (ITT) population. Analyses utilized both fixed and random effects models. Safety data from the five RCTs were summarized. RESULTS: A total of 1155 patients with radiologically confirmed knee OA were enrolled: 619 received three or five IA-HA injections; 536 received "placebo" saline injections. In the active and control groups, mean ages were 61.8 and 61.4 years; 62.4% and 58.8% were women; baseline total Lequèsne scores 11.03 and 11.30, respectively. Integrated analysis of the pooled data set found a statistically significant reduction (P < 0.001) in total Lequèsne score with hyaluronan (HA) (-2.68) vs placebo (-2.00); estimated difference -0.68 (95% CI: -0.56 to -0.79), effect size 0.20. Additional modeling approaches confirmed robustness of the analyses. CONCLUSIONS: This integrated analysis demonstrates that multiple design factors influence the results of RCTs assessing efficacy of intra-articular (IA) therapies, and that integrated analyses based on primary data differ from meta-analyses using transformed data.

Alcohol, tobacco and breast cancer--collaborative reanalysis of individual data from 53 epidemiological studies, including 58,515 women with breast cancer and 95,067 women without the disease.

Alcohol and tobacco consumption are closely correlated and published results on their association with breast cancer have not always allowed adequately for confounding between these exposures. Over 80% of the relevant information worldwide on alcohol and tobacco consumption and breast cancer were collated, checked and analysed centrally. Analyses included 58,515 women with invasive breast cancer and 95,067 controls from 53 studies. Relative risks of breast cancer were estimated, after stratifying by study, age, parity and, where appropriate, women's age when their first child was born and consumption of alcohol and tobacco. The average consumption of alcohol reported by controls from developed countries was 6.0 g per day, i.e. about half a unit/drink of alcohol per day, and was greater in ever-smokers than never-smokers, (8.4 g per day and 5.0 g per day, respectively). Compared with women who reported drinking no alcohol, the relative risk of breast cancer was 1.32 (1.19-1.45, P<0.00001) for an intake of 35-44 g per day alcohol, and 1.46 (1.33-1.61, P<0.00001) for >/=45 g per day alcohol. The relative risk of breast cancer increased by 7.1% (95% CI 5.5-8.7%; P<0.00001) for each additional 10 g per day intake of alcohol, i.e. for each extra unit or drink of alcohol consumed on a daily basis. This increase was the same in ever-smokers and never-smokers (7.1% per 10 g per day, P<0.00001, in each group). By contrast, the relationship between smoking and breast cancer was substantially confounded by the effect of alcohol. When analyses were restricted to 22 255 women with breast cancer and 40 832 controls who reported drinking no alcohol, smoking was not associated with breast cancer (compared to never-smokers, relative risk for ever-smokers=1.03, 95% CI 0.98-1.07, and for current smokers=0.99, 0.92-1.05). The results for alcohol and for tobacco did not vary substantially across studies, study designs, or according to 15 personal characteristics of the women; nor were the findings materially confounded by any of these factors. If the observed relationship for alcohol is causal, these results suggest that about 4% of the breast cancers in developed countries are attributable to alcohol. In developing countries, where alcohol consumption among controls averaged only 0.4 g per day, alcohol would have a negligible effect on the incidence of breast cancer. In conclusion, smoking has little or no independent effect on the risk of developing breast cancer; the effect of alcohol on breast cancer needs to be interpreted in the context of its beneficial effects, in moderation, on cardiovascular disease and its harmful effects on cirrhosis and cancers of the mouth, larynx, oesophagus and liver.

A prospective, randomized, pragmatic, health outcomes trial evaluating the incorporation of hylan G-F 20 into the treatment paradigm for patients with knee osteoarthritis (Part 1 of 2): clinical results.

OBJECTIVE: First, to assess the clinical effectiveness of hylan G-F 20 in an appropriate care treatment regimen (as defined by the American College of Rheumatology (ACR) 1995 guidelines) as measured by validated disease-specific outcomes and health-related quality of life endpoints for patients with osteoarthritis (OA) of the knee. Second, to utilize the measures of effectiveness and costs in an economic evaluation (see accompanying manuscript). DESIGN: A total of 255 patients with OA of the knee were enrolled by rheumatologists or orthopedic surgeons into a prospective, randomized, open-label, 1-year, multi-centred trial, conducted in Canada. Patients were randomized to 'Appropriate care with hylan G-F 20' (AC+H) or 'Appropriate care without hylan G-F 20' (AC). Data were collected at clinic visits (baseline, 12 months) and by telephone (1, 2, 4, 6, 8, 10, and 12 months). RESULTS: The AC+H group was superior to the AC group for all primary (% reduction in mean Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain scale: 38% vs 13%,P =0.0001) and secondary effectiveness outcome measures. These differences were all statistically significant and exceeded the 20% difference between groups set a priori by the investigators as the minimum clinically important difference. Health-related quality of life improvements in the AC+H group were statistically superior for the WOMAC pain, stiffness and physical function (all P< 0.0001), the SF-36 aggregate physical component (P< 0.0001) and the Health Utilities Index Mark 3 (HUI3) overall health utility score (P< 0.0001). Safety (adverse events and patient global assessments of side effects) differences favoured the AC+H group. CONCLUSION: The data presented here indicate that the provision to patients with knee OA of viscosupplementation with hylan G-F 20 within an appropriate care treatment regimen provides benefits in the knee, overall health and health related quality of life at reduced levels of co-therapy and systemic adverse reactions.

A prospective, randomized, pragmatic, health outcomes trial evaluating the incorporation of hylan G-F 20 into the treatment paradigm for patients with knee osteoarthritis (Part 2 of 2): economic results.

OBJECTIVE: Viscosupplementation with hylan G-F 20 has recently become registered for treatment of patients with osteoarthritis (OA) of the knee in most parts of the world. The cost effectiveness and cost utility of this new therapeutic modality were determined as part of a Canadian prospective, randomized, 1-year, open-label, multicentered trial. DESIGN: A total of 255 patients were randomized to 'Appropriate care with hylan G-F 20' (AC+H) or 'Appropriate care without hylan G-F 20' (AC). Costs (1999 Canadian dollars) were collected from the societal viewpoint and included all costs related to OA of the knee and OA in all joints. Patients completed a number of outcomes questionnaires including the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and the Health Utilities Index Mark 3 (HUI3). Data were collected at clinic visits (baseline, 12 months) and by telephone (1, 2, 4, 6, 8, 10, and 12 months). RESULTS: The AC+H group over the year had higher costs ($2125-$1415=$710, P< 0.05), more patients improved (69%-40%=29%,P =0.0001), greater increases in HUI3 (0.13-0.03=0.10, P< 0.0001) and increased quality-adjusted life years (QALYs) (0.071, P< 0.05). The incremental cost-effectiveness ratio was $2505/patient improved. The incremental cost-utility ratio was $10000/QALY gained. Sensitivity analyses and a second cost perspective gave similar results. CONCLUSION: The cost-utility ratio is below the suggested Canadian adoption threshold. The results provide strong evidence for adoption of treatment with hylan G-F 20 in the patients and settings studied in the trial.

Cohort cancer incidence among pulp and paper mill workers in British Columbia.

OBJECTIVES: A study was conducted to investigate cancer risks in a cohort of pulp and paper workers. METHODS: All male workers with > or =1 years of employment in 14 pulp and paper mills in 1950-1992 were studied. Standardized incidence ratios (SIR) were used to compare the cancer incidence of the cohort with that of the Canadian male population. Record linkage with the National Cancer Registry was performed using the generalized iterative record linkage method. RESULTS: Altogether 1756 cancer cases were observed in the entire cohort. For > or =15 years of work, the entire cohort had significantly increased SIR values for pleural and prostate cancer and skin melanoma; there was also a significantly increased risk for skin melanoma among workers in the kraft process only, rectal cancer among workers in the sulfite process only, and stomach and prostate cancer and all leukemias combined among workers in both the kraft and sulfite processes. A separate analysis comparing workers in pulping and papermaking with those in the pulping process only did not reveal any difference in cancer risk and hence did not modify the results. The SIR values for skin melanoma were not significantly increased in a comparison using the British Columbia male population. Nine of 10 pleural cancers were mesotheliomas, which likely reflect past asbestos exposure. CONCLUSIONS: The results suggest that long-term work in the pulp and paper industry is associated with excess risks of prostate and stomach cancers and all leukemias for work in both kraft and sulfite processes and of rectal cancer for work in the sulfite process only.

First analysis of cancer incidence and occupational radiation exposure based on the National Dose Registry of Canada.

A cohort study was conducted to investigate the relation between cancer incidence and occupational exposure to ionizing radiation. Records containing dose information from 1951 to 1988 for 191,333 persons were extracted from the National Dose Registry of Canada. The records were linked to the Canadian Cancer Data Base, with incidence data from 1969 to 1988. Standardized incidence ratios were calculated using Canadian cancer incidence rates stratified by age, sex, and calendar year. Excess relative risks were obtained from internally based dose-response analyses. The following significant results were found for males and females combined: a deficit in the standardized incidence ratio for all cancers combined; elevated standardized incidence ratios for thyroid cancer and melanoma; and elevated excess relative risks for rectum, leukemia, lung, all cancers combined, all except lung, and all except leukemia. For males, cancers of the colon, pancreas, and testis also showed significantly elevated excess relative risks. The specific cancer types listed above have been implicated in previous studies on occupational exposure to ionizing radiation, except for testis, colon, and melanoma, while the findings on thyroid cancer from previous studies are inconclusive. The thyroid standardized incidence ratios in this study are highly significant, but further investigation is needed to assess the possibility of association with occupational radiation exposure.

Visualizing the function computed by a feedforward neural network.

A method for visualizing the function computed by a feedforward neural network is presented. It is most suitable for models with continuous inputs and a small number of outputs, where the output function is reasonably smooth, as in regression and probabilistic classification tasks. The visualization makes readily apparent the effects of each input and the way in which the functions deviate from a linear function. The visualization can also assist in identifying interactions in the fitted model. The method uses only the input-output relationship and thus can be applied to any predictive statistical model, including bagged and committee models, which are otherwise difficult to interpret. The visualization method is demonstrated on a neural network model of how the risk of lung cancer is affected by smoking and drinking.

Identification of occupational cancer risks in British Columbia. A population-based case-control study of 995 incident breast cancer cases by menopausal status, controlling for confounding factors.

Lifetime occupational histories as well as information on known and suspected breast cancer risk factors were collected by means of a self-administered questionnaire from 1018 women with incident breast cancer ascertained from the British Columbia Cancer Registry, and from 1020 population controls. A matched case-control study design was used. Conditional logistic regression for matched sets data and the likelihood ratio were used in a two-step procedure and were performed separately for pre-menopausal women, post-menopausal women, and for all cases combined. Excess risk was noted for several white-collar occupations. Significantly increased risk was observed: (1) among pre-menopausal women: in electronic data-processing operators; barbers and hairdressers; in sales and material processing occupations; and in the food, clothing, chemical and transportation industries; (2) among post-menopausal women: in schoolteaching; in medicine, health, and nursing occupations; in laundry and dry-cleaning occupations; and in the aircraft and automotive, including gasoline service station, industries. Several significant associations were also seen in the combined group of pre- and post-menopausal women, particularly in crop farmers and in the fruit and vegetable, publishing and printing, and motor vehicle repair industries. The results of this study suggest excess breast cancer risk in a number of occupations and industries, notably those that entail exposure to solvents and pesticides.

Local tumor recurrence or emergence of a new primary lesion? A molecular analysis.

The distinction between a new primary oral tumor and recurrence may bear significant prognostic implications. Currently, this differentiation relies mainly on tumor location: when both lesions are at or near the same site, the new one is regarded as a recurrence; when the two are at different sites, the second lesion is regarded as a new primary. Recent investigations using molecular analysis have demonstrated that some oral squamous cell carcinomas (SCC) arising from different sites show the same clonogenical changes. In this case report, we studied the clonality of three SCC (one primary, two apparent recurrences) from the right lateral tongue of a young, non-smoking woman by using microsatellite analysis for loss of heterozygosity. The results showed that while the first two tumors were clonogenically similar, the third tumor was clonogenically different and was consistent with the development of a new primary. This result indicates that location of tumors alone is not always reliable in determining whether a new tumor is a recurrence or a new primary lesion.

Identification of occupational cancer risks in British Columbia. Part I: Methodology, descriptive results, and analysis of cancer risks, by cigarette smoking categories of 15,463 incident cancer cases.

To identify occupational cancer risk factors, lifetime occupational, smoking, and alcohol-consumption histories were collected by means of a self-administered questionnaire from 15,463 male cancer patients aged 20 years and over as ascertained from the British Columbia population-based cancer registry; all cases were histologically confirmed. The study methodology, descriptive results, and cancer risks from cigarette smoking are reported. Assessment of questionnaire validation and reliability showed very high correlations between all variables analysed. Non-response bias, assessed among 221 non-responders and 432 matched controls, revealed no statistically significant differences for smoking status, education, or for 11 usual (longest-held job) occupational groups, except for managerial occupations and for four pooled groups that represented 6.7% of all occupations. Except for pancreatic cancer, a significant relationship was found for all cancer sites known to be strongly associated with cigarette smoking.

Identification of occupational cancer risks in British Columbia. Part II: A population-based case-control study of 1516 Prostatic cancer cases.

We have, as part of a program aimed at detecting occupational risk factors in British Columbia, collected lifetime occupational histories from 15,643 incident cancer cases, of whom 1519 had a diagnosis of prostate cancer. Occupational risks for this cancer site are examined using this large data set, and the results are presented in this report.

Occupational risk factors for prostate cancer mortality in British Columbia, Canada.

BACKGROUND: Although prostate cancer is the most common life-threatening cancer among males in North America, relatively little is known about its etiology. We have conducted a proportional mortality study to generate hypotheses concerning occupational risk factors for the disease. METHODS: Age standardized proportional mortality ratios (PMR) for prostate cancer were calculated for a total of 216 occupations and 88 industries. Separate calculations were done for all male deaths age 20 and up and for deaths that occurred during men's working lifetime (age 20-65). RESULTS: Elevated mortality from prostate cancer was seen among business owners and managers (PMR = 110; 95% CI = 101-118), brokers (PMR = 184; 95% CI = 122-266), farmers and farm managers (PMR = 112; 95% CI = 105-120), and school teachers (PMR = 133; 95% CI = 101-174). Evaluation by industry shows elevated prostate cancer mortality in agriculture (PMR = 110; 95% CI = 103-118), financial institutions (PMR = 138, 95% CI = 112-170), and transportation equipment manufacture (PMR = 136; 95% CI = 109-168). CONCLUSIONS: The findings suggest that workers in a number of occupations have elevated risks of prostate cancer including farmers and teachers. More detailed cohort and case-control studies, evaluating specific exposures are required before primary prevention programs in the workplace are feasible.

Long term disability rates in a cohort of Air Canada pilots.

Causes of long term disability (LTD) were collected between January 1, 1981 and December 31, 1990 among all active pilots in a cohort of Air Canada pilots. During this 10-yr period, 474 (20.9%) of the 2271 pilots had LTD; there were 1107 cases of LTD corresponding to a total duration of leave of absence of 4161 mo. Frequencies of the main diagnostic categories were: injuries: 249 (22.5%); mental disorders: 175 (15.8%); circulatory system: 157 (14.2%); digestive system: 128 (11.6%); and musculoskeletal system: 121 (10.9%). LTD rates increased with age, ranging from 1.86-9.22 per 1000 pilots per year from the younger (20-29 yr) to the older age group (50-59 yr), respectively. Several causes of LTD could be potentially preventable, in particular injuries which accounted for 63.6% of all causes in the younger age group and remained a significant condition at subsequent ages.