Impact of Solitary Involved Lymph Node on Outcome in Localized Cancer of the Esophagus and Esophagogastric Junction Node-positive esophageal cancer is associated with a dismal prognosis . The impact of a solitary involved node , however , is unclear , and this study examined the implications of a solitary node compared with greater nodal involvement and node-negative disease . The clinical and pathologic details of 604 patients were entered prospectively into a database from1993 and 2005 . Four pathologic groups were analyzed : node-negative , one lymph node positive , two or three lymph nodes positive , and greater than three lymph nodes positive . Three hundred and fifteen patients -LRB- 52 % -RRB- were node-positive and 289 were node-negative . The median survival was 26 months in the node-negative group . Patients -LRB- n = 84 -RRB- who had one node positive had a median survival of 16 months -LRB- p = 0.03 vs node-negative -RRB- . Eighty-four patients who had two or three nodes positive had a median survival of 11 months compared with a median survival of 8 months in the 146 patients who had greater than three nodes positive -LRB- p = 0.01 -RRB- . The survival of patients with one node positive -LSB- number of nodes -LRB- N -RRB- = 1 -RSB- was also significantly greater than the survival of patients with 2 -- 3 nodes positive -LRB- N = 2 -- 3 -RRB- -LRB- p = 0.049 -RRB- and greater than three nodes positive -LRB- p < 0001 -RRB- . The presence of a solitary involved lymph node has a negative impact on survival compared with node-negative disease , but it is associated with significantly improved overall survival compared with all other nodal groups . Introduction Carcinoma of the esophagus carries a dismal prognosis , and for patients presenting with localized resectable disease , multivariate analysis has established that the presence or absence of involved lymph nodes confers the greatest prognostic significance .1 In surgical management , the extent and type of lymphadenectomy undertaken varies from no formal lymphadenectomy to two and three field dissection .2 -- 5 The presence and extent of lymph node involvement is important as selective approaches may be considered depending on the nodal stage at presentation . In early tumors , for instance , the sentinel node concept initially developed in melanoma and breast cancer was explored to help identify patients who may not require lymph node dissection .6 -- 8 The advent of minimally invasive esophagectomy may also highlight the need to subselect patients for lymphadenectomy .9 In the observations of the senior author -LRB- JVR -RRB- , patients with solitary involved lymph nodes may achieve good outcomes , and this hypothesis was evaluated in this analysis of a large prospective database . We report herein that the cohort with a solitary node involved had cancer outcomes closer to node-negative disease than other node-positive subgroups , and suggest that this represents a distinct prognostic subgroup . Patients and Methods The study population consisted of all patients with tumors of the esophagus and esophagogastric junction who underwent surgical resection , either alone or preceded by neoadjuvant chemoradiation , between 1993 and 2005 . Patients receiving multimodal therapy received cisplatin , 5-fluorouracil , and external beam radiotherapy -LRB- 40 -- 44 Gy , 2 -- 2.67 Gy/fraction -RRB- as previously described .10 Data concerning the clinical and pathologic parameters for all patients was obtained from a detailed prospective database maintained by a full-time data manager . Pathologic parameters analyzed included the location of the tumor , tumor morphology , i.e. , adenocarcinoma or squamous cell carcinoma , histological differentiation -LRB- grade -RRB- , TNM staging , number and site of involved lymph nodes , and R classification after surgical resection . Staging of tumors was performed according to the American Joint Committee on Cancer TNM system .11 A subtotal esophagectomy was performed with a sutured anastomosis either in the right thorax -LRB- two-stage -RRB- or neck -LRB- three-stage -RRB- . All cases underwent a formal abdominal lymphadenectomy and mediastinal lymph node dissection up to and including the subcarinal nodes . Thoracic nodes were submitted separately to abdominal nodes . Statistical Analysis Data are presented as frequencies , means , and percentages . ANOVA was used for comparison of the four demographic groups . Survival probability was estimated using the Kaplan -- Meier method . Survival was calculated from the date of clinical diagnosis to date of death or date last seen . In the multivariate analysis , independent prognostic factors for survival were determined by using a Cox regression hazard model . Two analyses were performed , one for all patients and the other exclusive to node-positive patients . All statistical analyses were performed using Stata software -LRB- version 9.1 for Windows , Statcorp , TX -RRB- . A p value < 0.05 was considered statistically significant .12 Results Patients/histology Six hundred and four patients underwent surgery for localized malignancy of the esophagus or esophagogastric junction . The mean age was 62 ± 10.4 -LRB- median = 64 , range 56 to 70 -RRB- . Four hundred and twelve -LRB- 68 % -RRB- patients were men . The mean number of lymph nodes examined per specimen was 12 ± 6 -LRB- median = 10 , range = 6 to 55 -RRB- . Two hundred and eighty-nine patients -LRB- 48 % -RRB- had node-negative disease -LSB- number of nodes -LRB- N -RRB- = 0 -RSB- , 84 -LRB- 14 % -RRB- had one node positive -LRB- N = 1 -RRB- , 84 had two or three nodes positive , and 147 -LRB- 24 % -RRB- had greater than three nodes positive -LRB- N > 3 -RRB- . In patients with one involved node , in all cases the node was adjacent to the tumor , mediastinal for esophageal tumors , and periesophageal or along the left gastric artery for junctional tumors -LRB- Tables 1 and 2 -RRB- . Table 1Demographics of Nodal SubgroupsHistologic DataN = 0 -LRB- n = 289 -RRB- N = 1 -LRB- n = 84 -RRB- N = 2 -- 3 -LRB- n = 84 -RRB- N > 3 -LRB- n = 147 -RRB- Tumor site -LRB- % -RRB- Lower esophagus138 -LRB- 47 -RRB- 39 -LRB- 46 -RRB- 37 -LRB- 44 -RRB- 57 -LRB- 39 -RRB- EG junction80 -LRB- 28 -RRB- 35 -LRB- 42 -RRB- 33 -LRB- 39 -RRB- 75 -LRB- 51 -RRB- Middle esophagus55 -LRB- 19 -RRB- 10 -LRB- 12 -RRB- 12 -LRB- 14 -RRB- 11 -LRB- 7 -RRB- Upper esophagus16 -LRB- 6 -RRB- 02 -LRB- 3 -RRB- 4 -LRB- 3 -RRB- Morphology -LRB- % -RRB- Adenocarcinoma140 -LRB- 48 -RRB- 51 -LRB- 61 -RRB- 57 -LRB- 68 -RRB- 113 -LRB- 77 -RRB- Squamous cell carcinoma140 -LRB- 48 -RRB- 29 -LRB- 35 -RRB- 25 -LRB- 30 -RRB- 32 -LRB- 22 -RRB- Others9 -LRB- 4 -RRB- 4 -LRB- 5 -RRB- 2 -LRB- 1 -RRB- 2 -LRB- 1 -RRB- Treatment -LRB- % -RRB- Multimodal therapy129 -LRB- 44 -RRB- 28 -LRB- 33 -RRB- 24 -LRB- 29 -RRB- 21 -LRB- 14 -RRB- Surgery alone161 -LRB- 56 -RRB- 56 -LRB- 76 -RRB- 60 -LRB- 71 -RRB- 125 -LRB- 86 -RRB- Residual tumor -LRB- % -RRB- R0 : no residual tumor250 -LRB- 86 -RRB- 71 -LRB- 85 -RRB- 64 -LRB- 76 -RRB- 108 -LRB- 73 -RRB- R1 : residual tumor found39 -LRB- 13 -RRB- 13 -LRB- 15 -RRB- 19 -LRB- 23 -RRB- 39 -LRB- 27 -RRB- Rx : unknown1 -LRB- 1 -RRB- -- 1 -LRB- 1 -RRB- -- Pathological stage -LRB- % -RRB- Stage 053 -LRB- 18 -RRB- -- -- -- Stage I59 -LRB- 20 -RRB- 1 -LRB- 1 -RRB- -- -- Stage II170 -LRB- 59 -RRB- 21 -LRB- 25 -RRB- 25 -LRB- 30 -RRB- 16 -LRB- 11 -RRB- Stage III5 -LRB- 2 -RRB- 58 -LRB- 29 -RRB- 53 -LRB- 63 -RRB- 110 -LRB- 76 -RRB- Stage IV1 -LRB- 1 -RRB- 4 -LRB- 5 -RRB- 6 -LRB- 7 -RRB- 20 -LRB- 13 -RRB- pT stage -LRB- % -RRB- Tx3 -LRB- 1 -RRB- 02 -LRB- 3 -RRB- 1 -LRB- 0.5 -RRB- Tis12 -LRB- 4 -RRB- 000T040 -LRB- 14 -RRB- 1 -LRB- 1 -RRB- 2 -LRB- 3 -RRB- 2 -LRB- 1 -RRB- T156 -LRB- 19 -RRB- 5 -LRB- 6 -RRB- 4 -LRB- 5 -RRB- 3 -LRB- 2 -RRB- T235 -LRB- 12 -RRB- 16 -LRB- 19 -RRB- 18 -LRB- 21 -RRB- 12 -LRB- 8 -RRB- T3138 -LRB- 48 -RRB- 60 -LRB- 71 -RRB- 54 -LRB- 64 -RRB- 120 -LRB- 82 -RRB- T46 -LRB- 2 -RRB- 2 -LRB- 3 -RRB- 4 -LRB- 5 -RRB- 8 -LRB- 5 -RRB- EG = esophagogastricTable 2Histology of Nodal SubgroupsHistologic DataN = 0N = 1N = 2 -- 3N > 3AdenoSCCAdenoSCCAdenoSCCAdenoSCCn = 140N = 140n = 51n = 29n = 57n = 25n = 113n = 32No % No % No % No % No % No % No % No % Tumor siteLower Esophagus64 -LRB- 46 -RRB- 66 -LRB- 47 -RRB- 19 -LRB- 52 -RRB- 15 -LRB- 52 -RRB- 23 -LRB- 40 -RRB- 13 -LRB- 52 -RRB- 39 -LRB- 35 -RRB- 17 -LRB- 53 -RRB- EG Junction73 -LRB- 52 -RRB- 6 -LRB- 4 -RRB- 31 -LRB- 10 -RRB- 3 -LRB- 10 -RRB- 33 -LRB- 58 -RRB- 0074 -LRB- 65 -RRB- 1 -LRB- 3 -RRB- Middle Esophagus3 -LRB- 2 -RRB- 52 -LRB- 37 -RRB- 1 -LRB- 28 -RRB- 8 -LRB- 28 -RRB- 1 -LRB- 2 -RRB- 10 -LRB- 40 -RRB- 0010 -LRB- 31 -RRB- Upper Esophagus0016 -LRB- 11 -RRB- 0 -LRB- 10 -RRB- 3 -LRB- 10 -RRB- 002 -LRB- 8 -RRB- 004 -LRB- 13 -RRB- TreatmentMultimodal80 -LRB- 57 -RRB- 46 -LRB- 34 -RRB- 23 -LRB- 45 -RRB- 5 -LRB- 17 -RRB- 20 -LRB- 35 -RRB- 4 -LRB- 16 -RRB- 19 -LRB- 13 -RRB- 3 -LRB- 10 -RRB- Surgery alone60 -LRB- 43 -RRB- 93 -LRB- 66 -RRB- 28 -LRB- 55 -RRB- 24 -LRB- 83 -RRB- 37 -LRB- 65 -RRB- 21 -LRB- 84 -RRB- 94 -LRB- 87 -RRB- 28 -LRB- 90 -RRB- Path stageStage 029 -LRB- 21 -RRB- 18 -LRB-13-RRB-000000000 000Stage 142 -LRB- 30 -RRB- 15 -LRB- 10 -RRB- 1 -LRB- 2 -RRB- 0000000000Stage 266 -LRB- 47 -RRB- 102 -LRB- 73 -RRB- 15 -LRB- 29 -RRB- 4 -LRB- 14 -RRB- 19 -LRB- 33 -RRB- 5 -LRB- 20 -RRB- 15 -LRB- 13 -RRB- 1 -LRB- 3 -RRB- Stage 32 -LRB- 1 -RRB- 4 -LRB- 3 -RRB- 32 -LRB- 63 -RRB- 24 -LRB- 83 -RRB- 35 -LRB- 61 -RRB- 17 -LRB- 68 -RRB- 82 -LRB- 73 -RRB- 27 -LRB- 84 -RRB- Stage 4001 -LRB- 1 -RRB- 3 -LRB- 6 -RRB- 1 -LRB- 3 -RRB- 3 -LRB- 6 -RRB- 3 -LRB- 12 -RRB- 16914 -RRB- 3 -LRB- 10 -RRB- Unknown1 -LRB- 1 -RRB- 0000000000001 -LRB- 3 -RRB- pT stageTx2 -LRB- 1 -RRB- 1 -LRB- 1 -RRB- 0000002 -LRB- 8 -RRB- 001 -LRB- 3 -RRB- Tis9 -LRB- 6 -RRB- 0000002 -LRB- 4 -RRB- 000000T019 -LRB- 14 -RRB- 17 -LRB- 12 -RRB- 1 -LRB- 2 -RRB- 003 -LRB- 5 -RRB- 002 -LRB- 2 -RRB- 00T139 -LRB- 29 -RRB- 15 -LRB- 11 -RRB- 4 -LRB- 8 -RRB- 0014 -LRB- 24 -RRB- 003 -LRB- 3 -RRB- 00T216 -LRB- 11 -RRB- 19 -LRB- 14 -RRB- 12 -LRB- 23 -RRB- 3 -LRB- 10 -RRB- 36 -LRB- 63 -RRB- 4 -LRB- 16 -RRB- 11 -LRB- 10 -RRB- 1 -LRB- 3 -RRB- T353 -LRB- 38 -RRB- 84 -LRB- 60 -RRB- 33 -LRB- 65 -RRB- 26 -LRB- 90 -RRB- 2 -LRB- 4 -RRB- 17 -LRB- 68 -RRB- 91 -LRB- 80 -RRB- 28 -LRB- 88 -RRB- T42 -LRB- 1 -RRB- 4 -LRB- 2 -RRB- 1 -LRB- 2 -RRB- 00002 -LRB- 8 -RRB- 6 -LRB- 5 -RRB- 2 -LRB- 6 -RRB- Adeno = adenocarcinoma , SCC = small cell carcinoma , EG = esophagogastric Two hundred and two patients -LRB- 33 % -RRB- had multimodal therapy and 402 patients -LRB- 67 % -RRB- had surgery alone . Of the multimodal cohort , 129 -LRB- 64 % -RRB- were ypN0 on histopathologic assessment , 28 -LRB- 14 % -RRB- had one node positive , 24 -LRB- 12 % -RRB- had two to three positive nodes , and 21 -LRB- 10 % -RRB- had greater than three positive nodes . The attainment of an R0 resection was significantly greater in patients with none or one node involved compared with both other groups -LRB- p < 0.05 -RRB- . The majority of patients in all groups had pT3 tumors , 48 % in the pN0 group compared with 71 , 64 , and 82 % in the N = 1 , N = 2 -- 3 , and N > 3 groups , respectively -LRB- p < 0.05 -RRB- . One hundred and forty -LRB- 62 % -RRB- of the squamous cell carcinoma cohort were node-negative -LRB- N = 0 -RRB- compared with 140 -LRB- 39 % -RRB- of cases with adenocarcinoma -LRB- 39 % -RRB- -LRB- p < 0.05 -RRB- . Survival The median survival for all patients was 20 months at a median follow-up of 19 months -LRB- 3 -- 167 -RRB- . Patients who were node-negative -LRB- N = 0 -RRB- had a median survival of 26 months -LRB- Table 3 -RRB- , compared with 16 months when one node was positive -LRB- p = 0.03 -RRB- . Patients who had two to three nodes positive had a median survival of 11 months , and 8 months in patients who had greater than three nodes positive -LRB- p = 0.01 ; N = 2 -- 3 vs N > 3 -RRB- . The survival of patients with one node positive -LRB- N = 1 -RRB- was significantly greater than the survival of patients with 2 -- 3 nodes positive -LRB- p = 0.04 -RRB- and the cohort with greater than three involved nodes -LRB- p < 0.0001 -RRB- . Table 3Univariate and Multivariate Analysis : All PatientsVariablesNo . of PatientsMedian Survival -LRB- moths -RRB- p Valuea -LRB- Univariate -RRB- HR95 % CIap valueb -LRB- Multivariate -RRB- HR95 % CITreatmentSurgery only401130 .0771 -- -- -- Multimodal203190 .840.69 -- 1.02 Tumor siteUpper esophagus25160 .3711 -- -- -- Middle esophagus87140 .9460.980.58 -- 1.66 Lower esophagus268140 .6581.160.69 -- 1.81 EG junction224140 .6241.130.69 -- 1.84 Depth of invasionT05755 < 0.00110.6521 T168260 .5371.160.73 -- 1.830.4720.710.21 -- 2.3 T281260 .4191.200.77 -- 1.850.5731.110.31 -- 3.94 T337311 < 0.0012.281.60 -- 3.260.8711.400.79 -- 2.41 T4197 < 0.0014.342.46 -- 7.680.6492.591.42 -- 4.08 No . of nodes028926 < 0.0011 < 0.00110.63 -- 1.87184160.0381.361.02 -- 1.820.7741.080.83 -- 2.432 -- 38411 < 0.0011.911.45 -- 2.520.2021.421.07 -- 3.18 > 31478 < 0.0012.612.08 -- 3.290.0271.84 HistologySquamous361140 .9161 Adenocarcinoma224130 .5961.050.87 -- 1.28 -- -- -- Other19260 .4830.800.44 -- 1.48 Stage05355 < 0.00110.1181 I63550 .7470.920.56 -- 1.510.5760.680.18 -- 2.59 II230200 .0371.491.02 -- 2.170.5081.550.42 -- 4.69 III22510 < 0.0012.711.86 -- 3.950.5271.680.34 -- 5.58 IV316 < 0.0016.163.72 -- 10.20.1823.141.14 -- 7.76 Residual tumorR049217 < 0.00110.0521 R111081 .701.37 -- 2.121.250.99 -- 1.58 aχ2bCox regressionHR = hazard ratio , CI = 95 % confidence intervals , EG = esophagogastric The 1 - , 3 - , and 5-year survival of the pN0 group was 78 , 51 , and 44 % , respectively -LRB- Fig. 1 -RRB- . Where one node was involved , survival was 67 , 41 , and 35 % , respectively . Where two to three nodes were involved , the 1 - , 3 - , and 5-year survival was 57 , 25 , and 13 % , respectively , and where greater than three nodes were involved , this was 40 , 14 , and 8 % , respectively . Figure 1Overall survival by number of nodes positive . Univariate analysis -LRB- Table 3 -RRB- revealed nodal status , pT stage , pathologic stage , and R status as predictors of survival . Multivariate analysis revealed nodal status alone to significantly -LRB- p < 0.0001 -RRB- impact on survival . By this analysis the hazards ratio increased from 1.08 for one involved node to 1.42 for two to three involved nodes , and 1.84 for greater than three nodes . Excluding node-negative patients , univariate analysis -LRB- Table 4 -RRB- revealed pT stage , pathologic stage , R status , and number of nodes as predictive of survival . By multivariate analysis -LRB- Table 5 -RRB- , pathologic stage -LRB- p = 0.010 -RRB- and number of nodes were significant determinants of survival . Compared with the cohort with one involved node , the hazard ratio for two to three nodes was 1.56 -LRB- p = 0.049 -RRB- and 2.06 -LRB- p = 0.007 -RRB- for greater than three nodes . Table 4Univariate Analysis : Node-positive AloneVariablesNo . of PatientsMedian Survival -LRB- moths -RRB- p valuea -LRB- Univariate -RRB- HR95 % CITreatmentSurgery only241110 .23410.63 -- 1.11 Multimodal74110 .84 Tumor siteUpper esophagus9180 .6501 Middle esophagus32100 .5561.310.54 -- 3.18 Lower esophagus130100 .1831.750.77 -- 3.98 OG junction144120 .3501.480.65 -- 3.36 Depth of invasionT05110 .0011 T11280 .9171.060.33 -- 3.41 T246240 .1761.120.43 -- 1.78 T3235110 .7571.430.74 -- 2.14 T41450 .1572.230.74 -- 6.78 HistologySquamous86110 .6381 Adenocarcinoma221110 .6381.070.81 -- 1.40 Other830 .8481.070.49 -- 2.35 Stage1 -- II6319 < 0.0011 III -- IV251102 .011.43 -- 2.83 Residual tumorR0259120 .0351 R16191 .331.02 -- 1.73 No . of nodes18417 < 0.00112 -- 384130.0211.671.06 -- 2.29 > 31479 < 0.0012.531.50 -- 3.62 aχ2HR = hazard ratio , CI = 95 % confidence intervalsTable 5Mutivariate Analysis : Node-positive OnlyVariablesp valuea -LRB- Multivariate -RRB- HR95 % CIDepth of invasionT01T10 .5440.820.31 -- 1.75 T20 .6791.230.74 -- 1.81 T30 .3131.490.99 -- 2.21 T40 .2021.831.39 -- 3.24 StageI -- II0 .0101 III -- IV1 .590.82 -- 3.06 No . of nodes112 -- 30.0491.561.21 -- 2.35 > 30.0072.061.51 -- 2.82 Residual tumorR00 .2831 R11 .220.80 -- 1.79 aCox regressionHR = hazard ratio , CI = 95 % confidence intervals Discussion Cancers of the esophagus and esophagogastric junction are aggressive tumors , which are typically diagnosed at an advanced stage of disease progression .13 This large retrospective review of a tertiary center 's experiences over 12 years highlights the importance of lymph node involvement in the prognosis of these tumors . The study shows that the presence of a solitary node , although a significantly negative factor compared with pN0 disease , is associated with significantly improved median and 1 - , 3 - , and 5-year survival compared with cohorts of patients with greater nodal involvement . The 5-year survival , for instance , was 35 % compared with 13 and 8 % , respectively , for cohorts with two to three positive nodes and greater than three positive nodes . There is no uniform consensus on the number of lymph nodes that must be sampled . In a study by Ito et al. ,3 the median number of lymph nodes examined per specimen was 6 -LRB- range 0 to 35 -RRB- and only 20 % of patients had at least 15 lymph nodes examined . In this study , the median number of lymph nodes examined per specimen was 12 -LRB- range 6 to 55 -RRB- , and 24 % of the patients had at least 15 lymph nodes examined . These results appear consistent with practice in the United States where an analysis of the National Cancer Database indicated that only 18 % of patients undergoing surgery for gastric cancer have more than 15 lymph nodes analyzed .14 In this Unit , lymph node clearance involves a D2 dissection of abdominal nodes , and wide mediastinal clearance to the carina and paratracheal node dissection if they appear involved . No cervical dissection is performed , consistent with recommendations from another group .15 It is acknowledged that variation in lymph node yield may mask stage migration , particularly in a retrospective analysis , but the standardization of lymphadenectomy is likely to minimize the impact of this potential bias . The association between extent of nodal involvement and outcome is well described .16 -- 18 No study to our knowledge has previously focused on the impact of one positive node on outcome in esophageal cancer . The observation , however , of the unique prognostic significance of a solitary involved node was recently reported .19 In a study of 187 patients with esophageal adenocarcinoma treated with neoadjuvant chemoradiotherapy , Gu et al. 19 at the MD Anderson observed from their analysis that patients with a solitary involved node had better overall and relapse-free survival compared with other nodal groups . Moreover , the 5-year survival outcomes and 2-year relapse-free survival was not significantly different from the node-negative cohort . Although in our series survival figures were better for node-negative patients than patients with a solitary involved node , the overall pattern of outcome data in our series is consistent with the report from the Anderson group , with prognosis in this cohort closer to node-negative than other node-positive subgroups . The clinical implication of this finding is not clear at this time , but it should , at minimum , encourage a more optimistic view of patients who have a solitary lymph node identified after adequate lymphadenectomy , as approximately 35 % of patients with this pathologic stage may be cured . In the future , it is possible that advances in endoscopic US staging , fluorodeoxyglucose PET , and sentinel node assessment may improve pre - and intraoperative assessment of nodal involvement , defining node-negative , solitary involved node and micrometastatic-involved subgroups , and selective lymphadenectomy and minimally invasive approaches may be evaluated in these situations . This demands prospective evaluation , but it may be noteworthy that all involved nodes in the solitary involved node cohort were close to the primary site and may possibly have been identified as sentinel nodes . In conclusion , this study shows that in a large cohort of patients , lymph node status and the number of lymph nodes positive at the time of surgical resection is directly linked to survival . Extensive nodal involvement is confirmed as carrying a dismal prognosis , but greater optimism is justified where a solitary involved lymph gland defines the pN stage after an adequate lymphadenectomy .

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

lymph node
esophagectomy
lymphadenectomy
survival


Performances in cerebellar and neuromuscular transmission tests are correlated in migraine with aura In previous studies , we described subclinical abnormalities of neuromuscular transmission and cerebellar functions in migraineurs . The aim of this study was to search if these two functions are correlated in the same patient . Thirteen migraineurs -LSB- five without aura -LRB- MO -RRB- and eight with aura -LRB- MA -RRB- -RSB- underwent both stimulation-SFEMG and 3D-movement analysis . Single fiber EMG -LRB- SFEMG -RRB- results were expressed as the `` mean value of consecutive differences '' -LRB- mean MCD -RRB- . Precision of arm-reaching movements -LRB- measured with an infrared optoelectronic tracking system -RRB- was expressed as the average deviation in the horizontal plane . Median values of mean MCD and mean horizontal deviation were not different between MO and MA . However , in MA , but not in MO , both variables were positively correlated . Thus , we conclude that neuromuscular transmission and cerebellar functions are correlated in the same patient when affected by migraine with aura . We suggest that this correlation might be due to a common molecular abnormality . Introduction Migraine is a paroxysmal neurological disorder with a high prevalence in the general population . There is strong epidemiological and genetic evidence that genetic factors play a major , though variable role , in its pathogenesis . Migraine patients are characterized between attacks on various CNS-evoked responses by a deficit of habituation -LSB- 1 , 2 -RSB- , which may have a familial character -LSB- 3 -- 5 -RSB- . The lack of habituation may play a role in migraine pathogenesis -LSB- 6 -RSB- . By contrast , other mild abnormalities have been identified that are unlikely to play a pathogenic role : a decreased safety factor at the neuromuscular junction on single fiber EMG -LRB- SFEMG -RRB- -LSB- 7 -- 9 -RSB- and subclinical cerebellar hypermetria in the horizontal plane on opto-electronic analysis of upper arm-reaching movements -LSB- 10 -RSB- . It was suggested that these two abnormalities might reflect the same underlying genetic abnormality . If this is correct , one may expect that in the same individual they be of a similar degree . We have therefore compared in the same migraine patient the SFEMG and 3D-movement analysis . Materials and methods Patients Thirteen migraine patients -LRB- ICHD-II -RRB- -LSB- 11 -RSB- were recruited from the Headache Clinic of the Headache Research Unit in Liège , Belgium . Eight patients suffering from typical aura with migraine headache -LRB- MTA -- ICHD-II code 1.2.1 ; three women and five men ; median age 28.5 years ; range 13 -- 67 -RRB- and five patients with migraine without aura -LRB- MO -- ICHD-II code 1.1 ; three women and two men ; median age 40.0 years ; range 31 -- 51 -RRB- underwent both stimulation-SFEMG and 3D-movement analysis . All patients were right-handed . None of them had any other medical condition detectable by history and clinical examination ; none was taking drugs on a regular basis , nor had taken any drug within 3 days before the recordings . The recordings took place at least 3 days after and before an attack -LRB- checked by telephone-interview -RRB- . The study was conducted after approval of our Institution 's ethics committee and performed in accordance with the ethical standards of the 1964 Declaration of Helsinki , with the understanding and consent of each involved subject . SFEMG recordings A Nicolet Viking IV device -LRB- Nicolet ® Biomedical , Madison , Wisconsin , USA -RRB- was used for stimulation single fiber electromyography -LSB- 12 -RSB- . Single muscle fiber activity was recorded with 25-mm-long single fiber needles -LRB- Medelec Neurodiagnostic Accessories , ref : 16829 , Witney , Oxfordshire , UK -RRB- , and the motor nerve was stimulated with Nicolet teflon-insulated monopolar needles . We stimulated suprathreshold the motor branch of the radial nerve and assessed the variability in latency , i.e. the jitter -LRB- Fig. 1 -RRB- , of single fiber action potentials in m. extensor digitorum communis -LRB- EDC -RRB- of the right arm . Stimulations -- acquisitions were 100 per muscle fiber , and stimulation rate was 10 Hz . We recorded 25 EDC muscle fibers per patient . Off-line analyses of recordings were performed , and on average 18 artifact-free EDC muscle fibers per patient were selected to assess their mean MCD . Results were expressed as the `` mean value of consecutive differences '' -LRB- MCD -RRB- of successive interpotential intervals , as usual in SFEMG studies . Fig. 1Figures representing a normally -LRB- on the top -RRB- and an abnormally -LRB- on the bottom -RRB- jittered fibers 3D-movement analysis Movements were recorded at 100 Hz in three dimensions -LRB- 3D -RRB- using an infrared optoelectronic-tracking-system -LRB- ELITE ™ , Milan , Italy -RRB- with a reflective marker attached to the tip of the index finger and another marker to the movement target . Participants were seated with the target in the medio-sagittal plane on eye level . They were instructed to start with the right arm extended to the right , to touch the target with high precision -LRB- but fast -RRB- without any trunk movement , to go back to the starting position and to repeat above movements , in a given pace over 15 s -LRB- one trial -RRB- to result in 8 -- 10 movements -LRB- Fig. 2 -RRB- . The used Cartesian coordinate system is head-fixed with a nasooccipital , a horizontal and a vertical axis and the origin in the target . Since in our previous study -LSB- 10 -RSB- abnormalities in migraineurs were most pronounced in the horizontal plane , we limited ourselves to an analysis of the mean deviation in the horizontal plane -LRB- in millimeters -RRB- , measured over four trials , each consisting of 8 -- 10 arm movements . Fig. 2Experimental setup for the movement task Quantitative variables in each group of migraine patients -LRB- MO and MTA -RRB- were expressed as medians . Differences between groups were analysed with the Mann -- Whitney U test . The Spearman rank order correlation test was used to compare the values of the mean MCD on SFEMG and the mean horizontal deviation on 3D-movement analysis . Results On SFEMG , the median value for mean MCD was not significantly different between MO -LRB- 16.05 μs ; range 9.50 -- 22.93 -RRB- and MTA -LRB- 18.91 μs ; range 11.50 -- 24.55 -RRB- . The median value of mean horizontal deviation was 4.01 mm -LRB- range − 3.25 to 18.12 -RRB- in MO and 10.74 mm -LRB- range 1.60 -- 17.03 -RRB- in MTA , a nonsignificant difference . In MO , there was no significant correlation between mean MCD and mean horizontal deviation . By contrast , in MTA , both variables were positively correlated -LRB- R = 0.71 , P = 0.046 -RRB- -LRB- Fig. 3 -RRB- . Fig. 3Scatter plot relating mean MCD on SFEMG -LRB- X axis , μs -RRB- and mean horizontal deviation on 3D analysis of a reaching arm movement -LRB- Y axis , mm -RRB- , and linear regression lines . Migraine without aura patients -LRB- MO -RRB- : squares , dashed line . Migraine with aura patients -LRB- MTA -RRB- : triangles , continuous line Discussion Our within-patient analysis shows that , in migraine with aura , the mean MCD on SFEMG increases significantly with the degree of horizontal deviation in a visually guided reaching movement . This suggests that , in subgroups of migraine patients , neuromuscular transmission -LRB- NMT -RRB- performance and control of ballistic movements by the lateral cerebellum are similarly influenced by a common biochemical and/or neural mechanism . Although no gene mutations have been identified till now , the genetic load is thought to be higher in the pathogenesis of migraine with aura than that without aura -LSB- 13 -RSB- . In familial hemiplegic migraine 1 -LRB- FHM1 -RRB- -LSB- 14 -RSB- , mutations have been found in the CACNA1A gene , which codifies for the main subunit of P/Q-type Ca2 + channels , heavily concentrated at the neuromuscular junction and in the cerebellum -LSB- 15 -- 18 -RSB- . Thus , we initially hypothesized that the NMJ and cerebellar abnormalities found in some migraine patients might be due to dysfunctioning Ca + + channels . However , SFEMG studies were normal in FHM1 -LSB- 19 -RSB- , and mutations in the CACNA1A gene are not found in patients suffering from the common forms of migraine , with or without aura -LSB- 20 -RSB- . Some evidence that the CACNA1A gene may be involved in migraine with typical aura -LSB- 21 -RSB- , and the facts that NMT impairment can be found in episodic ataxia type 2 , an allelic disorder of FHM1 -LSB- 22 -RSB- , and normalizes after treatment with acetazolamide -LSB- 23 -RSB- are still in favor of a possible involvement of Ca + + channels , particularly in migraine with aura . Other proteins implicated in migraine pathophysiology may constitute a common link between neuromuscular junctions -LRB- NMJ -RRB- and the cerebellum . This is unlikely for the alpha-2 subunit of the Na-K ATPase , of which the gene ATP1A2 is mutated in FHM2 -LSB- 24 -RSB- , because the alpha-2 isoform is found at intracellular membranes -LSB- 25 -RSB- and not at the NMJ , where the major role is played by the alpha-3 isoform -LSB- 26 -RSB- . Moreover , SFEMG results were found normal in FHM2 patients -LSB- 19 -RSB- . By contrast , a different group of calcium channels , the R-type , influence neuromuscular transmission and can compensate for dysfunctioning P/Q channels -LSB- 27 -RSB- . Moreover , they seem to play a role in cerebellar functions -LSB- 28 -RSB- ; thus , their activity may influence in parallel NMJ and cerebellar performances , similarly to what we found in the subgroup of migraineurs with aura . The CACNA1E gene , which codes for the alpha-1E subunit of R-type channels , is precisely located on locus 1q31 , for which significant linkage was found in the common forms of migraine -LSB- 29 -RSB- , and a single nucleotide polymorphism was more frequent in subgroups of patients affected by migraine with aura -LSB- 30 -RSB- . In conclusion , the correlation between NMJ and cerebellar performances that we have found in migraine with aura patients might be due to a common genetically determined molecular mechanism , possibly influencing ion channels functions , but this has still to be proven by appropriate genetic studies .

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 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 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 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 B 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 O O O O 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 O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O 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 B 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 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 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 O O O O O O O O O B 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 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 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 O O O O O O O O O O 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 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 O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O 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 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

migraine
cerebellum
neuromuscular junction


Healthcare Utilization of Individuals with Opiate Use Disorders : An Analysis of Integrated Medicaid and State Mental Health/Substance Abuse Agency Data Data from the Substance Abuse and Mental Health Services Administration 's Integrated Database -LRB- IDB -RRB- were used to examine the service use patterns of individuals with possible opiate use disorders in Washington State . Results indicate that regardless of Medicaid enrollment status , individuals who received mental health -LRB- MH -RRB- or substance abuse -LRB- SA -RRB- services only through state agencies received no inpatient substance abuse service . Furthermore , when compared with individuals who received at least one MH/SA service through Medicaid , those who received services only through the state agencies were less likely to have received any MH services and were more likely to have received residential SA services . This analysis highlights the importance of using integrated client data in providing a more comprehensive understanding of services to inform policy and raises significant questions about how regulatory requirements affecting different funding mechanisms might drive settings of care in ways not related to the care needed . Introduction The use of , abuse of , and dependence on opiates is a major public health concern .1,2 Although only about 0.1 % of the U.S. population reported past-year heroin use in 1998,3 heroin and other opiate use accounted for about 30 % of total spending for illicit drug use treatment and almost 18 % of spending on drug-related crime .4 Psychological and physical health problems were also common among heroin and other opiate users in the mid - to late-1990s.5 As recently as 2003 , heroin accounted for 23 % of the mentions of substances used among emergency room patients and 41 % of drug-related deaths recorded by medical examiners or coroners .6 The social costs of opiate abuse are not limited to illegal drugs . A recent study suggests that in 2001 , the social cost of prescription opioid abuse in the United States was $ 8.6 billion .7 Despite the overwhelming societal costs associated with opiate use disorders , few studies have investigated the substance abuse -LRB- SA -RRB- or mental health -LRB- MH -RRB- treatment service patterns of individuals suffering from opiate abuse or dependence ; rather , most studies focus almost exclusively on those in methadone maintenance treatment .8 -- 10 These studies suggest that the co-occurrence of MH problems and other illicit drug dependence is quite high among individuals with an opiate use disorder .11 -- 13 Yet , despite the increased incidence of MH conditions , individuals with a substance use disorder may not receive adequate levels of MH care beyond that directly related to their substance use disorder .10,11,14,15 Given these findings and the major public health concerns caused by opiate abuse and dependence , the lack of information about the broader MH/SA treatment service patterns of individuals with an opiate use disorder is a critical gap in the knowledge base informing policies affecting this population . This study used data from the Substance Abuse and Mental Health Services Administration 's -LRB- SAMHSA -RRB- Integrated Database -LRB- IDB -RRB- on individuals in Washington State with an indication of an opiate use disorder to determine what MH/SA services they received and through which auspice -LRB- i.e. , Medicaid or state agency -RRB- they received them . Findings from this study offer two contributions to the current literature . First , the IDB presents a unique opportunity to study the behavioral health care utilization of individuals with opiate use disorders because it contains service use data linked at the client level from Washington Medicaid and from the Washington State Department of Social and Health Services ' -LRB- DSHS -RRB- Mental Health Division -LRB- MHD -RRB- and Division of Alcohol and Substance Abuse -LRB- DASA -RRB- . The combination of Medicaid and DSHS data represented in the IDB provides a more comprehensive picture of service use patterns than might be obtained from studies that focus on only one data source . Second , the late 1990s is often characterized as a time of a heroin epidemic in the United States .16 Therefore , examining the MH/SA treatment service use patterns of individuals with opiate use disorders during this period can provide an especially relevant baseline for today 's policy makers as they attempt to address issues surrounding the emergence of new opiates . Data and Methods This paper uses IDB data on Washington State from three full calendar years -LRB- 1996 -- 1998 -RRB- . For a more detailed description of the IDB , see Coffey et al. ,17 and for a detailed description of the methods used to link IDB service records across state organizations , see Whalen et al. 18 In addition to service use information , the IDB contains information on patient demographics -LRB- e.g. , age , gender , race/ethnicity -RRB- , Medicaid enrollment status , MH/SA diagnosis and service codes , and limited provider information . Study population The study population for this analysis consists of individuals who have at least one record in the IDB indicating an opiate use disorder . An opiate use disorder could be indicated by one or more of the following : a diagnosis -LRB- either primary or secondary -RRB- of an opiate use disorder , a provider type indicative of opiate treatment , a service or procedure code indicative of opiate treatment -LRB- including methadone maintenance therapy but excluding methadone used for pain management -RRB- , or a report of an opioid as the drug of choice . Opiate use disorder diagnoses were defined using the International Classification of Diseases , 9th Revision , Clinical Modification -LRB- ICD-9-CM -RRB- . ICD-9-CM codes of 304.0 or 305.5 , including any subclassifications , were used to identify opiate dependence and abuse , respectively . State-specific provider codes were used to identify opiate treatment providers . Both standard -LSB- e.g. , Healthcare Common Procedure Coding System -LRB- HCPCS -RRB- -RSB- and local procedure codes were used to identify opiate treatment services . Finally , drug-of-choice information was available from self-reports obtained by state agencies during client intake . In some cases , the drug-of-choice information was obtained more than 1 year before or after any SA or MH service provision , but these cases represent less than 3 % of the sample . Preliminary analyses revealed that very few agency service records include diagnosis codes , but most Medicaid records do . Further investigation revealed that this is not an issue of Medicaid requiring a diagnosis for eligibility , but rather an issue of the data systems themselves . Agency services do not require a diagnosis code for reimbursement , so agency data systems do not track diagnosis . Conversely , Medicaid services often require a diagnosis for reimbursement , so Medicaid data systems track diagnosis . Because the presence or absence of a diagnosis is almost completely confounded by the use or nonuse of Medicaid services , information on service use differences associated with an opiate use disorder diagnosis is not presented . Client classification One of the primary objectives of this study was to examine the extent to which the MH/SA service use patterns of individuals with an opiate use disorder varied based on whether their MH/SA services were tracked by Medicaid or a state MH/SA agency . Importantly , service tracking may , or may not , be associated with full or partial financial coverage . Accordingly , for this study , individuals were classified based on the data source -LRB- Medicaid or state MH/SA agency -RRB- from which their IDB MH/SA service records were obtained . Based on this information , individuals were classified into three categories : Any Medicaid service : individuals who have at least one Medicaid MH/SA service record , regardless of whether they have MH/SA state agency service recordsAgency services only with Medicaid enrollment : individuals who have at least one MH/SA state agency service record and were Medicaid-enrolled at some point between their first and last observed MH/SA service record but have no record of receiving an MH/SA service through MedicaidAgency services only without Medicaid enrollment : individuals who have at least one MH/SA state agency service record and were not Medicaid-enrolled at any time between their first and last observed MH/SA service record Because the IDB integrates information from state Medicaid and state MH/SA agency data sources , overlapping records may occur if Medicaid reimburses a bill , but the state agency provides the service . To avoid overstating utilization rates , only one service date was counted for cases in which the same client , service type -LRB- MH or SA -RRB- , modality/setting of service -LSB- i.e. , inpatient -LRB- IP -RRB- , residential/long-term care , or outpatient -LRB- OP -RRB- -RSB- , and service date were reported on both the Medicaid and state agency databases . Individuals with these types of records were classified as any Medicaid service . Importantly , although individuals in the any Medicaid service group may have received any number , or even the majority , of their services through the state agency , preliminary analyses indicated that individuals who received both Medicaid and agency services were more similar to those who received only Medicaid services than they were to those who received only agency services . For this reason , individuals receiving any Medicaid service were combined into a single category . In addition to the client categorization described above , the standard IDB client classification was also used . The IDB client classification was used to identify individuals who received services for only MH conditions -LRB- MH-only -RRB- , only SA conditions -LRB- SA-only -RRB- , or co-occurring conditions -LRB- both MH and SA -RRB- during the study period . The IDB classifies individuals as having co-occurring conditions if they had any of the following within the 3-year study period : -LRB- 1 -RRB- both a primary MH and a SA diagnosis , -LRB- 2 -RRB- a primary MH and a secondary SA diagnosis , or -LRB- 3 -RRB- a primary SA and a secondary MH diagnosis . Individuals classified as having co-occurring conditions did not necessarily have MH and SA conditions concurrently . A client with an MH record at the beginning of the study period and an SA record at the end of the study period , for example , is classified by the IDB as having co-occurring conditions . In the absence of diagnosis information , MH-only and SA-only classifications were assigned based on the type of service received during the study period -LRB- see Coffey et al. 17 and Bray et al. 19 for a detailed definition of the primary MH/SA diagnosis category -RRB- . The IDB client classification does not incorporate information on secondary diagnoses unless a primary MH/SA diagnosis is also present , nor does it incorporate drug-of-choice information from state agency intake records . Because both of these pieces of information were used to identify individuals with an opiate use disorder for this study , it is possible for individuals with an opiate use disorder to be classified as MH-only or having received no MH/SA service based on the IDB client classification . Service classification Standard IDB service type classifications were used to classify the MH/SA services received by individuals with an opiate use disorder . The IDB MH/SA service type classifies MH/SA service records as either MH or SA and within MH/SA as IP , residential , or OP . Many inpatient programs are part of psychiatric or general hospitals and generally use a medical model of substance disorders in which intensive medication and counseling are provided over a relatively short period of time .20 Residential programs typically are provided in a free-standing , designated residential treatment facility . Residential treatment is usually of longer duration than IP treatment and relies less on medical professionals . Residential treatment provides organized services by designated treatment personnel who provide a planned regimen of care in a 24-h setting and is intended to serve clients who need a safe and stable living environment to develop sufficient recovery skills .21 For a complete description of the criteria used to classify services , see Coffey et al. 17 The vast majority of individuals with a possible opiate use disorder have at least 1 SA service record , but relatively few have MH service records ; therefore , the IP , residential , and OP subclassifications were examined for SA service records but not for MH service records . Service encounters An individual 's total number of service encounter dates was defined as the count of unique dates within the MH/SA service window on which the individual had a record with at least one service of a given service category -LRB- MH , IP SA , residential SA , or OP SA -RRB- . Within a single IP or residential stay , each daily service encounter date was counted separately . Using standard IDB definitions for the full SA population , this same information is presented for the broader SA population , excluding individuals with an indication of an opiate use disorder . Methods To characterize the level of contact individuals with an opiate use disorder have with the public treatment system , the analysis examined four key domains : -LRB- 1 -RRB- the proportion of clients using services , -LRB- 2 -RRB- the median length of the service window -LRB- i.e. , the length of time between an individual 's first and last MH/SA service -RRB- , -LRB- 3 -RRB- the number of days of Medicaid enrollment within the service window , and -LRB- 4 -RRB- the number of unique MH/SA encounter dates within the service window . Regression analyses were conducted to assess whether the service use patterns of individuals with an opiate use disorder differed significantly across the client classification categories after controlling for differences in the length of the MH/SA service window , the length of Medicaid enrollment , and demographics across the client categories . First , logistic regression models of the following form were estimated : where SERVi is a series of indicators for receipt of services of a given type . For the regression analyses , any MH services and OP and residential SA services were considered . Regression analyses for IP SA services were not conducted because those services were received solely by the any Medicaid service group . DEMOGi is a set of demographic characteristics -LRB- i.e. , gender , age , and race/ethnicity -RRB- ; GROUPi is a vector of variables representing the data source categories of any Medicaid service -LRB- the referent -RRB- , agency services only with Medicaid enrollment , and agency services only without Medicaid enrollment ; WINDOWi is the MH/SA service window length in days ; and ENROLLi is the months of Medicaid enrollment -LRB- including 0 months -RRB- . The βs are vectors of coefficients to be estimated . Variables reflecting the primary diagnosis categories are not included because much of the information used to classify individuals as MH-only , SA-only , or co-occurring was also used to classify services as MH or SA . Next , regressions of the following form were run on days of service , conditional on service use : where DAYSi is a set of variables reflecting the unique days of care for each of the same types of care , and all other terms are as previously defined . Consistent with the recommendations of Manning and Mullahy ,22 generalized linear model -LRB- GLM -RRB- estimation with a log link and a gamma distribution on the natural scale was used rather than ordinary least squares -LRB- OLS -RRB- on the log scale . Results Table 1 presents the demographic characteristics of the individuals identified as having an opiate use disorder in the IDB . For a point of comparison , Table 1 also presents the same information for the general IDB SA population , as defined in Coffey et al. ,17 but excluding individuals with an opiate use disorder . Individuals with an opiate use disorder accounted for approximately 16 % of the population with any SA disorder . In terms of demographics , when compared with individuals with a non-opiate SA disorder , individuals with an opiate use disorder are less likely to be male and more likely to be adults -LRB- as opposed to youth or elderly -RRB- , but only minor differences in the distribution of clients across racial/ethnic categories are observed . Individuals with an opiate use disorder are less likely to be in the SA-only IDB client classification category . This is largely by construction because as discussed earlier , the current paper uses more inclusive data to identify individuals with a possible opiate use disorder than is used by the IDB client classification . Individuals with an opiate use disorder were more likely to have IP and residential SA services than the general SA population , but less likely to have any OP SA service . Individuals with an opiate use disorder were also more likely to have received any MH service compared to the general SA population . They also had longer MH/SA service windows , indicating longer periods of contact with the public MH/SA treatment system , and were more likely to be in the any Medicaid service and the agency services only with Medicaid enrollment groups . Table 1Characteristics of individuals with a possible opiate use disorder compared with the non-opiate SA populationPopulation characteristicNon-opiate SA populationOpiate usersAll users -LRB- N -RRB- 83,79315,652 Percentage of total SA population -LRB- % -RRB- 84.315.7 Gender -LRB- % -RRB- Male63 .256.8 Female36 .843.2 Unknown0 .00.0 Age -LRB- % -RRB- Youth -LRB- 0 -- 17 -RRB- 19.93.1 Adult -LRB- 18 -- 64 -RRB- 78.896.5 Elderly -LRB- 65 + -RRB- 1.30.4 Unknown0 .00.0 Race/ethnicity -LRB- % -RRB- White70 .077.6 Black9 .010.6 Hispanic8 .54.3 Native American7 .84.5 Other3 .62.6 Unknown1 .00.3 IDB client category -LRB- % -RRB- SA-only68.859 .9 Co-occurring -LRB- MH+SA -RRB- 31.234.7 MH-only0.01 .9 Neither MH nor SA0 .03.4 MH/SA service type -LRB- % -RRB- SA services -LRB- % -RRB- Any setting94 .994.6 Inpatient3 .06.2 Residential31 .957.7 Outpatient80 .971.4 No SA services5 .15.4 Any MH service31 .236.5 MH/SA service window length 25th percentile -LRB- days -RRB- 38.078.0 Median -LRB- days -RRB- 168.0348.0 75th percentile -LRB- days -RRB- 446.0770.0 MH/SA service data source -LRB- % -RRB- Any Medicaid46 .051.0 Agency services only with Medicaid enrollment17 .322.7 Agency services only without Medicaid enrollment36 .826.3 SA Substance abuse , MH mental health Figure 1 presents the median MH/SA service window and length of Medicaid enrollment across individuals with a possible opiate use disorder in each of the data source categories . The any Medicaid service group has the longest median MH/SA service window and the most median days of Medicaid enrollment within that window , followed by the agency services only with Medicaid enrollment group and then the agency services only without Medicaid enrollment group . Because the analysis only examines Medicaid enrollment within the MH/SA service window , the length of Medicaid enrollment is always less than the total service window length . The total Medicaid enrollment of an individual may be greater than that reported here , but by definition of the service window , no MH/SA service use occurred during days of Medicaid enrollment not captured by this measure . Importantly , the any Medicaid service group may have received substantial services from MH or SA state agencies , because individuals in this group are categorized as any Medicaid service only because they received at least one Medicaid service . Figure 1Median MH/SA service window length and days of medicaid enrollment among individuals with a possible opiate use disorder by data source category Figures 2 and 3 present the probability of service use and the median days of service conditional on service utilization for each of the data source categories . IP SA care was not included in Figures 2 and 3 because only individuals in the any Medicaid service group had IP SA utilization -LRB- the conditional median days of IP SA care for that group were 6 -RRB- . Figure 2 suggests that the two agency services only groups are more likely to receive residential SA services and are less likely to receive OP SA services or MH services . Conditional on receipt of services , Figure 3 suggests that the agency services only with Medicaid enrollment group received the most days of residential SA service , the agency services only without Medicaid enrollment group received the most days of OP SA care , and the any Medicaid services group received the most days of MH care . Figure 2Percentage of individuals with a possible opiate use disorder using MH/SA services by service type and data source categoryFigure 3Median days of care conditional on service use among individuals with a possible opiate use disorder by service type and data source category Table 2 presents results from the logistic regressions , including logit coefficients , their standard errors , and associated odds ratios -LRB- ORs -RRB- for the data source grouping variables . For all other covariates , only the estimated logit coefficients and their standard errors are presented . Table 2 shows that even after controlling for the longer service window and more months of Medicaid enrollment , the pattern observed in Figure 2 still holds . Compared with individuals in the any Medicaid service group , individuals in the agency services only with Medicaid enrollment and the agency services only without Medicaid enrollment groups had significantly higher odds of receiving at least residential SA service -LRB- OR = 2.941 and OR = 1.376 , respectively -RRB- and lower odds of receiving any OP SA -LRB- OR = 0.311 and OR = 0.162 , respectively -RRB- or any MH service -LRB- OR = 0.217 and OR = 0.110 , respectively -RRB- . Briefly examining the results for the control variables in the regression , females are significantly less likely to receive residential SA services . The racial/ethnic categories that are statistically significant suggest that racial/ethnic minorities are less likely than non-Hispanic whites to receive services of any type . Age categories reflecting individuals both younger and older than the referent of 36 to 40 were also , in general , less likely to receive services of any type when the associated coefficients were statistically significant . The exception is that individuals aged 21 to 35 with an opiate use disorder were more likely to receive residential SA services . Results with regard to demographic characteristics , especially race/ethnicity , should not be interpreted as evidence of disparities , however . Rather , they indicate the differential representation of demographic groups across the data and highlight the importance of controlling for those factors when assessing statistical significance . Unexpectedly , months of Medicaid enrollment are positively associated with a greater likelihood of service use only for MH services . For both types of SA care examined , longer Medicaid enrollment was negatively associated with the probability of service use , although the relationship was not significant for residential care . Table 2Logistic regression results for the probability of service useParametersProbability of residential SA service useProbability of OP SA service useProbability of any MH service useAgency services only with Medicaid enrollment1 .079 *** − 1.167 *** − 1.526 *** Standard error0 .0500.0610.052 Odds ratio2 .9410.3110.217 Agency services only without Medicaid enrollment0 .319 *** − 1.819 *** − 2.210 *** Standard error0 .0520.0690.072 Odds ratio1 .3760.1620.110 Control variablesIntercept0 .446 *** 1.091 − 0.274 *** Standard error0 .0590.0780.065 Female − 0.519 *** 0.344 − 0.064 Standard error0 .0360.0460.042 Race/ethnicity -LRB- referent is non-Hispanic White -RRB- Black − 0.269 *** 0.371 − 0.493 *** Standard error0 .0570.0750.069 Hispanic − 0.0810.036 − 0.402 *** Standard error0 .0860.0970.116 Native American0 .342 *** − 0.067 − 0.221 ** Standard error0 .0870.1010.101 Other − 0.357 *** 0.229 − 0.169 Standard error0 .1100.1450.128 Unknown − 1.656 *** − 1.122 ** 0.863 * Standard error0 .5070.4410.459 Age -LRB- referent is 36 to 40 -RRB- 0 to 17 − 0.384 *** 0.765 − 0.058 Standard error0 .1030.1460.12418 to 20 − 0.032 − 0.037 − 0.126 Standard error0 .1120.1320.13421 to 250.361 *** − 0.0980.097 Standard error0 .0750.0860.08526 to 300.279 *** − 0.0600.027 Standard error0 .0630.0760.07231 to 350.175 *** 0.0340.093 Standard error0 .0580.0720.06641 to 45 − 0.205 *** − 0.047 − 0.116 * Standard error0 .0550.0690.06546 to 50 − 0.465 *** − 0.010 − 0.268 *** Standard error0 .0650.0820.07851 to 55 − 0.537 *** 0.001 − 0.425 *** Standard error0 .0990.1290.12156 to 60 − 1.096 *** 0.443 ** − 0.718 *** Standard error0 .1590.2200.18361 to 64 − 0.656 *** − 0.713 ** − 0.729 ** Standard error0 .2410.2970.28865 plus − 1.417 *** − 0.285 − 0.675 ** Standard error0 .3010.3440.322 Service window length -LRB- days -RRB- 0.0000.0030.001 *** Standard error0 .00010.00010.0001 Medicaid enrollment -LRB- months -RRB- − 0.005 − 0.017 ** 0.053 *** Standard error0 .0040.0070.005 IP Inpatient , SA substance abuse , OP outpatient , MH mental health * p < 0.10 ** p < 0.05 *** p < 0.01 Table 3 presents the regression results for days of care , conditional on having at least 1 day of service of that type of care . Because the natural logarithm of days of care is the dependent variable , the coefficient estimates , standard errors , and associated percentage changes for the data source categories are presented . For all other variables , only the estimated coefficients and their standard errors are presented . For residential SA care , the agency services only with Medicaid enrollment group is significantly associated with more days of residential SA care -LRB- 28 % increase -RRB- , while the agency services only without Medicaid enrollment group is significantly associated with fewer days of care -LRB- 56 % decrease -RRB- . Both agency services only groups are significantly and positively related to OP SA days of care : an estimated 18 % increase for the agency services only with Medicaid enrollment group and an estimated 60 % increase for the agency services only without Medicaid enrollment group . Finally , the agency services only without Medicaid enrollment group is associated with significantly more days of MH care than the any Medicaid service group -LRB- 56 % increase -RRB- . Unlike in Table 2 , no consistent pattern emerges with regard to the demographic control variables included in the linear regression . The length of the MH/SA service window is positively and significantly associated with days of care . Months of Medicaid enrollment are negatively and significantly associated with days of residential and OP SA care , but positively and significantly associated with days of MH care . Table 3Linear Regression Results for Unique Health Care Service Dates ParametersUnique dates of residential SA serviceUnique dates of OP SA serviceUnique dates of MH serviceAgency services only with Medicaid enrollment0 .248 *** 0.169 *** − 0.009 Standard error0 .0300.0450.063 Percentage change0 .2820.185 − 0.009 Agency services only without Medicaid enrollment − 0.818 *** 0.472 *** 0.448 *** Standard error0 .0380.0770.094 Percentage change − 0.5590.6040.564 Control variablesIntercept3 .310 *** 2.552 *** 2.337 *** Standard error0 .0420.0650.067 Female − 0.0170.322 *** − 0.045 Standard error0 .0250.0390.041 Race/ethnicity -LRB- referent is non-Hispanic White -RRB- Black − 0.0070.121 ** − 0.010 Standard error0 .0400.0610.074 Hispanic0 .208 *** 0.013 − 0.153 Standard error0 .0570.1060.133 Native American0 .254 *** − 0.039 − 0.700 *** Standard error0 .0520.0840.106 Other − 0.057 − 0.0160.211 * Standard error0 .0790.1230.128 Unknown − 1.268 *** 0.000 − 1.340 *** Standard error0 .4830.0000.443 Age -LRB- referent is 36 to 40 -RRB- 0 to 170.549 *** 0.374 *** 0.224 * Standard error0 .0760.1120.12318 to 200.193 *** 0.1350.366 ** Standard error0 .0740.1230.14321 to 25 − 0.0280.188 *** 0.062 Standard error0 .0450.0720.08526 to 300.0030.174 *** 0.071 Standard error0 .0390.0610.07131 to 35 − 0.0260.0390.040 Standard error0 .0370.0570.06541 to 45 − 0.0310.137 ** 0.115 * Standard error0 .0370.0580.06446 to 500.0370.1150.309 *** Standard error0 .0460.0750.07851 to 550.0400.317 *** − 0.080 Standard error0 .0730.1220.12356 to 60 − 0.229 * 0.264 − 0.037 Standard error0 .1340.2100.19661 to 64 − 0.618 *** 0.283 − 0.093 Standard error0 .1900.3570.30865 plus0 .701 *** − 0.7000.116 Standard error0 .2711.3210.353 Service window length -LRB- days -RRB- 0.001 *** 0.003 *** 0.002 *** Standard error0 .0000.0000.000 Medicaid enrollment -LRB- months -RRB- − 0.019 *** − 0.024 *** 0.013 *** Standard error0 .0030.0040.003 IP Inpatient , SA substance abuse , OP outpatient , MH mental health * p < 0.10 ** p < 0.05 *** p < 0.01 Implications for Behavioral Health This analysis examined the service use patterns of individuals with an indication of an opiate use disorder using IDB data from Washington for the period 1996 through 1998 . Among individuals with opiate use disorders , the receipt of at least one MH/SA service through Medicaid appears to be positively associated with IP SA service use in that only individuals who met this condition had any record of an IP SA service . The receipt of at least one MH/SA service through Medicaid was also positively associated with OP SA service and with MH service use among individuals with opiate use disorders . The use of only state MH/SA agency services , on the other hand , was positively associated with the use of residential SA services . The findings suggest that the regulatory restrictions faced by state agencies and Medicaid may drive observed patterns of care for individuals with opiate use disorders . Specifically , the finding that agency-only MH/SA service use is associated with higher rates of residential service use and with no IP SA service use is likely tied to regulatory differences between Medicaid and the state agencies in Washington . For example , SA block grant funds , which are a key source of funding for both DASA and MHD , could not be used for IP hospital care during the period covered by this analysis . This restriction most likely induced state agencies to route patients for whom outpatient care is insufficient to residential care . Similarly , the Medicaid Institutions of Mental Disorders exclusion prohibits payment for psychiatric services received by adults in residential care facilities with more than 16 beds and so may induce providers to route more severe patients to IP care rather than to residential care . This explanation suggests that using administrative data to track service use patterns may be misleading because the collection of service data is driven by regulatory environments and billing systems that may not capture the actual intensity of care given . The results are subject to several limitations . First , although the IDB represents one of the most comprehensive cross-system databases used to examine this critical issue to date , it does not capture all possible services that could be used by individuals with possible opiate use disorders in Washington . Other possible sources include self-pay , private insurance , and the Department of Veterans Affairs -LRB- VA -RRB- system , among others . Another important limitation common to all administrative databases is that the actual treatment need of the population studied is unknown , so definitive statements can not be made about the appropriateness of the services received . Furthermore , because of the limited time frame of the IDB , data are unavailable for individuals who used MH/SA services either before 1996 or after 1998 . As a result , it is possible that this study has not captured the full service use history of some individuals who appear in the treatment system briefly at the beginning or end of the study period . A final limitation of this study is that information on prescription drug use is not available in the agency service records contained in the IDB and is therefore not considered in this study . Despite these limitations , the analysis of service use patterns of individuals with possible opiate use disorders during the late 1990s offers key implications for today 's policy makers as they attempt to address issues surrounding the emergence of new opiates . First and foremost , if policy makers are trying to track the service use of a small but important segment of the overall SA population , using integrated data is a necessity . When funding for treatment services is cut in an effort to contain costs , it is important to determine if those services have simply been shifted to other state programs , reflecting little net cost savings for states overall . The present study combines state MH/SA agency data with state Medicaid data , but including additional data sources -LRB- e.g. , VA or criminal justice system -RRB- would provide an even more complete picture of service use patterns . Second , the utility of administrative data for analyses such as these is often limited by the influence of the regulatory environment , clinical practice patterns , and the institutional history of the data systems used . Given that state and federal policy makers increasingly rely on administrative data to assess the performance of the treatment system , the results clearly highlight the need to better track service provision . SAMHSA 's IDB , therefore , represents the vanguard of a new , expansive , cross-agency philosophy regarding administrative data sources and serves as a model for new and more comprehensive data integration efforts .

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

mh/sa service utilization
state mh/sa agencies