Ethnic and Socioeconomic Associations with Multiple Sclerosis Risk.

OBJECTIVE: Epidemiological research in multiple sclerosis (MS) has mainly been performed in socioeconomically and ethnically limited populations; influences on MS risk have not been studied in prospectively collected non-White populations. We set out to study the influence of previously described MS risk factors in an ethnically diverse population. METHODS: A nested case-control study was created using primary care records of >1 million individuals, >50% of whom identify as Black, Asian, and Minority Ethnic (BAME). MS cases were compared to an age- and sex-matched control cohort (1:4), and to a large unmatched cohort. Odds ratios (ORs) of disease were determined according to exposure of interest, and a multivariate model including all exposures was created. Potential pairwise interactions were considered where both indicated a significant effect. RESULTS: A total of 1,344 confirmed MS cases were included. MS OR in blacks aged <40 years was 1.15 (95% confidence interval [CI] = 0.81-1.62) compared to whites. MS odds in BAME current (OR = 1.71, 95% CI = 1.24-2.31) and ex-smokers (OR = 2.83, 95% CI = 2.14-3.72) were considerably higher than in Whites (OR = 1.09, 95% CI = 0.88-1.34; OR = 1.44, 95% CI = 1.19-1.74, respectively). Prior infectious mononucleosis was associated with increased odds of MS in Blacks (OR = 4.94, 95% CI = 1.23-17.89). An increase in MS odds was seen in the least-deprived quintile (OR = 2.46, 95% CI = 1.40-4.24), but no effect across deprived quintiles was seen. INTERPRETATION: This cohort provides novel data on factors potentially driving MS susceptibility in a diverse population, one-third of whom live in poverty. Environmental exposures have differential risk across ethnicity. ANN NEUROL 2020;87:599-608.

Prognostic factors for recurrence and survival in anal cancer: generating hypotheses from the mature outcomes of the first United Kingdom Coordinating Committee on Cancer Research Anal Cancer Trial (ACT I).

BACKGROUND: Only 2 prospective studies have previously reported prognostic factors for anal cancer, European Organization for Research and Treatment of Cancer trial 22861 (EORTC 22861) and Radiation Therapy Oncology Group trial 98-11 (RTOG 98-11). Both of those trials reported that clinically positive lymph nodes and male sex predicted poorer overall survival (OS). The EORTC 22861 trial indicated that the same factors were prognostic for locoregional control. In the current report, the authors investigated potential prognostic factors from the first United Kingdom Coordinating Committee on Cancer Research Anal Cancer Trial (ACT I), in which patients were randomized to receive either radiotherapy alone or chemoradiation (CRT) with concurrent 5-fluorouracil/mitomycin C. METHODS: In the ACT I trial, associations between several baseline characteristics and 3 endpoints were investigated: locoregional failure (LRF), anal cancer death (ACD), and OS. The analyses were restricted to 292 patients who received CRT, which subsequently became standard treatment. A score was derived using multivariable Cox regression to identify the set of factors that, together, had the best prognostic performance. This score was then validated with a large, independent prospective trial (the ACT II trial). RESULTS: Palpable, clinically positive lymph nodes were associated with LRF (P = .012), a greater risk of ACD (P = .031), and decreased OS (P = .006) in multivariable analyses. Men had worse outcomes than women for LRF (P = .036), ACD (P = .039), and OS (P = .008). On average, a lower hemoglobin level had an adverse effect on ACD (P = .008), and a higher white blood cell count had an adverse effect on OS (P = .001). However, external validation of the score was poor for LRF (area under the curve [AUC] = 54%) but was better for ACD (AUC = 67%) and OS (AUC = 63%). CONCLUSIONS: The results from this analysis of the ACT I trial supported evidence for palpable lymph nodes and male sex as prognostic factors for LRF and OS, and lower hemoglobin levels and a higher white blood cell count were identified as prognostic factors for ACD and OS, respectively.

Dementia risk in a diverse population: A single-region nested case-control study in the East End of London.

Background: Most evidence about dementia risk comes from relatively affluent people of White European ancestry. We aimed to determine the association between ethnicity, area level socioeconomic deprivation and dementia risk, and the extent to which variation in risk might be attributable to known modifiable clinical risk factors and health behaviours. Methods: In this nested case-control study, we analysed data from primary care medical records of a population of 1,016,277 from four inner East London boroughs, United Kingdom, collected between 2009 and 2018. The outcome measures were odds ratios for dementia according to ethnicity and deprivation, before and after the addition of major modifiable risk factors for dementia; and weighted population attributable risk for comparison between individual risk factors. Findings: We identified 4137 dementia cases and 15,754 matched controls (mean age for cases and controls were 80·7 years, (SD 8·7); 81·3 years, (SD 8·9) respectively, range 27-103). Black and South Asian ethnicity were both associated with increased risk of dementia relative to White (odds ratios [95% CI]: Black 1·43 [1·31-1·56]; South Asian 1.17 [1·06-1·29]). Area-level deprivation was independently associated with an increased risk of dementia in a dose-dependent manner. Black and South Asian ethnicity were both associated with a younger age at dementia diagnosis (odds ratios [95%CI]: 0·70 [0·61-0·80] and 0·55 [0·47-0·65], respectively). Population attributable risk was higher for ethnicity (9·7%) and deprivation (11·7%) than for any established modifiable risk factor in this population. Interpretation: Ethnicity and area-level deprivation are independently associated with dementia risk in East London. This effect may not be attributable to the effect of known risk factors. Funding: Barts Charity (MGU0366).

Assessment of Risk Factors and Early Presentations of Parkinson Disease in Primary Care in a Diverse UK Population.

IMPORTANCE: Early features of Parkinson disease (PD) have been described through population-based studies that overrepresent White, affluent groups and may not be generalizable. OBJECTIVE: To investigate the association between risk factors and prediagnostic presentations of PD in an ethnically diverse UK population with high socioeconomic deprivation but universal access to health care. DESIGN, SETTING, AND PARTICIPANTS: A nested case-control study was conducted using electronic health care records on 1 016 277 individuals from primary care practices in East London to extract clinical information recorded between 1990 and February 6, 2018. The data were analyzed between September 3, 2020, and September 3, 2021. Individuals with a diagnosis of PD were compared with controls without PD or other major neurological conditions. MAIN OUTCOMES AND MEASURES: A matched analysis (10 controls matched for each patient with PD according to age and sex) and an unmatched analysis (adjusted for age and sex) were undertaken using multivariable logistic regression to determine associations between risk factors and prediagnostic presentations to primary care with subsequent diagnosis of PD. Three time periods (<2, 2-<5, and 5-10 years before diagnosis) were analyzed separately and together. RESULTS: Of 1 016 277 individuals included in the data set, 5699 were excluded and 1055 patients with PD and 1 009 523 controls were included in the analysis. Patients with PD were older than controls (mean [SD], 72.9 [11.3] vs 40.3 [15.2] years), and more were male (632 [59.9%] vs 516 862 [51.2%]). In the matched analysis (1055 individuals with PD and 10 550 controls), associations were found for tremor (odds ratio [OR], 145.96; 95% CI, 90.55-235.28) and memory symptoms (OR, 8.60; 95% CI, 5.91-12.49) less than 2 years before the PD diagnosis. The associations were also found up to 10 years before PD diagnosis for tremor and 5 years for memory symptoms. Among midlife risk factors, hypertension (OR, 1.36; 95% CI, 1.19-1.55) and type 2 diabetes (OR, 1.39; 95% CI, 1.19-1.62) were associated with subsequent diagnosis of PD. Associations with early nonmotor features, including hypotension (OR, 6.84; 95% CI, 3.38-13.85), constipation (OR, 3.29; 95% CI, 2.32-4.66), and depression (OR, 4.69; 95% CI, 2.88-7.63), were also noted. Associations were found for epilepsy (OR, 2.5; 95% CI, 1.63-3.83) and hearing loss (OR, 1.66; 95% CI, 1.06-2.58), which have not previously been well reported. These findings were replicated using data from the UK Biobank. No association with future PD diagnosis was found for ethnicity or deprivation index level. CONCLUSIONS AND RELEVANCE: This study provides data suggesting that a range of comorbidities and symptoms are encountered in primary care settings before PD diagnosis in an ethnically diverse and deprived population. Novel temporal associations were observed for epilepsy and hearing loss with subsequent development of PD. The prominence of memory symptoms suggests an excess of cognitive dysfunction in early PD in this population or difficulty in correctly ascertaining symptoms in traditionally underrepresented groups.

The Influence of Socioeconomic Deprivation on Dementia Mortality, Age at Death, and Quality of Diagnosis: A Nationwide Death Records Study in England and Wales 2001-2017.

BACKGROUND: Socioeconomic deprivation may be an important determinant of dementia risk, mortality, and access to diagnostic services. Premature mortality from other causes and under-representation of deprived individuals in research may lead to this effect being overlooked. OBJECTIVE: We assessed the relationship between deprivation and dementia mortality using comprehensive death certificate data for England and Wales from 2001 to 2017. METHODS: We used standardized mortality ratios (SMR) and a Poisson model to compare likelihood of dying from dementia in each deprivation decile. We also examined the associations of deprivation with age at death from dementia, and with likelihood of receiving a diagnosis of unspecified dementia. RESULTS: Risk of dying from dementia was higher in more deprived deciles (Mean SMR [95% CI] in decile 1 : 0.528 [0.506 to 0.550], decile 10:0.369 [0.338 to 0.400]). In 2017, 14,837 excess dementia deaths were attributable to deprivation (21.5% of all dementia deaths that year). There were dose-response associations of deprivation with likelihood of being older at death with dementia (odds ratio [95% CI] for decile 10 (least deprived): 1.31 [1.28 to 1.33] relative to decile 1), and with likelihood of receiving a diagnosis of unspecified dementia (odds ratio [95% CI] for decile 10:0.78 [0.76 to 0.80] relative to decile 1). CONCLUSION: Socioeconomic deprivation in England and Wales is associated with increased dementia mortality, younger age at death with dementia, and poorer access to specialist diagnosis. Reducing social inequality may have a role in the prevention of dementia mortality.

Improving estimation of Parkinson's disease risk-the enhanced PREDICT-PD algorithm.

We previously reported a basic algorithm to identify the risk of Parkinson's disease (PD) using published data on risk factors and prodromal features. Using this algorithm, the PREDICT-PD study identified individuals at increased risk of PD and used tapping speed, hyposmia and REM sleep behaviour disorder (RBD) as "intermediate" markers of prodromal PD in the absence of sufficient incident cases. We have now developed and tested an enhanced algorithm which incorporates the intermediate markers into the risk model. Risk estimates were compared using the enhanced and the basic algorithm in members of the PREDICT-PD pilot cohort. The enhanced PREDICT-PD algorithm yielded a much greater range of risk estimates than the basic algorithm (93-609-fold difference between the 10th and 90th centiles vs 10-13-fold respectively). There was a greater increase in the risk of PD with increasing risk scores for the enhanced algorithm than for the basic algorithm (hazard ratios per one standard deviation increase in log risk of 2.75 [95% CI 1.68-4.50; p < 0.001] versus 1.47 [95% CI 0.86-2.51; p = 0.16] respectively). Estimates from the enhanced algorithm also correlated more closely with subclinical striatal DaT-SPECT dopamine depletion (R2 = 0.164, p = 0.005 vs R2 = 0.043, p = 0.17). Incorporating the previous intermediate markers of prodromal PD and using likelihood ratios improved the accuracy of the PREDICT-PD prediction algorithm.

A Randomized Comparison of Different Vaginal Self-sampling Devices and Urine for Human Papillomavirus Testing-Predictors 5.1.

BACKGROUND: Human papillomavirus (HPV)-based screening is rapidly replacing cytology as the cervical screening modality of choice. In addition to being more sensitive than cytology, it can be done on self-collected vaginal or urine samples. This study will compare the high-risk HPV positivity rates and sensitivity of self-collected vaginal samples using four different collection devices and a urine sample. METHODS: A total of 620 women referred for colposcopy were invited to provide an initial stream urine sample collected with the Colli-Pee device and take two vaginal self-samples, using either a dry flocked swab (DF) and a wet dacron swab (WD), or a HerSwab (HS) and Qvintip (QT) device. HPV testing was performed by the BD Onclarity HPV Assay. RESULTS: A total of 600 vaginal sample pairs were suitable for analysis, and 505 were accompanied by a urine sample. Similar positivity rates and sensitivities for CIN2+ and CIN3+ were seen for DF, WD, and urine, but lower values were seen for QT and HS. No clear user preferences were seen between devices, but women found urine easiest to collect, and were more confident they had taken the sample correctly. The lowest confidence in collection was reported for HS. CONCLUSIONS: Urine, a DF swab, and WD swab all performed well and were well received by the women, whereas the Qvintip and HerSwab devices were less satisfactory. IMPACT: This is the first study to compare five self-sampling methods in the same women taken at the same time. It supports wider use of urine or vaginal self-sampling for cervical screening.

Reassessing the observational evidence for nitrogen deposition impacts in acid grassland: spatial Bayesian linear models indicate small and ambiguous effects on species richness.

Nitrogen deposition (Ndep) is considered a significant threat to plant diversity in grassland ecosystems around the world. The evidence supporting this conclusion comes from both observational and experimental research, with "space-for-time" substitution surveys of pollutant gradients a significant portion of the former. However, estimates of regression coefficients for Ndep impacts on species richness, derived with a focus on causal inference, are hard to locate in the observational literature. Some influential observational studies have presented estimates from univariate models, overlooking the effects of omitted variable bias, and/or have used P-value-based stepwise variable selection (PSVS) to infer impacts, a strategy known to be poorly suited to the accurate estimation of regression coefficients. Broad-scale spatial autocorrelation has also generally been unaccounted for. We re-examine two UK observational datasets that have previously been used to investigate the relationship between Ndep and plant species richness in acid grasslands, a much-researched habitat in this context. One of these studies (Stevens et al., 2004, Science, 303: 1876-1879) estimated a large negative impact of Ndep on richness through the use of PSVS; the other reported smaller impacts (Maskell et al., 2010, Global Change Biology, 16: 671-679), but did not explicitly report regression coefficients or partial effects, making the actual size of the estimated Ndep impact difficult to assess. We reanalyse both datasets using a spatial Bayesian linear model estimated using integrated nested Laplace approximation (INLA). Contrary to previous results, we found similar-sized estimates of the Ndep impact on plant richness between studies, both with and without bryophytes, albeit with some disagreement over the most likely direction of this effect. Our analyses suggest that some previous estimates of Ndep impacts on richness from space-for-time substitution studies are likely to have been over-estimated, and that the evidence from observational studies could be fragile when confronted with alternative model specifications, although further work is required to investigate potentially nonlinear responses. Given the growing literature on the use of observational data to estimate the impacts of pollutants on biodiversity, we suggest that a greater focus on clearly reporting important outcomes with associated uncertainty, the use of techniques to account for spatial autocorrelation, and a clearer focus on the aims of a study, whether explanatory or predictive, are all required.

Remote testing of vitamin D levels across the UK MS population-A case control study.

OBJECTIVE: The association between vitamin D deficiency and multiple sclerosis (MS) is well described. We set out to use remote sampling to ascertain vitamin D status and vitamin D supplementation in a cross-sectional study of people with MS across the UK. METHODS: People with MS and matched controls were recruited from across the UK. 1768 people with MS enrolled in the study; remote sampling kits were distributed to a subgroup. Dried blood spots (DBS) were used to assess serum 25(OH)D in people with MS and controls. RESULTS: 1768 MS participants completed the questionnaire; 388 MS participants and 309 controls provided biological samples. Serum 25(OH)D was higher in MS than controls (median 71nmol/L vs 49nmol/L). A higher proportion of MS participants than controls supplemented (72% vs 26%, p<0.001); people with MS supplemented at higher vD doses than controls (median 1600 vs 600 IU/day, p<0.001). People with MS who did not supplement had lower serum 25(OH)D levels than non-supplementing controls (median 38 nmol/L vs 44 nmol/L). Participants engaged well with remote sampling. CONCLUSIONS: The UK MS population have higher serum 25(OH)D than controls, mainly as a result of vitamin D supplementation. Remote sampling is a feasible way of carrying out large studies.

The design, launch and assessment of a new volunteer-based plant monitoring scheme for the United Kingdom.

Volunteer-based plant monitoring in the UK has focused mainly on distribution mapping; there has been less emphasis on the collection of data on plant communities and habitats. Abundance data provide different insights into ecological pattern and allow for more powerful inference when considering environmental change. Abundance monitoring for other groups of organisms is well-established in the UK, e.g. for birds and butterflies, and conservation agencies have long desired comparable schemes for plants. We describe a new citizen science scheme for the UK (the 'National Plant Monitoring Scheme'; NPMS), with the primary aim of monitoring the abundance of plants at small scales. Scheme development emphasised volunteer flexibility through scheme co-creation and feedback, whilst retaining a rigorous approach to design. Sampling frameworks, target habitats and species, field methods and power are all described. We also evaluate several outcomes of the scheme design process, including: (i) landscape-context bias in the first two years of the scheme; (ii) the ability of different sets of indicator species to capture the main ecological gradients of UK vegetation; and, (iii) species richness bias in returns relative to a professional survey. Survey rates have been promising (over 60% of squares released have been surveyed), although upland squares are under-represented. Ecological gradients present in an ordination of an independent, unbiased, national survey were well-represented by NPMS indicator species, although further filtering to an entry-level set of easily identifiable species degraded signal in an ordination axis representing succession and disturbance. Comparison with another professional survey indicated that different biases might be present at different levels of participation within the scheme. Understanding the strengths and limitations of the NPMS will guide development, increase trust in outputs, and direct efforts for maintaining volunteer interest, as well as providing a set of ideas for other countries to experiment with.

PHOTOSTENT-02: porfimer sodium photodynamic therapy plus stenting versus stenting alone in patients with locally advanced or metastatic biliary tract cancer.

BACKGROUND: Endobiliary stenting is standard practice for palliation of obstructive jaundice due to biliary tract cancer (BTC). Photodynamic therapy (PDT) may also improve biliary drainage and previous small studies suggested survival benefit. AIMS: To assess the difference in outcome between patients with BTC undergoing palliative stenting plus PDT versus stenting alone. METHODS: 92 patients with confirmed locally advanced or metastatic BTC, ECOG performance status 0-3 and adequate biliary drainage were randomised (46 per group) to receive porfimer sodium PDT plus stenting or stenting alone. The primary end point was overall survival (OS). Toxicity and progression-free survival (PFS) were secondary end points. Treatment arms were well balanced for baseline factors and prior therapy. RESULTS: No significant differences in grade 3-4 toxicities and no grade 3-4 adverse events due to PDT were observed. Thirteen (28%) PDT patients and 24 (52%) stent alone patients received subsequent palliative chemotherapy. After a median follow-up of 8.4 months, OS and PFS were worse in patients receiving PDT compared with stent alone group (OS median 6.2 vs 9.8 months (HR 1.56, 95% CI 1.00 to 2.43, p=0.048) and PFS median 3.4 vs 4.3 months (HR 1.43, 95% CI: 0.93 to 2.18, p=0.10), respectively). CONCLUSION: In patients with locally advanced or metastatic BTC, PDT was associated with worse outcome than stenting alone, explained only in part by the differences in chemotherapy treatments. We conclude that optimal stenting remains the treatment of choice for malignant biliary obstruction and the use of PDT for this indication cannot be recommended outside of clinical trials. TRIAL REGISTRATION NUMBER: ISRCTN 87712758; EudraCT 2005-001173-96; UKCRN ID: 1461.

A Multicenter Randomized Trial of Ibandronate Compared With Single-Dose Radiotherapy for Localized Metastatic Bone Pain in Prostate Cancer.

BACKGROUND: The radiotherapy or ibandronate (RIB) trial was a randomized multicenter nonblind two-arm trial to compare intravenous ibandronate given as a single infusion with single-dose radiotherapy for metastatic bone pain. METHODS: Four hundred seventy prostate cancer patients with metastatic bone pain who were suitable for local radiotherapy were randomly assigned to radiotherapy (single dose, 8 Gy) or intravenous infusion of ibandronate (6mg) in a noninferiority trial. Pain was measured using the Brief Pain Inventory at baseline and four, eight, 12, 26, and 52 weeks. Pain response was assessed using World Health Organization (WHO) criteria and the Effective Analgesic Score (EAS); the maximum allowable difference was ±15%. Patients failing to respond at four weeks were offered retreatment with the alternative treatment. Quality of life (QoL) was assessed at baseline and four and 12 weeks. Because the trial was designed with a 5% one-sided test, we provide 90% confidence intervals (two-sided) for differences in pain response. RESULTS: Overall, pain response was not statistically different at four or 12 weeks (WHO: -3.7%, 90% confidence interval [CI] = -12.4% to 5.0%; and 6.7%, 90% CI = -2.6 to 16.0%, respectively). Corresponding differences using the EAS were -7.5% and -3.5%. However, a more rapid initial response with radiotherapy was observed. There was no overall difference in toxicity, although each treatment had different side effects. QoL was similar at four and 12 weeks. Overall survival was similar between the two groups but was better among patients having retreatment than those who did not. CONCLUSIONS: A single infusion of ibandronate had outcomes similar to a single dose of radiotherapy for metastatic prostate bone pain. Ibandronate could be considered when radiotherapy is not available.

Decline in CA19-9 during chemotherapy predicts survival in four independent cohorts of patients with inoperable bile duct cancer.

BACKGROUND: Carbohydrate associated antigen (CA19-9) has been approved by the FDA as a biomarker for monitoring treatment effect in pancreatic cancer. However, the value of serum CA19-9 as a biomarker of response to chemotherapy in bile duct cancer is unclear. The aim of this study was to determine if a decline in CA19-9 (CA19-9 response) during chemotherapy is predictive of survival in patients with inoperable bile duct cancer. METHODS: Consecutive patients with inoperable bile duct cancer treated at a University Hospital were retrospectively included in an investigational cohort (n = 212). Three validation cohorts were established including patients 1) participating in phase I/II trials at a Danish Hospital (n = 71), 2) identified retrospectively in a Canadian cohort (n = 196) and 3) randomized in the ABC-02 trial (n = 410). Patients with a baseline CA19-9 and at least one CA19-9 value measured 10-12 weeks after the start of chemotherapy were included. Multivariate Cox regression analyses were performed. RESULTS: Patients meeting the criteria to be included were 54 in the investigational cohort and 34, 68 and 148 in the three validation sets, respectively. Multivariate analysis included radiological response, performance status, bilirubin, gender, site of cancer, extend of disease, CA19-9 at baseline and age. A hazard ratio (HR) of 0.60 (95%CI: 0.44-0.80, p = 0.0005) for death in CA19-9 responders was reached in the investigational cohort. The predictive value of CA 19-9 response was confirmed in all three validation cohorts. CONCLUSIONS: CA19-9 response is a robust predictor of survival in patients with inoperable bile duct cancer in four independent data sets.

"Mind the gap"--the impact of variations in the duration of the treatment gap and overall treatment time in the first UK Anal Cancer Trial (ACT I).

PURPOSE: The United Kingdom Coordinating Committee on Cancer Research anal cancer trial demonstrated the benefit of combined modality treatment (CMT) using radiotherapy (RT), infusional 5-fluorouracil, and mitomycin C over RT alone. The present study retrospectively examines the impact of the recommended 6-week treatment gap and local RT boost on long-term outcome. METHODS AND MATERIALS: A total of 577 patients were randomly assigned RT alone or CMT. After a 6-week gap responders received a boost using either additional external beam radiotherapy (EBRT) (15 Gy) or iridium-192 implant (25 Gy). The effect of boost, the gap between initial treatment (RT alone or CMT) and boost (Tgap), and overall treatment time (OTT) were examined for their impact on outcome. RESULTS: Among the 490 good responders, 436 (89%) patients received a boost after initial treatment. For boosted patients, the risk of anal cancer death decreased by 38% (hazard ratio [HR]: 0.62, 99% CI 0.35-1.12; p=0.04), but there was no evidence this was mediated via a reduction in locoregional failure (LRF) (HR: 0.90, 99% CI 0.48-1.68; p=0.66). The difference in Tgap was only 1.4 days longer for EBRT boost, compared with implant (p=0.51). OTT was longer by 6.1 days for EBRT (p=0.006). Tgap and OTT were not associated with LRF. Radionecrosis was reported in 8% of boosted, compared with 0% in unboosted patients (p=0.03). CONCLUSIONS: These results question the benefit of a radiotherapy boost after a 6-week gap. The higher doses of a boost may contribute more to an increased risk of late morbidity, rather than local control.

Inhibition of carboplatin-induced DNA interstrand cross-link repair by gemcitabine in patients receiving these drugs for platinum-resistant ovarian cancer.

BACKGROUND: The potential of gemcitabine to interact with carboplatin was explored in a phase II trial in platinum-resistant ovarian cancer. Peripheral blood lymphocytes were sampled after drug administration to measure DNA interstrand cross-link formation and repair. PATIENTS AND METHODS: Forty patients received carboplatin target area under concentration-time curve (AUC 4) followed by gemcitabine 1,000 mg/m(2) with a second dose of gemcitabine on day 8. Peripheral blood lymphocytes were obtained in 12 patients before and at intervals during the first cycle of chemotherapy. DNA cross-link formation and repair (unhooking) were measured by the single-cell gel electrophoresis (comet) assay following ex vivo incubation. RESULTS: The global response rate was 47% (Response Evaluation Criteria in Solid Tumors rate, 29%; CA125 rate, 63%). Delays in treatment were seen in 24% of cycles largely due to myelosuppression; 15% of day 8 administration was omitted. Peak carboplatin-induced DNA cross-linking was seen by 24 hours. Significant reduction was seen in the repair of in vivo carboplatin-induced DNA cross-links following administration of gemcitabine. CONCLUSION: An enhanced activity of carboplatin in platinum-resistant ovarian cancer may be due to synergy with gemcitabine through inhibition of repair of DNA cross-links. Future studies should explore coadministration of these drugs, as this may be a more effective schedule.

Anti-angiogenic therapy using thalidomide combined with chemotherapy in small cell lung cancer: a randomized, double-blind, placebo-controlled trial.

BACKGROUND: Cancer cells rely on angiogenesis for growth and dissemination, and small cell lung cancer (SCLC) is a highly angiogenic tumor. We evaluated thalidomide, an anti-angiogenic agent, when combined with chemotherapy and as maintenance treatment. METHODS: A total of 724 patients (51% with limited and 49% with extensive disease) were randomly assigned to receive placebo or thalidomide capsules, 100-200 mg daily for up to 2 years. All patients received etoposide and carboplatin every 3 weeks for up to six cycles. Endpoints were overall survival, progression-free survival, tumor response rate, toxicity, and quality of life (QoL). Hazard ratios (HRs) for comparing thalidomide against placebo were estimated using Cox regression modeling. Statistical tests were two-sided. RESULTS: The median overall survival was 10.5 months (placebo) and 10.1 months (thalidomide) (HR for death = 1.09, 95% confidence interval [CI] = 0.93 to 1.27; P = .28). Among patients with limited-stage disease, there was no evidence of a survival difference (HR for death = 0.91, 95% CI = 0.73 to 1.15), but among patients with extensive disease, survival was worse in the thalidomide group (HR for death = 1.36, 95% CI = 1.10 to 1.68). Progression-free survival rates were also similar in the two groups (HR = 1.07, 95% CI = 0.92 to 1.24). Thalidomide was associated with an increased risk of having a thrombotic event, mainly pulmonary embolus and deep vein thrombosis (19% thalidomide vs 10% placebo; HR = 2.13, 95% CI = 1.41 to 3.20; P < .001). There were no statistically significant differences between treatments in hematological and nonhematological toxic effects, except more patients in the thalidomide group had rash, constipation, or neuropathy. Overall, QoL scores were similar in the two treatment groups, but thalidomide was associated with less insomnia and diarrhea and more constipation and peripheral neuropathy. CONCLUSIONS: In this large randomized trial, thalidomide in combination with chemotherapy did not improve survival of patients with SCLC but was associated with an increased risk of thrombotic events.

Randomized double-blind placebo-controlled trial of thalidomide in combination with gemcitabine and Carboplatin in advanced non-small-cell lung cancer.

PURPOSE: Cancers rely on angiogenesis for their growth and dissemination. We hypothesized that thalidomide, an oral antiangiogenic agent, when combined with chemotherapy, and as maintenance treatment, would improve survival in patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Seven hundred twenty-two patients were randomly assigned to receive placebo or thalidomide capsules 100 to 200 mg daily for up to 2 years. All patients received gemcitabine and carboplatin every 3 weeks for up to four cycles. End points were overall survival (OS), progression-free survival (PFS), response rate, grade 3/4 toxicity, and quality of life (QoL). RESULTS: The median OS rates were 8.9 months (placebo) and 8.5 months (thalidomide). The hazard ratio (HR) was 1.13 (95% CI, 0.97 to 1.32; P = .12). The 2-year survival rate was 16% and 12% in the placebo and thalidomide arms, respectively. The PFS results were consistent with those for OS. The risk of having a thrombotic event was increased by 74% in the thalidomide group: HR of 1.74 (95% CI, 1.20 to 2.52; P = .003). There were no differences in hematologic toxicities, but a slight excess of rash and neuropathy in the thalidomide group. QoL scores were similar but thalidomide was associated with less insomnia, and more constipation and peripheral neuropathy. In a retrospective analysis, patients with nonsquamous histology in the thalidomide group had a poorer survival: 2-year risk difference of 10% (95% CI, 4% to 16%; P < .001). CONCLUSION: In this large trial of patients with NSCLC, thalidomide in combination with chemotherapy did not improve survival overall, but increased the risk of thrombotic events. Unexpectedly, survival was significantly worse in patients with nonsquamous histology.

Socio-demographic variations in moves to institutional care 1991-2001: a record linkage study from England and Wales.

BACKGROUND: Only a minority of older people in England and Wales live in institutional care, but among the older of the old, this minority is large. Disability is the major driver of admissions, but socio-demographic factors are also relevant. Understanding more about the influence of these is important for planning by long-term care. OBJECTIVE: To investigate effects of socio-demographic factors, including housing tenure, household type, marital status, and number of children, on the proportions of elderly people who made a transition from living in the community in 1991 to living in institutional care in 2001. SUBJECTS AND SETTING: Nationally representative record linkage study including 36,650 people aged 65 years and over, living in the community in England and Wales in 1991, who were still alive in 2001. Nineteen thousand women aged 75-89 years in 2001 were included in additional analyses of effects of parity (number of children borne). METHODS: Bi-variate and multivariate analyses of variations in sample proportions, who by 2001 were resident in institutional care. RESULTS: 4.3% of men and 9.3% of women in the surviving sample then aged 75 years and over, were in institutional care in 2001. Older age, living in rented accommodation, living alone in 1991 and being unmarried in 2001, as well as long-term illness, were associated with higher proportions making this transition. Women had higher risks than men. Childless women aged 64-79 years in 1991 had a 25% higher risk than women with children of being in institutional care in 2001. CONCLUSION: Socio-demographic factors continue to influence risks of entry to institutional care in England and Wales.