Trajectories of body mass index from early adulthood to late midlife and incidence of total knee arthroplasty for osteoarthritis: findings from a prospective cohort study.

OBJECTIVE: To examine the association between body mass index (BMI) trajectories from early adulthood to late midlife and risk of total knee arthroplasty (TKA) for osteoarthritis. METHODS: 24,368 participants from the Melbourne Collaborative Cohort Study with weight collected during 1990-1994, 1995-1998, and 2003-2007, recalled weight at age 18-21 years, and height measured during 1990-1994 were included. Incident TKA from 2003 to 2007 to December 2018 was determined by linking cohort records to the National Joint Replacement Registry. RESULTS: Using group-based trajectory modelling, six distinct trajectories (TR) of BMI from early adulthood (age 18-21 years) to late midlife (approximately 62 years) were identified: lower normal to normal BMI (TR1; 19.7% population), normal BMI to borderline overweight (TR2; 36.7%), normal BMI to overweight (TR3; 26.8%), overweight to borderline obese (TR4; 3.5%), normal BMI to class 1 obesity (TR5; 10.1%), overweight to class 2 obesity (TR6; 3.2%). Over 12.4 years, 1,328 (5.4%) had TKA. The hazard ratios for TKA increased in all TR compared to TR1 [from TR2: 2.03 (95% CI 1.64-2.52) to TR6: 8.59 (6.44-11.46)]. 28.4% of TKA could be prevented if individuals followed the trajectory one lower, an average weight reduction of 8-12 kg from early adulthood to late midlife, saving $AUS 373 million/year. Most reduction would occur in TR2 (population attributable fraction 37.9%, 95% CI 26.7-47.3%) and TR3 (26.8%, 20.0-31.2%). CONCLUSIONS: Prevention of weight gain from young adulthood to late midlife in order to reduce overweight/obesity has the potential to significantly reduce the cost and burden of TKA.

Crosswalks between the Oxford hip and knee scores and the HOOS-12 and KOOS-12 instruments.

OBJECTIVE: To develop and validate bi-directional crosswalks between the Oxford Hip Score (OHS) and HOOS-12 summary impact score, and between the Oxford Knee Score (OKS) and KOOS-12 summary impact score. METHODS: Data were sourced from the Australian Orthopaedic Association National Joint Replacement Registry Patient-Reported Outcome Measures Program. Patients undergoing primary joint replacement for osteoarthritis who completed the OHS and HOOS-12 or OKS and KOOS-12 instruments were included in the analysis. An equipercentile method was used to create four crosswalks, with the distribution of scores smoothed using log-linear models prior to equating. Crosswalk validity was assessed through comparison of actual vs derived scores, Pearson correlation coefficients, root mean square errors (RMSE) and Bland-Altman plots. RESULTS: Paired OHS/HOOS-12 data and paired OKS/KOOS-12 data were available for 4,513 patients undergoing total hip replacement and 5,942 patients undergoing total knee replacement, respectively. Minimal differences were observed between actual and crosswalk-derived mean scores (actual OHS 27.55 vs derived OHS 27.56; actual HOOS-12 53.28 vs derived HOOS-12 53.31; actual OKS 27.34 vs derived OKS 27.34; actual KOOS-12 50.51 vs derived KOOS-12 50.58). High correlation was observed between actual and derived scores (Pearson's r for hip-specific instruments: 0.943-0.946; Pearson's r for knee-specific instruments: 0.925-0.931). Plotted actual vs mean derived scores also indicated robust concordance across the breadth of the instrument scales. CONCLUSION: These crosswalks provide close approximations of actual OHS, OKS, HOOS-12 and KOOS-12 scores, as indicated by multiple validation metrics. They offer a resource for clinicians, researchers and arthroplasty registries to support PROMs score conversion and data harmonisation efforts.

Implications for research and clinical use from a Rasch analysis of the HOOS-12 and KOOS-12 instruments.

OBJECTIVE: To evaluate the structural validity of the 12-item Hip disability and Osteoarthritis Outcome Score (HOOS-12) and 12-item Knee injury and Osteoarthritis Outcome Score (KOOS-12) using Rasch analysis and consider psychometric implications for research and clinical use. METHOD: Individual-level HOOS-12 and KOOS-12 data from the Australian Orthopaedic Association National Joint Replacement Registry, collected before and after primary total hip and knee replacement, were used for this analysis. Using the Rasch analytic approach, overall model fit and item fit were examined, together with potential reasons for misfit including response threshold ordering, differential item functioning, internal consistency, unidimensionality and item targeting. RESULTS: Overall misfit to the Rasch model was evident for both instruments. A degree of item misfit was also observed, although most items demonstrated logical sequencing of response options. Only two items (hip/knee pain frequency and awareness of hip/knee problems) displayed disordered response thresholds. The pain, function, and quality of life domains of the HOOS-12 and KOOS-12 demonstrated excellent internal consistency reliability (person separation index: 0.80-0.93) and unidimensionality. A mismatch between item difficulty and person ability scores at the highest end of the HOOS-12 and KOOS-12 scales contributed to post-operative ceiling effects (mean logit for HOOS-12: 3.57; KOOS-12: 2.58; ≈0 indicates well-targeted scale). CONCLUSION: We found evidence to support the structural validity of the three HOOS-12 and KOOS-12 domains for evaluating joint replacement outcomes. However, there may be missing content in both instruments particularly for high-functioning patients. Minor refinement of some response options may be warranted to improve item performance.

Performance of the HOOS-12 and KOOS-12 instruments for evaluating outcomes from joint replacement surgery.

OBJECTIVE: To evaluate the psychometric properties of the 12-item Hip disability and Osteoarthritis Outcome Score (HOOS-12) and Knee injury and Osteoarthritis Outcome Score (KOOS-12) for use in evaluating outcomes after joint replacement for osteoarthritis. DESIGN: Patient-reported outcomes data collected by the Australian Orthopaedic Association National Joint Replacement Registry were used for this analysis. HOOS-12 and KOOS-12 domain (pain, function, quality of life) and summary impact data were available. The Oxford Hip Score (OHS), Oxford Knee Score (OKS) and EQ-5D-5L were used as comparators. Instruments were administered pre-operatively and at 6 months post-operatively. Internal consistency reliability, floor and ceiling effects, convergent validity, known groups validity, and responsiveness were evaluated using standard psychometric techniques. RESULTS: Baseline HOOS-12 and KOOS-12 data were available for 3,023 patients undergoing primary total hip replacement and 4,010 patients undergoing primary total knee replacement. At baseline, high internal consistency was demonstrated for all domains and summary scores (Cronbach's alpha: HOOS-12 = 0.81-0.93; KOOS-12 = 0.82-0.92). Post-operative ceiling effects (>15% of patients scoring the best possible score) were identified for the HOOS-12 pain (46%), function (39%) and quality of life domains (26%) and summary score (17%), and for the KOOS-12 pain (21%) and function domains (18%). The HOOS-12 and KOOS-12 could differentiate between two known groups (lowest/highest OHS or OKS quartiles post-operatively; p < 0.001) and were highly responsive to change (effect sizes for HOOS-12: 2.20-2.83; KOOS-12: 1.82-2.35). CONCLUSION: The HOOS-12 and KOOS-12 have good psychometric properties for capturing joint replacement outcomes including excellent responsiveness, although ceiling effects may limit monitoring of post-operative improvement.

Forecasting the future burden of opioids for osteoarthritis.

OBJECTIVE: To quantify the current national burden of opioids for osteoarthritis (OA) pain in Australia in terms of number of dispensed opioid prescriptions and associated costs, and to forecast the likely burden to the year 2030/31. DESIGN: Epidemiological modelling. METHODS: Published data were obtained on rates of opioid prescribing for people with OA and national OA prevalence projections. Trends in opioid dispensing from 2006 to 2016, and average costs for common opioid subtypes were obtained from the Pharmaceutical Benefits Scheme and Medicare Australia Statistics. Using these inputs, a model was developed to estimate the likely number of dispensed opioid prescriptions and costs to the public healthcare system by 2030/31. RESULTS: In 2015/16, an estimated 1.1 million opioid prescriptions were dispensed in Australia for 403,954 people with OA (of a total 2.2 million Australians with OA). Based on recent dispensing trends and OA prevalence projections, the number of dispensed opioid prescriptions is expected to nearly triple to 3,032,332 by 2030/31, for an estimated 562,610 people with OA. The estimated cost to the Australian healthcare system was $AUD25.2 million in 2015/16, rising to $AUD72.4 million by 2030/31. CONCLUSION: OA-related opioid dispensing and associated costs are set to increase substantially in Australia from 2015/16 to 2030/31. Use of opioids for OA pain is concerning given joint disease chronicity and the risk of adverse events, particularly among older people. These projections represent a conservative estimate of the full financial burden given additional costs associated with opioid-related harms and out-of-pocket costs borne by patients.

Prevalence of arthritis according to age, sex and socioeconomic status in six low and middle income countries: analysis of data from the World Health Organization study on global AGEing and adult health (SAGE) Wave 1.

BACKGROUND: In higher income countries, social disadvantage is associated with higher arthritis prevalence; however, less is known about arthritis prevalence or determinants in low to middle income countries (LMICs). We assessed arthritis prevalence by age and sex, and marital status and occupation, as two key parameters of socioeconomic position (SEP), using data from the World Health Organization Study on global AGEing and adult health (SAGE). METHODS: SAGE Wave 1 (2007-10) includes nationally-representative samples of older adults (≥50 yrs), plus smaller samples of adults aged 18-49 yrs., from China, Ghana, India, Mexico, Russia and South Africa (n = 44,747). Arthritis was defined by self-reported healthcare professional diagnosis, and a symptom-based algorithm. Marital status and education were self-reported. Arthritis prevalence data were extracted for each country by 10-year age strata, sex and SEP. Country-specific survey weightings were applied and weighted prevalences calculated. RESULTS: Self-reported (lifetime) diagnosed arthritis was reported by 5003 women and 2664 men (19.9% and 14.1%, respectively), whilst 1220 women and 594 men had current symptom-based arthritis (4.8% and 3.1%, respectively). For men, standardised arthritis rates were approximately two- to three-fold greater than for women. The highest rates were observed in Russia: 38% (95% CI 36%-39%) for men, and 17% (95% CI 14%-20%) for women. For both sexes and in all LMICs, arthritis was more prevalent among those with least education, and in separated/divorced/widowed women. CONCLUSIONS: High arthritis prevalence in LMICs is concerning and may worsen poverty by impacting the ability to work and fulfil community roles. These findings have implications for national efforts to prioritise arthritis prevention and management, and improve healthcare access in LMICs.

Substantial rise in the lifetime risk of primary total knee replacement surgery for osteoarthritis from 2003 to 2013: an international, population-level analysis.

OBJECTIVE: To estimate and compare the lifetime risk of total knee replacement surgery (TKR) for osteoarthritis (OA) between countries, and over time. METHOD: Data on primary TKR procedures performed for OA in 2003 and 2013 were extracted from national arthroplasty registries in Australia, Denmark, Finland, Norway and Sweden. Life tables and population data were also obtained for each country. Lifetime risk of TKR was calculated for 2003 and 2013 using registry, life table and population data. RESULTS: Marked international variation in lifetime risk of TKR was evident, with females consistently demonstrating the greatest risk. In 2013, Finland had the highest lifetime risk for females (22.8%, 95%CI 22.5-23.1%) and Australia had the highest risk for males (15.4%, 95%CI 15.1-15.6%). Norway had the lowest lifetime risk for females (9.7%, 95%CI 9.5-9.9%) and males (5.8%, 95%CI 5.6-5.9%) in 2013. All countries showed a significant rise in lifetime risk of TKR for both sexes over the 10-year study period, with the largest increases observed in Australia (females: from 13.6% to 21.1%; males: from 9.8% to 15.4%). CONCLUSIONS: Using population-based data, this study identified significant increases in the lifetime risk of TKR in all five countries from 2003 to 2013. Lifetime risk of TKR was as high as 1 in 5 women in Finland, and 1 in 7 males in Australia. These risk estimates quantify the healthcare resource burden of knee OA at the population level, providing an important resource for public health policy development and healthcare planning.

Return to sport matters-longer-term quality of life after ACL reconstruction in people with knee difficulties.

Many individuals experience long-term quality of life (QOL) impairment following anterior cruciate ligament reconstruction (ACLR). Factors contributing to poor QOL and psychological health >5 years after ACLR remain unclear. This study aimed to describe QOL and psychological health outcomes in people with knee difficulties (pain, symptoms, or functional limitations) 5-20 years following ACLR and identify factors explaining variability in these outcomes. Participants with knee difficulties 5-20 years following ACLR completed a battery of validated patient-reported outcomes [including the Knee injury and Osteoarthritis Outcome Score (KOOS), ACL-QOL, and the Assessment of QOL (AQoL-8D) instrument]. Multivariable linear regression was used to identify factors explaining variability in outcomes. One hundred sixty-two participants aged 38 ± 9 (mean ± SD) years completed questionnaires 9 ± 4 (range 5-20) years following ACLR. Thirty-nine percent of participants returned to competitive sport, 28% returned to a lower level, and 32% did not return to sport after ACLR. Not returning to sport after ACLR was associated with worse KOOS-QOL (ß = 0.29, P = 0.001 [mean ± SD (55 ± 20)], ACL-QOL [ß = 0.48, P < 0.001; (57 ± 21)], and AQoL-8D [ß = 0.22, P = 0.02 (0.80 ± 0.14)]) scores. Increased body mass index (56% were overweight/obese) was related to worse QOL and more depressive symptoms. Subsequent knee surgery and contralateral ACLR were also associated with poorer QOL outcomes in these individuals.

Quality of life in anterior cruciate ligament-deficient individuals: a systematic review and meta-analysis.

BACKGROUND: Physical and psychological impairments impacting quality of life (QOL) are common following ACL reconstruction. Rehabilitation alone is an effective alternative to reconstruction for some patients, warranting the investigation of QOL in ACL-deficient individuals. PURPOSE: To report and compare QOL in ACL-deficient individuals with population norms and ACL-reconstructed groups, and investigate relationships between participant characteristics and QOL. STUDY DESIGN: Systematic review and meta-analysis. METHODS: We systematically identified and methodologically appraised all studies reporting QOL in ACL-deficient individuals ≥5 years following ACL rupture. Knee-related and health-related QOL scores in ACL-deficient cohorts were compared to ACL-reconstructed groups using a random-effects meta-analysis. Descriptive comparisons were made with population norms. RESULTS: Eleven studies reported QOL in 473 ACL-deficient individuals, a mean of 10 (range 5-23) years following ACL rupture. Eight studies reported knee-related QOL using the Knee injury and Osteoarthritis Outcome Score QOL subscale (KOOS-QOL); scores (mean±SD) ranging from 54±17 to 77±22 were impaired compared to population norms. Health-related QOL, measured with the SF-36 domain scores in five studies, was similar to population norms, but impaired compared to physically active populations. Meta-analysis revealed no significant differences in KOOS-QOL (mean difference (95% CI) 2.9 (-3.3 to 9.1)) and SF-36 scores (for all SF-36 domains except Vitality) between ACL-deficient and ACL-reconstructed groups. CONCLUSIONS: This systematic review found impaired knee-related QOL in ACL-deficient individuals ≥5 years after ACL rupture, compared to population norms. Meta-analysis revealed similar knee-related QOL in ACL-deficient and ACL-reconstructed groups, and no difference in health-related QOL scores for seven of the eight SF-36 domains.

The substantial personal burden experienced by younger people with hip or knee osteoarthritis.

OBJECTIVE: To compare Health-Related Quality of Life (HRQoL) and psychological distress in younger people with hip or knee osteoarthritis (OA) to age- and sex-matched population norms, and evaluate work limitations in this group. METHOD: People aged 20-55 years with hip or knee OA were recruited from major hospitals (n = 126) and community advertisements (n = 21). HRQoL was assessed using the Assessment of Quality of Life (AQoL) instrument (minimal important difference 0.06 AQoL units) and compared to population norms. Psychological distress was assessed using the Kessler Psychological Distress Scale (K10) and the prevalence of high/very high distress (K10 score ≥22) was compared to Australian population data. Work limitations were evaluated using the Workplace Activity Limitations Scale (WALS). RESULTS: Considering most participants had a relatively recent OA diagnosis (<5 years), the extent of HRQoL impairment was unexpected. A very large reduction in HRQoL was evident for the overall sample, compared with population norms (mean difference -0.35 AQoL units, 95% CI -0.40 to -0.31). Females, people aged 40-49 years, and those with hip OA reported average HRQoL impairment of almost 40% (mean reductions -0.38 to -0.39 AQoL units). The overall prevalence of high/very high distress was 4 times higher than for the population (relative risk 4.19, 95% CI 3.53-4.98) and 67% reported moderate to considerable OA-related work disability, according to WALS scores. CONCLUSIONS: These results clearly demonstrate the substantial personal burden experienced by younger people with hip or knee OA, and support the provision of targeted services to improve HRQoL and maximise work participation in this group.

Interobserver agreement for endometrial cancer characteristics evaluated on biopsy material.

A shift toward a disease-based therapy designed according to patterns of failure and likelihood of nodal involvement predicted by pathologic determinants has recently led to considering a selective approach to lymphadenectomy for endometrial cancer. Therefore, it became critical to examine reproducibility of diagnosing the key determinants of risk, on preoperative endometrial tissue samples as well as the concordance between preoperative and postresection specimens. Six gynaecologic pathologists assessed 105 consecutive endometrial biopsies originally reported as positive for endometrial cancer for cell type (endometrioid versus nonendometrioid), tumor grade (FIGO 3-tiered and 2-tiered), nuclear grade, and risk category (low risk defined as endometrioid histology, grade 1 + 2 and nuclear grade <3). Interrater agreement levels were substantial for identification of nonendometrioid histology (κ = 0.63; SE = 0.025), high tumor grade (κ = 0.64; SE = 0.025), and risk category (κ = 0.66; SE = 0.025). The overall agreement was fair for nuclear grade (κ = 0.21; SE = 0.025). There is agreement amongst pathologists in identifying high-risk pathologic determinants on endometrial cancer biopsies, and these highly correlate with postresection specimens. This is ascertainment prerequisite adaptation of the paradigm shift in surgical staging of patients with endometrial cancer.

Prospective comparison of clinical and computed tomography assessment in detecting uterine perforation with intracavitary brachytherapy for carcinoma of the cervix.

Brachytherapy (BT) is an essential component of radical treatment for cervix cancer. Uterine perforation is a potential complication of intrauterine applicator (tandem) insertion. Postprocedure pelvic computed tomography (CT) scans are routinely performed at this center. The objective of this study was to prospectively compare radiation oncologists' (RO) clinical impression of satisfactory tandem placement with actual tandem placement as determined from pelvic CT. Patients with cervix cancer undergoing low-dose rate BT from April 2003 to December 2005 were prospectively identified. After tandem placement, patients were brought to the radiotherapy department for pelvic imaging (plain films and CT). Prior to viewing imaging, the RO specified whether they were concerned vs not concerned about uterine perforation. The CT was then reviewed to determine actual tandem placement (perforation vs no perforation). One hundred twenty-four sequential tandem insertions were performed in 114 patients and eligible for analysis. The incidence of CT detected uterine perforation was 13.7% (17/124). Physician concern, age greater than or equal to 60, and tumor size were significant predictors of uterine perforation (P < 0.0001, P= 0.0019, and P= 0.0016, respectively). The overall sensitivity and specificity for physician concern was 52.9% and 84.1%, respectively. CT detected perforation in 8.2% (8/98) of insertions where the RO was clinically confident of correct tandem placement. Pelvic CT was a useful modality to accompany clinical assessment in identifying uterine perforation in cervix BT. As a low but potentially clinical significant number of perforations identified on CT were not suspected clinically, we recommend acquiring pelvic imaging in all patients following tandem insertion to ensure intrauterine tandem positioning.

Optimal management for surgically Stage 1 serous cancer of the uterus.

OBJECTIVE: To describe the outcomes of patients who have undergone well-conducted surgery and found to have Stage 1 serous uterine cancer. METHODS: This retrospective cohort study includes women who have been treated for Stage 1 serous cancer of the uterus from 1985 to 2001. Cases were included from the regional cancer centers in Hamilton, London, Sunnybrook Toronto and Cancer Care Manitoba. RESULTS: Forty-three women met the inclusion criteria: Complete surgical staging (n = 27), surgery followed by pelvic radiation therapy (n = 4), surgery followed by whole abdominal radiation therapy (n = 6), surgery followed by adjuvant chemotherapy (n = 6). Patient age or depth of invasion did not influence survival. Progression free interval was 22 months (SD = 14.29). Recurrence rate was highest for adjuvant chemotherapy (66%). Survival was assessed by treatment modality and a statistically significant poorer survival was seen in the adjuvant chemotherapy group (OR 17.5; 95% CI 1.3-227.6). No comment can be made on a superior treatment regimen given the small numbers in each treatment strata. CONCLUSION: This study supports the findings of others in the literature. In a group of patients where surgical staging shows limited disease (i.e., surgically Stage 1 disease), then surgery alone appears to be adequate treatment.

Familial and hormonal risk factors for papillary serous uterine cancer.

OBJECTIVES: To identify genetic and non-genetic risk factors for papillary serous uterine cancer. METHODS: A case-control study was conducted. Case women with papillary serous uterine cancer were compared with two control groups: 1) women with endometrioid uterine cancer and 2) healthy women with no past history of cancer. Cases and controls were matched for age (within two years) and ethnic group. All study subjects completed a questionnaire addressing family history. The cases and healthy controls were assessed for factors associated with estrogen exposure. RESULTS: The risks of breast cancer (RR 1.84, CI 1.03-3.31) and of prostate cancer (RR 2.21, CI 0.77-6.37) were higher among the relatives of patients with papillary serous uterine cancer, than among relatives of those with endometrioid uterine cancer. Other significant risk factors included weight at 18 years (p = 0.04) and the use of estrogen replacement therapy (p = 0.04). CONCLUSION: Relatives of women with papillary serous cancer of the uterus had an increased risk of breast and prostate cancer. Hormonal exposure also increases the risk for this cancer. These findings suggest that predisposing genetic factors, possibly related to hormone metabolism, may be common to the three forms of cancer.

Phase II study assessing the effectiveness of Biafine cream as a prophylactic agent for radiation-induced acute skin toxicity to the breast in women undergoing radiotherapy with concomitant CMF chemotherapy.

PURPOSE: To assess the efficacy of Biafine cream in preventing Grade 2 acute radiation dermatitis, according to the National Cancer Institute of Canada skin radiation toxicity criteria in patients undergoing concomitant adjuvant chemotherapy and radiotherapy to the breast. METHODS AND MATERIALS: Sixty patients participated in this study. Patients were treated with a lumpectomy followed by concomitant chemotherapy and radiotherapy to the breast. Biafine cream was applied daily, starting on the first day and ending 2 weeks post-radiotherapy. Patients underwent weekly skin assessments throughout radiotherapy and at 2 and 4 weeks after treatment. Outcome measures were assessed using a Skin Assessment Questionnaire that was scored according to the National Cancer Institute of Canada skin radiation toxicity criteria and a self-administered questionnaire that evaluated skin symptoms. RESULTS: The maximum skin toxicity observed during the course of treatment was as follows: less than Grade 2 toxicity, 15% (9 patients); Grade 2, 83% (50 patients); Grade 3, 2% (1 patient); Grade 4, 0% (0 patients). The majority of the radiation dermatitis was observed after 3 weeks of radiotherapy. CONCLUSION: The majority of patients who underwent concomitant chemo- and radiotherapy for breast cancer developed Grade 2 radiation dermatitis with the use of Biafine cream. However, no treatment delays or interruptions were observed because of skin toxicity.

A comparison of four treatment strategies for ductal carcinoma in situ using decision analysis.

BACKGROUND: The goals of the current study were to compare four treatment approaches in the management of ductal carcinoma in situ (DCIS), to determine the conditions where mastectomy may be preferred to breast-conserving therapy (BCT), and to determine conditions where the addition of tamoxifen produces better results than BCT alone. METHODS: A decision analysis model was used to compare four treatment approaches after local excision for DCIS: mastectomy, irradiation, irradiation plus adjuvant tamoxifen, or observation. The model weighed the potential benefits of each treatment approach (reduction of ipsilateral and/or contralateral breast carcinoma) against the potential risks of treatment-related toxicities. In addition, the model adjusted for the potential detrimental impact of local recurrence or treatment-related toxicity on health-related quality of life (HRQOL). Base-case estimates were obtained from published randomized trial data. One-way and two-way sensitivity analyses were performed. RESULTS: According to the model, the optimal treatment for DCIS was strongly dependent on the individual's risk of local recurrence and the patient's attitudes toward mastectomy. Mastectomy was preferred in patients whose estimated 10-year risk of local recurrence was > 15%, provided that mastectomy resulted in a very low reduction in quality of life (i.e., utility estimate > 0.97). Conditions where the addition of tamoxifen was preferred to breast-conserving therapy alone included the following: estimated 10-year risk of local recurrence > 38%, estimated 10-year risk of developing a contralateral breast carcinoma > 6%, or a significant decrement in HRQOL associated with the development of an invasive local recurrence or salvage mastectomy (utility estimates < 0.85). CONCLUSION: Based on this quality-adjusted model, BCT appeared to be the preferred treatment for DCIS. The most important determinants of optimal management for DCIS included the risk of local recurrence and the utility of mastectomy. Formal evaluation of utilities in the context of DCIS and more accurate determination of the risk of recurrence are required.

Is uterine papillary serous adenocarcinoma a manifestation of the hereditary breast-ovarian cancer syndrome?

BACKGROUND: Uterine papillary serous carcinoma (UPSC) shares common pathologic, genetic, and clinical features with other serous cancers of müllerian origin. The most common histologic type of ovarian tumor associated with BRCA mutations is papillary serous. Because of these histologic similarities, we postulated that, in some cases, UPSC may be a manifestation of a field defect in BRCA1 carriers, which also includes ovarian carcinoma, fallopian tube carcinoma, and primary peritoneal carcinoma. METHODS: Fifty-six living patients with UPSC were contacted through their treating physicians and agreed to a family history interview and to provide a blood specimen for BRCA testing. The protein truncation test was used to detect mutations in exons 10 and 11 of BRCA1 and in exon 11 of BRCA2. The presence of four common mutations was assessed by PCR-based specific assays. RESULTS: A high proportion of patients had a past history of breast cancer (11%) or a first-degree relative with breast cancer (29%). Four patients were from families with site-specific hereditary breast cancer. However, there was no clear example of the hereditary breast-ovarian cancer syndrome, and none of the 56 patients was found to carry a BRCA1 or BRCA2 mutation. CONCLUSIONS: BRCA mutations do not appear to predispose to UPSC and this type of cancer does not appear to be a manifestation of the classical hereditary breast-ovarian cancer syndrome. The observed association between UPSC and breast cancer may be due to the presence of mutations in other cancer predisposing genes.

Does the dose fractionation schedule influence local control of adjuvant radiotherapy for early stage breast cancer?

PURPOSE: To explore the correlation between dose fractionation and local control for the adjuvant radiotherapy of early stage breast cancer. METHODS AND MATERIALS: A matched-pair analysis of early stage invasive breast cancer treated adjuvantly with two different dose fractionation schedules, 4000 cGy in 16 fractions (Cohort A) vs. 5000 cGy in 25 fractions (Cohort B) was undertaken to compare local control rates. A systematic review of the published experience in similar patient populations was conducted and the reported dose fractionation schedule was converted to a biologic effect dose (BED) based upon the linear quadratic equation. The BED was then used as a basis for comparing reported local control rates with different dose fractionation schemes. RESULTS: The 118 patient pairs were matched from Cohort A and Cohort B using known significant prognostic factors including age, histology, surgical margins, receptor status, lymphvascular space invasion, extensive intraductal disease, lymph node status, and systemic therapy. The local recurrence rate at 5 years for those treated with 4000 cGy (BED = 65 cGy4) and 5000 cGy (BED = 75 cGy4) was 12.7% and 6.8%, respectively, and this difference was not statistically significant (p = 0.09). Overall survival was 84% at 5 years for both groups. Comparison of the different dose fractionation schemes reported in the literature revealed a highly statistically significant difference between those treated with less than a BED of 75 Cy4 and those treated with a BED of 75 Gy4 or greater. CONCLUSION: Although not statistically significant, there was a trend in the matched pair analysis which suggests that 4000 cGy in 16 fractions (BED = 65 cGy4) provides inferior local control compared to 5000 cGy in 25 fractions (BED = 75 cGy4). Moreover, the literature review demonstrates that a dose control relationship may exist for local control in the adjuvant setting. A dose fractionation schedule equivalent to 5000 cGy in 25 fractions to the whole breast may represent the optimal dose fractionation schedule for local control.

Total but not resting energy expenditure is increased in infants with ventricular septal defects.

OBJECTIVE: The purpose of this study was to determine the effect of left-to-right shunting on the resting energy expenditure (REE), total energy expenditure (TEE), and energy intake in a group of 3- to 5-month-old infants with moderate to large unrepaired ventricular septal defects (VSDs) compared with age-matched, healthy infants. METHODS: Eight infants with VSDs and 10 healthy controls between 3 to 5 months of age participated in the study. Indirect calorimetry was used to measure REE and the doubly-labeled water method was used to measure TEE and energy intake. An echocardiogram and anthropometric measurements were performed on all study participants. Daily urine samples were collected at home for 7 days. Samples were analyzed by isotope ratio mass spectrometry. Data were compared using analysis of variance. RESULTS: No significant differences were found in REE (VSD, 42.2 +/- 8.7 kcal/kg/d; control, 43.9 +/- 14.1 kcal/kg/d) or energy intake (VSD, 90.8 +/- 19.9 kcal/kg/d; control, 87.1 +/- 11.7 kcal/kg/d) between the groups. The percent total body water was significantly higher in the VSD infants and the percent fat mass was significantly lower. TEE was 40% higher in the VSD group (VSD, 87.6 +/- 10.8 kcal/kg/d; control, 61.9 +/- 10.3 kcal/kg/d). The difference between TEE and REE, reflecting the energy of activity, was 2.5 times greater in the VSD group. CONCLUSIONS: REE and energy intake are virtually identical between the two groups. Despite this, infants with VSDs have substantially higher TEE than age-matched healthy infants. The large difference between TEE and REE in VSD infants suggests a substantially elevated energy cost of physical activity in these infants. These results demonstrate that, although infants with VSDs may match the energy intake of healthy infants, they are unable to meet their increased energy demands, resulting in growth retardation.