HOPON (Hyperbaric Oxygen for the Prevention of Osteoradionecrosis): A Randomized Controlled Trial of Hyperbaric Oxygen to Prevent Osteoradionecrosis of the Irradiated Mandible After Dentoalveolar Surgery.

PURPOSE: Hyperbaric oxygen (HBO) has been advocated in the prevention and treatment of osteoradionecrosis (ORN) of the jaw after head and neck radiation therapy, but supporting evidence is weak. The aim of this randomized trial was to establish the benefit of HBO in the prevention of ORN after high-risk surgical procedures to the irradiated mandible. METHODS AND MATERIALS: HOPON was a randomized, controlled, phase 3 trial. Participants who required dental extractions or implant placement in the mandible with prior radiation therapy >50 Gy were recruited. Eligible patients were randomly assigned 1:1 to receive or not receive HBO. All patients received chlorhexidine mouthwash and antibiotics. For patients in the HBO arm, oxygen was administered in 30 daily dives at 100% oxygen to a pressure of 2.4 atmospheres absolute for 80 to 90 minutes. The primary outcome measure was the diagnosis of ORN 6 months after surgery, as determined by a blinded central review of clinical photographs and radiographs. The secondary endpoints included grade of ORN, ORN at other time points, acute symptoms, pain, and quality of life. RESULTS: A total of 144 patients were randomized, and data from 100 patients were analyzed for the primary endpoint. The incidence of ORN at 6 months was 6.4% and 5.7% for the HBO and control groups, respectively (odds ratio, 1.13; 95% confidence interval, 0.14-8.92; P = 1). Patients in the hyperbaric arm had fewer acute symptoms but no significant differences in late pain or quality of life. Dropout was higher in the HBO arm, but the baseline characteristics of the groups that completed the trial were comparable between the 2 arms. CONCLUSIONS: The low incidence of ORN makes recommending HBO for dental extractions or implant placement in the irradiated mandible unnecessary. These findings are in contrast with a recently published Cochrane review and previous trials reporting rates of ORN (non-HBO) of 14% to 30% and challenge a long-established standard of care.

HOPON (Hyperbaric Oxygen for the Prevention of Osteoradionecrosis): a randomised controlled trial of hyperbaric oxygen to prevent osteoradionecrosis of the irradiated mandible: study protocol for a randomised controlled trial.

BACKGROUND: Osteoradionecrosis of the mandible is the most common serious complication of radiotherapy for head and neck malignancy. For decades, hyperbaric oxygen has been employed in efforts to prevent those cases of osteoradionecrosis that are precipitated by dental extractions or implant placement. The evidence for using hyperbaric oxygen remains poor and current clinical practice varies greatly. We describe a protocol for a clinical trial to assess the benefit of hyperbaric oxygen in the prevention of osteoradionecrosis during surgery on the irradiated mandible. METHODS/DESIGN: The HOPON trial is a phase III, randomised controlled, multi-centre trial. It employs an unblinded trial design, but the assessment of the primary endpoint, i.e. the diagnosis of osteoradionecrosis, is assessed on anonymised clinical photographs and radiographs by a blinded expert panel. Eligibility is through the need for a high-risk dental procedure in the mandible where at least 50-Gy radiotherapy has been received. Patients are randomised 1:1 to hyperbaric oxygen arm (Marx protocol) : control arm, but both groups receive antibiotics and chlorhexidine mouthwash. The primary endpoint is the presence of osteoradionecrosis at 6 months following surgery, but secondary endpoints include other time points, acute symptoms and pain, quality of life, and where implants are placed, their successful retention. DISCUSSION: The protocol presented has evolved through feasibility stages and through analysis of interim data. The classification of osteoradionecrosis has undergone technical refinement to ensure that robust definitions are employed. The HOPON trial is the only multi-centre RCT conducted in this clinical setting despite decades of use of hyperbaric oxygen for the prevention of osteoradionecrosis. TRIAL REGISTRATION: European Clinical Trials Database, ID: EudraCT200700622527 . First registered on 5 November 2007.

Refining the definition of mandibular osteoradionecrosis in clinical trials: The cancer research UK HOPON trial (Hyperbaric Oxygen for the Prevention of Osteoradionecrosis).

INTRODUCTION: Mandibular osteoradionecrosis (ORN) is a common and serious complication of head and neck radiotherapy for which there is little reliable evidence for prevention or treatment. The diagnosis and classification of ORN have been inconsistently and imprecisely defined, even in clinical trials. METHODS: A systematic review of diagnosis and classifications of ORN with specific focus on clinical trials is presented. The most suitable classification was evaluated for consistency using blinded independent review of outcome data (clinical photographs and radiographs) in the HOPON trial. RESULTS: Of 16 ORN classifications found, only one (Notani) appeared suitable as an endpoint in clinical trials. Clinical records of 217 timepoints were analysed amongst 94 randomised patients in the HOPON trial. The only inconsistency in classification arose where minor bone spicules (MBS) were apparent, which occurred in 19% of patients. Some trial investigators judged MBS as clinically unimportant and not reflecting ORN, others classified as ORN based on rigid definitions in common clinical use. When MBS was added as a distinct category to the Notani classification this ambiguity was resolved and agreement between observers was achieved. DISCUSSION: Most definitions and clinical classifications are based on retrospective case series and may be unsuitable for prospective interventional trials of ORN prevention or treatment. When ORN is used as a primary or secondary outcome in prospective clinical trials, the use of Notani classification with the additional category of MBS is recommended as it avoids subjectivity and enhances reliability and consistency of reporting.

Gemcitabine and capecitabine with or without telomerase peptide vaccine GV1001 in patients with locally advanced or metastatic pancreatic cancer (TeloVac): an open-label, randomised, phase 3 trial.

BACKGROUND: We aimed to assess the efficacy and safety of sequential or simultaneous telomerase vaccination (GV1001) in combination with chemotherapy in patients with locally advanced or metastatic pancreatic cancer. METHODS: TeloVac was a three-group, open-label, randomised phase 3 trial. We recruited patients from 51 UK hospitals. Eligible patients were treatment naive, aged older than 18 years, with locally advanced or metastatic pancreatic ductal adenocarcinoma, and Eastern Cooperative Oncology Group performance status of 0-2. Patients were randomly assigned (1:1:1) to receive either chemotherapy alone, chemotherapy with sequential GV1001 (sequential chemoimmunotherapy), or chemotherapy with concurrent GV1001 (concurrent chemoimmunotherapy). Treatments were allocated with equal probability by means of computer-generated random permuted blocks of sizes 3 and 6 in equal proportion. Chemotherapy included six cycles of gemcitabine (1000 mg/m(2), 30 min intravenous infusion, at days 1, 8, and 15) and capecitabine (830 mg/m(2) orally twice daily for 21 days, repeated every 28 days). Sequential chemoimmunotherapy included two cycles of combination chemotherapy, then an intradermal lower abdominal injection of granulocyte-macrophage colony-stimulating factor (GM-CSF; 75 µg) and GV1001 (0·56 mg; days 1, 3, and 5, once on weeks 2-4, and six monthly thereafter). Concurrent chemoimmunotherapy included giving GV1001 from the start of chemotherapy with GM-CSF as an adjuvant. The primary endpoint was overall survival; analysis was by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN4382138. FINDINGS: The first patient was randomly assigned to treatment on March 29, 2007, and the trial was terminated on March 27, 2011. Of 1572 patients screened, 1062 were randomly assigned to treatment (358 patients were allocated to the chemotherapy group, 350 to the sequential chemoimmunotherapy group, and 354 to the concurrent chemoimmunotherapy group). We recorded 772 deaths; the 290 patients still alive were followed up for a median of 6·0 months (IQR 2·4-12·2). Median overall survival was not significantly different in the chemotherapy group than in the sequential chemoimmunotherapy group (7·9 months [95% CI 7·1-8·8] vs 6·9 months [6·4-7·6]; hazard ratio [HR] 1·19, 98·25% CI 0·97-1·48, p=0·05), or in the concurrent chemoimmunotherapy group (8·4 months [95% CI 7·3-9·7], HR 1·05, 98·25% CI 0·85-1·29, p=0·64; overall log-rank of χ(2)2df=4·3; p=0·11). The commonest grade 3-4 toxic effects were neutropenia (68 [19%] patients in the chemotherapy group, 58 [17%] patients in the sequential chemoimmunotherapy group, and 79 [22%] patients in the concurrent chemoimmunotherapy group; fatigue (27 [8%] in the chemotherapy group, 35 [10%] in the sequential chemoimmunotherapy group, and 44 [12%] in the concurrent chemoimmunotherapy group); and pain (34 [9%] patients in the chemotherapy group, 39 [11%] in the sequential chemoimmunotherapy group, and 41 [12%] in the concurrent chemoimmunotherapy group). INTERPRETATION: Adding GV1001 vaccination to chemotherapy did not improve overall survival. New strategies to enhance the immune response effect of telomerase vaccination during chemotherapy are required for clinical efficacy. FUNDING: Cancer Research UK and KAEL-GemVax.

Activity of eribulin mesylate in heavily pretreated breast cancer granted access via the Cancer Drugs Fund.

AIM: Eribulin mesylate is a synthetic analog of halichondrin B and is licensed for the treatment of patients with locally advanced or metastatic breast cancer that has progressed following treatment with anthracyclines and taxanes. It was not deemed to be cost effective based on a cost analysis by the National Institute for Health and Care Excellence in England and therefore it is not funded routinely by the National Health Service. The establishment of the Cancer Drugs Fund in England subsequently enabled access. As with any new chemotherapy drug that enters clinical practice for metastatic breast cancer (MBC) it is often used in heavily pretreated patients and the experience in a routine clinical setting can differ from that in a clinical study. We therefore present the experience of the first 25 cases treated at our institution via the Cancer Drugs Fund. MATERIALS & METHODS: A total of 25 patients were treated and in the 22 assessable cases the objective response rate was 18% (four out of 22), with a clinical benefit rate of 41.0% (9 out of 22). RESULTS: The median time-to-progression and overall survival were 4.08 months and 5.89 months, respectively. There was a significant difference in clinical benefit rate (odds ratio: 0.065; 95% CI: 0-0.529; p = 0.0055), as well as time-to-progression (hazard ratio: 9.18; 95% CI: 2.26-37.38; p = 0.002 adjusted for age at diagnosis and interval between initial MBC diagnosis and commencing eribulin) favoring those patients who had not been rechallenged. There was no significant difference in overall survival (hazard ratio: 1.16; 95% CI: 0.44-3.05; p = 0.770 adjusted for age at diagnosis and interval between initial diagnosis of MBC and commencing eribulin). CONCLUSION: Eribulin mesylate shows clinical activity; however, there appears to be differences in terms of benefit in patients based on whether patients have been rechallenged with an anthracycline and/or a taxane. These data require confirmation in larger patient groups.

Validation of the IMPACT outcome prediction score using the Nottingham Head Injury Register dataset.

BACKGROUND: Comparison of traumatic brain injury (TBI) outcomes is severely limited by the absence of a universally accepted and validated outcome prediction score. The IMPACT group recently reported models predicting mortality and unfavorable outcome after TBI, based on the outcomes of patients with moderate and severe head injury reported in two large clinical trials. METHODS: We have used prospectively collected data from 1,276 adult patients from the Nottingham Head Injury Register admitted to a single UK neurosurgical unit during a 10-year period to validate the IMPACT score models. The two models were validated for discrimination, calibration, and accuracy, using multiple imputation to adjust for missing data. RESULTS: One thousand sixty-one patients (83%) had a complete set of data. For the multiply imputed analysis, the IMPACT prognostic models showed satisfactory discrimination (area under the receiver operator curve for mortality, 0.835; 95% confidence interval, 0.811-0.858; unfavorable outcome, 0.828; 95% confidence interval, 0.805-0.851) and accuracy (Brier Accuracy Score for mortality, 0.403, p < 0.01; unfavorable outcome, 0.371, p < 0.01). Good calibration was evident for unfavorable outcome, but mortality risk was underestimated by the scoring system in our sample (Hosmer-Lemeshow test: mortality: p < 0.01; unfavorable outcome: p = 0.6). These results were not significantly changed when repeated using patients with complete data only. CONCLUSION: The 2005 IMPACT model for unfavorable outcome performs well when used to predict outcome in adults with moderate and severe TBI presenting to a British neurosurgical center. However, the model for mortality fitted less well, slightly overestimating mortality in the higher-risk groups.

P3MC: a double blind parallel group randomised placebo controlled trial of Propranolol and Pizotifen in preventing migraine in children.

BACKGROUND: A recent Cochrane Review demonstrated the remarkable lack of reliable clinical trials of migraine treatments for children, especially for the two most prescribed preventative treatments in the UK, Propranolol and Pizotifen.Migraine trials in both children and adults have high placebo responder rates, e.g. of 23%, but for a trial's results to be generalisable "placebo responders" should not be excluded and for a drug to be worthwhile it should be clearly superior, both clinically and statistically, to placebo. METHODS/DESIGN: Two multicentre, two arm double blind parallel group randomised controlled trials, with allocation ratio of 2:1 for each comparison, Propranolol versus placebo and Pizotifen versus placebo. The trial is designed to test whether Propranolol is superior to placebo and whether Pizotifen is superior to placebo for the prevention of migraine attacks in children aged 5-16 years referred to secondary care out-patient settings with frequent migraine (2-6/4 weeks). The primary outcome measure is the number of migraine attacks during trial weeks 11 to 14. DISCUSSION: A strength of this trial is the participation of clinically well defined migraine patients who will also be approached to help with future longer-term follow-up studies. TRIAL REGISTRATION: ISRCTN97360154.

Spatial effects should be allowed for in primary care and other community-based cluster RCTS.

BACKGROUND: Typical advice on the design and analysis of cluster randomized trials (C-RCTs) focuses on allowance for the clustering at the level of the unit of allocation. However often C-RCTs are also organised spatially as may occur in the fields of Public Health and Primary Care where populations may even overlap. METHODS: We allowed for spatial effects on the error variance by a multiple membership model. These are a form of hierarchical model in which each lower level unit is a member of more than one higher level unit. Membership may be determined through adjacency or through Euclidean distance of centroids or in other ways such as the proportion of overlapping population. Such models may be estimated for Normal, binary and Poisson responses in Stata (v10 or above) as well as in WinBUGS or MLWin. We used this to analyse a dummy trial and two real, previously published cluster-allocated studies (one allocating general practices within one City and the other allocating general practices within one County) to investigate the extent to which ignoring spatial effects affected the estimate of treatment effect, using different methods for defining membership with Akaike's Information Criterion to determine the "best" model. RESULTS: The best fitting model included both a fixed North-South gradient and a random cluster effect for the dummy RCT. For one of the real RCTs the best fitting model included both a random practice effect plus a multiple membership spatial term, while for the other RCT the best fitting model ignored the clustering but included a fixed North-South gradient. Alternative models which fitted only slightly less well all included spatial effects in one form or another, with some variation in parameter estimates (greater when less well fitting models were included). CONCLUSIONS: These particular results are only illustrative. However, we believe when designing C-RCTs in a primary care setting the possibility of spatial effects should be considered in relation to the intervention and response, as well as any explanatory effect of fixed covariates, together with any implications for sample size and methods for planned analyses.

Autoimmunity to SOX2, clinical phenotype and survival in patients with small-cell lung cancer.

OBJECTIVE: Autoantibodies to SOXB1 antigens are commonly found in patients with small-cell lung cancer (SCLC). It has not been established whether the presence of circulating SOX antibodies is associated with a specific paraneoplastic clinical phenotype, or if a tumour immune response to SOX antigens can affect prognosis in patients with SCLC in relation to other established prognostic factors. METHODS: Using recombinant SOX2 in an ELISA, we analysed sera in a prospective study from 212 unselected SCLC patients, which included 35 patients with neurological paraneoplastic disorders, or other well characterised onconeural antibodies. RESULTS: Overall, SOX2 antibodies were detected in 70 SCLC patients, with a sensitivity of 33% (95% CI 27-40%) and specificity of 97% (95% CI 94-99%) compared to controls matched for age, gender and smoking history. No single clinical phenotype was seen in relation to the presence of SOX2 antibodies in isolation. Multivariate analysis showed that the presence of SOX2 antibodies in SCLC patients without evidence of neurological paraneoplastic disorders or onconeural antibodies did not have a significant effect on survival when known prognostic factors were accounted for. CONCLUSIONS: SOX2 antibodies are very specific markers for SCLC compared to matched non-tumour controls, but their presence does not seem to alter prognosis in this tumour type.

Correcting population-based survival for DCOs - why a simple method works and when to avoid it.

A high proportion of cancer registrations solely based on a death certificate (DCOs) indicates poor data quality and biases cancer survival estimates. Intensive trace-back of registrations initiated after death (DCIs) can reduce the proportion of DCOs to an acceptable level and also improve data quality in other areas (such as increasing the information on disease extent, morphology and treatment) but is expensive in staff time. Our approach - based on a proportional hazards model for DCOs relative to all other cases - can be used to predict what the likely effect of the trace-back will be on survival and to justify the extra work involved. It can also be used to correct results from other sources (including historical data) especially when these sources contain high percentages of DCOs. Of course, the ability to make this correction is no excuse for omitting trace-back of DCI cases when resources permit. With our model the true survival tends ultimately to (1-p) *S where p is the proportion of DCOs and S is the observed survival, which is a simple correction noted by others. The worse the assumed survival of DCOs is relative to all other cases, the earlier is the time for the maximum difference between observed and true survival. Correction to the later part of survival curves is easy and an example is shown using EUROCARE data. This paper shows why the simple method works and suggests that researchers should always think about adjusting their survival estimates with regard to the percentage of DCOs. This paper also shows when the simple correction can (on 5-year survival estimates) and cannot (on 1-year survival estimates, generally) be used to adjust survival figures when comparisons are made across regions or countries with differing percentages of DCOs. We also present examples of some hazard ratios found in practice.

Effects of dietary intervention and quadriceps strengthening exercises on pain and function in overweight people with knee pain: randomised controlled trial.

OBJECTIVE: To determine whether dietary intervention or knee strengthening exercise, or both, can reduce knee pain and improve knee function in overweight and obese adults in the community. DESIGN: Pragmatic factorial randomised controlled trial. SETTING: Five general practices in Nottingham. PARTICIPANTS: 389 men and women aged 45 and over with a body mass index (BMI) of > or = 28.0 and self reported knee pain. INTERVENTIONS: Participants were randomised to dietary intervention plus quadriceps strengthening exercises; dietary intervention alone; quadriceps strengthening exercises alone; advice leaflet only (control group). Dietary intervention consisted of individualised healthy eating advice that would reduce normal intake by 2.5 MJ (600 kcal) a day. Interventions were delivered at home visits over a two year period. MAIN OUTCOME MEASURES: The primary outcome was severity of knee pain scored with the Western Ontario McMaster (WOMAC) osteoarthritis index at 6, 12, and 24 months. Secondary outcomes (all at 24 months) included WOMAC knee physical function and stiffness scores and selected domains on the SF-36 and the hospital anxiety and depression index. RESULTS: 289 (74%) participants completed the trial. There was a significant reduction in knee pain in the knee exercise groups compared with those in the non-exercise groups at 24 months (percentage risk difference 11.61, 95% confidence interval 1.81% to 21.41%). The absolute effect size (0.25) was moderate. The number needed to treat to benefit from a > or = 30% improvement in knee pain at 24 months was 9 (5 to 55). In those randomised to knee exercise improvement in function was evident at 24 months (mean difference -3.64, -6.01 to -1.27). The mean difference in weight loss at 24 months in the dietary intervention group compared with no dietary intervention was 2.95 kg (1.44 to 4.46); for exercise versus no exercise the difference was 0.43 kg (-0.82 to 1.68). This difference in weight loss was not associated with improvement in knee pain or function but was associated with a reduction in depression (absolute effect size 0.19). CONCLUSIONS: A home based, self managed programme of simple knee strengthening exercises over a two year period can significantly reduce knee pain and improve knee function in overweight and obese people with knee pain. A moderate sustained weight loss is achievable with dietary intervention and is associated with reduced depression but is without apparent influence on pain or function. TRIAL REGISTRATION: Current Controlled Trials ISRCTN93206785.

Local recruitment experience in a study comparing the effectiveness of a low glycaemic index diet with a low calorie healthy eating approach at achieving weight loss and reducing the risk of endometrial cancer in women with polycystic ovary syndrome (PCOS).

OBJECTIVE: Feasibility of a clinical-trial comparing a low-glycaemic diet with a low-calorie healthy eating approach at achieving weight loss and reducing the risk of endometrial cancer in women with PCOS. DESIGN: A pilot Randomised-Controlled-Trial using different recruitment strategies. SETTING: A University Hospital in the United Kingdom. PATIENTS: Women seen at specialist gynaecology clinics over a 12 month period in one University Hospital, and women self identified through a website and posters. INTERVENTIONS: Potential recruits were assessed for eligibility, gave informed consent, randomised, treated and assessed as in the definitive trial. MAIN OUTCOME MEASURES: Eligibility and recruitment rates, compliance with the allocated diet for 6 months and with clinical assessments, blood tests, pelvic ultrasound scans and endometrial biopsies. RESULTS: 1433 new and 2598 follow up patients were seen in 153 gynaecology clinics for over 12 months. 441 (11%) potentially eligible women were identified, 19 (0.4%) of whom met the trial entry criteria. Eleven consented to take part, of which 8 (73%) completed the study. CONCLUSIONS: Planned future trials on over-weight women with PCOS should be multicentre and should incorporate primary care. This data will help other researchers plan and calculate the sample size and potential recruitment rates in future clinical trials in PCOS. The results will also be useful for inclusion in future meta-analyses.

Simulation modelling to validate the flow method for estimating completeness of case ascertainment by cancer registries.

BACKGROUND: To validate estimates of completeness of cancer ascertainment obtained by the flow method. METHODS: We generated a computer simulation of patient-level cancer registration processes, based loosely on the age distribution and survival of colorectal carcinoma patients, and utilizing a mixture of 'cured' and 'killed' subjects with an age-dependent fraction of 'cured' cases. The simulated data were then used in an analysis of completeness using the flow method. Validation of the simulation process was based on similarity of outputs to those obtained using real data, and validation of the flow method on its ability to correctly estimate the known proportion of cases in the simulated data which would never be registered. RESULTS: We successfully generated realistic data and have shown that completeness estimated by the flow method is close to the true value, whereas another method of estimating completeness (Ajiki's) was shown to be strongly biased. We also modelled what happens to completeness estimates when a new registry is set up. CONCLUSIONS: When its assumptions are met (steady state for incidence, survival and stable population structure), the flow method works well but is biased for cancers with good survival. Further research is required to assess the robustness of the method when these conditions are not met.

Risk of malignancy after gamma knife stereotactic radiosurgery.

OBJECTIVE: To assess the risk of radiosurgery to cause malignant transformation in benign tumors or to induce new malignancies. METHODS: A retrospective cohort study comparing the Sheffield, England, radiosurgery patient database with national mortality and cancer registries. This data set comprises approximately 5000 patients and 30,000 patient-years of follow-up, with more than 1200 patients having a follow-up period longer than 10 years. RESULTS: In this material, a single new astrocytoma was diagnosed, whereas, based on national incidence figures, 2.47 cases would have been predicted. CONCLUSION: No increased risk of malignancy was detected in this series, supporting the safety of radiosurgery. Pragmatically, in advising patients, the risks of malignancy would seem small, particularly if such risks are considered in the context of the other risks faced by patients with intracranial pathologies requiring radiosurgical treatments.

Effect of chemotherapy on skeletal health in male survivors from testicular cancer and lymphoma.

PURPOSE: There are concerns over the late effects of cancer therapy, including accelerated bone loss leading to increased risk of osteoporosis. Treatment-related bone loss is well recognized in breast and prostate cancer, due to overt hypogonadism, but there has been little evaluation of the skeletal effects of chemotherapy alone in adults. This study assesses the extent of bone loss due to previous chemotherapy in men. EXPERIMENTAL DESIGN: The bone mineral density (BMD) of men who had received previously chemotherapy with curative intent for lymphoma or testicular cancers was compared with that of an age-matched population of men from a cancer control population that had not received chemotherapy. BMD was measured by dual-energy X-ray scanning. Additionally, measurement of sex hormones and the bone turnover markers N-telopeptide fragment of type I collagen and bone-specific alkaline phosphatase were done. All statistical tests were two sided. RESULTS: One hundred fifteen chemotherapy-treated patients and 102 cancer controls were recruited. There was no statistical difference in BMD between the chemotherapy and control groups at either spine or hip and the mean BMD values in both groups were no lower than that of a reference population. There were no significant differences in estradiol, luteinizing hormone, and testosterone, but follicle-stimulating hormone values were significantly higher in the chemotherapy group (P=0.011). The mean values of NH2-terminal telopeptide fragment of type I collagen and bone-specific alkaline phosphatase were within the reference ranges. CONCLUSIONS: The absence of accelerated bone loss following chemotherapy is reassuring and suggests that standard dose cytotoxic chemotherapy has no lasting clinically important direct effects on bone metabolism.

An easy approach to the Robins-Breslow-Greenland variance estimator.

The Mantel-Haenszel estimate for the odds ratio (and its logarithm) in stratified case control studies lacked a generally acceptable variance estimate for many years. The Robins-Breslow-Greenland estimate has met this need, but standard textbooks still do not provide an explanation of how it is derived. This article provides an accessible derivation which demonstrates the link between the Robins-Breslow-Greenland estimate and the familiar Woolf estimate for the variance of the log odds ratio, and which could easily be included in Masters level courses in epidemiology. The relationships to the unconditional and conditional maximum likelihood estimates are also reviewed.

The effects of twins, parity and age at first birth on cancer risk in Swedish women.

The effect of reproductive history on the risk of cervical, colorectal and thyroid cancers and melanoma has been explored but the results to date are inconsistent. We aimed to examine in a record-linkage cohort study the risk of developing these cancers, as well as breast, ovarian and endometrial cancers, among mothers who had given birth to twins compared with those who had only singleton pregnancies. Women who delivered a baby in Sweden between 1961 and 1996 and who were 15 years or younger in 1961 were selected from the Swedish civil birth register and linked with the Swedish cancer registry. We used Poisson regression to assess associations between reproductive factors and cancer. Twinning was associated with reduced risks of breast, colorectal, ovarian and uterine cancers, although no relative risks were statistically significant. The delivery of twins did not increase the risk of any cancers studied. Increasing numbers of maternities were associated with significantly reduced risks of all tumors except thyroid cancer. We found positive associations between a later age at first birth and breast cancer and melanoma, while there were inverse associations with cervix, ovarian, uterine and colorectal cancers. These findings lend weight to the hypothesis that hormonal factors influence the etiology of colorectal cancer in women, but argue against any strong effect of hormones on the development of melanoma or tumors of the thyroid.

Using BNP to develop a risk score for heart failure in primary care.

AIMS: Chronic heart failure is a common condition with high mortality. Accurate diagnosis in primary care is difficult. Elevated B-type natriuretic peptide (BNP) is associated with left ventricular systolic dysfunction and increased mortality. Prognostic scoring systems using BNP may help to stratify risk in primary care patients. The aim of this research was to establish the independent variables which predict mortality in a primary care population-prescribed loop diuretics and to generate and validate a scoring system for heart failure in general practice. METHODS AND RESULTS: Five hundred and thirty-two patients were followed up for a mean of 6.4 years after attending a research clinic for clinical assessment, electrocardiogram (ECG), echocardiography, and BNP. Multivariate analysis was used to establish independent prognostic variables and to generate a prognostic scoring system. The score generated was [0.50 x BNP+5 x age+50 x (CVA+sex+diabetes+ECG)]. The cut-off scores for risk groups were; 25th percentile, 411; 50th percentile, 475; 75th percentile, 524; Harrell's c=0.75. CONCLUSION: Developing prognostic scoring systems provides a means of risk stratifying patients without relying on a single cut-off diagnostic value for BNP. Further validation of such scoring systems may improve future management of community heart failure patients.