GIS Approaches for the Estimation of Residential-Level Ambient PM Concentrations Spatial estimations are increasingly used to estimate geocoded ambient particulate matter -LRB- PM -RRB- concentrations in epidemiologic studies because measures of daily PM concentrations are unavailable in most U.S. locations . This study was conducted to a -RRB- assess the feasibility of large-scale kriging estimations of daily residential-level ambient PM concentrations , b -RRB- perform and compare cross-validations of different kriging models , c -RRB- contrast three popular kriging approaches , and d -RRB- calculate SE of the kriging estimations . We used PM data for PM with aerodynamic diameter ≤ 10 μm -LRB- PM10 -RRB- and aerodynamic diameter ≤ 2.5 μm -LRB- PM2 .5 -RRB- from the U.S. Environmental Protection Agency for the year 2000 . Kriging estimations were performed at 94,135 geocoded addresses of Women 's Health Initiative study participants using the ArcView geographic information system . We developed a semiautomated program to enable large-scale daily kriging estimation and assessed validity of semivariogram models using prediction error -LRB- PE -RRB- , standardized prediction error -LRB- SPE -RRB- , root mean square standardized -LRB- RMSS -RRB- , and SE of the estimated PM . National - and regional-scale kriging performed satisfactorily , with the former slightly better . The average PE , SPE , and RMSS of daily PM10 semivariograms using regular ordinary kriging with a spherical model were 0.0629 , − 0.0011 , and 1.255 μg/m3 , respectively ; the average SE of the estimated residential-level PM10 was 27.36 μg/m3 . The values for PM2 .5 were 0.049 , 0.0085 , 1.389 , and 4.13 μg/m3 , respectively . Lognormal ordinary kriging yielded a smaller average SE and effectively eliminated out-of-range predicted values compared to regular ordinary kriging . Semiautomated daily kriging estimations and semivariogram cross-validations are feasible on a national scale . Lognormal ordinary kriging with a spherical model is valid for estimating daily ambient PM at geocoded residential addresses . Large-scale , population-based epidemiologic investigations of the health effects of ambient air pollution often rely on measurements from a network of air quality monitors maintained by the U.S. Environmental Protection Agency -LRB- U.S. EPA 1995a , 1995b , 2005 -RRB- . The Air Quality System -LRB- AQS -RRB- is the only national ambient air pollution database currently available for public use in the United States . The availability of individual-level health outcome and covariable data from national-scale studies that often characterize participants over the course of several years enables researchers to study the acute effects of ambient air pollution using individual-level data -LRB- Liao et al. 2004 , 2005a ; Sullivan et al. 2005 ; Wellenius et al. 2005 ; Whitsel et al. 2004 -RRB- . This approach requires measures of daily particulate matter -LRB- PM -RRB- exposures , ideally assessed as close to the individual level as possible , such as at participant residences or in immediate proximity to participants themselves . Because daily measures of ambient PM concentrations from the AQS are unavailable in the large majority of locations , spatial estimation methods using geographic information systems -LRB- GIS -RRB- are increasingly being considered to estimate geocoded location-specific ambient PM concentrations , such as kriging methods . Important methodologic and practical issues still need to be resolved , however . This study was designed to a -RRB- assess the feasibility of large-scale kriging estimation of daily residential-level ambient PM concentrations , b -RRB- perform and compare cross-validations of different kriging models , c -RRB- determine and contrast the most appropriate kriging approaches , and d -RRB- calculate the SEs of the kriging estimations . Materials and Methods We obtained from AQS the PM10 and PM2 .5 -LRB- PM with aerodynamic diameter ≤ 10 and 2.5 μm , respectively -RRB- data from 1993 -- 2004 -LRB- U.S. EPA 2005 -RRB- . The data from 2000 were used for this study after eliminating duplicate records and converting all measures to the same units and denominator . We calculated `` monitor-specific '' daily averages based on ≥ 18 hourly measures . Monitor-specific daily averages were set to missing for monitors reporting < 18 hourly measures on any given day . If more than one monitor was operating at the same location on a given day , we then computed `` site-specific '' daily PM10 and PM2 .5 averages by taking the mean of the monitors ' measures . We also obtained the longitude and latitude for each site from the AQS database . These data served as pollutant - and site-specific daily source data for our study -LRB- Liao et al. 2005b -RRB- . We geocoded 94,135 addresses of Women 's Health Initiative -LRB- WHI -RRB- Clinical Trial -LRB- CT -RRB- participant residences and examination sites in the contiguous 48 United States and District of Columbia , after assessing geocoding vendor error -LRB- Whitsel et al. 2004 , 2005 -RRB- . Daily PM10 and PM2 .5 concentrations and the associated estimation errors -LRB- SEs -RRB- are estimated at these geographic locations by the Environmental Epidemiology of Arrhythmogenesis in WHI study -LRB- Whitsel 2006 -RRB- . We used ArcView GIS -LRB- version 8.3 -RRB- and its Geostatistical Analyst Extension -LRB- ESRI Inc. , Redlands , CA -RRB- for semivariogram determination and cross-validation and for subsequent spatial estimation of daily location-specific PM concentrations . Three frequently referenced spatial models -LRB- spherical , exponential , Gaussian -RRB- -LRB- Cressie 1993a ; Davis 2002 -RRB- were considered using the weighted least-squares method -LRB- Gribov et al. 2004 ; Jian et al. 1996 -RRB- to obtain the `` optimal '' daily semivariogram parameters -LRB- range , partial sill , and nugget -RRB- . Based on the daily semivariograms , we performed ordinary kriging to estimate the daily mean PM concentration and its SE at each of the 94,135 geocoded addresses . Next , we performed the standard cross-validation -- an iterative procedure that omits site-specific PM data points one at a time and refits the model using the remaining data to estimate the PM concentration at the site of the omitted observation . We assessed the validity -LRB- also termed `` goodness of fit '' -RRB- of each semivariogram using three cross-validation parameters readily available from the ArcView software package : a -RRB- the average of prediction error -LRB- PE -RRB- , where PE is the average of the difference between the predicted and measured daily PM values at each monitoring site ; b -RRB- the average of standardized prediction error -LRB- SPE -RRB- , where SPE is the PE divided by the SE of estimation across all sites ; and c -RRB- root mean square standardized -LRB- RMSS -RRB- , the standard deviation -LRB- SD -RRB- of all SPEs across all sites . Additionally , we assessed the goodness of fit of each semivariogram by the average of the SEs of the estimations , generated by the kriging procedure , across all 94,135 geocoded addresses . The expectations for a good-fitting semivariogram and kriging model are an average PE and SPE near 0 , an RMSS near 1 , and a small SE . If RMSS < 1 , there is a tendency toward overestimation of the variance ; if > 1 , there is a tendency toward underestimation -LRB- ESRI Inc. 2001 -RRB- . These criteria were consistently used to guide our model selection processes throughout this study -LRB- Liao et al. 2005c -RRB- . As an alternative to using the automatically calculated semivariogram -LRB- calculated using the weighted least-squares method -LRB- Gribov et al. 2004 ; Jian et al. 1996 -RRB- , one can also manually specify the semivariogram parameters to improve the cross-validation parameters in ArcView . We selected six least satisfactory daily semivariograms throughout year 2000 and manually adjusted the semivariogram parameters to obtain the best achievable average RMSS and SPE -LRB- RMSS as close to 1 and average SPE as close to 0 as possible -RRB- . The cross-validation parameters from the weighted least-squares method -- calculated semivariograms were then compared to those of the manually adjusted semivariograms . We performed daily ordinary krigings on both the original scale -LRB- regular ordinary krig-ing -RRB- and the lognormal scale -LRB- lognormal ordinary kriging -RRB- -LRB- Cressie 1993b ; Johnston 2001 -RRB- for all WHI CT addresses for the year 2000 and compared the cross-validation parameters between the two kriging procedures . Log-normal ordinary kriging was used because it has the ability to eliminate the negative predicted values , which is a problem in ordinary kriging , especially when the source data contain extreme values . Results Characteristics of the site-specific daily average PM10 and PM2 .5 concentrations During 1994 -- 2003 , the number of monitoring sites that provided GIS-usable daily PM10 data varied widely -LRB- range , 120 -- 1,340 -RRB- . On 17 % of days , GIS-usable data were provided by ≥ 400 monitoring sites ; on 39 % of days , by 200 -- 400 sites ; and on 44 % of days , by 120 -- 200 sites . The corresponding values for PM2 .5 during 1999 -- 2003 were 33 % of days by ≥ 400 sites and 67 % of days by 148 -- 400 sites . Specific to the year 2000 , there were averages of 325 PM10 and 456 PM2 .5 monitoring sites operating per day across the contiguous United States , with minima and maxima of 148 and 1,061 sites for PM10 and 178 and 1,019 sites for PM2 .5 . As a result , there were 118,791 site-days during 2000 for which we can retrieve measured PM10 data and 166,796 site-days for PM2 .5 data . The mean -LRB- ± SD -RRB- of PM10 and PM2 .5 from these retrievable site-days were 26.29 ± 58.13 and 13.14 ± 8.59 μg/m3 , respectively , with medians of 21.33 and 11.20 μg/m3 , respectively . A right-skewed distribution of both PM10 and PM2 .5 are evident , especially for PM10 . Figure 1 illustrates the spatial relationships between the geocoded addresses and the PM monitoring sites on an optimal day and a typical day . The mean distance between each address and its nearest PM monitor was 12.35 km , with an SD of 13.98 km , a median of 7.81 km , an interquartile range of 10.53 km , and 99th percentile of 68.36 km . Comparisons of three widely used spatial models Tables 1 and 2 present summary statistics of the cross-validation parameters -LRB- PE , SPE , and RMSS -RRB- comparing three widely used spatial models -LRB- spherical , exponential , Gaussian -RRB- for PM10 and PM2 .5 , respectively . In general , both average PE and average SPE are very close to 0 , with a very narrow range of variation from the 366 daily cross-validations . More specifically , > 95 % of average PEs were within ± 2 μg/m3 of measured PM10 , and ± 0.5 μg/m3 of measured PM2 .5 , an average measurement error that we considered acceptable . In terms of RMSS , we considered > 95 % of cross-validations as acceptable , but there were days when RMSS indicated a slight over-or underestimation of the prediction variability . These data support the overall validity of using kriging-based estimation approaches to estimate location-specific PM concentrations across the contiguous United States . Comparisons of default and manually adjusted semivariograms Table 3 presents the cross-validations and actual kriging estimations from the weighted least-squares mean method calculated semivariogram and manually adjusted semivariogram . For the 6 days when the PE , SPE , or RMSS indicated a less satisfactory default-calculated semivariogram , these three cross-validation parameters could be improved satisfactorily through adjustment of the semivariogram parameters by an operator . However , the application of such `` improved '' semivariograms to the estimation of PM10 concentrations at geocoded locations across the United States did not necessarily provide better estimation of location-specific PM -LRB- i.e. , smaller SEs -RRB- . To the contrary , the average SEs from the default semivariograms were smaller than those from manually adjusted semivariograms . Because each average SPE of the default-calculated daily semivariograms was close to 0 , and each default-calculated daily semivariogram produced a smaller estimation error , we recommend using the default-calculated semivariogram , even though the RMSS from the default-calculated semivariogram was not fully satisfactory . Comparisons of regular versus lognormal ordinary krigings We applied regular ordinary kriging -LRB- spherical model , default-calculated daily semivariograms -RRB- to estimate daily PM10 concentrations at geocoded addresses -LRB- n = 94,135 -RRB- of WHI CT participants and examination sites in the contiguous United States . We examined the estimated PM10 concentrations and identified 22 days during 2000 when estimated values exceeded the range of observed values . In some cases , the estimated values were negative . The number of addresses affected by this problem ranged from a few on most days to 3.5 % of all addresses . This problem was related to skewed PM10 distributions and to small numbers of extreme outlying values or operating sites on some days . We therefore compared regular ordinary kriging and log-normal ordinary kriging anticipating that log-normal kriging would attenuate this problem . Table 4 lists the 22 days on which regular ordinary kriging yielded estimated PM10 values that were outside the range of measured values . For comparison , the minima and maxima of the measured and estimated PM10 concentrations from both regular and log-normal ordinary krigings are also listed in Table 4 . In summary , during 2000 , lognor-mal ordinary kriging effectively reduced the number of problematic days from 22 to 1 . Even on this one day , lognormal ordinary kriging yielded a minimum value that was closer to the range of measured data than that from regular ordinary kriging . Table 5 shows the mean values of cross-validation parameters of daily PM10 semivariograms for both regular ordinary kriging and lognormal ordinary kriging . Cross-validation parameters were within the acceptable range from both regular and lognormal ordinary krigings , except for the 22 `` out-of-range '' days as defined above . On these out-of-range days , the SPE was well within the acceptable range for both regular and lognormal krigings , but the RMSS was > 1 from both approaches . Even so , for these out-of-range days RMSS from lognormal ordinary kriging was closer to 1 than that from regular ordinary kriging . We then performed regular and lognormal ordinary kriging to estimate PM10 concentrations at geocoded addresses of WHI CT participants and examination sites , based on year 2000 PM10 data -LRB- 94,135 locations and 366 days -RRB- . The mean , SD , median , and maximum of the daily mean SE of the estimated PM10 from the regular ordinary kriging were 27.36 , 83.35 , 13.93 , and 1160.20 μg/m3 , respectively . In contrast , those from the lognormal ordinary kriging were 16.29 , 6.65 , 15.05 , and 67.46 μg/m3 . Clearly , the distribution of the estimation errors from lognormal ordinary kriging was considerably less skewed and had fewer outlying values than that from regular ordinary kriging . Alternative methods -LRB- winsorizing extreme PM10 values ; using ArcView 's `` no-sector '' option to search for measured data points from a circle centered around a location that needs of an estimation -- i.e. , disabling the default `` sector '' search for measured data points in the four sectors of a circle , reducing the range or nugget -RRB- were less effective in estimating predicted values within the range of measured values -LRB- data not shown -RRB- . Similar to the situation observed in PM10 estimations , lognormal ordinary kriging also effectively eliminated the negative or out-of-range problem that occurred in about 5 % of PM2 .5 data when using regular ordinary kriging . Other cross-validation parameters were comparable between the lognormal and regular ordinary krigings -LRB- data not shown -RRB- . Comparisons between national and regional krigings From the 61 days when 900 or more monitoring sites were operating in the year 2000 in the 48 contiguous states , the first of such days from each month was selected for comparisons between ordinary kriging models on a national versus regional scale . National krigings and cross-validations were performed on these 12 selected days using daily site-specific PM10 data . Regional krigings and cross-validations were performed on the same data using the regional map -LRB- Figure 1 -RRB- that divides the U.S. continent into five regions -LRB- northwest , southwest , middle north , southeast , and northeast -RRB- . These five regions were created based on the assumption that different semivariogram parameters would be needed for different geographic areas . In general , for both regional and national krigings , the average SPE and RMSS from cross-validations of semivariograms calculated for the 12 selected days were very close to 0 and 1 , respectively -LRB- Table 6 -RRB- Discussion Classical methods often assume that measures are uniformly or randomly distributed . The assumptions are often inappropriate for analysis of environmental measures because values at neighboring locations are rarely independent , particularly over short distances . This form of dependence -LRB- spatial autocorrelation -RRB- nonetheless makes it possible to interpolate values at unmonitored locations from known values at monitored locations . Kriging is one such interpolation method originally developed by mining engineers -LRB- Krige 1966 -RRB- . It is especially attractive in this setting because it takes the spatial autocorrelation structure function -LRB- variogram -RRB- into account by considering known values from monitored locations , weighting them with values read from the variogram at corresponding distances , and splitting weights among adjacent locations . The method thereby ensures that interpolations do not depend on monitor density -LRB- Legendre and Fortin 1989 -RRB- . By doing so , kriging yields best linear unbiased estimates , in this setting , of location-specific daily mean ambient PM concentrations and their SEs . Large-scale population-based epidemiologic investigations of the health effects of ambient air pollution often rely on data collected from a network of air quality monitors maintained by the U.S. EPA -- the AQS data -LRB- U.S. EPA 1995a , 1995b , 2005 -RRB- . It is revealing to compare kriging with interpolation methods used in the well-known time-series and cohort studies of PM effects on mortality and cardiovascular disease -LRB- Abbey et al. 1991 , 1999 ; Dockery et al. 1993 ; Katsouyanni et al. 1996 , 2001 ; Miller et al. 2004 , 2005 ; Pope et al. 2004 ; Samet et al. 2000a , 2000b -RRB- . These studies uniformly estimated PM exposures using area-based arithmetic averaging or nearest-neighbor imputation -- alternative methods that have important limitations -LRB- Moore and Carpenter 1999 -RRB- . Such limitations include the assumption of homogeneous exposures within study areas and the inability -LRB- or failure -RRB- to estimate exposures or associated PEs . For example , when daily exposure was of interest and there were no operating PM monitors with a study area , data pairs -LRB- daily PM concentrations , death counts -RRB- were unavailable in these studies . In addition , when longer-term -LRB- monthly to yearly -RRB- exposure was of interest , area aggregated exposures were based on available measurements within a given time frame . If there were five 24-hr measures in a month , for example , the monthly average exposure was calculated as the mean of the five readings . In contrast , our kriging-based approach estimated daily mean exposures and SEs at geocoded addresses of participants and their examination sites across the contiguous United States that can be readily integrated over time with little influence of missing data . Studies in the geosciences have also found that kriging provides consistently improved interpolation accuracy over traditional inverse-distance weighting and other , simpler spatial interpolation methods -LRB- Zimmerman 1999 -RRB- . Another important advantage of GIS-based estimation over the traditional area-average approach is the availability of both the location-specific estimated pollutant concentrations and their SEs . Our goal in this study was to contribute methodologic and practical insights toward standardized , semiautomated GIS approaches to estimation of daily air pollution concentrations and their associated estimation errors . The air pollution data estimated using these approaches will support the Environmental Epidemiology of Arrhythmogenesis in WHI study -LRB- Whitsel 2006 -RRB- examining the cardiac effects of air pollution in 68,133 post-menopausal women 50 -- 79 years of age at baseline in the WHI CT -LRB- WHI Study Group 1998 -RRB- . Here we describe our experience resolving several important methodologic and practical issues in adopting a systematic , standardized , and semiautomated kriging approach to estimate daily air pollution concentrations and the associated estimation errors at geocoded addresses across the contiguous United States over 10 years . We successfully downloaded from AQS the PM10 and PM2 .5 raw data from 1993 -- 2004 . We then cleaned , calculated , and reconstructed site-specific daily PM concentration data ready for GIS applications . It is well known that the monitoring sites in AQS are not randomly distributed , which is one of the assumptions in kriging estimation , and the density of the monitoring sites is relatively low given the size of the contiguous United States . However , the AQS is the only currently available nationwide database . Our cross-validation studies suggest that the AQS data can be used as source data for kriging estimation of ambient pollution concentrations at various locations across the 48 contiguous states . In this study , we performed cross-validation to assess the goodness of fit of various semivariogram and spatial models using four major parameters : the average PE , SPE , RMSS , and SE of estimation . Details can be found elsewhere -LRB- Webster and Oliver 2001 -RRB- , but it is worth noting that in addition to using the SE as a measure of the goodness of fit of a kriging model , one could improve the health effects models by incorporating SE in the models to account for the error in the estimation of location-specific PM concentrations . We consider this an important advantage of GIS-based estimation over the traditional area-average approach and are performing studies of using SE in health effects models . We compared the performance of three widely spatial models -LRB- spherical , exponential , Gaussian -RRB- for PM10 and PM2 .5 estimations using regular ordinary kriging on a national scale -LRB- Tables 1 and 2 -RRB- . In general , the cross-validation parameters suggest that all three models performed fairly well . Overall , the spherical model seemed to perform slightly better , consistent with the observation that the spatial distribution pattern of ambient air pollutants is closest to the assumption of the spherical model . The spherical model has been used most often in modeling spatially distributed data , providing a further rationale for its use in our large-scale population-based study of the health effects of PM . Furthermore , from the perspective of the cross-validation results , both average PE and average SPE are very close to 0 , with a very narrow range of variation from the 366 daily cross-validations . These data support the overall validity of using kriging-based estimation approaches to estimate location-specific PM concentrations across the contiguous United States . We completed an empirical analysis to investigate whether manually adjusting semivariogram parameters improves a -RRB- cross-validation parameters and b -RRB- estimated PM10 concentrations and their SEs -LRB- Table 3 -RRB- . From these data , we conclude that manually adjusting semivariogram parameters improves cross-validation parameters . However , the application of such `` improved '' semivariograms to the estimation of PM10 concentrations at geocoded locations across the United States did not necessarily provide better estimation of location-specific PM . Therefore , we recommend using the default-calculated semivariogram . Semivariograms are sensitive to strong positive skewness . As a result , regular ordinary kriging can yield negative predicted values or values exceeding the range of the source data . Kriging works best if the input data have a normal distribution . One solution is to log-transform the input data -- using `` lognormal kriging . '' In the ArcView software package , performing lognormal kriging is a standard option . This option log-transforms the input data to normalize its distribution and attenuate the impact of very large values . It also back-transforms the estimated values and the `` unbiased '' SE of the estimation to the original scale -LRB- Cressie 1993b ; Johnston 2001 -RRB- . Our results comparing lognormal ordinary kriging versus regular-scale ordinary kriging suggest that lognormal ordinary kriging not only effectively estimated location-specific PM concentrations within the range of the measured data for the days regular ordinary kriging yielded negative or `` out of range '' PM estimations , but also yielded a smaller average SE than did regular ordinary kriging and estimations . Therefore , our results support the use of lognormal ordinary kriging as an acceptable solution to the problem commonly posed by positively skewed distributions of environmental data . Our comparisons of national - versus regional-scale kriging indicate that , in terms of cross-validation results , both performed similarly . However , such comparisons are based on krigings using the source data from optimal days -LRB- when > 900 sites across the country were reporting data -RRB- , which account for only 17 % of all days in a year . Therefore , there is additional justification for using national-scale kriging : Usually , there were very few operating sites within a region . On typical days -- when only about 200 monitoring sites were operating -- ability to derive stable and meaningful semivariograms was greatly impaired . Regional kriging also poses problems for estimation at locations near regional borders . For example , at locations within Washington State but near the Washington -- Idaho border , regional kriging is based solely on PM10 concentrations in the `` Washington/Oregon , Northern California '' region . It is not based on PM10 concentrations measured immediately across the border in Idaho , despite the real possibility that they would have the largest weights in national-scale kriging estimation . For all these reasons , we recommend national-scale kriging . Considering the number of study participants and the length of study period -LRB- 1994 -- 2003 -RRB- for the Environmental Epidemiology of Arrhythmogenesis in WHI study , development of an automated procedure enabling large-scale daily krigings and semivariogram cross-validations was critical . In this study , we decided to use ArcView for predicting individuals ' PM exposure concentrations because of the flexibility it offers for automation . Because ArcView GIS relies on either the weighted least-squares method or visual adjustment to create semivariograms , we did not compare the relative performance of semivariograms generated using alternative methods such as maximum likelihood and restricted maximum likelihood . For generating semivariograms , we compared only three popular spatial models -LRB- spherical , exponential , and Gaussian -RRB- . Our results , however , do not invalidate alternative spatial models -LRB- e.g. , power -RRB- . In the end , we selected the spherical model for our study because it is the most studied model , and its assumption pertaining to the spatial correlation of data is probably closest to our pollutant data . Furthermore , the spherical model seemed to perform as well as or slightly better than the remaining models in terms of cross-validation parameters . We chose ordinary kriging instead of universal or simple kriging for several reasons . First , the assumption for simple kriging of a known mean concentration on any given day across space is not practical for our data . Although it may seem more appropriate because of the `` varying mean '' concentration across the contiguous U.S. assumption , universal kriging requires a predetermined set of `` exploratory variables '' to explain the varying means . The candidates , many of which are spatial variables , include emissions , land use , population , road network distribution , altitude , rainfall , latitude , climatology , and other quality data . Denby et al. -LRB- 2005 -RRB- recently recommended a method that uses measured concentration data in combination with some `` exploratory variables '' as suggested above . However , their approach may not be feasible for a national-scale study such as ours , because little guiding information is available as to how to identify a set of widely acceptable variables that can be applied to the entire nation . Moreover , even if we could identify a set of exploratory variables , we do not know the forms or shapes of their independent and joint relations to the air pollution measures . Further studies that involve large-scale national data using universal kriging are still needed . In this study , we empirically tested whether the non-constant mean assumption for universal kriging was needed ; we performed five regional ordinary krigings so that different parts of the country would assume a different mean PM concentration . Our data suggested that regional and national ordinary kriging performed similarly . Therefore , our data indirectly validated and supported the use of national ordinary kriging . Although the primary objective of our study is to assess the short-term relationship between PM and cardiac responses , the proposed kriging method also enables us to calculate the long-term cumulative exposure of an individual by taking into account the change of his or her residences over time , because the WHI study recorded the residential location history over 10 years . Nevertheless , from the environmental perspective , an inherited limitation of the kriging-based approach is that the estimations of the PM concentrations will provide only surrogates , or the best guesses , of the true exposure levels at the locations of interest . Thus , the accuracy of the estimations depends highly on the quality of the measured data and their spatial correlation . Even if the estimations were made with a high level of confidence , they can not be directly interpreted as the true individual-level exposures . However , to correlate individual level cardiac responses with a surrogate of location-specific exposure , our approach represents one of the best available methods for a large-scale population-based study . In summary , our investigation of GIS approaches for estimating daily mean geocoded location-specific air pollutant concentrations and their SEs supports the use of a spherical model to perform lognormal ordinary kriging on a national scale . Our findings also support the use of default-generated semivariograms -LRB- estimated using the weighted least-squares method -RRB- without visual adjustment . We developed a semiautomated program to access and execute ArcView to implement these approaches for large-scale daily kriging estimations and semivariogram cross-validations . Detailed information about this program can be obtained on request .

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O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O B O O O O O O O O O O B O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O B O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O B O O O B O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O B O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O B O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O B O O O O B O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O B O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O

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population-based studies


Re-irradiation of a second localization of idiopathic midline destructive disease in the head and neck area Idiopathic midline destructive disease is a rare disease , characterized by a progressive ulceration and destruction of midline facial structures . We report a case with localization on the palate for which she received radiotherapy . Later she developed a second localization on the posterior pharyngeal wall for which she was re-irradiated , without severe sequels . Twice a complete regression was observed . Introduction Idiopathic midline destructive disease is a rare , which is characterized by a progressive ulceration and destruction of midline facial structures , including the nasal cavity , the paranasal sinuses and the palate . In most cases , radiotherapy is an effective treatment -LSB- 1 -RSB- . We describe a woman with twice a localization of idiopathic midline destructive disease , which were both treated with irradiation . Case report A woman , 46 years of age , was referred with complaints of nasal discharge while drinking . She was otherwise healthy and there was no history of substance use . Physical examination revealed an almost complete destruction of the membranous nasal septum and perforations of the soft and hard palate of 3 and 5 mm , respectively . Further examination of the head and neck region and general examination showed no abnormalities . Computed tomography showed extensive destruction of the hard palate . Biopsy showed a non-specific inflammation and fibrosis -LRB- Fig. 1 -RRB- . There were no signs of Wegener 's granulomatosis , malignant lymphoma , tuberculosis or Epstein-Barr virus infection . Serum tests showed negative results for anti-neutrophil cytoplasmic antibodies -LRB- ANCA -RRB- and syphilis . A diagnosis of idiopathic midline destructive disease was made . Fig. 1Histological picture of idiopathic midline destructive disease detail -LRB- 40 × objective , Hematoxilin & Eosin stain -RRB- showing predominantly small irregular lymphocytes admixed with histiocytes and some granulocytes . The lymphoid cells do not appear obviously malignant . Low power view of biopsy -LRB- 5 × objective , Hematoxilin & Eosin stain -RRB- show an ulcerative surface -LRB- left -RRB- and the infiltrate -LRB- right -RRB- with prominent vessels with swollen endothelial cells The patient was then treated with radiation therapy to a total dose of 52 Gy in 26 fractions . At the end of the radiation course , a grade 1 mucositis and grade 1 erythema were observed . A complete regression of the disease occurred . After 4 years , the defect in the palate was closed surgically using a temporalis muscle flap . Four years later she developed a sore throat and swallowing complaints . On examination , a tumor-like lesion with a central ulcer was seen on the posterior pharyngeal wall . A CT-scan of the head and neck region showed a soft tissue mass on the posterior pharyngeal wall with extension from the level of the soft palate and nasopharynx to the level of the epiglottis . Biopsy showed the same histologic appearance as previously . The site of the original lesion was without any signs of abnormalities . It was decided to treat this new localization with re-irradiation . During treatment , the patient experienced grade 1 erythema and grade 2 mucositis . She experienced swallowing complaints for 4 months . Complete regression occurred again . Four years after re-irradiation the patient presented again with progressive swallowing complaints and nasal speech . On physical examination , an ulcer was seen on the posterior pharyngeal wall with a diameter of 1-cm , which had a different clinical appearance than the former two lesions . Therefore , the differential diagnosis included a radiation-induced ulcer or recurrence midline destructive disease . Biopsy was not taken because it was most likely that pathological examination of this lesion could not distinguish between these two entities and because of an increased probability of wound-healing problems after biopsy in a highly irradiated area . We decided to treat this lesion as a radiation ulcer and the patient was proposed to undergo hyperbaric oxygen therapy , which she refused . Therefore , as an alternative , we decided to treat her with pentoxyfilline and high dose vitamin E , which she has used for one year . In the subsequent 12 months , the ulcer as well as her complaints gradually decreased . During the last follow-up visit -LRB- more than 5 years after re-irradiation -RRB- , there were no signs of recurrent tumor or other severe radiation sequels , while a small ulcer still persists . Besides a mild xerostomia , she had no other complaints . Discussion Idiopathic midline destructive disease -LRB- IMDD -RRB- , also known as lethal midline granuloma -LRB- LMG -RRB- , is a rare disease which is clinically characterized by a progressive , unrelenting ulceration and necrosis of the nasal cavity or the midline facial structures . This disorder has to be distinguished from other progressive , ulcerative disorders of the midline facial tissues , including cocaine use , sarcoidosis , infections like tuberculosis and syphilis , various neoplasms like vestibular or septal carcinoma , Wegener 's granulomatosis , and polymorphic reticulosis -LRB- PMR -RRB- -LSB- 2 -RSB- . In contrast to all the other diseases , which have distinct histopathological features that distinguish them from IMDD , the histopathological findings of IMDD are nonspecific . It is essentially a diagnosis per exclusionem . Some authors believe that IMDD is an early phase of PMR -LSB- 2 -RSB- . Others state that all cases referred to as IMDD or PMR are in fact nasal T-cell -LRB- natural killer cell -RRB- lymphomas -LRB- NTL -RRB- -LSB- 1 , 3 -RSB- , with a possible association with the Epstein-Barr virus -LSB- 4 -RSB- . However , Barker and Hosni recently reported a case of IMDD in which no other cause could be diagnosed by current techniques and they proposed that IMDD remains a valid description in a small number of cases -LSB- 5 -RSB- . In our case the clinical course -LRB- with only localized disease -RRB- and histology -LRB- no atypia or Epstein-Barr virus in the tumor -RRB- argue strongly against lymphoma and for IMDD . Untreated IMDD is eventually fatal . No more than approximately 100 cases have been reported , of which only part is characterized as IMDD and the other cases as PMR or NTL . Therefore outcome parameters , such as survival and local control , are difficult to interpret . The preferred treatment of IMDD is radiation therapy to a dose of at least 50 Gy -LSB- 1 , 3 -RSB- . A 5-year overall survival after radiation therapy has been reported from 15 to 75 % . Local control varies between 63 and 77 % -LSB- 1 -- 4 -RSB- . Cases reported as NTL do worse compared to IMDD -LSB- 1 -RSB- . Some authors administer chemotherapy in case of NTL , although no difference in survival in patients with or without the addition of chemotherapy could be established -LSB- 3 -RSB- . In our case , a total dose of 52 Gy in 26 fractions was used which is generally considered to be sufficient . The margins taken during the first treatment were adequate according to the clinical tumor extension . Also because of the long time-interval , the second lesion can be considered to be a new localization of the disease . It was decided to treat this new localization with re-irradiation for the following reasons . The largest part of the new localization was outside the initial treatment field implying that only part of the previously irradiated area would be treated again with the second course of radiotherapy . Second , the interval between the initial course of radiotherapy and relapse was more than 8 years and the total dose administered was 52 Gy , which may imply that a substantial amount of initial radiation damage to the normal tissues could have recovered -LSB- 6 -- 8 -RSB- . Data on re-treatment of IMDD after local failure are scarce . Both Chen et al. -LSB- 1 -RSB- and Sakata et al. -LSB- 3 -RSB- mention a case with local relapse with successful re-irradiation without giving any detailed information . One patient with a local relapse of IMDD benefited from salvage chemotherapy -LSB- 3 -RSB- , whereas two other patients , who were diagnosed as NTL , failed on a combination of re-irradiation and chemotherapy -LSB- 1 -RSB- ; also on these patients no detailed information regarding radiotherapy was provided . In conclusion , radiation therapy is the treatment of choice for idiopathic midline destructive disease . In case of a second localization in the irradiated area re-irradiation should be considered .

O O O O O O B I I I O O O O O O B I I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O B I I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I I O O O O O O O B I I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I I O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O B I I I O O O O O O O O O O O O O O O O

idiopathic midline destructive disease
radiotherapy
midline granuloma


Quality of life and functional status in patients with cancer of the oral cavity and oropharynx : pretreatment values of a prospective study We assessed the pretreatment health-related quality of life -LRB- HRQOL -RRB- and functional status of patients with advanced oral and oropharyngeal cancer . Eighty patients were investigated . HRQOL was assessed by EORTC QLQ-C30 / QLQ-H & N35 questionnaires . Functional status assessment comprised speech and oral function tests . The results revealed a wide range of HRQOL and functional deficits before treatment . HRQOL appeared to be related to some extent to tumor site -LRB- patients with oral tumors reported more pain compared to patients with oropharyngeal tumors -RRB- and tumor classification -LRB- patients with T3 -- T4 tumors reported more trouble opening the mouth and felt more ill compared to patients with T2 tumors -RRB- . Comorbidity appeared to have a major impact . Patients with comorbidity had significantly worse scores on several scales/items on both the EORTC questionnaires . Functional deficits were related to tumor site , classification and comorbidity . Patients with oral cavity tumors -LRB- versus oropharyngeal tumors -RRB- , patients with T3 -- T4 tumors -LRB- versus T2 tumors -RRB- , and patients with comorbidity -LRB- versus without comorbidity -RRB- scored significantly worse on several speech and oral function tests . Impaired speech and oral function appeared to be clearly related to global quality of life -LRB- QLQ-C30 -RRB- and self-reported speech -LRB- QLQ-H & N35 -RRB- . Many patients with advanced oral and oropharyngeal cancer have compromised HRQOL and functional status before the start of treatment . In addition to tumor site and tumor classification , comorbidity appears to have a major impact on HRQOL and functional status . Knowledge of pretreatment HRQOL and functional status levels is useful for better understanding the impact of treatment on these outcomes over time . Introduction The most important outcome for cancer patients is overall survival . However , the disease and its treatment often have a major impact on health-related quality of life -LRB- HRQOL -RRB- and functional status in patients with head and neck cancer -LSB- 1 -RSB- . Therefore , HRQOL and functional status are important aspects to consider in treatment evaluation . To interpret outcome following treatment , it is necessary to assess HRQOL and functional status following diagnosis , but before the start of treatment -LSB- 2 -RSB- . Studies on pretreatment HRQOL -LSB- 2 -- 5 -RSB- and functional status -LSB- 6 , 7 -RSB- often include heterogeneous groups of head and neck cancer patients . However , there are substantial differences between patient groups that are related to tumor site and stage -LSB- 7 -RSB- . Patients with advanced oral or pharyngeal cancer , for example , often have the poorest HRQOL and functional status -LSB- 5 , 8 -RSB- . Pretreatment HRQOL among patients with oral or oropharyngeal cancer is often compromised , although it tends to be better compared to HRQOL following treatment -LSB- 9 -- 11 -RSB- . There is also evidence that functional status , including oral function , speech and swallowing abilities is significantly deteriorated before treatment -LSB- 12 -- 15 -RSB- . Comorbidity is another important factor that varies substantially among subpopulations of patients , and can have a significant influence on the choice of initial treatment , the care that patients receive , and on treatment outcomes -LSB- 16 -RSB- . Therefore , comorbidity should be taken into consideration evaluating the HRQOL of patients , both at time of diagnosis , and over the course of treatment -LSB- 17 -- 19 -RSB- . The primary objective of the present study is to assess pretreatment HRQOL and functional status in relation to tumor site , tumor classification and comorbidity , in a well-defined group of patients with advanced oral and oropharyngeal cancer . Patients and methods Patients Between January 1998 and December 2001 , 92 consecutive patients diagnosed with stage II-IV oral or oropharyngeal squamous cell carcinomas were asked to participate in the study . The planned treatment was composite resection with microvascular soft tissue transfer -LRB- i.e. , radial forearm free flap -RRB- for the reconstruction of surgical defects , and radiotherapy on indication . Exclusion criteria were age greater than 75 years , serious cognitive impairment and lack of basic fluency in the Dutch language . Twelve patients declined to participate , resulting in a final sample of 80 patients -LRB- response rate = 87 % -RRB- . All patients were treated at the Department of Otolaryngology/Head and Neck Surgery of the VU University Medical Center , Amsterdam , The Netherlands . Data collection and study measures All data were collected prior to the start of treatment , including sociodemographics -LRB- age and gender -RRB- , disease stage , comorbidity , HRQOL , and functional status . Comorbidity was assessed dichotomously -LRB- yes or no -RRB- by review of medical records and on the basis of self-report , and was noted if one or more relevant medical ailments accompanied the primary medical illness . The comorbid conditions were cardiovascular , respiratory , gastro-intestinal , renal , endocrine , neurological , and immunological disorders , previous malignancy and considerable weight loss or alcohol abuse . For example , cardiovascular problems such as a myocardial infarct or hypertension , respiratory problems such as restrictive lung disease or COPD , or endocrine disorders such as diabetes mellitus with insulin usage were defined as relevant comorbid conditions . HRQOL was assessed by means of the European Organization for Research and Treatment of Cancer -LRB- EORTC -RRB- QLQ-C30 questionnaire -LRB- version 2.0 -RRB- -LSB- 20 -RSB- and the EORTC head and neck cancer module QLQ-H & N35 -LSB- 21 -RSB- . The QLQ-C30 is composed of multi-item scales and single items assessing five areas of functioning -LRB- physical , role , emotional , cognitive , and social -RRB- , fatigue , pain , emesis , dyspnea , insomnia , appetite loss , constipation , and diarrhea . Overall quality of life and the perceived financial impact of the disease and treatment are also assessed . The head and neck cancer-specific QLQ-H & N35 module comprises seven symptom scales : pain , swallowing , senses , speech , social eating , social contact , and sexuality . There are 11 additional , single items covering problems with teeth , opening the mouth wide , dry mouth , sticky saliva , cough , feeling ill , weight loss , weight gain , use of nutritional supplements , feeding tubes , and painkillers . The scores of both the QLQ-C30 and of the QLQ-H & N35 are linearly transformed to a scale of 0 -- 100 , with a higher score indicating a higher -LRB- i.e. , more positive -RRB- level of functioning or global HRQOL , or a higher -LRB- i.e. , more negative -RRB- level of symptoms or problems . The QLQ-C30 data of the patients were compared with published normative data from the general population of Norway -LSB- 22 -RSB- . Comparisons were made with the normative subsample that corresponded closely to the age and gender distribution of the patient sample -LRB- i.e. , age range of 50 -- 59 years and 48 % female -RRB- . The QLQ-H & N35 results were compared with reference values derived from a randomly selected sample of the Swedish general population -LSB- 8 -RSB- . Speech and oral functional status Speech analyses were performed according to a standardized speech assessment protocol . Speech recordings of a read aloud text were performed in a sound-treated room and digitized using Cool Edit PRO 1.2 -LRB- Adobe Systems Incorporated , San Jose , CA , USA -RRB- with 22 kHz sample frequency and 16 bit resolution . Recording level was adjusted for each speaker to optimize signal-to-noise ratio . All recordings were made with a mouth-to-microphone distance of 30 cm . A computer program was developed to perform blinded randomized speech evaluation and to score overall intelligibility , and quality of articulation and nasal resonance . Overall intelligibility was assessed on a 10-point scale ranging from poor to excellent by two trained speech therapists . Scores below six were defined as insufficient intelligibility -LRB- according to the Dutch educational system -RRB- . To obtain more insight into the cause of decreased intelligibility , evaluation of the quality of articulation and nasal resonance was performed by the same two speech therapists on a 4-point scale ranging from deviant -LRB- score 1 -- 3 -RRB- to normal -LRB- score 4 -RRB- . Speech rate was measured by calculating words per minute on a read aloud standardized text . Oral function was evaluated by a trained investigator -LRB- blinded for the clinical data regarding tumor site and stage -RRB- according to a protocol described by Teichgraeber et al. -LSB- 23 -RSB- . All assessments were based on 5-point scales ranging from poor to excellent -LRB- transformed scores ranging from 0 -- 100 -RRB- . The oral function evaluation included three tests ; -LRB- 1 -RRB- tongue mobility -LRB- mean score of tongue straight out , elevation of tongue tip , elevation of the base of the tongue , tongue deviation left and right , symmetry left and right , and tongue withdrawal -RRB- , -LRB- 2 -RRB- lip mobility -LRB- mean score of general movement , spreading and rounding , symmetry left/right , lip closure without speech , and lip closure during speaking -RRB- , and -LRB- 3 -RRB- diadochokinesis -LRB- mean score of repetitive motion ability concerning tongue movement left/right , up/down , and in/out , and repeating the syllables / ta / / cha / , and / ka / -RRB- . Tongue and lip strength were quantified by a calibrated digital voltameter . To measure tongue strength the patient was asked to push the tongue against a metallic disc with the lips positioned around a cylinder , and to resist the force . To measure lip strength , the patient was asked to keep his lips around a button with a string attached to it on which the examiner pulled . Scores ranged from 0 -LRB- no strength -RRB- to 0.5 mV -LRB- normal strength -RRB- . Statistical analyses Chi-square tests were used to assess associations between the independent variables tumor site , classification and comorbid condition . Student 's t-tests were performed to test for differences between the patient sample and the normative samples . These tests were based on the mean scores of the study and normative samples and the standard deviations of the study sample only , because no standard deviations of normative samples were available . Student 's t-tests -LRB- HRQOL -RRB- and Mann -- Whitney tests -LRB- functional status -RRB- were performed to determine the impact of tumor site -LRB- oral versus oropharyngeal -RRB- , tumor classification -LRB- T2 versus T3 -- T4 -RRB- and comorbidity -LRB- yes or no -RRB- . Spearman correlation coefficients -LRB- r -RRB- were calculated to investigate the association between self-reported HRQOL -LRB- i.e. , the QLQ-C30 global quality of life scale and the QLQ-H & N35 speech scale -RRB- and speech and oral functional status . Statistical significance was defined as a P-value less than or equal to 0.05 . Results Sample description Patient characteristics are shown in Table 1 . The patients ' age ranged from 23 to 74 years -LRB- mean 58 years -RRB- . Forty-one percent of the sample was female . One patient was operated on for a recurrent tumor after prior transoral excision -LRB- 1 year earlier -RRB- in which the rTNM stage was used , and one patient had undergone previous radiotherapy -LRB- 3 years earlier -RRB- for a neck node of an unknown primary . Four patients had a synchronous second primary tumor , and in these cases the stage of the largest tumor was used . An equal percentage -LRB- 50 % -RRB- of patients had a tumor originating on the left or right side , and in the majority of patients -LRB- 73 % -RRB- the tumor did not extend over the median line . All 80 patients completed the EORTC questionnaires , speech rate tests -LRB- word count -RRB- and oral function tests -LRB- mobility and strength -RRB- . In one patient speech recording could not be done due to logistical problems , and in three patients speech recordings were inadequate for interpretation due to technical problems . Speech quality analyses could thus be performed on 76 patients . Presence of comorbid conditions and tumor classification were significantly associated . Significantly more patients with comorbidity were diagnosed with a larger tumor -LRB- χ2 = 10.37 , P < 0.01 -RRB- . No other significant associations were observed between tumor site , tumor classification , age , gender and comorbidity . Table 1Characteristics of 80 patients included in this studyAge -LRB- years -RRB- Range23 -- 74 Mean58n -LRB- % -RRB- Gender Male47 -LRB- 59 -RRB- Female33 -LRB- 41 -RRB- General condition Comorbidity48 -LRB- 60 -RRB- No comorbidity32 -LRB- 40 -RRB- Tumour site Oral cavity38 -LRB- 47 -RRB- Oropharynx42 -LRB- 53 -RRB- T 2 35 -LRB- 44 -RRB- 3 42 -LRB- 52 -RRB- 4 3 -LRB- 4 -RRB- N 024 -LRB- 30 -RRB- 116 -LRB- 19 -RRB- 2a2 -LRB- 3 -RRB- 2b30 -LRB- 38 -RRB- 2c6 -LRB- 7 -RRB- 3 2 -LRB- 3 -RRB- Health-related quality of life Compared to the general population , the patients with oral or oropharyngeal cancer scored significantly worse on 5 -LRB- out of 15 -RRB- scales or single items regarding the QLQ-C30 : role functioning -LRB- P = 0.000 -RRB- , emotional functioning -LRB- P = 0.000 -RRB- , pain -LRB- P = 0.026 -RRB- , insomnia -LRB- P = 0.016 -RRB- and appetite loss -LRB- P = 0.003 -RRB- . Conversely , patients scored significantly better regarding social functioning -LRB- P = 0.009 -RRB- , fatigue -LRB- P = 0.030 -RRB- , emesis -LRB- P = 0.001 -RRB- , and diarrhea -LRB- P = 0.001 -RRB- . Regarding the QLQ-H & N35 , the patients scored significantly worse on 7 -LRB- out of 10 -RRB- scales or single items compared to the general population : pain -LRB- P = 0.000 -RRB- , swallowing -LRB- P = 0.000 -RRB- , senses -LRB- P = 0.050 -RRB- , social eating -LRB- P = 0.000 -RRB- , teeth -LRB- P = 0.009 -RRB- , opening the mouth wide -LRB- P = 0.000 -RRB- and sticky saliva -LRB- P = 0.005 -RRB- . Conversely , the patients scored significantly better on two items : coughing -LRB- P = 0.002 -RRB- and feeling ill -LRB- P = 0.025 -RRB- . Regarding tumor site , the QLQ-C30 results were comparable between oral cavity and oropharynx cancer patients . Only the pain score was significantly worse -LRB- P = 0.027 -RRB- for patients with oral cavity tumors as compared to patients with oropharynx tumors . The QLQ-H & N35 also revealed that patients with oral cavity tumors had significantly more pain -LRB- P = 0.002 -RRB- ; furthermore , problems with their teeth appeared to be different -LRB- P = 0.001 -RRB- . No statistically significant differences were observed for any of the QLQ-C30 scores as a function of tumor classification -LRB- T2 versus T3 -- T4 -RRB- . Regarding the QLQ-H & N35 , patients with T3 -- T4 tumors scored significantly worse on opening the mouth -LRB- P = 0.009 -RRB- and reported feeling more ill -LRB- P = 0.035 -RRB- compared to patients with T2 tumors . Regarding comorbidity -LRB- Table 2 -RRB- , patients with one or more comorbid conditions scored significantly worse on QLQ-C30 physical functioning -LRB- P = 0.002 -RRB- , global quality of life -LRB- P = 0.016 -RRB- , fatigue -LRB- P = 0.014 -RRB- , pain -LRB- P = 0.024 -RRB- , constipation -LRB- P = 0.042 -RRB- and diarrhea -LRB- P = 0.017 -RRB- compared to patients without comorbidity . Additionally , based on the QLQ-H & N35 data , patients with comorbidity reported significantly more pain -LRB- P = 0.007 -RRB- , trouble with social eating -LRB- P = 0.036 -RRB- , teeth problems -LRB- P = 0.034 -RRB- , problems with opening the mouth -LRB- P = 0.013 -RRB- and feeling ill -LRB- P = 0.003 -RRB- . The use of pain medication was significantly higher among patients with than those without comorbidity -LRB- 75 versus 50 % ; P = 0.025 -RRB- . Table 2EORTC QLQ-C30 and QLQ-H & N35 scores for comorbidityComorbidityNoYesMean -LRB- SD -RRB- n = 32Mean -LRB- SD -RRB- n = 48PEORTC QLQ-C30 Physical functioning95 .0 -LRB- 12.4 -RRB- 81.7 -LRB- 21.4 -RRB- 0.002 Role functioning85 .4 -LRB- 18.3 -RRB- 79.2 -LRB- 24.9 -RRB- 0.228 Cognitive functioning89 .6 -LRB- 18.3 -RRB- 87.2 -LRB- 19.2 -RRB- 0.574 Emotional functioning69 .5 -LRB- 23.4 -RRB- 72.2 -LRB- 24.6 -RRB- 0.626 Social functioning93 .2 -LRB- 13.3 -RRB- 88.5 -LRB- 21.5 -RRB- 0.275 Global quality of life82 .6 -LRB- 19.6 -RRB- 71.5 -LRB- 19.7 -RRB- 0.016 Fatigue13 .9 -LRB- 20.0 -RRB- 26.9 -LRB- 24.1 -RRB- 0.014 Emesis1 .6 -LRB- 4.9 -RRB- 1.4 -LRB- 4.7 -RRB- 0.874 Pain22 .4 -LRB- 25.3 -RRB- 37.8 -LRB- 31.8 -RRB- 0.024 Dyspnea6 .3 -LRB- 19.7 -RRB- 10.4 -LRB- 18.4 -RRB- 0.338 Insomnia36 .5 -LRB- 36.3 -RRB- 31.3 -LRB- 39.1 -RRB- 0.550 Appetite loss7 .3 -LRB- 20.3 -RRB- 18.7 -LRB- 31.4 -RRB- 0.072 Constipation5 .2 -LRB- 20.9 -RRB- 18.7 -LRB- 32.9 -RRB- 0.042 Diarrhea1 .0 -LRB- 5.9 -RRB- 8.3 -LRB- 16.1 -RRB- 0.017 Financial impact2 .1 -LRB- 8.2 -RRB- 7.6 -LRB- 20.9 -RRB- 0.157 EORTC QLQ-H & N35 Pain27 .1 -LRB- 17.6 -RRB- 41.5 -LRB- 25.5 -RRB- 0.007 Swallowing14 .6 -LRB- 22.6 -RRB- 24.1 -LRB- 22.6 -RRB- 0.068 Senses 6.3 -LRB- 14.5 -RRB- 8.7 -LRB- 21.5 -RRB- 0.577 Speech 9.4 -LRB- 14.1 -RRB- 13.0 -LRB- 17.5 -RRB- 0.336 Social eating14 .6 -LRB- 25.3 -RRB- 27.4 -LRB- 27.1 -RRB- 0.036 Social contact3 .1 -LRB- 7.0 -RRB- 3.7 -LRB- 6.1 -RRB- 0.674 Sexuality16 .1 -LRB- 24.9 -RRB- 16.3 -LRB- 27.6 -RRB- 0.981 Teeth13 .5 -LRB- 26.6 -RRB- 30.6 -LRB- 38.8 -RRB- 0.034 Opening mouth7 .3 -LRB- 20.3 -RRB- 25.7 -LRB- 37.2 -RRB- 0.013 Dry mouth15 .6 -LRB- 26.8 -RRB- 22.2 -LRB- 28.6 -RRB- 0.303 Sticky saliva12 .5 -LRB- 29.0 -RRB- 21.5 -LRB- 31.1 -RRB- 0.196 Coughing6 .3 -LRB- 13.2 -RRB- 14.6 -LRB- 21.6 -RRB- 0.055 Feeling ill0 -LRB- 0 -RRB- 9.7 -LRB- 18.1 -RRB- 0.003 % Yes % YesPain medication50 .075.00.022 Speech and oral functional status Abnormal scores were observed in 17 % of the patients regarding overall intelligibility , in 25 % regarding nasality and in 37 % regarding articulation . Functional results in relation to tumor site , classification and comorbidity are shown in Table 3 . Regarding tumor site , patients with oral cavity tumors scored significantly worse on intelligibility -LRB- P = 0.015 -RRB- , articulation -LRB- P = 0.039 -RRB- , nasality -LRB- P = 0.040 -RRB- , tongue and lip mobility -LRB- P = 0.000 , 0.009 -RRB- , diadochokinesis -LRB- P = 0.004 -RRB- , and tongue strength -LRB- P = 0.001 -RRB- compared to patients with oropharyngeal tumors . Regarding tumor stage , patients with T3 -- T4 tumors scored significantly worse on intelligibility -LRB- P = 0.011 -RRB- , articulation -LRB- P = 0.003 -RRB- , tongue mobility -LRB- P = 0.001 -RRB- , diadochokinesis -LRB- P = 0.012 -RRB- , and tongue and lip strength -LRB- P = 0.021 , 0.018 -RRB- than patients with T2 tumors . Patients with comorbidity scored significantly worse on articulation -LRB- P = 0.043 -RRB- , diadochokinesis -LRB- P = 0.026 -RRB- , and tongue strength -LRB- P = 0.045 -RRB- as compared to patients without comorbidity . Table 3Functional status tests for tumour site , tumour stage and comorbidityTumour siteTumour stageComorbidityOral cavityOropharynxT2T3 -- T4NoYesMean -LRB- SD -RRB- n = 37Mean -LRB- SD -RRB- n = 39PMean -LRB- SD -RRB- n = 32Mean -LRB- SD -RRB- n = 44PMean -LRB- SD -RRB- n = 29Mean -LRB- SD -RRB- n = 47PSpeech Intelligibility -LRB- 0 -- 10 -RRB- 6.0 -LRB- 1.3 -RRB- 6.7 -LRB- 1.0 -RRB- 0.0156.8 -LRB- 1.0 -RRB- 6.0 -LRB- 1.2 -RRB- 0.0116.6 -LRB- 1.0 -RRB- 6.2 -LRB- 1.3 -RRB- 0.132 Articulation -LRB- 0 -- 4 -RRB- 3.4 -LRB- 0.8 -RRB- 3.7 -LRB- 0.6 -RRB- 0.0393.8 -LRB- 0.4 -RRB- 3.3 -LRB- 0.8 -RRB- 0.0033.8 -LRB- 0.4 -RRB- 3.4 -LRB- 0.8 -RRB- 0.043 Nasality -LRB- 0 -- 4 -RRB- 3.6 -LRB- 0.6 -RRB- 3.8 -LRB- 0.4 -RRB- 0.0403.8 -LRB- 0.4 -RRB- 3.7 -LRB- 0.6 -RRB- 0.9113.7 -LRB- 0.4 -RRB- 3.7 -LRB- 0.5 -RRB- 0.771 n = 38n = 42n = 35n = 45n = 32n = 48 Rate Words per minute183 -LRB- 31.6 -RRB- 182 -LRB- 38.5 -RRB- 0.988189 -LRB- 33.8 -RRB- 178 -LRB- 35.8 -RRB- 0.201189 -LRB- 31.4 -RRB- 179 -LRB- 38.1 -RRB- 0.233 n = 38n = 42n = 35n = 45n = 32n = 48Oral functions Mobility Tongue -LRB- 0 -- 100 -RRB- 82.3 -LRB- 20.0 -RRB- 96.4 -LRB- 5.4 -RRB- 0.00096.0 -LRB- 5.8 -RRB- 84.8 -LRB- 19.3 -RRB- 0.00193.9 -LRB- 9.9 -RRB- 89.9 -LRB- 14.4 -RRB- 0.209 Lip -LRB- 0 -- 100 -RRB- 87.4 -LRB- 5.7 -RRB- 99.7 -LRB- 0.9 -RRB- 0.00999.4 -LRB- 2.0 -RRB- 98.0 -LRB- 5.1 -RRB- 0.14099.3 -LRB- 2.2 -RRB- 98.5 -LRB- 3.9 -RRB- 0.239 Diadoch -LRB- 0 -- 100 -RRB- 87.4 -LRB- 20.7 -RRB- 97.2 -LRB- 6.1 -RRB- 0.00497.5 -LRB- 5.0 -RRB- 88.7 -LRB- 19.6 -RRB- 0.01297.4 -LRB- 5.1 -RRB- 91.5 -LRB- 15.4 -RRB- 0.026 Strength Tongue -LRB- 0 -- 0.5 -RRB- 0.2 -LRB- 0.2 -RRB- 0.4 -LRB- 0.2 -RRB- 0.0010.4 -LRB- 0.2 -RRB- 0.3 -LRB- 0.2 -RRB- 0.0210.4 -LRB- 0.2 -RRB- 0.2 -LRB- 0.2 -RRB- 0.045 Lip -LRB- 0 -- 0.5 -RRB- 0.3 -LRB- 0.1 -RRB- 0.4 -LRB- 0.2 -RRB- 0.3280.4 -LRB- 0.2 -RRB- 0.3 -LRB- 0.1 -RRB- 0.0180.4 -LRB- 0.2 -RRB- 0.3 -LRB- 0.1 -RRB- 0.370 Correlations between self-report and observer rated data Significant correlations -LRB- P < 0.01 -RRB- were observed between self-reported global quality of life scale -LRB- QLQ-C30 -RRB- and observer ratings of intelligibility -LRB- r = 0.41 -RRB- and articulation -LRB- r = 0.36 -RRB- -LRB- Table 4 -RRB- . Additionally , statistically significant -LRB- P < 0.05 -RRB- but relatively low correlations were found between self-reported speech -LRB- QLQ-H & N35 -RRB- and observer ratings of intelligibility -LRB- r = − 0.28 -RRB- , articulation -LRB- r = − 0.24 -RRB- , nasality -LRB- r = − 0.27 -RRB- and diadochokinesis -LRB- r = − 0.28 -RRB- . Table 4Correlations between functional status tests and QLQ-C30 global quality of life scale/QLQ-H & N35 speech problemsScalesQLQ-C30 global quality of lifeQLQ-H & N35 speech problemsCorrelation coefficient -LRB- r -RRB- n = 76PCorrelation coefficient -LRB- r -RRB- n = 76PSpeech Intelligibility0 .4110.000 − 0.2850.013 Articulation0 .3550.002 − 0.2420.035 Nasality0 .1520.190 − 0.2700.019 n = 80n = 80 Rate0 .1290.267 − 0.1420.221 n = 80n = 80Oral functions Mobility Tongue0 .0780.490 − 0.1880.095 Lip0 .1570.164 − 0.1760.119 Diadochokinesis0 .1090.337 − 0.2800.012 Strength Tongue0 .1880.095 − 0.1750.121 Lip0 .0560.624 − 0.0490.665 Discussion Pretreatment HRQOL and functional status were investigated in a well-defined sample of patients with advanced oral and oropharyngeal cancer . Deteriorated HRQOL and functional status before treatment have been reported in earlier studies , albeit for less well defined patient groups -LSB- 9 -- 15 -RSB- . The results of the present study indicate a wide range of HRQOL and functional deficits in patients with advanced oral and oropharyngeal cancer before treatment . Impaired speech and oral function , as assessed objectively , was associated significantly with self-reported global HRQOL and speech problems , which is in accordance with the conclusions of Rogers et al. and Karnell et al. -LSB- 14 , 24 -RSB- . Compared to the general population , patients scored significantly worse on 5 of 15 scales or items of the EORTC QLQ-C30 but , conversely , they scored significantly better on four others . Regarding the QLQ-H & N35 , patients scored significantly worse on most scales or items but significantly better on coughing and feeling ill . The significantly better scores for patients compared to the reference groups on some scales or items may be explained by the fact that people from the general population may have -LRB- other -RRB- chronic conditions as well . Alonso et al. -LSB- 25 -RSB- reported that , 55 % of the general population has one chronic health condition , and 30 % has more than one chronic condition . They also found that comorbidity can have a substantial impact on HRQOL , and stated that the presence of comorbidity limits the ability to attribute HRQOL deficits to one specific disease -LRB- e.g. , to head and neck cancer -RRB- . In head and neck cancer patients , comorbidity has proven to be an important factor associated with complications and mortality rates -LSB- 26 -- 29 -RSB- . Studies on the impact of comorbidity on functional status in head and neck cancer patients are lacking . Studies that have examined the impact of comorbid status on HRQOL are scarce , have yielded conflicting results , and have examined the post-treatment period only . Pourel et al. -LSB- 17 -RSB- found no significant association between comorbidity and HRQOL in 113 long-term survivors 2 years after treatment for oropharyngeal carcinomas . Similarly , Taylor et al. -LSB- 30 -RSB- found no impact of comorbidity on work-related disability among 384 patients after treatment for head and neck cancer . However , Terrel et al. -LSB- 19 -RSB- in a study on HRQOL of 570 head and neck cancer patients after treatment , reported a clear effect of comorbidity in patients with two or more comorbid conditions . In our study on patients with oral or oropharyngeal carcinomas before treatment , comorbidity was present in 60 % of the patients , and proved to have a major impact on HRQOL and functional status . Patients with comorbidity had significantly worse scores on several general and head and neck specific quality of life aspects and on speech and oral function tests compared to patients without comorbidity . Unfortunately , the cause of comorbidity was not systematically noted in the present study ; future studies may provide more insight into the relation between the cause of comorbidity and HRQOL . The impact of tumor site and classification on HRQOL appeared to be limited , with patients with oral cavity tumors reporting more pain , and patients with T3 -- T4 tumors reporting more trouble opening the mouth and feeling more ill . With regard to tumor site , comparisons with earlier studies are difficult because most studies included patients with oral cavity tumors only or reported on heterogeneous samples not stratified by -LRB- sub -RRB- sites -LSB- 4 , 9 -- 11 -RSB- . Regarding tumor classification , other studies have reported worse HRQOL for patients with higher tumor classifications and stages before treatment -LSB- 2 , 14 -RSB- . Tumor site and classification were found to have a clear impact on functional status . Patients with oral cavity tumors -LRB- versus oropharyngeal tumors -RRB- and patients with T3 -- T4 tumors -LRB- versus T2 tumors -RRB- had worse speech and oral function scores , which is in accordance with the results of earlier studies -LSB- 13 , 14 -RSB- . In conclusion , we observed compromised HRQOL and functional deficits among patients with advanced oral and oropharyngeal cancer before the start of treatment . In addition to the impact of tumor site and classification , comorbidity proved to have a major impact on HRQOL and functional status . Prospective studies are needed to obtain insight into the relation between pretreatment HRQOL and functional status and outcome after treatment , and the relationship between changes in HRQOL and functioning over time and tumor site , tumor classification , and comorbid conditions .

B I I O B I O O O O O O O O O O O O O O O O O O O O O O B I I O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O B O O O O O O O O O O B I I O O O O O B O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O B I O O O B I I I O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O B I I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O B I B O O O O O O O B O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O B O O O B O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O B O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O B I I O O O B O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I I O O O B I I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O B I I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I I I O O O O O O O O O O O O O O O O B I I I O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O B I I O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O B O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O B I O O O O O O O O O O O O O O O O O O O O O O O O O O O

head and neck cancer
quality of life
functional status
speech


Rectal GIST Presenting as a Submucosal Calculus This case report presents an incidental finding of a rectal GIST -LRB- gastrointestinal stromal tumor -RRB- presenting as a submucosal calculus , not previously reported . A 53-year-old man without a significant medical history presented with abdominal pain in the left lower quadrant , and with constipation . Upon rectal examination , a hard submucosal swelling was palpated 4 cm from the anus , at 3 o'clock , in the left rectum wall . X-ray photos , computerized tomography -LRB- CT -RRB- - scan and a magnetic resonance imaging -LRB- MRI -RRB- scan clearly showed a calculus . Excision revealed a turnip-like lesion , 3.1 × 2.3 × 1.8 cm . Analysis showed it was a rectal GIST , a rare mesenchymal tumor of the gastrointestinal tract , which expressed CD117 -LRB- or c-kit , a marker of kit-receptor tyrosine kinase -RRB- and CD34 . Calcification is not a usual clinicopathological feature of GISTs -LSB- 1 -- 3 -RSB- , and although a number of rectal GISTs have been reported -LSB- 4 -- 9 -RSB- , we have found no cases so far of rectal GIST presenting as a submucosal calculus . Case Report A 53-year-old man without significant medical history presented with abdominal pain in the left lower quadrant and constipation . He got up that morning with a cramping abdominal ache that lasted over the day . He was nauseous , had vomited once , and ructus was present . There had been a small amount of hard stool and discomfort during defecation initially , but after the general practitioner had administered laxatives , he had liquid diarrhea . There was no complaint of constipation on a regular basis ; this was a new finding . Tenesmus was absent . There was no bleeding or mucous discharge . He was feverish , with a temperature of 38.2 °C . On examination , the abdomen was slightly distended . Auscultation showed diminished intestinal peristalsis , without borborygmi , and percussion was tympanic . Upon palpation , the abdomen was supple : there was no reflex rigidity nor guarding , and no rebound tenderness . Upon rectal examination , a hard submucosal swelling was palpated 4 cm from the anus , at 3 o'clock , in the left rectum wall . At the time , this was considered an accidental finding that was to be investigated later . There were no specific deviations in the lab results . Ultrasound investigation displayed some hydronephrosis of the left kidney and a stone -LRB- size : 0.13 × 0.7 cm -RRB- of the left ureter . X-ray photos displayed a spherical lesion , projecting in the pelvis and situated in the rectum , and some phleboliths projecting on the left colon , but not the ureter stone -LRB- Fig. 1 -RRB- . Proctoscopy was not conclusive , so further investigation was performed . A computerized tomography -LRB- CT -RRB- scan and a magnetic resonance imaging -LRB- MRI -RRB- scan also clearly showed the submucosal calculus -LRB- Figs. 2 and 3 -RRB- . Fig. 1X-ray photo showing the rectal calculus projecting in the pelvis -LRB- thick arrow -RRB- above the pubic symphysis and the phleboliths projecting on the left colon -LRB- thin arrow -RRB- Fig. 2Computerized tomography -LRB- CT -RRB- scan showing the rectal calculus in the center -LRB- arrow -RRB- Fig. 3Magnetic resonance imaging -LRB- MRI -RRB- scan . The arrow shows the rectal calculus in the rectum wallFig . 4Excision of the rectal calculus in the operating roomFig . 5Excision revealed a turnip-like lesion , dimensions 3.1 × 2.3 × 1.8 cm Our patient was diagnosed with abdominal pain and constipation based on a ureter stone and slight hydronephrosis of the left kidney , with coincidental finding of a rectal tumor . He was sent home with adequate analgesia and spontaneously released the ureter stone . An appointment was made for elective excision of the rectal calculus . Transanal excision was performed in the operating room -LRB- Fig. 4 -RRB- and revealed a turnip-like lesion , dimensions 3.1 × 2.3 × 1.8 cm -LRB- Fig. 5 -RRB- . No normal tissue margins were excised because the tumor was not connected to the surrounding tissues . After surgery , the patient went home and recovered well , without any further complaints or complications . The calculus was analyzed and consisted of fibroid and bony tissue , together with bundles of spindle-shaped cells with cigar-like nuclei . A partially calcified leiomyoma was considered at first , but supplementary immunoperoxidase analysis showed that the spindle-shaped cells were positive for CD117 -LRB- c-kit -RRB- and CD34 . Unfortunately , histopathologic slides showing CD117 staining are not available to us . There was some focally positive smooth muscle actin , and MIB1 expression appeared negative . The mitotic count was low : fewer than five mitoses per 50 HPF . Only then did this analysis lead to the conclusion of rectal GIST , with extended calcification and ossification . It was classified as low-risk GIST because of the size -LRB- between 2 and 5 cm -RRB- and low mitotic count -LRB- Table 1 -RRB- . Table IPrognosis of primary GISTRiskSize -LRB- cm -RRB- Mitotic count -LRB- per 50 HPF -RRB- Very low risk < 2 < 5Low risk2 -- 5 < 5Intermediate risk < 56 -- 105 -- 10 < 5High risk > 5 > 5 > 10 > Any mitotic rateAny tumor > 10Note . from Fletcher et al -LRB- 13 -RRB- . Abbreviations : HPF , high-power field . Conclusion Calcification is not a usual clinicopathologic feature of GISTs -LSB- 1 -- 3 -RSB- , and although a number of rectal GISTs have been reported , we have found no cases so far of rectal GIST presenting as a submucosal calculus . Furthermore , in the literature we found no cases of calcified GIST in other sites of the body . Expression of CD117 -LRB- c-kit -RRB- and CD34 proved that our calculus was in fact a rectal GIST . Calcification might be explained by internal bleeding of the tumor . The abdominal pain of our patient could be explained entirely by the ureteral stone . The rectal tumor might only explain the constipation . Because of the unpredictable biological behavior of gastrointestinal stromal tumors , the prognosis for our patient is uncertain , in spite of the low-risk character . For this reason , at multidisciplinary oncological deliberation , an expectant policy with regular follow-up was arranged .

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gastrointestinal stromal tumors
rectal tumor
calculus