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/Title (A 20 gene model for predicting nodal involvement in bladder cancer patients with muscle invasive tumors � PLOS Currents Evidence on Genomic Tests)
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BT 15.000 718.042 Td /F2 21.0 Tf  [(A 20 gene model for predicting nodal involvement in bladder )] TJ ET
BT 15.000 693.094 Td /F2 21.0 Tf  [(cancer patients with muscle invasive tumors)] TJ ET
Q
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BT 15.000 675.088 Td /F3 9.8 Tf  [(August 11, 2011)] TJ ET
BT 26.250 663.247 Td /F1 9.8 Tf  [(, )] TJ ET
BT 31.671 663.247 Td /F1 9.8 Tf  [(, )] TJ ET
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BT 37.092 663.247 Td /F1 9.8 Tf  [(Garrett Dancik)] TJ ET
0.271 0.267 0.267 rg
BT 99.941 663.247 Td /F1 9.8 Tf  [(, )] TJ ET
0.267 0.267 0.267 rg
BT 105.362 663.247 Td /F1 9.8 Tf  [(Dara Aisner)] TJ ET
0.271 0.267 0.267 rg
BT 156.832 663.247 Td /F1 9.8 Tf  [(, )] TJ ET
0.267 0.267 0.267 rg
BT 162.253 663.247 Td /F1 9.8 Tf  [(Dan Theodorescu)] TJ ET
0.271 0.267 0.267 rg
BT 26.250 651.342 Td /F1 9.8 Tf  [(Dancik G, Aisner D, Theodorescu D. A 20 gene model for predicting nodal involvement in bladder cancer patients with muscle )] TJ ET
BT 26.250 639.438 Td /F1 9.8 Tf  [(invasive tumors. PLOS Currents Evidence on Genomic Tests. 2011 Aug 11 . Edition 1. doi: 10.1371/currents.RRN1248.)] TJ ET
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BT 26.250 610.335 Td /F4 12.0 Tf  [(Abstract)] TJ ET
BT 26.250 590.381 Td /F1 9.8 Tf  [(Bladder cancer is the fourth most common cancer in males worldwide and also the most expensive cancer to treat. )] TJ ET
BT 26.250 578.476 Td /F1 9.8 Tf  [(Approximately 25% of patients with muscle invasive disease are found to harbor occult lymph node involvement at the time of )] TJ ET
BT 26.250 566.571 Td /F1 9.8 Tf  [(cystectomy and this finding is associated with a 5-year survival rate of <30%. If these patients could be identified pre-)] TJ ET
BT 26.250 554.667 Td /F1 9.8 Tf  [(operatively, use of neoadjuvant chemotherapy may be advantageous because this approach has been shown to confer a small )] TJ ET
BT 26.250 542.762 Td /F1 9.8 Tf  [(survival advantage in patients with muscle invasive disease. However, because only a few patients benefit from this approach it )] TJ ET
BT 26.250 530.857 Td /F1 9.8 Tf  [(has not been used extensively in the United States with fewer than 2% of patients undergoing this treatment. This is largely due )] TJ ET
BT 26.250 518.952 Td /F1 9.8 Tf  [(to concerns that since neoadjuvant therapy is beneficial for only a few patients, it has the potential to delay surgery in the )] TJ ET
BT 26.250 507.048 Td /F1 9.8 Tf  [(majority who do not benefit. However, since neoadjuvant therapy is most likely to benefit those patients at highest risk for )] TJ ET
BT 26.250 495.143 Td /F1 9.8 Tf  [(progression of disease, it follows that patients with lymph node metastases would constitute an ideal group for such treatment. )] TJ ET
BT 26.250 483.238 Td /F1 9.8 Tf  [(Hence, if patients with occult node involvement prior to cystectomy could be identified, they would constitute an ideal group for )] TJ ET
BT 26.250 471.333 Td /F1 9.8 Tf  [(application of neoadjuvant therapy as they are most likely to benefit. In this summary, we describe the first multi-analyte gene )] TJ ET
BT 26.250 459.429 Td /F1 9.8 Tf  [(expression model developed for predicting occult nodal involvement at cystectomy in bladder cancer patients, for the purpose of )] TJ ET
BT 26.250 447.524 Td /F1 9.8 Tf  [(making better informed decisions regarding neoadjuvant therapy. The 20 gene model, which was developed on Affymetrix )] TJ ET
BT 26.250 435.619 Td /F1 9.8 Tf  [(Human Genome U133A and U133 Plus 2.0 arrays, identified individuals with high relative risk \(RR\) of nodal involvement \(RR = )] TJ ET
BT 26.250 423.714 Td /F1 9.8 Tf  [(1.74, 95% CI, 1.03 � 2.93\) intermediate risk \(RR = 1.05, 95% CI, .45 � 2.41\), and low risk \(RR = 0.74, 95% CI, 0.51 � 0.96\), )] TJ ET
BT 26.250 411.810 Td /F1 9.8 Tf  [(when evaluated in an independent test dataset. The 20 gene model can be applied to formalin-fixed paraffin embedded tissue )] TJ ET
BT 26.250 399.905 Td /F1 9.8 Tf  [(with sufficient tumor content, making implementation in routine diagnostic tissue highly feasible. Although a clinical assay for the )] TJ ET
BT 26.250 388.000 Td /F1 9.8 Tf  [(gene panel has not undergone analytic validation in a clinical laboratory setting, multiple platforms are available which could be )] TJ ET
BT 26.250 376.095 Td /F1 9.8 Tf  [(utilized for routine testing, including real-time reverse transcriptase PCR directed against individual analytes as well as )] TJ ET
BT 26.250 364.191 Td /F1 9.8 Tf  [(microarray approaches.)] TJ ET
BT 26.250 327.588 Td /F4 12.0 Tf  [(Funding Statement)] TJ ET
BT 26.250 307.634 Td /F1 9.8 Tf  [(This work was supported by National Institutes of Health grant CA104106 to D.T.)] TJ ET
BT 26.250 278.531 Td /F4 12.0 Tf  [(Background)] TJ ET
BT 26.250 258.577 Td /F1 9.8 Tf  [(Approximately 20-30% of bladder cancer patients harbor muscle-invasive tumors at the time of diagnosis )] TJ ET
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BT 480.346 258.577 Td /F1 9.8 Tf  [([1])] TJ ET
0.271 0.267 0.267 rg
BT 491.188 258.577 Td /F1 9.8 Tf  [( and the five year )] TJ ET
BT 26.250 246.672 Td /F1 9.8 Tf  [(survival rate of these patients is approximately 50% )] TJ ET
0.267 0.267 0.267 rg
BT 251.134 246.672 Td /F1 9.8 Tf  [([2])] TJ ET
0.271 0.267 0.267 rg
BT 261.976 246.672 Td /F1 9.8 Tf  [(. Lymph node involvement is a strong indicator of poor prognosis, as )] TJ ET
BT 26.250 234.768 Td /F1 9.8 Tf  [(evidenced in a long term study of over 1,000 patients treated by radical cystectomy and pelvic lymph node dissection, with or )] TJ ET
BT 26.250 222.863 Td /F1 9.8 Tf  [(without adjuvant radiation or chemotherapy. Whereas the 5-year overall survival rate was 69% in patients with node negative )] TJ ET
BT 26.250 210.958 Td /F1 9.8 Tf  [(tumors, the 5-year survival rate drops to 31% in patients with node positive tumors )] TJ ET
0.267 0.267 0.267 rg
BT 383.353 210.958 Td /F1 9.8 Tf  [([3])] TJ ET
0.271 0.267 0.267 rg
BT 394.195 210.958 Td /F1 9.8 Tf  [(. Several clinical trials )] TJ ET
0.267 0.267 0.267 rg
BT 490.633 210.958 Td /F1 9.8 Tf  [([4])] TJ ET
BT 501.475 210.958 Td /F1 9.8 Tf  [([5])] TJ ET
0.271 0.267 0.267 rg
BT 512.317 210.958 Td /F1 9.8 Tf  [( and a meta-)] TJ ET
BT 26.250 199.053 Td /F1 9.8 Tf  [(analysis )] TJ ET
0.267 0.267 0.267 rg
BT 64.178 199.053 Td /F1 9.8 Tf  [([6])] TJ ET
BT 75.019 199.053 Td /F1 9.8 Tf  [([7])] TJ ET
0.271 0.267 0.267 rg
BT 85.862 199.053 Td /F1 9.8 Tf  [( analyzing outcomes in over 3,000 patients across 11 clinical trials have found that neoadjuvant chemotherapy )] TJ ET
BT 26.250 187.149 Td /F1 9.8 Tf  [(confers a 5% absolute improvement in 5-year survival rates in patients with advanced bladder cancer. The clinical trial with the )] TJ ET
BT 26.250 175.244 Td /F1 9.8 Tf  [(longest followup \(8.7 years in the cystectomy only group and 8.4 years in the cystectomy + chemotherapy group\) found that )] TJ ET
BT 26.250 163.339 Td /F1 9.8 Tf  [(administration of neoadjuvant chemotherapy increased median survival \(77 months vs. 46 months\), according to an intention to )] TJ ET
BT 26.250 151.434 Td /F1 9.8 Tf  [(treat analysis, conferred a 5% absolute improvement in 10-year survival rates, and decreased residual disease at the time of )] TJ ET
BT 26.250 139.530 Td /F1 9.8 Tf  [(cystectomy \(15% vs. 38% of patients\) )] TJ ET
0.267 0.267 0.267 rg
BT 191.522 139.530 Td /F1 9.8 Tf  [([5])] TJ ET
0.271 0.267 0.267 rg
BT 202.364 139.530 Td /F1 9.8 Tf  [(. In addition, the benefit from chemotherapy is greater in patients with more invasive )] TJ ET
BT 26.250 127.625 Td /F1 9.8 Tf  [(tumors \(a 2.7 fold increase in median survival in patients with T3-T4a tumors vs. a 1.4 fold increase in median survival in )] TJ ET
BT 26.250 115.720 Td /F1 9.8 Tf  [(patients with T2 tumors\) )] TJ ET
0.267 0.267 0.267 rg
BT 132.993 115.720 Td /F1 9.8 Tf  [([4])] TJ ET
0.271 0.267 0.267 rg
BT 143.835 115.720 Td /F1 9.8 Tf  [(, indicating that some patients are much more likely to benefit than others from neoadjuvant therapy. )] TJ ET
BT 26.250 103.815 Td /F1 9.8 Tf  [(Because risk of nodal involvement increases with tumor stage )] TJ ET
0.267 0.267 0.267 rg
BT 295.565 103.815 Td /F1 9.8 Tf  [([3])] TJ ET
0.271 0.267 0.267 rg
BT 306.406 103.815 Td /F1 9.8 Tf  [(, these patients are likely those with occult node positive )] TJ ET
BT 26.250 91.911 Td /F1 9.8 Tf  [(disease. Additional advantages to neoadjuvant therapy include delivery during a time when micrometastatic disease is low, )] TJ ET
BT 26.250 80.006 Td /F1 9.8 Tf  [(increased tolerance compared to adjuvant chemotherapy, and the potential to measure chemosensitivity )] TJ ET
0.267 0.267 0.267 rg
BT 478.211 80.006 Td /F1 9.8 Tf  [([8])] TJ ET
0.271 0.267 0.267 rg
BT 489.053 80.006 Td /F1 9.8 Tf  [(. However, a review )] TJ ET
BT 26.250 68.101 Td /F1 9.8 Tf  [(of treatment patterns covering approximately 60% of all patients diagnosed with stage III bladder cancer between 1998-2003 )] TJ ET
BT 26.250 56.196 Td /F1 9.8 Tf  [(found that only 1.2% of patients received neoadjuvant therapy )] TJ ET
0.267 0.267 0.267 rg
BT 296.159 56.196 Td /F1 9.8 Tf  [([9])] TJ ET
0.271 0.267 0.267 rg
BT 307.001 56.196 Td /F1 9.8 Tf  [(, probably due to concerns of disease progression resulting )] TJ ET
BT 26.250 44.292 Td /F1 9.8 Tf  [(from surgical delay, treatment side effects which may affect surgical outcomes, and overtreatment in patients without )] TJ ET
Q
q
15.000 684.354 577.500 53.646 re W n
0.267 0.267 0.267 rg
BT 15.000 718.042 Td /F2 21.0 Tf  [(A 20 gene model for predicting nodal involvement in bladder )] TJ ET
BT 15.000 693.094 Td /F2 21.0 Tf  [(cancer patients with muscle invasive tumors)] TJ ET
Q
0.271 0.267 0.267 rg
BT 15.000 675.088 Td /F3 9.8 Tf  [(August 11, 2011)] TJ ET
BT 26.250 663.247 Td /F1 9.8 Tf  [(, )] TJ ET
BT 31.671 663.247 Td /F1 9.8 Tf  [(, )] TJ ET
0.267 0.267 0.267 rg
BT 37.092 663.247 Td /F1 9.8 Tf  [(Garrett Dancik)] TJ ET
0.271 0.267 0.267 rg
BT 99.941 663.247 Td /F1 9.8 Tf  [(, )] TJ ET
0.267 0.267 0.267 rg
BT 105.362 663.247 Td /F1 9.8 Tf  [(Dara Aisner)] TJ ET
0.271 0.267 0.267 rg
BT 156.832 663.247 Td /F1 9.8 Tf  [(, )] TJ ET
0.267 0.267 0.267 rg
BT 162.253 663.247 Td /F1 9.8 Tf  [(Dan Theodorescu)] TJ ET
0.271 0.267 0.267 rg
BT 26.250 651.342 Td /F1 9.8 Tf  [(Dancik G, Aisner D, Theodorescu D. A 20 gene model for predicting nodal involvement in bladder cancer patients with muscle )] TJ ET
BT 26.250 639.438 Td /F1 9.8 Tf  [(invasive tumors. PLOS Currents Evidence on Genomic Tests. 2011 Aug 11 . Edition 1. doi: 10.1371/currents.RRN1248.)] TJ ET
q
15.000 30.006 577.500 607.051 re W n
0.271 0.267 0.267 rg
BT 26.250 610.335 Td /F4 12.0 Tf  [(Abstract)] TJ ET
BT 26.250 590.381 Td /F1 9.8 Tf  [(Bladder cancer is the fourth most common cancer in males worldwide and also the most expensive cancer to treat. )] TJ ET
BT 26.250 578.476 Td /F1 9.8 Tf  [(Approximately 25% of patients with muscle invasive disease are found to harbor occult lymph node involvement at the time of )] TJ ET
BT 26.250 566.571 Td /F1 9.8 Tf  [(cystectomy and this finding is associated with a 5-year survival rate of <30%. If these patients could be identified pre-)] TJ ET
BT 26.250 554.667 Td /F1 9.8 Tf  [(operatively, use of neoadjuvant chemotherapy may be advantageous because this approach has been shown to confer a small )] TJ ET
BT 26.250 542.762 Td /F1 9.8 Tf  [(survival advantage in patients with muscle invasive disease. However, because only a few patients benefit from this approach it )] TJ ET
BT 26.250 530.857 Td /F1 9.8 Tf  [(has not been used extensively in the United States with fewer than 2% of patients undergoing this treatment. This is largely due )] TJ ET
BT 26.250 518.952 Td /F1 9.8 Tf  [(to concerns that since neoadjuvant therapy is beneficial for only a few patients, it has the potential to delay surgery in the )] TJ ET
BT 26.250 507.048 Td /F1 9.8 Tf  [(majority who do not benefit. However, since neoadjuvant therapy is most likely to benefit those patients at highest risk for )] TJ ET
BT 26.250 495.143 Td /F1 9.8 Tf  [(progression of disease, it follows that patients with lymph node metastases would constitute an ideal group for such treatment. )] TJ ET
BT 26.250 483.238 Td /F1 9.8 Tf  [(Hence, if patients with occult node involvement prior to cystectomy could be identified, they would constitute an ideal group for )] TJ ET
BT 26.250 471.333 Td /F1 9.8 Tf  [(application of neoadjuvant therapy as they are most likely to benefit. In this summary, we describe the first multi-analyte gene )] TJ ET
BT 26.250 459.429 Td /F1 9.8 Tf  [(expression model developed for predicting occult nodal involvement at cystectomy in bladder cancer patients, for the purpose of )] TJ ET
BT 26.250 447.524 Td /F1 9.8 Tf  [(making better informed decisions regarding neoadjuvant therapy. The 20 gene model, which was developed on Affymetrix )] TJ ET
BT 26.250 435.619 Td /F1 9.8 Tf  [(Human Genome U133A and U133 Plus 2.0 arrays, identified individuals with high relative risk \(RR\) of nodal involvement \(RR = )] TJ ET
BT 26.250 423.714 Td /F1 9.8 Tf  [(1.74, 95% CI, 1.03 � 2.93\) intermediate risk \(RR = 1.05, 95% CI, .45 � 2.41\), and low risk \(RR = 0.74, 95% CI, 0.51 � 0.96\), )] TJ ET
BT 26.250 411.810 Td /F1 9.8 Tf  [(when evaluated in an independent test dataset. The 20 gene model can be applied to formalin-fixed paraffin embedded tissue )] TJ ET
BT 26.250 399.905 Td /F1 9.8 Tf  [(with sufficient tumor content, making implementation in routine diagnostic tissue highly feasible. Although a clinical assay for the )] TJ ET
BT 26.250 388.000 Td /F1 9.8 Tf  [(gene panel has not undergone analytic validation in a clinical laboratory setting, multiple platforms are available which could be )] TJ ET
BT 26.250 376.095 Td /F1 9.8 Tf  [(utilized for routine testing, including real-time reverse transcriptase PCR directed against individual analytes as well as )] TJ ET
BT 26.250 364.191 Td /F1 9.8 Tf  [(microarray approaches.)] TJ ET
BT 26.250 327.588 Td /F4 12.0 Tf  [(Funding Statement)] TJ ET
BT 26.250 307.634 Td /F1 9.8 Tf  [(This work was supported by National Institutes of Health grant CA104106 to D.T.)] TJ ET
BT 26.250 278.531 Td /F4 12.0 Tf  [(Background)] TJ ET
BT 26.250 258.577 Td /F1 9.8 Tf  [(Approximately 20-30% of bladder cancer patients harbor muscle-invasive tumors at the time of diagnosis )] TJ ET
0.267 0.267 0.267 rg
BT 480.346 258.577 Td /F1 9.8 Tf  [([1])] TJ ET
0.271 0.267 0.267 rg
BT 491.188 258.577 Td /F1 9.8 Tf  [( and the five year )] TJ ET
BT 26.250 246.672 Td /F1 9.8 Tf  [(survival rate of these patients is approximately 50% )] TJ ET
0.267 0.267 0.267 rg
BT 251.134 246.672 Td /F1 9.8 Tf  [([2])] TJ ET
0.271 0.267 0.267 rg
BT 261.976 246.672 Td /F1 9.8 Tf  [(. Lymph node involvement is a strong indicator of poor prognosis, as )] TJ ET
BT 26.250 234.768 Td /F1 9.8 Tf  [(evidenced in a long term study of over 1,000 patients treated by radical cystectomy and pelvic lymph node dissection, with or )] TJ ET
BT 26.250 222.863 Td /F1 9.8 Tf  [(without adjuvant radiation or chemotherapy. Whereas the 5-year overall survival rate was 69% in patients with node negative )] TJ ET
BT 26.250 210.958 Td /F1 9.8 Tf  [(tumors, the 5-year survival rate drops to 31% in patients with node positive tumors )] TJ ET
0.267 0.267 0.267 rg
BT 383.353 210.958 Td /F1 9.8 Tf  [([3])] TJ ET
0.271 0.267 0.267 rg
BT 394.195 210.958 Td /F1 9.8 Tf  [(. Several clinical trials )] TJ ET
0.267 0.267 0.267 rg
BT 490.633 210.958 Td /F1 9.8 Tf  [([4])] TJ ET
BT 501.475 210.958 Td /F1 9.8 Tf  [([5])] TJ ET
0.271 0.267 0.267 rg
BT 512.317 210.958 Td /F1 9.8 Tf  [( and a meta-)] TJ ET
BT 26.250 199.053 Td /F1 9.8 Tf  [(analysis )] TJ ET
0.267 0.267 0.267 rg
BT 64.178 199.053 Td /F1 9.8 Tf  [([6])] TJ ET
BT 75.019 199.053 Td /F1 9.8 Tf  [([7])] TJ ET
0.271 0.267 0.267 rg
BT 85.862 199.053 Td /F1 9.8 Tf  [( analyzing outcomes in over 3,000 patients across 11 clinical trials have found that neoadjuvant chemotherapy )] TJ ET
BT 26.250 187.149 Td /F1 9.8 Tf  [(confers a 5% absolute improvement in 5-year survival rates in patients with advanced bladder cancer. The clinical trial with the )] TJ ET
BT 26.250 175.244 Td /F1 9.8 Tf  [(longest followup \(8.7 years in the cystectomy only group and 8.4 years in the cystectomy + chemotherapy group\) found that )] TJ ET
BT 26.250 163.339 Td /F1 9.8 Tf  [(administration of neoadjuvant chemotherapy increased median survival \(77 months vs. 46 months\), according to an intention to )] TJ ET
BT 26.250 151.434 Td /F1 9.8 Tf  [(treat analysis, conferred a 5% absolute improvement in 10-year survival rates, and decreased residual disease at the time of )] TJ ET
BT 26.250 139.530 Td /F1 9.8 Tf  [(cystectomy \(15% vs. 38% of patients\) )] TJ ET
0.267 0.267 0.267 rg
BT 191.522 139.530 Td /F1 9.8 Tf  [([5])] TJ ET
0.271 0.267 0.267 rg
BT 202.364 139.530 Td /F1 9.8 Tf  [(. In addition, the benefit from chemotherapy is greater in patients with more invasive )] TJ ET
BT 26.250 127.625 Td /F1 9.8 Tf  [(tumors \(a 2.7 fold increase in median survival in patients with T3-T4a tumors vs. a 1.4 fold increase in median survival in )] TJ ET
BT 26.250 115.720 Td /F1 9.8 Tf  [(patients with T2 tumors\) )] TJ ET
0.267 0.267 0.267 rg
BT 132.993 115.720 Td /F1 9.8 Tf  [([4])] TJ ET
0.271 0.267 0.267 rg
BT 143.835 115.720 Td /F1 9.8 Tf  [(, indicating that some patients are much more likely to benefit than others from neoadjuvant therapy. )] TJ ET
BT 26.250 103.815 Td /F1 9.8 Tf  [(Because risk of nodal involvement increases with tumor stage )] TJ ET
0.267 0.267 0.267 rg
BT 295.565 103.815 Td /F1 9.8 Tf  [([3])] TJ ET
0.271 0.267 0.267 rg
BT 306.406 103.815 Td /F1 9.8 Tf  [(, these patients are likely those with occult node positive )] TJ ET
BT 26.250 91.911 Td /F1 9.8 Tf  [(disease. Additional advantages to neoadjuvant therapy include delivery during a time when micrometastatic disease is low, )] TJ ET
BT 26.250 80.006 Td /F1 9.8 Tf  [(increased tolerance compared to adjuvant chemotherapy, and the potential to measure chemosensitivity )] TJ ET
0.267 0.267 0.267 rg
BT 478.211 80.006 Td /F1 9.8 Tf  [([8])] TJ ET
0.271 0.267 0.267 rg
BT 489.053 80.006 Td /F1 9.8 Tf  [(. However, a review )] TJ ET
BT 26.250 68.101 Td /F1 9.8 Tf  [(of treatment patterns covering approximately 60% of all patients diagnosed with stage III bladder cancer between 1998-2003 )] TJ ET
BT 26.250 56.196 Td /F1 9.8 Tf  [(found that only 1.2% of patients received neoadjuvant therapy )] TJ ET
0.267 0.267 0.267 rg
BT 296.159 56.196 Td /F1 9.8 Tf  [([9])] TJ ET
0.271 0.267 0.267 rg
BT 307.001 56.196 Td /F1 9.8 Tf  [(, probably due to concerns of disease progression resulting )] TJ ET
BT 26.250 44.292 Td /F1 9.8 Tf  [(from surgical delay, treatment side effects which may affect surgical outcomes, and overtreatment in patients without )] TJ ET
Q
q
15.000 684.354 577.500 53.646 re W n
0.267 0.267 0.267 rg
BT 15.000 718.042 Td /F2 21.0 Tf  [(A 20 gene model for predicting nodal involvement in bladder )] TJ ET
BT 15.000 693.094 Td /F2 21.0 Tf  [(cancer patients with muscle invasive tumors)] TJ ET
Q
0.271 0.267 0.267 rg
BT 15.000 675.088 Td /F3 9.8 Tf  [(August 11, 2011)] TJ ET
BT 26.250 663.247 Td /F1 9.8 Tf  [(, )] TJ ET
BT 31.671 663.247 Td /F1 9.8 Tf  [(, )] TJ ET
0.267 0.267 0.267 rg
BT 37.092 663.247 Td /F1 9.8 Tf  [(Garrett Dancik)] TJ ET
0.271 0.267 0.267 rg
BT 99.941 663.247 Td /F1 9.8 Tf  [(, )] TJ ET
0.267 0.267 0.267 rg
BT 105.362 663.247 Td /F1 9.8 Tf  [(Dara Aisner)] TJ ET
0.271 0.267 0.267 rg
BT 156.832 663.247 Td /F1 9.8 Tf  [(, )] TJ ET
0.267 0.267 0.267 rg
BT 162.253 663.247 Td /F1 9.8 Tf  [(Dan Theodorescu)] TJ ET
0.271 0.267 0.267 rg
BT 26.250 651.342 Td /F1 9.8 Tf  [(Dancik G, Aisner D, Theodorescu D. A 20 gene model for predicting nodal involvement in bladder cancer patients with muscle )] TJ ET
BT 26.250 639.438 Td /F1 9.8 Tf  [(invasive tumors. PLOS Currents Evidence on Genomic Tests. 2011 Aug 11 . Edition 1. doi: 10.1371/currents.RRN1248.)] TJ ET
q
15.000 30.006 577.500 607.051 re W n
0.271 0.267 0.267 rg
BT 26.250 610.335 Td /F4 12.0 Tf  [(Abstract)] TJ ET
BT 26.250 590.381 Td /F1 9.8 Tf  [(Bladder cancer is the fourth most common cancer in males worldwide and also the most expensive cancer to treat. )] TJ ET
BT 26.250 578.476 Td /F1 9.8 Tf  [(Approximately 25% of patients with muscle invasive disease are found to harbor occult lymph node involvement at the time of )] TJ ET
BT 26.250 566.571 Td /F1 9.8 Tf  [(cystectomy and this finding is associated with a 5-year survival rate of <30%. If these patients could be identified pre-)] TJ ET
BT 26.250 554.667 Td /F1 9.8 Tf  [(operatively, use of neoadjuvant chemotherapy may be advantageous because this approach has been shown to confer a small )] TJ ET
BT 26.250 542.762 Td /F1 9.8 Tf  [(survival advantage in patients with muscle invasive disease. However, because only a few patients benefit from this approach it )] TJ ET
BT 26.250 530.857 Td /F1 9.8 Tf  [(has not been used extensively in the United States with fewer than 2% of patients undergoing this treatment. This is largely due )] TJ ET
BT 26.250 518.952 Td /F1 9.8 Tf  [(to concerns that since neoadjuvant therapy is beneficial for only a few patients, it has the potential to delay surgery in the )] TJ ET
BT 26.250 507.048 Td /F1 9.8 Tf  [(majority who do not benefit. However, since neoadjuvant therapy is most likely to benefit those patients at highest risk for )] TJ ET
BT 26.250 495.143 Td /F1 9.8 Tf  [(progression of disease, it follows that patients with lymph node metastases would constitute an ideal group for such treatment. )] TJ ET
BT 26.250 483.238 Td /F1 9.8 Tf  [(Hence, if patients with occult node involvement prior to cystectomy could be identified, they would constitute an ideal group for )] TJ ET
BT 26.250 471.333 Td /F1 9.8 Tf  [(application of neoadjuvant therapy as they are most likely to benefit. In this summary, we describe the first multi-analyte gene )] TJ ET
BT 26.250 459.429 Td /F1 9.8 Tf  [(expression model developed for predicting occult nodal involvement at cystectomy in bladder cancer patients, for the purpose of )] TJ ET
BT 26.250 447.524 Td /F1 9.8 Tf  [(making better informed decisions regarding neoadjuvant therapy. The 20 gene model, which was developed on Affymetrix )] TJ ET
BT 26.250 435.619 Td /F1 9.8 Tf  [(Human Genome U133A and U133 Plus 2.0 arrays, identified individuals with high relative risk \(RR\) of nodal involvement \(RR = )] TJ ET
BT 26.250 423.714 Td /F1 9.8 Tf  [(1.74, 95% CI, 1.03 � 2.93\) intermediate risk \(RR = 1.05, 95% CI, .45 � 2.41\), and low risk \(RR = 0.74, 95% CI, 0.51 � 0.96\), )] TJ ET
BT 26.250 411.810 Td /F1 9.8 Tf  [(when evaluated in an independent test dataset. The 20 gene model can be applied to formalin-fixed paraffin embedded tissue )] TJ ET
BT 26.250 399.905 Td /F1 9.8 Tf  [(with sufficient tumor content, making implementation in routine diagnostic tissue highly feasible. Although a clinical assay for the )] TJ ET
BT 26.250 388.000 Td /F1 9.8 Tf  [(gene panel has not undergone analytic validation in a clinical laboratory setting, multiple platforms are available which could be )] TJ ET
BT 26.250 376.095 Td /F1 9.8 Tf  [(utilized for routine testing, including real-time reverse transcriptase PCR directed against individual analytes as well as )] TJ ET
BT 26.250 364.191 Td /F1 9.8 Tf  [(microarray approaches.)] TJ ET
BT 26.250 327.588 Td /F4 12.0 Tf  [(Funding Statement)] TJ ET
BT 26.250 307.634 Td /F1 9.8 Tf  [(This work was supported by National Institutes of Health grant CA104106 to D.T.)] TJ ET
BT 26.250 278.531 Td /F4 12.0 Tf  [(Background)] TJ ET
BT 26.250 258.577 Td /F1 9.8 Tf  [(Approximately 20-30% of bladder cancer patients harbor muscle-invasive tumors at the time of diagnosis )] TJ ET
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BT 480.346 258.577 Td /F1 9.8 Tf  [([1])] TJ ET
0.271 0.267 0.267 rg
BT 491.188 258.577 Td /F1 9.8 Tf  [( and the five year )] TJ ET
BT 26.250 246.672 Td /F1 9.8 Tf  [(survival rate of these patients is approximately 50% )] TJ ET
0.267 0.267 0.267 rg
BT 251.134 246.672 Td /F1 9.8 Tf  [([2])] TJ ET
0.271 0.267 0.267 rg
BT 261.976 246.672 Td /F1 9.8 Tf  [(. Lymph node involvement is a strong indicator of poor prognosis, as )] TJ ET
BT 26.250 234.768 Td /F1 9.8 Tf  [(evidenced in a long term study of over 1,000 patients treated by radical cystectomy and pelvic lymph node dissection, with or )] TJ ET
BT 26.250 222.863 Td /F1 9.8 Tf  [(without adjuvant radiation or chemotherapy. Whereas the 5-year overall survival rate was 69% in patients with node negative )] TJ ET
BT 26.250 210.958 Td /F1 9.8 Tf  [(tumors, the 5-year survival rate drops to 31% in patients with node positive tumors )] TJ ET
0.267 0.267 0.267 rg
BT 383.353 210.958 Td /F1 9.8 Tf  [([3])] TJ ET
0.271 0.267 0.267 rg
BT 394.195 210.958 Td /F1 9.8 Tf  [(. Several clinical trials )] TJ ET
0.267 0.267 0.267 rg
BT 490.633 210.958 Td /F1 9.8 Tf  [([4])] TJ ET
BT 501.475 210.958 Td /F1 9.8 Tf  [([5])] TJ ET
0.271 0.267 0.267 rg
BT 512.317 210.958 Td /F1 9.8 Tf  [( and a meta-)] TJ ET
BT 26.250 199.053 Td /F1 9.8 Tf  [(analysis )] TJ ET
0.267 0.267 0.267 rg
BT 64.178 199.053 Td /F1 9.8 Tf  [([6])] TJ ET
BT 75.019 199.053 Td /F1 9.8 Tf  [([7])] TJ ET
0.271 0.267 0.267 rg
BT 85.862 199.053 Td /F1 9.8 Tf  [( analyzing outcomes in over 3,000 patients across 11 clinical trials have found that neoadjuvant chemotherapy )] TJ ET
BT 26.250 187.149 Td /F1 9.8 Tf  [(confers a 5% absolute improvement in 5-year survival rates in patients with advanced bladder cancer. The clinical trial with the )] TJ ET
BT 26.250 175.244 Td /F1 9.8 Tf  [(longest followup \(8.7 years in the cystectomy only group and 8.4 years in the cystectomy + chemotherapy group\) found that )] TJ ET
BT 26.250 163.339 Td /F1 9.8 Tf  [(administration of neoadjuvant chemotherapy increased median survival \(77 months vs. 46 months\), according to an intention to )] TJ ET
BT 26.250 151.434 Td /F1 9.8 Tf  [(treat analysis, conferred a 5% absolute improvement in 10-year survival rates, and decreased residual disease at the time of )] TJ ET
BT 26.250 139.530 Td /F1 9.8 Tf  [(cystectomy \(15% vs. 38% of patients\) )] TJ ET
0.267 0.267 0.267 rg
BT 191.522 139.530 Td /F1 9.8 Tf  [([5])] TJ ET
0.271 0.267 0.267 rg
BT 202.364 139.530 Td /F1 9.8 Tf  [(. In addition, the benefit from chemotherapy is greater in patients with more invasive )] TJ ET
BT 26.250 127.625 Td /F1 9.8 Tf  [(tumors \(a 2.7 fold increase in median survival in patients with T3-T4a tumors vs. a 1.4 fold increase in median survival in )] TJ ET
BT 26.250 115.720 Td /F1 9.8 Tf  [(patients with T2 tumors\) )] TJ ET
0.267 0.267 0.267 rg
BT 132.993 115.720 Td /F1 9.8 Tf  [([4])] TJ ET
0.271 0.267 0.267 rg
BT 143.835 115.720 Td /F1 9.8 Tf  [(, indicating that some patients are much more likely to benefit than others from neoadjuvant therapy. )] TJ ET
BT 26.250 103.815 Td /F1 9.8 Tf  [(Because risk of nodal involvement increases with tumor stage )] TJ ET
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BT 295.565 103.815 Td /F1 9.8 Tf  [([3])] TJ ET
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BT 306.406 103.815 Td /F1 9.8 Tf  [(, these patients are likely those with occult node positive )] TJ ET
BT 26.250 91.911 Td /F1 9.8 Tf  [(disease. Additional advantages to neoadjuvant therapy include delivery during a time when micrometastatic disease is low, )] TJ ET
BT 26.250 80.006 Td /F1 9.8 Tf  [(increased tolerance compared to adjuvant chemotherapy, and the potential to measure chemosensitivity )] TJ ET
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BT 478.211 80.006 Td /F1 9.8 Tf  [([8])] TJ ET
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BT 489.053 80.006 Td /F1 9.8 Tf  [(. However, a review )] TJ ET
BT 26.250 68.101 Td /F1 9.8 Tf  [(of treatment patterns covering approximately 60% of all patients diagnosed with stage III bladder cancer between 1998-2003 )] TJ ET
BT 26.250 56.196 Td /F1 9.8 Tf  [(found that only 1.2% of patients received neoadjuvant therapy )] TJ ET
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BT 296.159 56.196 Td /F1 9.8 Tf  [([9])] TJ ET
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BT 307.001 56.196 Td /F1 9.8 Tf  [(, probably due to concerns of disease progression resulting )] TJ ET
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0.267 0.267 0.267 rg
BT 133.529 767.476 Td /F1 9.8 Tf  [([10])] TJ ET
0.271 0.267 0.267 rg
BT 149.792 767.476 Td /F1 9.8 Tf  [(.)] TJ ET
BT 26.250 748.071 Td /F1 9.8 Tf  [(A test predicting nodal involvement prior to cystectomy would identify high risk patients likely to benefit from neoadjuvant )] TJ ET
BT 26.250 736.167 Td /F1 9.8 Tf  [(therapy and low risk patients for which neoadjuvant therapy is unnecessarily aggressive and may negatively affect survival as )] TJ ET
BT 26.250 724.262 Td /F1 9.8 Tf  [(cystectomy is delayed. There is currently one published gene expression model for quantifying the risk of nodal involvement in )] TJ ET
BT 26.250 712.357 Td /F1 9.8 Tf  [(bladder cancer patients with muscle invasive tumors. This test is based on the expression profile of 20 genes and determines )] TJ ET
BT 26.250 700.452 Td /F1 9.8 Tf  [(whether a patient has a �high� or �low� risk of nodal involvement.)] TJ ET
BT 26.250 681.048 Td /F4 9.8 Tf  [(Clinical Scenario)] TJ ET
BT 26.250 661.643 Td /F1 9.8 Tf  [(The clinical situation in which this test is most likely to be beneficial is in the newly-diagnosed patient with muscle-invasive )] TJ ET
BT 26.250 649.738 Td /F1 9.8 Tf  [(bladder carcinoma, with this test aiding in the decision to treat with neoadjuvant chemotherapy in those patients at high risk for )] TJ ET
BT 26.250 637.833 Td /F1 9.8 Tf  [(nodal disease, versus the decision to proceed directly to surgical intervention in those with low risk of occult nodal metastasis.)] TJ ET
BT 26.250 618.429 Td /F4 9.8 Tf  [(Test Description)] TJ ET
BT 26.250 599.024 Td /F1 9.8 Tf  [(This gene expression test utilizes RNA extracted from either frozen or formalin-fixed paraffin-embedded \(FFPE\) tumor tissue )] TJ ET
BT 26.250 587.119 Td /F1 9.8 Tf  [(obtained from transurethral resection \(TUR\), which is performed as a diagnostic procedure to determine depth of tumor )] TJ ET
BT 26.250 575.214 Td /F1 9.8 Tf  [(invasion. The expression values for the twenty genes \(21 microarray probes\) in the signature is then obtained and a probability )] TJ ET
BT 26.250 563.310 Td /F1 9.8 Tf  [(of lymph node involvement at cystectomy calculated. The test was developed and validated using gene expression data from )] TJ ET
BT 26.250 551.405 Td /F1 9.8 Tf  [(Affymetrix Human Genome U133A and U133 Plus 2.0 arrays. A Bayesian weighted nearest neighbor prediction algorithm )] TJ ET
BT 26.250 539.500 Td /F1 9.8 Tf  [(generates a posterior risk probability \()] TJ ET
BT 189.348 539.500 Td /F5 9.8 Tf  [(p)] TJ ET
BT 194.769 539.500 Td /F1 9.8 Tf  [(\) of nodal involvement based on the Spearman�s rank correlation between a patient�s 20-)] TJ ET
BT 26.250 527.595 Td /F1 9.8 Tf  [(gene expression profile and the expression profiles from a training dataset containing patients with known nodal staging )] TJ ET
BT 26.250 515.691 Td /F1 9.8 Tf  [(information. The risk probability is compared with a 23% baseline prevalence of nodal involvement in patients undergoing )] TJ ET
BT 26.250 503.786 Td /F1 9.8 Tf  [(radical cystectomy )] TJ ET
0.267 0.267 0.267 rg
BT 109.144 503.786 Td /F1 9.8 Tf  [([3])] TJ ET
0.271 0.267 0.267 rg
BT 119.986 503.786 Td /F1 9.8 Tf  [( to classify a patient as high risk \( )] TJ ET
BT 266.295 503.786 Td /F5 9.8 Tf  [(p)] TJ ET
BT 271.716 503.786 Td /F1 9.8 Tf  [( > .247\), intermediate risk \(.227 = )] TJ ET
BT 418.034 503.786 Td /F5 9.8 Tf  [(p)] TJ ET
BT 423.455 503.786 Td /F1 9.8 Tf  [( = .247\) or low risk \( )] TJ ET
BT 512.044 503.786 Td /F5 9.8 Tf  [(p)] TJ ET
BT 517.465 503.786 Td /F1 9.8 Tf  [( < .227\). )] TJ ET
BT 26.250 491.881 Td /F1 9.8 Tf  [(High, intermediate, and low risk groups have relative risks of 1.74, 1.05, and 0.74, respectively.)] TJ ET
BT 26.250 472.476 Td /F1 9.8 Tf  [(Utilization of this gene expression panel approach in a clinical setting requires extensive technical validation, and at least two )] TJ ET
BT 26.250 460.572 Td /F1 9.8 Tf  [(approaches for clinical implementation can be envisioned. The first is seen in several clinically available expression-based tests, )] TJ ET
BT 26.250 448.667 Td /F1 9.8 Tf  [(including Oncotype DX )] TJ ET
BT 128.128 452.555 Td /F1 8.7 Tf  [(�)] TJ ET
BT 134.515 448.667 Td /F1 9.8 Tf  [( \(Genomic Health\) )] TJ ET
0.267 0.267 0.267 rg
BT 216.327 448.667 Td /F1 9.8 Tf  [([11])] TJ ET
0.271 0.267 0.267 rg
BT 232.590 448.667 Td /F1 9.8 Tf  [(, miRView� mets and mets2 assays \(Rosetta Genomics\) )] TJ ET
0.267 0.267 0.267 rg
BT 483.448 448.667 Td /F1 9.8 Tf  [([12])] TJ ET
0.271 0.267 0.267 rg
BT 499.711 448.667 Td /F1 9.8 Tf  [(, and )] TJ ET
BT 26.250 436.762 Td /F1 9.8 Tf  [(CancerTYPE ID )] TJ ET
BT 98.312 440.650 Td /F1 8.7 Tf  [(�)] TJ ET
BT 104.700 436.762 Td /F1 9.8 Tf  [( \(bioTheranostics\) )] TJ ET
0.267 0.267 0.267 rg
BT 185.430 436.762 Td /F1 9.8 Tf  [([13])] TJ ET
0.271 0.267 0.267 rg
BT 201.693 436.762 Td /F1 9.8 Tf  [( where each analyte is tested individually using a quantitative reverse-transcriptase )] TJ ET
BT 26.250 424.857 Td /F1 9.8 Tf  [(qPCR \(RT-PCR\) approach. This allows for more stringent control over the evaluation of each analyte, but is expensive and )] TJ ET
BT 26.250 412.953 Td /F1 9.8 Tf  [(labor-intensive. An alternative methodology is the clinical implementation of array-based technology, an approach which is )] TJ ET
BT 26.250 401.048 Td /F1 9.8 Tf  [(increasingly embraced in clinical laboratories. Although there is limited experience with issues related to technical validation, )] TJ ET
BT 26.250 389.143 Td /F1 9.8 Tf  [(data interpretation and quality control of expression arrays in the clinical setting, two )] TJ ET
BT 390.413 389.143 Td /F5 9.8 Tf  [(in vitro)] TJ ET
BT 419.126 389.143 Td /F1 9.8 Tf  [( diagnostic multivariate index assays )] TJ ET
BT 26.250 377.238 Td /F1 9.8 Tf  [(\(IVD-MIA\) utilizing microarray technology have been FDA approved for cancer diagnostics: the MammaPrint )] TJ ET
BT 494.406 381.127 Td /F1 8.7 Tf  [(TM)] TJ ET
BT 506.921 377.238 Td /F1 9.8 Tf  [( microarray )] TJ ET
BT 26.250 365.334 Td /F1 9.8 Tf  [(\(Agendia\) )] TJ ET
0.267 0.267 0.267 rg
BT 71.227 365.334 Td /F1 9.8 Tf  [([14])] TJ ET
0.271 0.267 0.267 rg
BT 87.490 365.334 Td /F1 9.8 Tf  [(, which measures recurrence risk in breast cancer patients, and the Pathwork )] TJ ET
BT 423.455 369.222 Td /F1 8.7 Tf  [(�)] TJ ET
BT 429.843 365.334 Td /F1 9.8 Tf  [( Tissue of Origin test \(Pathwork )] TJ ET
BT 26.250 353.429 Td /F1 9.8 Tf  [(Diagnostics\) )] TJ ET
0.267 0.267 0.267 rg
BT 82.595 353.429 Td /F1 9.8 Tf  [([15])] TJ ET
0.271 0.267 0.267 rg
BT 98.858 353.429 Td /F1 9.8 Tf  [(. Regardless of the approach, technical validation requires determination of multiple test parameters, including )] TJ ET
BT 26.250 341.524 Td /F1 9.8 Tf  [(accuracy, precision, analytic sensitivity, limit of quantification, and robustness as well as identification of standards for )] TJ ET
BT 26.250 329.619 Td /F1 9.8 Tf  [(calibration and control of the test system.)] TJ ET
BT 26.250 293.017 Td /F4 12.0 Tf  [(Public Health Importance)] TJ ET
BT 26.250 273.063 Td /F1 9.8 Tf  [(Worldwide, bladder cancer is the fourth most common cancer and the ninth most common cause of cancer related deaths in )] TJ ET
BT 26.250 261.158 Td /F1 9.8 Tf  [(males )] TJ ET
0.267 0.267 0.267 rg
BT 54.964 261.158 Td /F1 9.8 Tf  [([2])] TJ ET
0.271 0.267 0.267 rg
BT 65.806 261.158 Td /F1 9.8 Tf  [(. Lymph node involvement is a strong predictor of survival, however definitive evaluation of lymph node status can only )] TJ ET
BT 26.250 249.253 Td /F1 9.8 Tf  [(be performed after the window for neoadjuvant therapy has elapsed. A non-invasive modality by which patients most likely to )] TJ ET
BT 26.250 237.348 Td /F1 9.8 Tf  [(harbor lymph node metastases can be identified has the potential to dramatically alter practice patterns with regard to )] TJ ET
BT 26.250 225.444 Td /F1 9.8 Tf  [(implementation of neo-adjuvant therapy, and dramatically improve survival in a subset of patients. As approximately 1/4 of )] TJ ET
BT 26.250 213.539 Td /F1 9.8 Tf  [(patients with invasive bladder cancer have lymph node positive disease )] TJ ET
0.267 0.267 0.267 rg
BT 337.304 213.539 Td /F1 9.8 Tf  [([3])] TJ ET
0.271 0.267 0.267 rg
BT 348.146 213.539 Td /F1 9.8 Tf  [(, the potential impact of such a �personalized )] TJ ET
BT 26.250 201.634 Td /F1 9.8 Tf  [(medicine� approach to treatment is substantial.)] TJ ET
BT 26.250 165.032 Td /F4 12.0 Tf  [(Published Reviews, Recommendations and Guidelines)] TJ ET
BT 26.250 145.077 Td /F4 9.8 Tf  [(Systematic evidence reviews)] TJ ET
0.271 0.267 0.267 RG
40.337 128.640 m 
40.337 129.087 40.154 129.531 39.838 129.847 c
39.522 130.163 39.078 130.347 38.631 130.347 c
38.185 130.347 37.741 130.163 37.425 129.847 c
37.109 129.531 36.925 129.087 36.925 128.640 c
36.925 128.194 37.109 127.750 37.425 127.434 c
37.741 127.118 38.185 126.934 38.631 126.934 c
39.078 126.934 39.522 127.118 39.838 127.434 c
40.154 127.750 40.337 128.194 40.337 128.640 c f
BT 45.750 125.673 Td /F1 9.8 Tf  [(The Cochrane Collaboration encourages the use of combination neoadjuvant therapy on the basis of a meta-analysis of )] TJ ET
BT 45.750 113.768 Td /F1 9.8 Tf  [(over 3,000 invasive bladder cancer patients across 11 trials which found a statistically significant 5% absolute improvement )] TJ ET
BT 45.750 101.863 Td /F1 9.8 Tf  [(in overall survival and 9% absolute improvement in disease free survival at 5 years associated with platinum-based )] TJ ET
BT 45.750 89.958 Td /F1 9.8 Tf  [(combination chemotherapy)] TJ ET
0.267 0.267 0.267 rg
BT 162.799 89.958 Td /F1 9.8 Tf  [([6])] TJ ET
BT 173.641 89.958 Td /F1 9.8 Tf  [([7])] TJ ET
0.271 0.267 0.267 rg
BT 184.483 89.958 Td /F1 9.8 Tf  [(.)] TJ ET
BT 26.250 66.804 Td /F4 9.8 Tf  [(Recommendations by independent group)] TJ ET
40.337 50.366 m 
40.337 50.813 40.154 51.257 39.838 51.573 c
39.522 51.889 39.078 52.073 38.631 52.073 c
38.185 52.073 37.741 51.889 37.425 51.573 c
37.109 51.257 36.925 50.813 36.925 50.366 c
36.925 49.920 37.109 49.476 37.425 49.160 c
37.741 48.844 38.185 48.660 38.631 48.660 c
39.078 48.660 39.522 48.844 39.838 49.160 c
40.154 49.476 40.337 49.920 40.337 50.366 c f
BT 45.750 47.399 Td /F1 9.8 Tf  [(The National Comprehensive Cancer Network \(NCCN\) )] TJ ET
0.267 0.267 0.267 rg
BT 284.674 47.399 Td /F1 9.8 Tf  [([16])] TJ ET
0.271 0.267 0.267 rg
BT 300.937 47.399 Td /F1 9.8 Tf  [( recommends considering neoadjuvant therapy for T3 bladder )] TJ ET
Q
q
15.000 33.113 577.500 743.887 re W n
0.271 0.267 0.267 rg
BT 26.250 767.476 Td /F1 9.8 Tf  [(micrometastatic disease )] TJ ET
0.267 0.267 0.267 rg
BT 133.529 767.476 Td /F1 9.8 Tf  [([10])] TJ ET
0.271 0.267 0.267 rg
BT 149.792 767.476 Td /F1 9.8 Tf  [(.)] TJ ET
BT 26.250 748.071 Td /F1 9.8 Tf  [(A test predicting nodal involvement prior to cystectomy would identify high risk patients likely to benefit from neoadjuvant )] TJ ET
BT 26.250 736.167 Td /F1 9.8 Tf  [(therapy and low risk patients for which neoadjuvant therapy is unnecessarily aggressive and may negatively affect survival as )] TJ ET
BT 26.250 724.262 Td /F1 9.8 Tf  [(cystectomy is delayed. There is currently one published gene expression model for quantifying the risk of nodal involvement in )] TJ ET
BT 26.250 712.357 Td /F1 9.8 Tf  [(bladder cancer patients with muscle invasive tumors. This test is based on the expression profile of 20 genes and determines )] TJ ET
BT 26.250 700.452 Td /F1 9.8 Tf  [(whether a patient has a �high� or �low� risk of nodal involvement.)] TJ ET
BT 26.250 681.048 Td /F4 9.8 Tf  [(Clinical Scenario)] TJ ET
BT 26.250 661.643 Td /F1 9.8 Tf  [(The clinical situation in which this test is most likely to be beneficial is in the newly-diagnosed patient with muscle-invasive )] TJ ET
BT 26.250 649.738 Td /F1 9.8 Tf  [(bladder carcinoma, with this test aiding in the decision to treat with neoadjuvant chemotherapy in those patients at high risk for )] TJ ET
BT 26.250 637.833 Td /F1 9.8 Tf  [(nodal disease, versus the decision to proceed directly to surgical intervention in those with low risk of occult nodal metastasis.)] TJ ET
BT 26.250 618.429 Td /F4 9.8 Tf  [(Test Description)] TJ ET
BT 26.250 599.024 Td /F1 9.8 Tf  [(This gene expression test utilizes RNA extracted from either frozen or formalin-fixed paraffin-embedded \(FFPE\) tumor tissue )] TJ ET
BT 26.250 587.119 Td /F1 9.8 Tf  [(obtained from transurethral resection \(TUR\), which is performed as a diagnostic procedure to determine depth of tumor )] TJ ET
BT 26.250 575.214 Td /F1 9.8 Tf  [(invasion. The expression values for the twenty genes \(21 microarray probes\) in the signature is then obtained and a probability )] TJ ET
BT 26.250 563.310 Td /F1 9.8 Tf  [(of lymph node involvement at cystectomy calculated. The test was developed and validated using gene expression data from )] TJ ET
BT 26.250 551.405 Td /F1 9.8 Tf  [(Affymetrix Human Genome U133A and U133 Plus 2.0 arrays. A Bayesian weighted nearest neighbor prediction algorithm )] TJ ET
BT 26.250 539.500 Td /F1 9.8 Tf  [(generates a posterior risk probability \()] TJ ET
BT 189.348 539.500 Td /F5 9.8 Tf  [(p)] TJ ET
BT 194.769 539.500 Td /F1 9.8 Tf  [(\) of nodal involvement based on the Spearman�s rank correlation between a patient�s 20-)] TJ ET
BT 26.250 527.595 Td /F1 9.8 Tf  [(gene expression profile and the expression profiles from a training dataset containing patients with known nodal staging )] TJ ET
BT 26.250 515.691 Td /F1 9.8 Tf  [(information. The risk probability is compared with a 23% baseline prevalence of nodal involvement in patients undergoing )] TJ ET
BT 26.250 503.786 Td /F1 9.8 Tf  [(radical cystectomy )] TJ ET
0.267 0.267 0.267 rg
BT 109.144 503.786 Td /F1 9.8 Tf  [([3])] TJ ET
0.271 0.267 0.267 rg
BT 119.986 503.786 Td /F1 9.8 Tf  [( to classify a patient as high risk \( )] TJ ET
BT 266.295 503.786 Td /F5 9.8 Tf  [(p)] TJ ET
BT 271.716 503.786 Td /F1 9.8 Tf  [( > .247\), intermediate risk \(.227 = )] TJ ET
BT 418.034 503.786 Td /F5 9.8 Tf  [(p)] TJ ET
BT 423.455 503.786 Td /F1 9.8 Tf  [( = .247\) or low risk \( )] TJ ET
BT 512.044 503.786 Td /F5 9.8 Tf  [(p)] TJ ET
BT 517.465 503.786 Td /F1 9.8 Tf  [( < .227\). )] TJ ET
BT 26.250 491.881 Td /F1 9.8 Tf  [(High, intermediate, and low risk groups have relative risks of 1.74, 1.05, and 0.74, respectively.)] TJ ET
BT 26.250 472.476 Td /F1 9.8 Tf  [(Utilization of this gene expression panel approach in a clinical setting requires extensive technical validation, and at least two )] TJ ET
BT 26.250 460.572 Td /F1 9.8 Tf  [(approaches for clinical implementation can be envisioned. The first is seen in several clinically available expression-based tests, )] TJ ET
BT 26.250 448.667 Td /F1 9.8 Tf  [(including Oncotype DX )] TJ ET
BT 128.128 452.555 Td /F1 8.7 Tf  [(�)] TJ ET
BT 134.515 448.667 Td /F1 9.8 Tf  [( \(Genomic Health\) )] TJ ET
0.267 0.267 0.267 rg
BT 216.327 448.667 Td /F1 9.8 Tf  [([11])] TJ ET
0.271 0.267 0.267 rg
BT 232.590 448.667 Td /F1 9.8 Tf  [(, miRView� mets and mets2 assays \(Rosetta Genomics\) )] TJ ET
0.267 0.267 0.267 rg
BT 483.448 448.667 Td /F1 9.8 Tf  [([12])] TJ ET
0.271 0.267 0.267 rg
BT 499.711 448.667 Td /F1 9.8 Tf  [(, and )] TJ ET
BT 26.250 436.762 Td /F1 9.8 Tf  [(CancerTYPE ID )] TJ ET
BT 98.312 440.650 Td /F1 8.7 Tf  [(�)] TJ ET
BT 104.700 436.762 Td /F1 9.8 Tf  [( \(bioTheranostics\) )] TJ ET
0.267 0.267 0.267 rg
BT 185.430 436.762 Td /F1 9.8 Tf  [([13])] TJ ET
0.271 0.267 0.267 rg
BT 201.693 436.762 Td /F1 9.8 Tf  [( where each analyte is tested individually using a quantitative reverse-transcriptase )] TJ ET
BT 26.250 424.857 Td /F1 9.8 Tf  [(qPCR \(RT-PCR\) approach. This allows for more stringent control over the evaluation of each analyte, but is expensive and )] TJ ET
BT 26.250 412.953 Td /F1 9.8 Tf  [(labor-intensive. An alternative methodology is the clinical implementation of array-based technology, an approach which is )] TJ ET
BT 26.250 401.048 Td /F1 9.8 Tf  [(increasingly embraced in clinical laboratories. Although there is limited experience with issues related to technical validation, )] TJ ET
BT 26.250 389.143 Td /F1 9.8 Tf  [(data interpretation and quality control of expression arrays in the clinical setting, two )] TJ ET
BT 390.413 389.143 Td /F5 9.8 Tf  [(in vitro)] TJ ET
BT 419.126 389.143 Td /F1 9.8 Tf  [( diagnostic multivariate index assays )] TJ ET
BT 26.250 377.238 Td /F1 9.8 Tf  [(\(IVD-MIA\) utilizing microarray technology have been FDA approved for cancer diagnostics: the MammaPrint )] TJ ET
BT 494.406 381.127 Td /F1 8.7 Tf  [(TM)] TJ ET
BT 506.921 377.238 Td /F1 9.8 Tf  [( microarray )] TJ ET
BT 26.250 365.334 Td /F1 9.8 Tf  [(\(Agendia\) )] TJ ET
0.267 0.267 0.267 rg
BT 71.227 365.334 Td /F1 9.8 Tf  [([14])] TJ ET
0.271 0.267 0.267 rg
BT 87.490 365.334 Td /F1 9.8 Tf  [(, which measures recurrence risk in breast cancer patients, and the Pathwork )] TJ ET
BT 423.455 369.222 Td /F1 8.7 Tf  [(�)] TJ ET
BT 429.843 365.334 Td /F1 9.8 Tf  [( Tissue of Origin test \(Pathwork )] TJ ET
BT 26.250 353.429 Td /F1 9.8 Tf  [(Diagnostics\) )] TJ ET
0.267 0.267 0.267 rg
BT 82.595 353.429 Td /F1 9.8 Tf  [([15])] TJ ET
0.271 0.267 0.267 rg
BT 98.858 353.429 Td /F1 9.8 Tf  [(. Regardless of the approach, technical validation requires determination of multiple test parameters, including )] TJ ET
BT 26.250 341.524 Td /F1 9.8 Tf  [(accuracy, precision, analytic sensitivity, limit of quantification, and robustness as well as identification of standards for )] TJ ET
BT 26.250 329.619 Td /F1 9.8 Tf  [(calibration and control of the test system.)] TJ ET
BT 26.250 293.017 Td /F4 12.0 Tf  [(Public Health Importance)] TJ ET
BT 26.250 273.063 Td /F1 9.8 Tf  [(Worldwide, bladder cancer is the fourth most common cancer and the ninth most common cause of cancer related deaths in )] TJ ET
BT 26.250 261.158 Td /F1 9.8 Tf  [(males )] TJ ET
0.267 0.267 0.267 rg
BT 54.964 261.158 Td /F1 9.8 Tf  [([2])] TJ ET
0.271 0.267 0.267 rg
BT 65.806 261.158 Td /F1 9.8 Tf  [(. Lymph node involvement is a strong predictor of survival, however definitive evaluation of lymph node status can only )] TJ ET
BT 26.250 249.253 Td /F1 9.8 Tf  [(be performed after the window for neoadjuvant therapy has elapsed. A non-invasive modality by which patients most likely to )] TJ ET
BT 26.250 237.348 Td /F1 9.8 Tf  [(harbor lymph node metastases can be identified has the potential to dramatically alter practice patterns with regard to )] TJ ET
BT 26.250 225.444 Td /F1 9.8 Tf  [(implementation of neo-adjuvant therapy, and dramatically improve survival in a subset of patients. As approximately 1/4 of )] TJ ET
BT 26.250 213.539 Td /F1 9.8 Tf  [(patients with invasive bladder cancer have lymph node positive disease )] TJ ET
0.267 0.267 0.267 rg
BT 337.304 213.539 Td /F1 9.8 Tf  [([3])] TJ ET
0.271 0.267 0.267 rg
BT 348.146 213.539 Td /F1 9.8 Tf  [(, the potential impact of such a �personalized )] TJ ET
BT 26.250 201.634 Td /F1 9.8 Tf  [(medicine� approach to treatment is substantial.)] TJ ET
BT 26.250 165.032 Td /F4 12.0 Tf  [(Published Reviews, Recommendations and Guidelines)] TJ ET
BT 26.250 145.077 Td /F4 9.8 Tf  [(Systematic evidence reviews)] TJ ET
0.271 0.267 0.267 RG
40.337 128.640 m 
40.337 129.087 40.154 129.531 39.838 129.847 c
39.522 130.163 39.078 130.347 38.631 130.347 c
38.185 130.347 37.741 130.163 37.425 129.847 c
37.109 129.531 36.925 129.087 36.925 128.640 c
36.925 128.194 37.109 127.750 37.425 127.434 c
37.741 127.118 38.185 126.934 38.631 126.934 c
39.078 126.934 39.522 127.118 39.838 127.434 c
40.154 127.750 40.337 128.194 40.337 128.640 c f
BT 45.750 125.673 Td /F1 9.8 Tf  [(The Cochrane Collaboration encourages the use of combination neoadjuvant therapy on the basis of a meta-analysis of )] TJ ET
BT 45.750 113.768 Td /F1 9.8 Tf  [(over 3,000 invasive bladder cancer patients across 11 trials which found a statistically significant 5% absolute improvement )] TJ ET
BT 45.750 101.863 Td /F1 9.8 Tf  [(in overall survival and 9% absolute improvement in disease free survival at 5 years associated with platinum-based )] TJ ET
BT 45.750 89.958 Td /F1 9.8 Tf  [(combination chemotherapy)] TJ ET
0.267 0.267 0.267 rg
BT 162.799 89.958 Td /F1 9.8 Tf  [([6])] TJ ET
BT 173.641 89.958 Td /F1 9.8 Tf  [([7])] TJ ET
0.271 0.267 0.267 rg
BT 184.483 89.958 Td /F1 9.8 Tf  [(.)] TJ ET
BT 26.250 66.804 Td /F4 9.8 Tf  [(Recommendations by independent group)] TJ ET
40.337 50.366 m 
40.337 50.813 40.154 51.257 39.838 51.573 c
39.522 51.889 39.078 52.073 38.631 52.073 c
38.185 52.073 37.741 51.889 37.425 51.573 c
37.109 51.257 36.925 50.813 36.925 50.366 c
36.925 49.920 37.109 49.476 37.425 49.160 c
37.741 48.844 38.185 48.660 38.631 48.660 c
39.078 48.660 39.522 48.844 39.838 49.160 c
40.154 49.476 40.337 49.920 40.337 50.366 c f
BT 45.750 47.399 Td /F1 9.8 Tf  [(The National Comprehensive Cancer Network \(NCCN\) )] TJ ET
0.267 0.267 0.267 rg
BT 284.674 47.399 Td /F1 9.8 Tf  [([16])] TJ ET
0.271 0.267 0.267 rg
BT 300.937 47.399 Td /F1 9.8 Tf  [( recommends considering neoadjuvant therapy for T3 bladder )] TJ ET
Q
q
0.000 0.000 0.000 rg
BT 291.710 19.825 Td /F1 11.0 Tf  [(2)] TJ ET
BT 25.000 19.825 Td /F1 11.0 Tf  [(PLOS Currents Evidence on Genomic Tests)] TJ ET

Q
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BT 45.750 708.607 Td /F1 9.8 Tf  [(The European Association of Urology \(EAU\) )] TJ ET
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BT 45.750 672.893 Td /F1 9.8 Tf  [(bladder carcinoma, irrespective of definitive treatment.�)] TJ ET
BT 26.250 632.540 Td /F4 12.0 Tf  [(Evidence Overview)] TJ ET
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BT 110.236 612.586 Td /F1 9.8 Tf  [( Test accuracy and reliability in measuring the gene expression profile for nodal involvement \(analytic )] TJ ET
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36.925 80.881 37.109 80.437 37.425 80.121 c
37.741 79.806 38.185 79.622 38.631 79.622 c
39.078 79.622 39.522 79.806 39.838 80.121 c
40.154 80.437 40.337 80.881 40.337 81.328 c f
BT 45.750 78.360 Td /F1 9.8 Tf  [(The authors have provided us with the predicted risk scores of the patients in their validation dataset, allowing us to )] TJ ET
BT 45.750 66.456 Td /F1 9.8 Tf  [(calculate additional performance measures. Using the recommended high and low risk cutoffs )] TJ ET
0.267 0.267 0.267 rg
BT 452.705 66.456 Td /F1 9.8 Tf  [([17])] TJ ET
0.271 0.267 0.267 rg
BT 468.968 66.456 Td /F1 9.8 Tf  [(, in the validation dataset )] TJ ET
BT 45.750 54.551 Td /F1 9.8 Tf  [(the model has a sensitivity for nodal involvement of 0.44, a specificity of 0.70, a positive predictive value \(PPV\) of 0.30, and )] TJ ET
BT 45.750 42.646 Td /F1 9.8 Tf  [(a negative predictive value \(NPV\) of 0.81. PPV and NPV calculations assume a 23% prevalence of nodal involvement at )] TJ ET
Q
q
15.000 28.360 577.500 748.640 re W n
0.271 0.267 0.267 rg
BT 45.750 767.476 Td /F1 9.8 Tf  [(cancer patients, noting that a �modest survival benefit of neoadjuvant chemotherapy patients with muscle-invasive bladder )] TJ ET
BT 45.750 755.571 Td /F1 9.8 Tf  [(cancer was noted in randomized trials and meta-analysis performed in patients receiving 3 cycles prior to cystectomy but )] TJ ET
BT 45.750 743.667 Td /F1 9.8 Tf  [(not radiotherapy.�)] TJ ET
BT 26.250 720.512 Td /F4 9.8 Tf  [(Guidelines by professional groups)] TJ ET
0.271 0.267 0.267 RG
40.337 711.575 m 
40.337 712.021 40.154 712.465 39.838 712.781 c
39.522 713.097 39.078 713.281 38.631 713.281 c
38.185 713.281 37.741 713.097 37.425 712.781 c
37.109 712.465 36.925 712.021 36.925 711.575 c
36.925 711.128 37.109 710.684 37.425 710.368 c
37.741 710.052 38.185 709.869 38.631 709.869 c
39.078 709.869 39.522 710.052 39.838 710.368 c
40.154 710.684 40.337 711.128 40.337 711.575 c f
BT 45.750 708.607 Td /F1 9.8 Tf  [(The European Association of Urology \(EAU\) )] TJ ET
0.267 0.267 0.267 rg
BT 239.200 708.607 Td /F1 9.8 Tf  [([8])] TJ ET
0.271 0.267 0.267 rg
BT 250.042 708.607 Td /F1 9.8 Tf  [( notes that as �a result of a 5-8% overall survival \(OS\) advantage in recently )] TJ ET
BT 45.750 696.702 Td /F1 9.8 Tf  [(published studies and meta-analyses, neoadjuvant cisplatin-containing combination chemotherapy should be considered )] TJ ET
BT 45.750 684.798 Td /F1 9.8 Tf  [(and discussed with the patient in cases of muscle-invasive, clinically node-negative, and nonmetastatic \(N0 M0\) urinary )] TJ ET
BT 45.750 672.893 Td /F1 9.8 Tf  [(bladder carcinoma, irrespective of definitive treatment.�)] TJ ET
BT 26.250 632.540 Td /F4 12.0 Tf  [(Evidence Overview)] TJ ET
BT 26.250 612.586 Td /F6 9.8 Tf  [(Analytic Validity)] TJ ET
BT 101.569 612.586 Td /F4 9.8 Tf  [( : )] TJ ET
BT 110.236 612.586 Td /F1 9.8 Tf  [( Test accuracy and reliability in measuring the gene expression profile for nodal involvement \(analytic )] TJ ET
BT 26.250 600.681 Td /F1 9.8 Tf  [(sensitivity and specificity\).)] TJ ET
40.337 584.244 m 
40.337 584.691 40.154 585.135 39.838 585.451 c
39.522 585.767 39.078 585.950 38.631 585.950 c
38.185 585.950 37.741 585.767 37.425 585.451 c
37.109 585.135 36.925 584.691 36.925 584.244 c
36.925 583.798 37.109 583.354 37.425 583.038 c
37.741 582.722 38.185 582.538 38.631 582.538 c
39.078 582.538 39.522 582.722 39.838 583.038 c
40.154 583.354 40.337 583.798 40.337 584.244 c f
BT 45.750 581.277 Td /F1 9.8 Tf  [(The gene expression model was developed and validated using gene expression data profiled on Affymetrix GeneChip� )] TJ ET
BT 45.750 569.372 Td /F1 9.8 Tf  [(Human Genome U133A and U133 Plus 2.0 arrays and processed by either Microarray Suite \(MAS5\) or Robust Multichip )] TJ ET
BT 45.750 557.467 Td /F1 9.8 Tf  [(Average \(RMA\) algorithms )] TJ ET
0.267 0.267 0.267 rg
BT 163.315 557.467 Td /F1 9.8 Tf  [([17])] TJ ET
0.271 0.267 0.267 rg
BT 179.578 557.467 Td /F1 9.8 Tf  [(.)] TJ ET
40.337 537.280 m 
40.337 537.727 40.154 538.171 39.838 538.487 c
39.522 538.802 39.078 538.986 38.631 538.986 c
38.185 538.986 37.741 538.802 37.425 538.487 c
37.109 538.171 36.925 537.727 36.925 537.280 c
36.925 536.833 37.109 536.389 37.425 536.073 c
37.741 535.758 38.185 535.574 38.631 535.574 c
39.078 535.574 39.522 535.758 39.838 536.073 c
40.154 536.389 40.337 536.833 40.337 537.280 c f
BT 45.750 534.312 Td /F1 9.8 Tf  [(Affymetrix announced on May 9, 2011 that the U.S. Food and Drug Administration has cleared the addition of new gene )] TJ ET
BT 45.750 522.408 Td /F1 9.8 Tf  [(expression reagents as accessories to its GeneChip� Microarray Instrument System for in vitro diagnostic \(IVD\) use )] TJ ET
BT 45.750 510.503 Td /F1 9.8 Tf  [(\(www.affymetrix.com\). Affymetrix microarray platforms are already in use with two FDA-cleared tests, the Roche )] TJ ET
BT 45.750 498.598 Td /F1 9.8 Tf  [(AmpliChip� CYP450 Test, which detects genetic variants for the metabolic genes CYP2D6 and CYP2C19, and Pathwork� )] TJ ET
BT 45.750 486.693 Td /F1 9.8 Tf  [(Diagnostics� Tissue of Origin Test which measures gene expression in > 2000 genes )] TJ ET
0.267 0.267 0.267 rg
BT 413.423 486.693 Td /F1 9.8 Tf  [([15])] TJ ET
0.271 0.267 0.267 rg
BT 429.685 486.693 Td /F1 9.8 Tf  [(.)] TJ ET
40.337 466.506 m 
40.337 466.953 40.154 467.397 39.838 467.713 c
39.522 468.029 39.078 468.212 38.631 468.212 c
38.185 468.212 37.741 468.029 37.425 467.713 c
37.109 467.397 36.925 466.953 36.925 466.506 c
36.925 466.060 37.109 465.616 37.425 465.300 c
37.741 464.984 38.185 464.800 38.631 464.800 c
39.078 464.800 39.522 464.984 39.838 465.300 c
40.154 465.616 40.337 466.060 40.337 466.506 c f
BT 45.750 463.539 Td /F1 9.8 Tf  [(One of the gene expression datasets used for model development was profiled from formalin-fixed, paraffin embedded )] TJ ET
BT 45.750 451.634 Td /F1 9.8 Tf  [(\(FFPE\) tumor samples obtained from cystectomy. To ensure clinical applicability of the test to transurethral resection \(TUR\) )] TJ ET
BT 45.750 439.729 Td /F1 9.8 Tf  [(specimens preserved by fresh freezing \(FF\), the 20 gene model utilizes 21 �high fidelity� probes whose expression values )] TJ ET
BT 45.750 427.824 Td /F1 9.8 Tf  [(show strong correlation across FFPE and FF tissue preservation methods and whose expression values are similar )] TJ ET
BT 45.750 415.920 Td /F1 9.8 Tf  [(between specimens obtained from cystectomy and TUR)] TJ ET
0.267 0.267 0.267 rg
BT 287.423 415.920 Td /F1 9.8 Tf  [( [17])] TJ ET
0.271 0.267 0.267 rg
BT 306.397 415.920 Td /F1 9.8 Tf  [(. Specifically, a probe is considered �high fidelity� if the )] TJ ET
BT 45.750 404.015 Td /F1 9.8 Tf  [(correlation in its expression values across 32 matched FFPE-FF samples was greater than 0 \(p < 0.025, one-tailed test\) )] TJ ET
BT 45.750 392.110 Td /F1 9.8 Tf  [(and if its expression values were )] TJ ET
BT 189.348 392.110 Td /F5 9.8 Tf  [(not)] TJ ET
BT 202.901 392.110 Td /F1 9.8 Tf  [( significantly different \(p< 0.01, two-tailed test\) between 30 TUR specimens obtained )] TJ ET
BT 45.750 380.205 Td /F1 9.8 Tf  [(from advanced Stage IV, node positive or metastatic patients and 25 cystectomies from node positive patients. The )] TJ ET
BT 45.750 368.301 Td /F1 9.8 Tf  [(validation cohort was evaluated based on archival FFPE material.)] TJ ET
40.337 348.114 m 
40.337 348.560 40.154 349.004 39.838 349.320 c
39.522 349.636 39.078 349.820 38.631 349.820 c
38.185 349.820 37.741 349.636 37.425 349.320 c
37.109 349.004 36.925 348.560 36.925 348.114 c
36.925 347.667 37.109 347.223 37.425 346.907 c
37.741 346.591 38.185 346.407 38.631 346.407 c
39.078 346.407 39.522 346.591 39.838 346.907 c
40.154 347.223 40.337 347.667 40.337 348.114 c f
BT 45.750 345.146 Td /F1 9.8 Tf  [(Although several studies have found that Affymetrix microarray platforms are reliable, on average, across all probes on the )] TJ ET
BT 45.750 333.241 Td /F1 9.8 Tf  [(array )] TJ ET
0.267 0.267 0.267 rg
BT 70.671 333.241 Td /F1 9.8 Tf  [([18])] TJ ET
0.271 0.267 0.267 rg
BT 86.934 333.241 Td /F1 9.8 Tf  [(, the reliability of the 21 probes in the gene model is currently not known. If implemented in a clinical laboratory )] TJ ET
BT 45.750 321.336 Td /F1 9.8 Tf  [(setting, the analytic parameters of the test, regardless of platform, would be thoroughly evaluated.)] TJ ET
BT 26.250 298.182 Td /F6 9.8 Tf  [(Clinical Validity)] TJ ET
BT 98.322 298.182 Td /F4 9.8 Tf  [( : )] TJ ET
BT 106.990 298.182 Td /F1 9.8 Tf  [( Test accuracy and reliability in identifying patients with nodal involvement \(predictive value\).)] TJ ET
40.337 281.745 m 
40.337 282.191 40.154 282.635 39.838 282.951 c
39.522 283.267 39.078 283.451 38.631 283.451 c
38.185 283.451 37.741 283.267 37.425 282.951 c
37.109 282.635 36.925 282.191 36.925 281.745 c
36.925 281.298 37.109 280.854 37.425 280.538 c
37.741 280.222 38.185 280.038 38.631 280.038 c
39.078 280.038 39.522 280.222 39.838 280.538 c
40.154 280.854 40.337 281.298 40.337 281.745 c f
BT 45.750 278.777 Td /F1 9.8 Tf  [(The gene expression data sets used to develop and evaluate the model were obtained from patients profiled at the )] TJ ET
BT 45.750 266.872 Td /F1 9.8 Tf  [(Memorial Sloan Kettering Cancer Center \(MSKCC cohort, 66 patients\) )] TJ ET
0.267 0.267 0.267 rg
BT 351.354 266.872 Td /F1 9.8 Tf  [([19])] TJ ET
0.271 0.267 0.267 rg
BT 367.617 266.872 Td /F1 9.8 Tf  [(, patients profiled at l�H�pital de l�H�tel-Dieu at )] TJ ET
BT 45.750 254.967 Td /F1 9.8 Tf  [(Laval University, Qu�bec, Canada \(Laval Cohort, 188 patients\), and patients from a phase III, multicenter randomized )] TJ ET
BT 45.750 243.063 Td /F1 9.8 Tf  [(controlled trial comparing two adjuvant chemotherapy regimens )] TJ ET
0.267 0.267 0.267 rg
BT 322.104 243.063 Td /F1 9.8 Tf  [([20])] TJ ET
0.271 0.267 0.267 rg
BT 338.367 243.063 Td /F1 9.8 Tf  [( \(AUO-AB 05/95, AUO cohort, 185 patients\). The )] TJ ET
BT 45.750 231.158 Td /F1 9.8 Tf  [(MSKCC and Laval cohorts were used for training while the AUO cohort was used for independent validation. Given the )] TJ ET
BT 45.750 219.253 Td /F1 9.8 Tf  [(potential bias of gene profiling studies performed on small specimen sets, the large training and validation sets utilized in )] TJ ET
BT 45.750 207.348 Td /F1 9.8 Tf  [(this study confer additional substantiation of the clinical utility of this assay.)] TJ ET
40.337 187.161 m 
40.337 187.608 40.154 188.052 39.838 188.368 c
39.522 188.684 39.078 188.868 38.631 188.868 c
38.185 188.868 37.741 188.684 37.425 188.368 c
37.109 188.052 36.925 187.608 36.925 187.161 c
36.925 186.715 37.109 186.271 37.425 185.955 c
37.741 185.639 38.185 185.455 38.631 185.455 c
39.078 185.455 39.522 185.639 39.838 185.955 c
40.154 186.271 40.337 186.715 40.337 187.161 c f
BT 45.750 184.194 Td /F1 9.8 Tf  [(Model evaluation was carried out using Receiver Operating Characteristic \(ROC\) curve analysis. The area under the curve )] TJ ET
BT 45.750 172.289 Td /F1 9.8 Tf  [(\(AUC\) is 0.72 and 0.67 in the training and validation datasets, respectively )] TJ ET
0.267 0.267 0.267 rg
BT 368.192 172.289 Td /F1 9.8 Tf  [([17])] TJ ET
0.271 0.267 0.267 rg
BT 384.455 172.289 Td /F1 9.8 Tf  [(.)] TJ ET
40.337 152.102 m 
40.337 152.548 40.154 152.992 39.838 153.308 c
39.522 153.624 39.078 153.808 38.631 153.808 c
38.185 153.808 37.741 153.624 37.425 153.308 c
37.109 152.992 36.925 152.548 36.925 152.102 c
36.925 151.655 37.109 151.211 37.425 150.895 c
37.741 150.579 38.185 150.395 38.631 150.395 c
39.078 150.395 39.522 150.579 39.838 150.895 c
40.154 151.211 40.337 151.655 40.337 152.102 c f
BT 45.750 149.134 Td /F1 9.8 Tf  [(The thresholds were established based on the training set for distinguishing high, intermediate, and low risk groups, with )] TJ ET
BT 45.750 137.229 Td /F1 9.8 Tf  [(relative risks of 2.25 \(95% CI, 1.18-4.28\), 1.02 \(95% CI, 0.46 � 2.26\), and 0.47 \(95% CI, 0.31, 0.70\), respectively. When )] TJ ET
BT 45.750 125.325 Td /F1 9.8 Tf  [(applied to the independent validation set, these thresholds demonstrated relative risks of 1.74, \(95% CI, 1.03 � 2.93\) 1.05 )] TJ ET
BT 45.750 113.420 Td /F1 9.8 Tf  [(\(95% CI, .45 � 2.41\), and 0.74 \(95% CI, 0.51 � 0.96\), for high, intermediate and low risk groups respectively, demonstrating )] TJ ET
BT 45.750 101.515 Td /F1 9.8 Tf  [(a high degree of concordance between the training and validation sets )] TJ ET
0.267 0.267 0.267 rg
BT 351.422 101.515 Td /F1 9.8 Tf  [([17])] TJ ET
0.271 0.267 0.267 rg
BT 367.685 101.515 Td /F1 9.8 Tf  [(.)] TJ ET
40.337 81.328 m 
40.337 81.775 40.154 82.219 39.838 82.535 c
39.522 82.850 39.078 83.034 38.631 83.034 c
38.185 83.034 37.741 82.850 37.425 82.535 c
37.109 82.219 36.925 81.775 36.925 81.328 c
36.925 80.881 37.109 80.437 37.425 80.121 c
37.741 79.806 38.185 79.622 38.631 79.622 c
39.078 79.622 39.522 79.806 39.838 80.121 c
40.154 80.437 40.337 80.881 40.337 81.328 c f
BT 45.750 78.360 Td /F1 9.8 Tf  [(The authors have provided us with the predicted risk scores of the patients in their validation dataset, allowing us to )] TJ ET
BT 45.750 66.456 Td /F1 9.8 Tf  [(calculate additional performance measures. Using the recommended high and low risk cutoffs )] TJ ET
0.267 0.267 0.267 rg
BT 452.705 66.456 Td /F1 9.8 Tf  [([17])] TJ ET
0.271 0.267 0.267 rg
BT 468.968 66.456 Td /F1 9.8 Tf  [(, in the validation dataset )] TJ ET
BT 45.750 54.551 Td /F1 9.8 Tf  [(the model has a sensitivity for nodal involvement of 0.44, a specificity of 0.70, a positive predictive value \(PPV\) of 0.30, and )] TJ ET
BT 45.750 42.646 Td /F1 9.8 Tf  [(a negative predictive value \(NPV\) of 0.81. PPV and NPV calculations assume a 23% prevalence of nodal involvement at )] TJ ET
Q
q
15.000 28.360 577.500 748.640 re W n
0.271 0.267 0.267 rg
BT 45.750 767.476 Td /F1 9.8 Tf  [(cancer patients, noting that a �modest survival benefit of neoadjuvant chemotherapy patients with muscle-invasive bladder )] TJ ET
BT 45.750 755.571 Td /F1 9.8 Tf  [(cancer was noted in randomized trials and meta-analysis performed in patients receiving 3 cycles prior to cystectomy but )] TJ ET
BT 45.750 743.667 Td /F1 9.8 Tf  [(not radiotherapy.�)] TJ ET
BT 26.250 720.512 Td /F4 9.8 Tf  [(Guidelines by professional groups)] TJ ET
0.271 0.267 0.267 RG
40.337 711.575 m 
40.337 712.021 40.154 712.465 39.838 712.781 c
39.522 713.097 39.078 713.281 38.631 713.281 c
38.185 713.281 37.741 713.097 37.425 712.781 c
37.109 712.465 36.925 712.021 36.925 711.575 c
36.925 711.128 37.109 710.684 37.425 710.368 c
37.741 710.052 38.185 709.869 38.631 709.869 c
39.078 709.869 39.522 710.052 39.838 710.368 c
40.154 710.684 40.337 711.128 40.337 711.575 c f
BT 45.750 708.607 Td /F1 9.8 Tf  [(The European Association of Urology \(EAU\) )] TJ ET
0.267 0.267 0.267 rg
BT 239.200 708.607 Td /F1 9.8 Tf  [([8])] TJ ET
0.271 0.267 0.267 rg
BT 250.042 708.607 Td /F1 9.8 Tf  [( notes that as �a result of a 5-8% overall survival \(OS\) advantage in recently )] TJ ET
BT 45.750 696.702 Td /F1 9.8 Tf  [(published studies and meta-analyses, neoadjuvant cisplatin-containing combination chemotherapy should be considered )] TJ ET
BT 45.750 684.798 Td /F1 9.8 Tf  [(and discussed with the patient in cases of muscle-invasive, clinically node-negative, and nonmetastatic \(N0 M0\) urinary )] TJ ET
BT 45.750 672.893 Td /F1 9.8 Tf  [(bladder carcinoma, irrespective of definitive treatment.�)] TJ ET
BT 26.250 632.540 Td /F4 12.0 Tf  [(Evidence Overview)] TJ ET
BT 26.250 612.586 Td /F6 9.8 Tf  [(Analytic Validity)] TJ ET
BT 101.569 612.586 Td /F4 9.8 Tf  [( : )] TJ ET
BT 110.236 612.586 Td /F1 9.8 Tf  [( Test accuracy and reliability in measuring the gene expression profile for nodal involvement \(analytic )] TJ ET
BT 26.250 600.681 Td /F1 9.8 Tf  [(sensitivity and specificity\).)] TJ ET
40.337 584.244 m 
40.337 584.691 40.154 585.135 39.838 585.451 c
39.522 585.767 39.078 585.950 38.631 585.950 c
38.185 585.950 37.741 585.767 37.425 585.451 c
37.109 585.135 36.925 584.691 36.925 584.244 c
36.925 583.798 37.109 583.354 37.425 583.038 c
37.741 582.722 38.185 582.538 38.631 582.538 c
39.078 582.538 39.522 582.722 39.838 583.038 c
40.154 583.354 40.337 583.798 40.337 584.244 c f
BT 45.750 581.277 Td /F1 9.8 Tf  [(The gene expression model was developed and validated using gene expression data profiled on Affymetrix GeneChip� )] TJ ET
BT 45.750 569.372 Td /F1 9.8 Tf  [(Human Genome U133A and U133 Plus 2.0 arrays and processed by either Microarray Suite \(MAS5\) or Robust Multichip )] TJ ET
BT 45.750 557.467 Td /F1 9.8 Tf  [(Average \(RMA\) algorithms )] TJ ET
0.267 0.267 0.267 rg
BT 163.315 557.467 Td /F1 9.8 Tf  [([17])] TJ ET
0.271 0.267 0.267 rg
BT 179.578 557.467 Td /F1 9.8 Tf  [(.)] TJ ET
40.337 537.280 m 
40.337 537.727 40.154 538.171 39.838 538.487 c
39.522 538.802 39.078 538.986 38.631 538.986 c
38.185 538.986 37.741 538.802 37.425 538.487 c
37.109 538.171 36.925 537.727 36.925 537.280 c
36.925 536.833 37.109 536.389 37.425 536.073 c
37.741 535.758 38.185 535.574 38.631 535.574 c
39.078 535.574 39.522 535.758 39.838 536.073 c
40.154 536.389 40.337 536.833 40.337 537.280 c f
BT 45.750 534.312 Td /F1 9.8 Tf  [(Affymetrix announced on May 9, 2011 that the U.S. Food and Drug Administration has cleared the addition of new gene )] TJ ET
BT 45.750 522.408 Td /F1 9.8 Tf  [(expression reagents as accessories to its GeneChip� Microarray Instrument System for in vitro diagnostic \(IVD\) use )] TJ ET
BT 45.750 510.503 Td /F1 9.8 Tf  [(\(www.affymetrix.com\). Affymetrix microarray platforms are already in use with two FDA-cleared tests, the Roche )] TJ ET
BT 45.750 498.598 Td /F1 9.8 Tf  [(AmpliChip� CYP450 Test, which detects genetic variants for the metabolic genes CYP2D6 and CYP2C19, and Pathwork� )] TJ ET
BT 45.750 486.693 Td /F1 9.8 Tf  [(Diagnostics� Tissue of Origin Test which measures gene expression in > 2000 genes )] TJ ET
0.267 0.267 0.267 rg
BT 413.423 486.693 Td /F1 9.8 Tf  [([15])] TJ ET
0.271 0.267 0.267 rg
BT 429.685 486.693 Td /F1 9.8 Tf  [(.)] TJ ET
40.337 466.506 m 
40.337 466.953 40.154 467.397 39.838 467.713 c
39.522 468.029 39.078 468.212 38.631 468.212 c
38.185 468.212 37.741 468.029 37.425 467.713 c
37.109 467.397 36.925 466.953 36.925 466.506 c
36.925 466.060 37.109 465.616 37.425 465.300 c
37.741 464.984 38.185 464.800 38.631 464.800 c
39.078 464.800 39.522 464.984 39.838 465.300 c
40.154 465.616 40.337 466.060 40.337 466.506 c f
BT 45.750 463.539 Td /F1 9.8 Tf  [(One of the gene expression datasets used for model development was profiled from formalin-fixed, paraffin embedded )] TJ ET
BT 45.750 451.634 Td /F1 9.8 Tf  [(\(FFPE\) tumor samples obtained from cystectomy. To ensure clinical applicability of the test to transurethral resection \(TUR\) )] TJ ET
BT 45.750 439.729 Td /F1 9.8 Tf  [(specimens preserved by fresh freezing \(FF\), the 20 gene model utilizes 21 �high fidelity� probes whose expression values )] TJ ET
BT 45.750 427.824 Td /F1 9.8 Tf  [(show strong correlation across FFPE and FF tissue preservation methods and whose expression values are similar )] TJ ET
BT 45.750 415.920 Td /F1 9.8 Tf  [(between specimens obtained from cystectomy and TUR)] TJ ET
0.267 0.267 0.267 rg
BT 287.423 415.920 Td /F1 9.8 Tf  [( [17])] TJ ET
0.271 0.267 0.267 rg
BT 306.397 415.920 Td /F1 9.8 Tf  [(. Specifically, a probe is considered �high fidelity� if the )] TJ ET
BT 45.750 404.015 Td /F1 9.8 Tf  [(correlation in its expression values across 32 matched FFPE-FF samples was greater than 0 \(p < 0.025, one-tailed test\) )] TJ ET
BT 45.750 392.110 Td /F1 9.8 Tf  [(and if its expression values were )] TJ ET
BT 189.348 392.110 Td /F5 9.8 Tf  [(not)] TJ ET
BT 202.901 392.110 Td /F1 9.8 Tf  [( significantly different \(p< 0.01, two-tailed test\) between 30 TUR specimens obtained )] TJ ET
BT 45.750 380.205 Td /F1 9.8 Tf  [(from advanced Stage IV, node positive or metastatic patients and 25 cystectomies from node positive patients. The )] TJ ET
BT 45.750 368.301 Td /F1 9.8 Tf  [(validation cohort was evaluated based on archival FFPE material.)] TJ ET
40.337 348.114 m 
40.337 348.560 40.154 349.004 39.838 349.320 c
39.522 349.636 39.078 349.820 38.631 349.820 c
38.185 349.820 37.741 349.636 37.425 349.320 c
37.109 349.004 36.925 348.560 36.925 348.114 c
36.925 347.667 37.109 347.223 37.425 346.907 c
37.741 346.591 38.185 346.407 38.631 346.407 c
39.078 346.407 39.522 346.591 39.838 346.907 c
40.154 347.223 40.337 347.667 40.337 348.114 c f
BT 45.750 345.146 Td /F1 9.8 Tf  [(Although several studies have found that Affymetrix microarray platforms are reliable, on average, across all probes on the )] TJ ET
BT 45.750 333.241 Td /F1 9.8 Tf  [(array )] TJ ET
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BT 70.671 333.241 Td /F1 9.8 Tf  [([18])] TJ ET
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BT 86.934 333.241 Td /F1 9.8 Tf  [(, the reliability of the 21 probes in the gene model is currently not known. If implemented in a clinical laboratory )] TJ ET
BT 45.750 321.336 Td /F1 9.8 Tf  [(setting, the analytic parameters of the test, regardless of platform, would be thoroughly evaluated.)] TJ ET
BT 26.250 298.182 Td /F6 9.8 Tf  [(Clinical Validity)] TJ ET
BT 98.322 298.182 Td /F4 9.8 Tf  [( : )] TJ ET
BT 106.990 298.182 Td /F1 9.8 Tf  [( Test accuracy and reliability in identifying patients with nodal involvement \(predictive value\).)] TJ ET
40.337 281.745 m 
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BT 45.750 278.777 Td /F1 9.8 Tf  [(The gene expression data sets used to develop and evaluate the model were obtained from patients profiled at the )] TJ ET
BT 45.750 266.872 Td /F1 9.8 Tf  [(Memorial Sloan Kettering Cancer Center \(MSKCC cohort, 66 patients\) )] TJ ET
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BT 351.354 266.872 Td /F1 9.8 Tf  [([19])] TJ ET
0.271 0.267 0.267 rg
BT 367.617 266.872 Td /F1 9.8 Tf  [(, patients profiled at l�H�pital de l�H�tel-Dieu at )] TJ ET
BT 45.750 254.967 Td /F1 9.8 Tf  [(Laval University, Qu�bec, Canada \(Laval Cohort, 188 patients\), and patients from a phase III, multicenter randomized )] TJ ET
BT 45.750 243.063 Td /F1 9.8 Tf  [(controlled trial comparing two adjuvant chemotherapy regimens )] TJ ET
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BT 322.104 243.063 Td /F1 9.8 Tf  [([20])] TJ ET
0.271 0.267 0.267 rg
BT 338.367 243.063 Td /F1 9.8 Tf  [( \(AUO-AB 05/95, AUO cohort, 185 patients\). The )] TJ ET
BT 45.750 231.158 Td /F1 9.8 Tf  [(MSKCC and Laval cohorts were used for training while the AUO cohort was used for independent validation. Given the )] TJ ET
BT 45.750 219.253 Td /F1 9.8 Tf  [(potential bias of gene profiling studies performed on small specimen sets, the large training and validation sets utilized in )] TJ ET
BT 45.750 207.348 Td /F1 9.8 Tf  [(this study confer additional substantiation of the clinical utility of this assay.)] TJ ET
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BT 45.750 184.194 Td /F1 9.8 Tf  [(Model evaluation was carried out using Receiver Operating Characteristic \(ROC\) curve analysis. The area under the curve )] TJ ET
BT 45.750 172.289 Td /F1 9.8 Tf  [(\(AUC\) is 0.72 and 0.67 in the training and validation datasets, respectively )] TJ ET
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BT 368.192 172.289 Td /F1 9.8 Tf  [([17])] TJ ET
0.271 0.267 0.267 rg
BT 384.455 172.289 Td /F1 9.8 Tf  [(.)] TJ ET
40.337 152.102 m 
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BT 45.750 149.134 Td /F1 9.8 Tf  [(The thresholds were established based on the training set for distinguishing high, intermediate, and low risk groups, with )] TJ ET
BT 45.750 137.229 Td /F1 9.8 Tf  [(relative risks of 2.25 \(95% CI, 1.18-4.28\), 1.02 \(95% CI, 0.46 � 2.26\), and 0.47 \(95% CI, 0.31, 0.70\), respectively. When )] TJ ET
BT 45.750 125.325 Td /F1 9.8 Tf  [(applied to the independent validation set, these thresholds demonstrated relative risks of 1.74, \(95% CI, 1.03 � 2.93\) 1.05 )] TJ ET
BT 45.750 113.420 Td /F1 9.8 Tf  [(\(95% CI, .45 � 2.41\), and 0.74 \(95% CI, 0.51 � 0.96\), for high, intermediate and low risk groups respectively, demonstrating )] TJ ET
BT 45.750 101.515 Td /F1 9.8 Tf  [(a high degree of concordance between the training and validation sets )] TJ ET
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BT 351.422 101.515 Td /F1 9.8 Tf  [([17])] TJ ET
0.271 0.267 0.267 rg
BT 367.685 101.515 Td /F1 9.8 Tf  [(.)] TJ ET
40.337 81.328 m 
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BT 45.750 78.360 Td /F1 9.8 Tf  [(The authors have provided us with the predicted risk scores of the patients in their validation dataset, allowing us to )] TJ ET
BT 45.750 66.456 Td /F1 9.8 Tf  [(calculate additional performance measures. Using the recommended high and low risk cutoffs )] TJ ET
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BT 452.705 66.456 Td /F1 9.8 Tf  [([17])] TJ ET
0.271 0.267 0.267 rg
BT 468.968 66.456 Td /F1 9.8 Tf  [(, in the validation dataset )] TJ ET
BT 45.750 54.551 Td /F1 9.8 Tf  [(the model has a sensitivity for nodal involvement of 0.44, a specificity of 0.70, a positive predictive value \(PPV\) of 0.30, and )] TJ ET
BT 45.750 42.646 Td /F1 9.8 Tf  [(a negative predictive value \(NPV\) of 0.81. PPV and NPV calculations assume a 23% prevalence of nodal involvement at )] TJ ET
Q
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BT 291.710 19.825 Td /F1 11.0 Tf  [(3)] TJ ET
BT 25.000 19.825 Td /F1 11.0 Tf  [(PLOS Currents Evidence on Genomic Tests)] TJ ET

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0.271 0.267 0.267 rg
BT 45.750 767.476 Td /F1 9.8 Tf  [(time of cystectomy )] TJ ET
0.267 0.267 0.267 rg
BT 129.190 767.476 Td /F1 9.8 Tf  [([3])] TJ ET
0.271 0.267 0.267 rg
BT 140.032 767.476 Td /F1 9.8 Tf  [(. Importantly, if patients with higher stage disease were to be selected for testing, these )] TJ ET
BT 45.750 755.571 Td /F1 9.8 Tf  [(characteristics would change. For example, if only T3 patients were selected, the prevalence of occult nodal disease in )] TJ ET
BT 45.750 743.667 Td /F1 9.8 Tf  [(these patients would be 39% )] TJ ET
0.267 0.267 0.267 rg
BT 173.114 743.667 Td /F1 9.8 Tf  [([3])] TJ ET
0.271 0.267 0.267 rg
BT 183.956 743.667 Td /F1 9.8 Tf  [(. Hence the PPV and NPV in this scenario would be 0.48 and 0.66, respectively.)] TJ ET
BT 26.250 720.512 Td /F6 9.8 Tf  [(Clinical Utility)] TJ ET
BT 90.727 720.512 Td /F4 9.8 Tf  [( : )] TJ ET
BT 99.394 720.512 Td /F1 9.8 Tf  [( Net benefit of test in improving health outcomes.)] TJ ET
0.271 0.267 0.267 RG
40.337 704.075 m 
40.337 704.521 40.154 704.965 39.838 705.281 c
39.522 705.597 39.078 705.781 38.631 705.781 c
38.185 705.781 37.741 705.597 37.425 705.281 c
37.109 704.965 36.925 704.521 36.925 704.075 c
36.925 703.628 37.109 703.184 37.425 702.868 c
37.741 702.552 38.185 702.369 38.631 702.369 c
39.078 702.369 39.522 702.552 39.838 702.868 c
40.154 703.184 40.337 703.628 40.337 704.075 c f
BT 45.750 701.107 Td /F1 9.8 Tf  [(The gene expression model was validated in a prospectively collected cohort of patients enrolled in a phase III clinical trial )] TJ ET
0.267 0.267 0.267 rg
BT 45.750 689.202 Td /F1 9.8 Tf  [([20])] TJ ET
0.271 0.267 0.267 rg
BT 62.013 689.202 Td /F1 9.8 Tf  [(, indicating that the gene model can accurately identify high and low risk patients in clinically relevant patient )] TJ ET
BT 45.750 677.298 Td /F1 9.8 Tf  [(populations )] TJ ET
0.267 0.267 0.267 rg
BT 98.322 677.298 Td /F1 9.8 Tf  [([17])] TJ ET
0.271 0.267 0.267 rg
BT 114.585 677.298 Td /F1 9.8 Tf  [(. However, prospective studies are needed to fully define the clinical utility of the 20 gene node signature )] TJ ET
BT 45.750 665.393 Td /F1 9.8 Tf  [(and to assess whether neoadjuvant chemotherapy confers a larger survival benefit in the high risk patients identified by this )] TJ ET
BT 45.750 653.488 Td /F1 9.8 Tf  [(test.)] TJ ET
BT 26.250 630.333 Td /F4 9.8 Tf  [(Limitations)] TJ ET
BT 26.250 610.929 Td /F1 9.8 Tf  [(There is currently only a single peer-reviewed publication describing the development and validation of the genomic test. The )] TJ ET
BT 26.250 599.024 Td /F1 9.8 Tf  [(testing is not currently available in a clinical laboratory setting.)] TJ ET
BT 26.250 579.619 Td /F4 9.8 Tf  [(Conclusions)] TJ ET
BT 26.250 560.214 Td /F1 9.8 Tf  [(The 20 gene model described in this summary is the first published model for predicting nodal involvement in bladder cancer )] TJ ET
BT 26.250 548.310 Td /F1 9.8 Tf  [(patients and by providing this molecular intelligence, has the potential to strategically increase the use of neoadjuvant therapy )] TJ ET
BT 26.250 536.405 Td /F1 9.8 Tf  [(and increase bladder cancer survival rates while limiting unnecessary aggressive treatment. Importantly, the model was )] TJ ET
BT 26.250 524.500 Td /F1 9.8 Tf  [(developed with clinical applicability in mind. Specifically, the 20 genes \(21 probes\) used in the model are reliably expressed in )] TJ ET
BT 26.250 512.595 Td /F1 9.8 Tf  [(TUR specimens and can be reliably detected with both FF and FFPE preservation methods, the clinical conditions under which )] TJ ET
BT 26.250 500.691 Td /F1 9.8 Tf  [(the model will be employed and allowing for retrospective analysis of archival tissue after the patients has undergone TUR in )] TJ ET
BT 26.250 488.786 Td /F1 9.8 Tf  [(the course of routine clinical care and muscle invasive disease discovered. Although the model has been validated in )] TJ ET
BT 26.250 476.881 Td /F1 9.8 Tf  [(prospectively collected samples from an independent clinical trial, further refinement is needed in the clinical laboratory setting )] TJ ET
BT 26.250 464.976 Td /F1 9.8 Tf  [(to bring this test to routine clinical use. Nevertheless, the development of the model is an important milestone on the path to the )] TJ ET
BT 26.250 453.072 Td /F1 9.8 Tf  [(personalized treatment of bladder cancer.)] TJ ET
BT 26.250 433.667 Td /F4 9.8 Tf  [(Links)] TJ ET
BT 26.250 414.262 Td /F1 9.8 Tf  [(None identified)] TJ ET
BT 26.250 394.857 Td /F1 9.8 Tf  [(Last updated: August 4, 2011)] TJ ET
BT 26.250 358.255 Td /F4 12.0 Tf  [(Competing interests)] TJ ET
BT 26.250 338.301 Td /F1 9.8 Tf  [(GD and DT participated in the development and validation of the gene model and are coauthors on the publication describing its )] TJ ET
BT 26.250 326.396 Td /F1 9.8 Tf  [(development and validation )] TJ ET
0.267 0.267 0.267 rg
BT 147.647 326.396 Td /F1 9.8 Tf  [([17])] TJ ET
0.271 0.267 0.267 rg
BT 163.910 326.396 Td /F1 9.8 Tf  [(. IP rights on this test have been filed at the University of Colorado.)] TJ ET
BT 26.250 289.793 Td /F4 12.0 Tf  [(References)] TJ ET
BT 26.250 262.339 Td /F1 9.8 Tf  [(1.)] TJ ET
BT 38.132 262.339 Td /F1 9.8 Tf  [(Jacobs BL, Lee CT, Montie JE \(2010\) Bladder Cancer in 2010 How Far Have We Come? Ca-a Cancer Journal for Clinicians )] TJ ET
BT 26.250 250.434 Td /F1 9.8 Tf  [(60: 244-272.)] TJ ET
BT 26.250 231.030 Td /F1 9.8 Tf  [(2.)] TJ ET
BT 38.132 231.030 Td /F1 9.8 Tf  [(Jemal A, Siegel R, Xu J, Ward E \(2010\) Cancer statistics, 2010. CA Cancer J Clin 60: 277-300.)] TJ ET
BT 26.250 211.625 Td /F1 9.8 Tf  [(3.)] TJ ET
BT 38.132 211.625 Td /F1 9.8 Tf  [(Stein JP, Lieskovsky G, Cote R, Groshen S, Feng AC, et al. \(2001\) Radical cystectomy in the treatment of invasive bladder )] TJ ET
BT 26.250 199.720 Td /F1 9.8 Tf  [(cancer: long-term results in 1,054 patients. J Clin Oncol 19: 666-675.)] TJ ET
BT 26.250 180.315 Td /F1 9.8 Tf  [(4.)] TJ ET
BT 38.132 180.315 Td /F1 9.8 Tf  [(Grossman HB, Natale RB, Tangen CM, Speights VO, Vogelzang NJ, et al. \(2003\) Neoadjuvant chemotherapy plus )] TJ ET
BT 26.250 168.411 Td /F1 9.8 Tf  [(cystectomy compared with cystectomy alone for locally advanced bladder cancer. N Engl J Med 349: 859-866.)] TJ ET
BT 26.250 149.006 Td /F1 9.8 Tf  [(5.)] TJ ET
BT 38.132 149.006 Td /F1 9.8 Tf  [(Hall RR \(2002\) Updated results of a randomized trial of neoadjuvant cisplatin \(C\) methotrexate \(M\) and vinblastine \(V\) )] TJ ET
BT 26.250 137.101 Td /F1 9.8 Tf  [(chemotherapy for muscle-invasive bladder cancer. Proc Am Soc Clin Oncol 21: 178a \(ab 710\).)] TJ ET
BT 26.250 117.696 Td /F1 9.8 Tf  [(6.)] TJ ET
BT 38.132 117.696 Td /F1 9.8 Tf  [(Advanced Bladder Cancer Meta-analysis Collaboration \(2005\). Neoadjuvant chemotherapy in invasive bladder cancer: )] TJ ET
BT 26.250 105.792 Td /F1 9.8 Tf  [(update of a systematic review and meta-analysis of individual patient data advanced bladder cancer \(ABC\) meta-analysis )] TJ ET
BT 26.250 93.887 Td /F1 9.8 Tf  [(collaboration. Eur Urol 48: 202-205; discussion 205-206.)] TJ ET
BT 26.250 74.482 Td /F1 9.8 Tf  [(7.)] TJ ET
BT 38.132 74.482 Td /F1 9.8 Tf  [(Advanced Bladder Cancer Meta-analysis Collaboration \(2005\). Neoadjuvant chemotherapy for invasive bladder cancer. )] TJ ET
BT 26.250 62.577 Td /F1 9.8 Tf  [(Cochrane Database Syst Rev: CD005246.)] TJ ET
Q
q
15.000 52.696 577.500 724.304 re W n
0.271 0.267 0.267 rg
BT 45.750 767.476 Td /F1 9.8 Tf  [(time of cystectomy )] TJ ET
0.267 0.267 0.267 rg
BT 129.190 767.476 Td /F1 9.8 Tf  [([3])] TJ ET
0.271 0.267 0.267 rg
BT 140.032 767.476 Td /F1 9.8 Tf  [(. Importantly, if patients with higher stage disease were to be selected for testing, these )] TJ ET
BT 45.750 755.571 Td /F1 9.8 Tf  [(characteristics would change. For example, if only T3 patients were selected, the prevalence of occult nodal disease in )] TJ ET
BT 45.750 743.667 Td /F1 9.8 Tf  [(these patients would be 39% )] TJ ET
0.267 0.267 0.267 rg
BT 173.114 743.667 Td /F1 9.8 Tf  [([3])] TJ ET
0.271 0.267 0.267 rg
BT 183.956 743.667 Td /F1 9.8 Tf  [(. Hence the PPV and NPV in this scenario would be 0.48 and 0.66, respectively.)] TJ ET
BT 26.250 720.512 Td /F6 9.8 Tf  [(Clinical Utility)] TJ ET
BT 90.727 720.512 Td /F4 9.8 Tf  [( : )] TJ ET
BT 99.394 720.512 Td /F1 9.8 Tf  [( Net benefit of test in improving health outcomes.)] TJ ET
0.271 0.267 0.267 RG
40.337 704.075 m 
40.337 704.521 40.154 704.965 39.838 705.281 c
39.522 705.597 39.078 705.781 38.631 705.781 c
38.185 705.781 37.741 705.597 37.425 705.281 c
37.109 704.965 36.925 704.521 36.925 704.075 c
36.925 703.628 37.109 703.184 37.425 702.868 c
37.741 702.552 38.185 702.369 38.631 702.369 c
39.078 702.369 39.522 702.552 39.838 702.868 c
40.154 703.184 40.337 703.628 40.337 704.075 c f
BT 45.750 701.107 Td /F1 9.8 Tf  [(The gene expression model was validated in a prospectively collected cohort of patients enrolled in a phase III clinical trial )] TJ ET
0.267 0.267 0.267 rg
BT 45.750 689.202 Td /F1 9.8 Tf  [([20])] TJ ET
0.271 0.267 0.267 rg
BT 62.013 689.202 Td /F1 9.8 Tf  [(, indicating that the gene model can accurately identify high and low risk patients in clinically relevant patient )] TJ ET
BT 45.750 677.298 Td /F1 9.8 Tf  [(populations )] TJ ET
0.267 0.267 0.267 rg
BT 98.322 677.298 Td /F1 9.8 Tf  [([17])] TJ ET
0.271 0.267 0.267 rg
BT 114.585 677.298 Td /F1 9.8 Tf  [(. However, prospective studies are needed to fully define the clinical utility of the 20 gene node signature )] TJ ET
BT 45.750 665.393 Td /F1 9.8 Tf  [(and to assess whether neoadjuvant chemotherapy confers a larger survival benefit in the high risk patients identified by this )] TJ ET
BT 45.750 653.488 Td /F1 9.8 Tf  [(test.)] TJ ET
BT 26.250 630.333 Td /F4 9.8 Tf  [(Limitations)] TJ ET
BT 26.250 610.929 Td /F1 9.8 Tf  [(There is currently only a single peer-reviewed publication describing the development and validation of the genomic test. The )] TJ ET
BT 26.250 599.024 Td /F1 9.8 Tf  [(testing is not currently available in a clinical laboratory setting.)] TJ ET
BT 26.250 579.619 Td /F4 9.8 Tf  [(Conclusions)] TJ ET
BT 26.250 560.214 Td /F1 9.8 Tf  [(The 20 gene model described in this summary is the first published model for predicting nodal involvement in bladder cancer )] TJ ET
BT 26.250 548.310 Td /F1 9.8 Tf  [(patients and by providing this molecular intelligence, has the potential to strategically increase the use of neoadjuvant therapy )] TJ ET
BT 26.250 536.405 Td /F1 9.8 Tf  [(and increase bladder cancer survival rates while limiting unnecessary aggressive treatment. Importantly, the model was )] TJ ET
BT 26.250 524.500 Td /F1 9.8 Tf  [(developed with clinical applicability in mind. Specifically, the 20 genes \(21 probes\) used in the model are reliably expressed in )] TJ ET
BT 26.250 512.595 Td /F1 9.8 Tf  [(TUR specimens and can be reliably detected with both FF and FFPE preservation methods, the clinical conditions under which )] TJ ET
BT 26.250 500.691 Td /F1 9.8 Tf  [(the model will be employed and allowing for retrospective analysis of archival tissue after the patients has undergone TUR in )] TJ ET
BT 26.250 488.786 Td /F1 9.8 Tf  [(the course of routine clinical care and muscle invasive disease discovered. Although the model has been validated in )] TJ ET
BT 26.250 476.881 Td /F1 9.8 Tf  [(prospectively collected samples from an independent clinical trial, further refinement is needed in the clinical laboratory setting )] TJ ET
BT 26.250 464.976 Td /F1 9.8 Tf  [(to bring this test to routine clinical use. Nevertheless, the development of the model is an important milestone on the path to the )] TJ ET
BT 26.250 453.072 Td /F1 9.8 Tf  [(personalized treatment of bladder cancer.)] TJ ET
BT 26.250 433.667 Td /F4 9.8 Tf  [(Links)] TJ ET
BT 26.250 414.262 Td /F1 9.8 Tf  [(None identified)] TJ ET
BT 26.250 394.857 Td /F1 9.8 Tf  [(Last updated: August 4, 2011)] TJ ET
BT 26.250 358.255 Td /F4 12.0 Tf  [(Competing interests)] TJ ET
BT 26.250 338.301 Td /F1 9.8 Tf  [(GD and DT participated in the development and validation of the gene model and are coauthors on the publication describing its )] TJ ET
BT 26.250 326.396 Td /F1 9.8 Tf  [(development and validation )] TJ ET
0.267 0.267 0.267 rg
BT 147.647 326.396 Td /F1 9.8 Tf  [([17])] TJ ET
0.271 0.267 0.267 rg
BT 163.910 326.396 Td /F1 9.8 Tf  [(. IP rights on this test have been filed at the University of Colorado.)] TJ ET
BT 26.250 289.793 Td /F4 12.0 Tf  [(References)] TJ ET
BT 26.250 262.339 Td /F1 9.8 Tf  [(1.)] TJ ET
BT 38.132 262.339 Td /F1 9.8 Tf  [(Jacobs BL, Lee CT, Montie JE \(2010\) Bladder Cancer in 2010 How Far Have We Come? Ca-a Cancer Journal for Clinicians )] TJ ET
BT 26.250 250.434 Td /F1 9.8 Tf  [(60: 244-272.)] TJ ET
BT 26.250 231.030 Td /F1 9.8 Tf  [(2.)] TJ ET
BT 38.132 231.030 Td /F1 9.8 Tf  [(Jemal A, Siegel R, Xu J, Ward E \(2010\) Cancer statistics, 2010. CA Cancer J Clin 60: 277-300.)] TJ ET
BT 26.250 211.625 Td /F1 9.8 Tf  [(3.)] TJ ET
BT 38.132 211.625 Td /F1 9.8 Tf  [(Stein JP, Lieskovsky G, Cote R, Groshen S, Feng AC, et al. \(2001\) Radical cystectomy in the treatment of invasive bladder )] TJ ET
BT 26.250 199.720 Td /F1 9.8 Tf  [(cancer: long-term results in 1,054 patients. J Clin Oncol 19: 666-675.)] TJ ET
BT 26.250 180.315 Td /F1 9.8 Tf  [(4.)] TJ ET
BT 38.132 180.315 Td /F1 9.8 Tf  [(Grossman HB, Natale RB, Tangen CM, Speights VO, Vogelzang NJ, et al. \(2003\) Neoadjuvant chemotherapy plus )] TJ ET
BT 26.250 168.411 Td /F1 9.8 Tf  [(cystectomy compared with cystectomy alone for locally advanced bladder cancer. N Engl J Med 349: 859-866.)] TJ ET
BT 26.250 149.006 Td /F1 9.8 Tf  [(5.)] TJ ET
BT 38.132 149.006 Td /F1 9.8 Tf  [(Hall RR \(2002\) Updated results of a randomized trial of neoadjuvant cisplatin \(C\) methotrexate \(M\) and vinblastine \(V\) )] TJ ET
BT 26.250 137.101 Td /F1 9.8 Tf  [(chemotherapy for muscle-invasive bladder cancer. Proc Am Soc Clin Oncol 21: 178a \(ab 710\).)] TJ ET
BT 26.250 117.696 Td /F1 9.8 Tf  [(6.)] TJ ET
BT 38.132 117.696 Td /F1 9.8 Tf  [(Advanced Bladder Cancer Meta-analysis Collaboration \(2005\). Neoadjuvant chemotherapy in invasive bladder cancer: )] TJ ET
BT 26.250 105.792 Td /F1 9.8 Tf  [(update of a systematic review and meta-analysis of individual patient data advanced bladder cancer \(ABC\) meta-analysis )] TJ ET
BT 26.250 93.887 Td /F1 9.8 Tf  [(collaboration. Eur Urol 48: 202-205; discussion 205-206.)] TJ ET
BT 26.250 74.482 Td /F1 9.8 Tf  [(7.)] TJ ET
BT 38.132 74.482 Td /F1 9.8 Tf  [(Advanced Bladder Cancer Meta-analysis Collaboration \(2005\). Neoadjuvant chemotherapy for invasive bladder cancer. )] TJ ET
BT 26.250 62.577 Td /F1 9.8 Tf  [(Cochrane Database Syst Rev: CD005246.)] TJ ET
Q
q
15.000 52.696 577.500 724.304 re W n
0.271 0.267 0.267 rg
BT 45.750 767.476 Td /F1 9.8 Tf  [(time of cystectomy )] TJ ET
0.267 0.267 0.267 rg
BT 129.190 767.476 Td /F1 9.8 Tf  [([3])] TJ ET
0.271 0.267 0.267 rg
BT 140.032 767.476 Td /F1 9.8 Tf  [(. Importantly, if patients with higher stage disease were to be selected for testing, these )] TJ ET
BT 45.750 755.571 Td /F1 9.8 Tf  [(characteristics would change. For example, if only T3 patients were selected, the prevalence of occult nodal disease in )] TJ ET
BT 45.750 743.667 Td /F1 9.8 Tf  [(these patients would be 39% )] TJ ET
0.267 0.267 0.267 rg
BT 173.114 743.667 Td /F1 9.8 Tf  [([3])] TJ ET
0.271 0.267 0.267 rg
BT 183.956 743.667 Td /F1 9.8 Tf  [(. Hence the PPV and NPV in this scenario would be 0.48 and 0.66, respectively.)] TJ ET
BT 26.250 720.512 Td /F6 9.8 Tf  [(Clinical Utility)] TJ ET
BT 90.727 720.512 Td /F4 9.8 Tf  [( : )] TJ ET
BT 99.394 720.512 Td /F1 9.8 Tf  [( Net benefit of test in improving health outcomes.)] TJ ET
0.271 0.267 0.267 RG
40.337 704.075 m 
40.337 704.521 40.154 704.965 39.838 705.281 c
39.522 705.597 39.078 705.781 38.631 705.781 c
38.185 705.781 37.741 705.597 37.425 705.281 c
37.109 704.965 36.925 704.521 36.925 704.075 c
36.925 703.628 37.109 703.184 37.425 702.868 c
37.741 702.552 38.185 702.369 38.631 702.369 c
39.078 702.369 39.522 702.552 39.838 702.868 c
40.154 703.184 40.337 703.628 40.337 704.075 c f
BT 45.750 701.107 Td /F1 9.8 Tf  [(The gene expression model was validated in a prospectively collected cohort of patients enrolled in a phase III clinical trial )] TJ ET
0.267 0.267 0.267 rg
BT 45.750 689.202 Td /F1 9.8 Tf  [([20])] TJ ET
0.271 0.267 0.267 rg
BT 62.013 689.202 Td /F1 9.8 Tf  [(, indicating that the gene model can accurately identify high and low risk patients in clinically relevant patient )] TJ ET
BT 45.750 677.298 Td /F1 9.8 Tf  [(populations )] TJ ET
0.267 0.267 0.267 rg
BT 98.322 677.298 Td /F1 9.8 Tf  [([17])] TJ ET
0.271 0.267 0.267 rg
BT 114.585 677.298 Td /F1 9.8 Tf  [(. However, prospective studies are needed to fully define the clinical utility of the 20 gene node signature )] TJ ET
BT 45.750 665.393 Td /F1 9.8 Tf  [(and to assess whether neoadjuvant chemotherapy confers a larger survival benefit in the high risk patients identified by this )] TJ ET
BT 45.750 653.488 Td /F1 9.8 Tf  [(test.)] TJ ET
BT 26.250 630.333 Td /F4 9.8 Tf  [(Limitations)] TJ ET
BT 26.250 610.929 Td /F1 9.8 Tf  [(There is currently only a single peer-reviewed publication describing the development and validation of the genomic test. The )] TJ ET
BT 26.250 599.024 Td /F1 9.8 Tf  [(testing is not currently available in a clinical laboratory setting.)] TJ ET
BT 26.250 579.619 Td /F4 9.8 Tf  [(Conclusions)] TJ ET
BT 26.250 560.214 Td /F1 9.8 Tf  [(The 20 gene model described in this summary is the first published model for predicting nodal involvement in bladder cancer )] TJ ET
BT 26.250 548.310 Td /F1 9.8 Tf  [(patients and by providing this molecular intelligence, has the potential to strategically increase the use of neoadjuvant therapy )] TJ ET
BT 26.250 536.405 Td /F1 9.8 Tf  [(and increase bladder cancer survival rates while limiting unnecessary aggressive treatment. Importantly, the model was )] TJ ET
BT 26.250 524.500 Td /F1 9.8 Tf  [(developed with clinical applicability in mind. Specifically, the 20 genes \(21 probes\) used in the model are reliably expressed in )] TJ ET
BT 26.250 512.595 Td /F1 9.8 Tf  [(TUR specimens and can be reliably detected with both FF and FFPE preservation methods, the clinical conditions under which )] TJ ET
BT 26.250 500.691 Td /F1 9.8 Tf  [(the model will be employed and allowing for retrospective analysis of archival tissue after the patients has undergone TUR in )] TJ ET
BT 26.250 488.786 Td /F1 9.8 Tf  [(the course of routine clinical care and muscle invasive disease discovered. Although the model has been validated in )] TJ ET
BT 26.250 476.881 Td /F1 9.8 Tf  [(prospectively collected samples from an independent clinical trial, further refinement is needed in the clinical laboratory setting )] TJ ET
BT 26.250 464.976 Td /F1 9.8 Tf  [(to bring this test to routine clinical use. Nevertheless, the development of the model is an important milestone on the path to the )] TJ ET
BT 26.250 453.072 Td /F1 9.8 Tf  [(personalized treatment of bladder cancer.)] TJ ET
BT 26.250 433.667 Td /F4 9.8 Tf  [(Links)] TJ ET
BT 26.250 414.262 Td /F1 9.8 Tf  [(None identified)] TJ ET
BT 26.250 394.857 Td /F1 9.8 Tf  [(Last updated: August 4, 2011)] TJ ET
BT 26.250 358.255 Td /F4 12.0 Tf  [(Competing interests)] TJ ET
BT 26.250 338.301 Td /F1 9.8 Tf  [(GD and DT participated in the development and validation of the gene model and are coauthors on the publication describing its )] TJ ET
BT 26.250 326.396 Td /F1 9.8 Tf  [(development and validation )] TJ ET
0.267 0.267 0.267 rg
BT 147.647 326.396 Td /F1 9.8 Tf  [([17])] TJ ET
0.271 0.267 0.267 rg
BT 163.910 326.396 Td /F1 9.8 Tf  [(. IP rights on this test have been filed at the University of Colorado.)] TJ ET
BT 26.250 289.793 Td /F4 12.0 Tf  [(References)] TJ ET
BT 26.250 262.339 Td /F1 9.8 Tf  [(1.)] TJ ET
BT 38.132 262.339 Td /F1 9.8 Tf  [(Jacobs BL, Lee CT, Montie JE \(2010\) Bladder Cancer in 2010 How Far Have We Come? Ca-a Cancer Journal for Clinicians )] TJ ET
BT 26.250 250.434 Td /F1 9.8 Tf  [(60: 244-272.)] TJ ET
BT 26.250 231.030 Td /F1 9.8 Tf  [(2.)] TJ ET
BT 38.132 231.030 Td /F1 9.8 Tf  [(Jemal A, Siegel R, Xu J, Ward E \(2010\) Cancer statistics, 2010. CA Cancer J Clin 60: 277-300.)] TJ ET
BT 26.250 211.625 Td /F1 9.8 Tf  [(3.)] TJ ET
BT 38.132 211.625 Td /F1 9.8 Tf  [(Stein JP, Lieskovsky G, Cote R, Groshen S, Feng AC, et al. \(2001\) Radical cystectomy in the treatment of invasive bladder )] TJ ET
BT 26.250 199.720 Td /F1 9.8 Tf  [(cancer: long-term results in 1,054 patients. J Clin Oncol 19: 666-675.)] TJ ET
BT 26.250 180.315 Td /F1 9.8 Tf  [(4.)] TJ ET
BT 38.132 180.315 Td /F1 9.8 Tf  [(Grossman HB, Natale RB, Tangen CM, Speights VO, Vogelzang NJ, et al. \(2003\) Neoadjuvant chemotherapy plus )] TJ ET
BT 26.250 168.411 Td /F1 9.8 Tf  [(cystectomy compared with cystectomy alone for locally advanced bladder cancer. N Engl J Med 349: 859-866.)] TJ ET
BT 26.250 149.006 Td /F1 9.8 Tf  [(5.)] TJ ET
BT 38.132 149.006 Td /F1 9.8 Tf  [(Hall RR \(2002\) Updated results of a randomized trial of neoadjuvant cisplatin \(C\) methotrexate \(M\) and vinblastine \(V\) )] TJ ET
BT 26.250 137.101 Td /F1 9.8 Tf  [(chemotherapy for muscle-invasive bladder cancer. Proc Am Soc Clin Oncol 21: 178a \(ab 710\).)] TJ ET
BT 26.250 117.696 Td /F1 9.8 Tf  [(6.)] TJ ET
BT 38.132 117.696 Td /F1 9.8 Tf  [(Advanced Bladder Cancer Meta-analysis Collaboration \(2005\). Neoadjuvant chemotherapy in invasive bladder cancer: )] TJ ET
BT 26.250 105.792 Td /F1 9.8 Tf  [(update of a systematic review and meta-analysis of individual patient data advanced bladder cancer \(ABC\) meta-analysis )] TJ ET
BT 26.250 93.887 Td /F1 9.8 Tf  [(collaboration. Eur Urol 48: 202-205; discussion 205-206.)] TJ ET
BT 26.250 74.482 Td /F1 9.8 Tf  [(7.)] TJ ET
BT 38.132 74.482 Td /F1 9.8 Tf  [(Advanced Bladder Cancer Meta-analysis Collaboration \(2005\). Neoadjuvant chemotherapy for invasive bladder cancer. )] TJ ET
BT 26.250 62.577 Td /F1 9.8 Tf  [(Cochrane Database Syst Rev: CD005246.)] TJ ET
Q
q
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BT 291.710 19.825 Td /F1 11.0 Tf  [(4)] TJ ET
BT 25.000 19.825 Td /F1 11.0 Tf  [(PLOS Currents Evidence on Genomic Tests)] TJ ET

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BT 26.250 759.976 Td /F1 9.8 Tf  [(8.)] TJ ET
BT 38.132 759.976 Td /F1 9.8 Tf  [(Stenzl A, Cowan NC, De Santis M, Kuczyk MA, Merseburger AS, et al. \(2011\) Treatment of Muscle-invasive and Metastatic )] TJ ET
BT 26.250 748.071 Td /F1 9.8 Tf  [(Bladder Cancer: Update of the EAU Guidelines. Eur Urol.)] TJ ET
BT 26.250 728.667 Td /F1 9.8 Tf  [(9.)] TJ ET
BT 38.132 728.667 Td /F1 9.8 Tf  [(David KA, Milowsky MI, Ritchey J, Carroll PR, Nanus DM \(2007\) Low incidence of perioperative chemotherapy for stage III )] TJ ET
BT 26.250 716.762 Td /F1 9.8 Tf  [(bladder cancer 1998 to 2003: A report from the National Cancer Data Base. Journal of Urology 178: 451-454.)] TJ ET
BT 26.250 697.357 Td /F1 9.8 Tf  [(10.)] TJ ET
BT 43.553 697.357 Td /F1 9.8 Tf  [(Stenzl A, Cowan NC, De Santis M, Jakse G, Kuczyk MA, et al. \(2009\) The updated EAU guidelines on muscle-invasive and )] TJ ET
BT 26.250 685.452 Td /F1 9.8 Tf  [(metastatic bladder cancer. Eur Urol 55: 815-825.)] TJ ET
BT 26.250 666.048 Td /F1 9.8 Tf  [(11.)] TJ ET
BT 43.553 666.048 Td /F1 9.8 Tf  [(Cronin M, Sangli C, Liu ML, Pho M, Dutta D, et al. \(2007\) Analytical validation of the oncotype DX genomic diagnostic test )] TJ ET
BT 26.250 654.143 Td /F1 9.8 Tf  [(for recurrence prognosis and therapeutic response prediction in node-negative, estrogen receptor-positive breast cancer. )] TJ ET
BT 26.250 642.238 Td /F1 9.8 Tf  [(Clinical Chemistry 53: 1084-1091.)] TJ ET
BT 26.250 622.833 Td /F1 9.8 Tf  [(12.)] TJ ET
BT 43.553 622.833 Td /F1 9.8 Tf  [(Rosenfeld N, Aharonov R, Meiri E, Rosenwald S, Spector Y, et al. \(2008\) MicroRNAs accurately identify cancer tissue )] TJ ET
BT 26.250 610.929 Td /F1 9.8 Tf  [(origin. Nature Biotechnology 26: 462-469.)] TJ ET
BT 26.250 591.524 Td /F1 9.8 Tf  [(13.)] TJ ET
BT 43.553 591.524 Td /F1 9.8 Tf  [(Ma XJ, Patel R, Wang XQ, Salunga R, Murage J, et al. \(2006\) Molecular classification of human cancers using a 92-gene )] TJ ET
BT 26.250 579.619 Td /F1 9.8 Tf  [(real-time quantitative polymerase chain reaction assay. Archives of Pathology & Laboratory Medicine 130: 465-473.)] TJ ET
BT 26.250 560.214 Td /F1 9.8 Tf  [(14.)] TJ ET
BT 43.553 560.214 Td /F1 9.8 Tf  [(Buyse M, Loi S, van't Veer L, Viale G, Delorenzi M, et al. \(2006\) Validation and clinical utility of a 70-gene prognostic )] TJ ET
BT 26.250 548.310 Td /F1 9.8 Tf  [(signature for women with node-negative breast cancer. Journal of the National Cancer Institute 98: 1183-1192.)] TJ ET
BT 26.250 528.905 Td /F1 9.8 Tf  [(15.)] TJ ET
BT 43.553 528.905 Td /F1 9.8 Tf  [(Pillai R, Deeter R, Rigl CT, Nystrom JS, Miller MH, et al. \(2011\) Validation and Reproducibility of a Microarray-Based Gene )] TJ ET
BT 26.250 517.000 Td /F1 9.8 Tf  [(Expression Test for Tumor Identification in Formalin-Fixed, Paraffin-Embedded Specimens. Journal of Molecular Diagnostics )] TJ ET
BT 26.250 505.095 Td /F1 9.8 Tf  [(13: 48-56.)] TJ ET
BT 26.250 485.691 Td /F1 9.8 Tf  [(16.)] TJ ET
BT 43.553 485.691 Td /F1 9.8 Tf  [(National Comprehensvie Cancer Network. Bladder cancer including upper tract tumors and urothelial carcinoma of the )] TJ ET
BT 26.250 473.786 Td /F1 9.8 Tf  [(prostate. Accessed April 25. https://www.nccn.org/professionals/physician_gls/f_guidelines.asp [subscription required])] TJ ET
BT 26.250 454.381 Td /F1 9.8 Tf  [(17.)] TJ ET
BT 43.553 454.381 Td /F1 9.8 Tf  [(Smith SC, Baras AS, Dancik G, Ru Y, Ding KF, et al. \(2011\) A 20-gene model for molecular nodal staging of bladder )] TJ ET
BT 26.250 442.476 Td /F1 9.8 Tf  [(cancer: development and prospective assessment. Lancet Oncol 12: 137-143.)] TJ ET
BT 26.250 423.072 Td /F1 9.8 Tf  [(18.)] TJ ET
BT 43.553 423.072 Td /F1 9.8 Tf  [(Shi LM, Reid LH, Jones WD, Shippy R, Warrington JA, et al. \(2006\) The MicroArray Quality Control \(MAQC\) project shows )] TJ ET
BT 26.250 411.167 Td /F1 9.8 Tf  [(inter- and intraplatform reproducibility of gene expression measurements. Nature Biotechnology 24: 1151-1161.)] TJ ET
BT 26.250 391.762 Td /F1 9.8 Tf  [(19.)] TJ ET
BT 43.553 391.762 Td /F1 9.8 Tf  [(Sanchez-Carbayo M, Socci ND, Lozano J, Saint F, Cordon-Cardo C \(2006\) Defining molecular profiles of poor outcome in )] TJ ET
BT 26.250 379.857 Td /F1 9.8 Tf  [(patients with invasive bladder cancer using oligonucleotide microarrays. J Clin Oncol 24: 778-789.)] TJ ET
BT 26.250 360.453 Td /F1 9.8 Tf  [(20.)] TJ ET
BT 43.553 360.453 Td /F1 9.8 Tf  [(Lehmann J, Retz M, Wiemers C, Beck J, Thuroff J, et al. \(2005\) Adjuvant cisplatin plus methotrexate versus methotrexate, )] TJ ET
BT 26.250 348.548 Td /F1 9.8 Tf  [(vinblastine, epirubicin, and cisplatin in locally advanced bladder cancer: results of a randomized, multicenter, phase III trial )] TJ ET
BT 26.250 336.643 Td /F1 9.8 Tf  [(\(AUO-AB 05/95\). J Clin Oncol 23: 4963-4974.)] TJ ET
BT 26.250 317.238 Td /F1 9.8 Tf  [(21.)] TJ ET
BT 43.553 317.238 Td /F1 9.8 Tf  [(Pillai R, Deeter R, Rigl CT, Nystrom JS, Miller MH, et al. \(2011\) Validation and Reproducibility of a Microarray-Based Gene )] TJ ET
BT 26.250 305.334 Td /F1 9.8 Tf  [(Expression Test for Tumor Identification in Formalin-Fixed, Paraffin-Embedded Specimens. Journal of Molecular Diagnostics )] TJ ET
BT 26.250 293.429 Td /F1 9.8 Tf  [(13: 48-56.)] TJ ET
Q
q
15.000 276.048 577.500 500.952 re W n
0.271 0.267 0.267 rg
BT 26.250 759.976 Td /F1 9.8 Tf  [(8.)] TJ ET
BT 38.132 759.976 Td /F1 9.8 Tf  [(Stenzl A, Cowan NC, De Santis M, Kuczyk MA, Merseburger AS, et al. \(2011\) Treatment of Muscle-invasive and Metastatic )] TJ ET
BT 26.250 748.071 Td /F1 9.8 Tf  [(Bladder Cancer: Update of the EAU Guidelines. Eur Urol.)] TJ ET
BT 26.250 728.667 Td /F1 9.8 Tf  [(9.)] TJ ET
BT 38.132 728.667 Td /F1 9.8 Tf  [(David KA, Milowsky MI, Ritchey J, Carroll PR, Nanus DM \(2007\) Low incidence of perioperative chemotherapy for stage III )] TJ ET
BT 26.250 716.762 Td /F1 9.8 Tf  [(bladder cancer 1998 to 2003: A report from the National Cancer Data Base. Journal of Urology 178: 451-454.)] TJ ET
BT 26.250 697.357 Td /F1 9.8 Tf  [(10.)] TJ ET
BT 43.553 697.357 Td /F1 9.8 Tf  [(Stenzl A, Cowan NC, De Santis M, Jakse G, Kuczyk MA, et al. \(2009\) The updated EAU guidelines on muscle-invasive and )] TJ ET
BT 26.250 685.452 Td /F1 9.8 Tf  [(metastatic bladder cancer. Eur Urol 55: 815-825.)] TJ ET
BT 26.250 666.048 Td /F1 9.8 Tf  [(11.)] TJ ET
BT 43.553 666.048 Td /F1 9.8 Tf  [(Cronin M, Sangli C, Liu ML, Pho M, Dutta D, et al. \(2007\) Analytical validation of the oncotype DX genomic diagnostic test )] TJ ET
BT 26.250 654.143 Td /F1 9.8 Tf  [(for recurrence prognosis and therapeutic response prediction in node-negative, estrogen receptor-positive breast cancer. )] TJ ET
BT 26.250 642.238 Td /F1 9.8 Tf  [(Clinical Chemistry 53: 1084-1091.)] TJ ET
BT 26.250 622.833 Td /F1 9.8 Tf  [(12.)] TJ ET
BT 43.553 622.833 Td /F1 9.8 Tf  [(Rosenfeld N, Aharonov R, Meiri E, Rosenwald S, Spector Y, et al. \(2008\) MicroRNAs accurately identify cancer tissue )] TJ ET
BT 26.250 610.929 Td /F1 9.8 Tf  [(origin. Nature Biotechnology 26: 462-469.)] TJ ET
BT 26.250 591.524 Td /F1 9.8 Tf  [(13.)] TJ ET
BT 43.553 591.524 Td /F1 9.8 Tf  [(Ma XJ, Patel R, Wang XQ, Salunga R, Murage J, et al. \(2006\) Molecular classification of human cancers using a 92-gene )] TJ ET
BT 26.250 579.619 Td /F1 9.8 Tf  [(real-time quantitative polymerase chain reaction assay. Archives of Pathology & Laboratory Medicine 130: 465-473.)] TJ ET
BT 26.250 560.214 Td /F1 9.8 Tf  [(14.)] TJ ET
BT 43.553 560.214 Td /F1 9.8 Tf  [(Buyse M, Loi S, van't Veer L, Viale G, Delorenzi M, et al. \(2006\) Validation and clinical utility of a 70-gene prognostic )] TJ ET
BT 26.250 548.310 Td /F1 9.8 Tf  [(signature for women with node-negative breast cancer. Journal of the National Cancer Institute 98: 1183-1192.)] TJ ET
BT 26.250 528.905 Td /F1 9.8 Tf  [(15.)] TJ ET
BT 43.553 528.905 Td /F1 9.8 Tf  [(Pillai R, Deeter R, Rigl CT, Nystrom JS, Miller MH, et al. \(2011\) Validation and Reproducibility of a Microarray-Based Gene )] TJ ET
BT 26.250 517.000 Td /F1 9.8 Tf  [(Expression Test for Tumor Identification in Formalin-Fixed, Paraffin-Embedded Specimens. Journal of Molecular Diagnostics )] TJ ET
BT 26.250 505.095 Td /F1 9.8 Tf  [(13: 48-56.)] TJ ET
BT 26.250 485.691 Td /F1 9.8 Tf  [(16.)] TJ ET
BT 43.553 485.691 Td /F1 9.8 Tf  [(National Comprehensvie Cancer Network. Bladder cancer including upper tract tumors and urothelial carcinoma of the )] TJ ET
BT 26.250 473.786 Td /F1 9.8 Tf  [(prostate. Accessed April 25. https://www.nccn.org/professionals/physician_gls/f_guidelines.asp [subscription required])] TJ ET
BT 26.250 454.381 Td /F1 9.8 Tf  [(17.)] TJ ET
BT 43.553 454.381 Td /F1 9.8 Tf  [(Smith SC, Baras AS, Dancik G, Ru Y, Ding KF, et al. \(2011\) A 20-gene model for molecular nodal staging of bladder )] TJ ET
BT 26.250 442.476 Td /F1 9.8 Tf  [(cancer: development and prospective assessment. Lancet Oncol 12: 137-143.)] TJ ET
BT 26.250 423.072 Td /F1 9.8 Tf  [(18.)] TJ ET
BT 43.553 423.072 Td /F1 9.8 Tf  [(Shi LM, Reid LH, Jones WD, Shippy R, Warrington JA, et al. \(2006\) The MicroArray Quality Control \(MAQC\) project shows )] TJ ET
BT 26.250 411.167 Td /F1 9.8 Tf  [(inter- and intraplatform reproducibility of gene expression measurements. Nature Biotechnology 24: 1151-1161.)] TJ ET
BT 26.250 391.762 Td /F1 9.8 Tf  [(19.)] TJ ET
BT 43.553 391.762 Td /F1 9.8 Tf  [(Sanchez-Carbayo M, Socci ND, Lozano J, Saint F, Cordon-Cardo C \(2006\) Defining molecular profiles of poor outcome in )] TJ ET
BT 26.250 379.857 Td /F1 9.8 Tf  [(patients with invasive bladder cancer using oligonucleotide microarrays. J Clin Oncol 24: 778-789.)] TJ ET
BT 26.250 360.453 Td /F1 9.8 Tf  [(20.)] TJ ET
BT 43.553 360.453 Td /F1 9.8 Tf  [(Lehmann J, Retz M, Wiemers C, Beck J, Thuroff J, et al. \(2005\) Adjuvant cisplatin plus methotrexate versus methotrexate, )] TJ ET
BT 26.250 348.548 Td /F1 9.8 Tf  [(vinblastine, epirubicin, and cisplatin in locally advanced bladder cancer: results of a randomized, multicenter, phase III trial )] TJ ET
BT 26.250 336.643 Td /F1 9.8 Tf  [(\(AUO-AB 05/95\). J Clin Oncol 23: 4963-4974.)] TJ ET
BT 26.250 317.238 Td /F1 9.8 Tf  [(21.)] TJ ET
BT 43.553 317.238 Td /F1 9.8 Tf  [(Pillai R, Deeter R, Rigl CT, Nystrom JS, Miller MH, et al. \(2011\) Validation and Reproducibility of a Microarray-Based Gene )] TJ ET
BT 26.250 305.334 Td /F1 9.8 Tf  [(Expression Test for Tumor Identification in Formalin-Fixed, Paraffin-Embedded Specimens. Journal of Molecular Diagnostics )] TJ ET
BT 26.250 293.429 Td /F1 9.8 Tf  [(13: 48-56.)] TJ ET
Q
q
15.000 276.048 577.500 500.952 re W n
0.271 0.267 0.267 rg
BT 26.250 759.976 Td /F1 9.8 Tf  [(8.)] TJ ET
BT 38.132 759.976 Td /F1 9.8 Tf  [(Stenzl A, Cowan NC, De Santis M, Kuczyk MA, Merseburger AS, et al. \(2011\) Treatment of Muscle-invasive and Metastatic )] TJ ET
BT 26.250 748.071 Td /F1 9.8 Tf  [(Bladder Cancer: Update of the EAU Guidelines. Eur Urol.)] TJ ET
BT 26.250 728.667 Td /F1 9.8 Tf  [(9.)] TJ ET
BT 38.132 728.667 Td /F1 9.8 Tf  [(David KA, Milowsky MI, Ritchey J, Carroll PR, Nanus DM \(2007\) Low incidence of perioperative chemotherapy for stage III )] TJ ET
BT 26.250 716.762 Td /F1 9.8 Tf  [(bladder cancer 1998 to 2003: A report from the National Cancer Data Base. Journal of Urology 178: 451-454.)] TJ ET
BT 26.250 697.357 Td /F1 9.8 Tf  [(10.)] TJ ET
BT 43.553 697.357 Td /F1 9.8 Tf  [(Stenzl A, Cowan NC, De Santis M, Jakse G, Kuczyk MA, et al. \(2009\) The updated EAU guidelines on muscle-invasive and )] TJ ET
BT 26.250 685.452 Td /F1 9.8 Tf  [(metastatic bladder cancer. Eur Urol 55: 815-825.)] TJ ET
BT 26.250 666.048 Td /F1 9.8 Tf  [(11.)] TJ ET
BT 43.553 666.048 Td /F1 9.8 Tf  [(Cronin M, Sangli C, Liu ML, Pho M, Dutta D, et al. \(2007\) Analytical validation of the oncotype DX genomic diagnostic test )] TJ ET
BT 26.250 654.143 Td /F1 9.8 Tf  [(for recurrence prognosis and therapeutic response prediction in node-negative, estrogen receptor-positive breast cancer. )] TJ ET
BT 26.250 642.238 Td /F1 9.8 Tf  [(Clinical Chemistry 53: 1084-1091.)] TJ ET
BT 26.250 622.833 Td /F1 9.8 Tf  [(12.)] TJ ET
BT 43.553 622.833 Td /F1 9.8 Tf  [(Rosenfeld N, Aharonov R, Meiri E, Rosenwald S, Spector Y, et al. \(2008\) MicroRNAs accurately identify cancer tissue )] TJ ET
BT 26.250 610.929 Td /F1 9.8 Tf  [(origin. Nature Biotechnology 26: 462-469.)] TJ ET
BT 26.250 591.524 Td /F1 9.8 Tf  [(13.)] TJ ET
BT 43.553 591.524 Td /F1 9.8 Tf  [(Ma XJ, Patel R, Wang XQ, Salunga R, Murage J, et al. \(2006\) Molecular classification of human cancers using a 92-gene )] TJ ET
BT 26.250 579.619 Td /F1 9.8 Tf  [(real-time quantitative polymerase chain reaction assay. Archives of Pathology & Laboratory Medicine 130: 465-473.)] TJ ET
BT 26.250 560.214 Td /F1 9.8 Tf  [(14.)] TJ ET
BT 43.553 560.214 Td /F1 9.8 Tf  [(Buyse M, Loi S, van't Veer L, Viale G, Delorenzi M, et al. \(2006\) Validation and clinical utility of a 70-gene prognostic )] TJ ET
BT 26.250 548.310 Td /F1 9.8 Tf  [(signature for women with node-negative breast cancer. Journal of the National Cancer Institute 98: 1183-1192.)] TJ ET
BT 26.250 528.905 Td /F1 9.8 Tf  [(15.)] TJ ET
BT 43.553 528.905 Td /F1 9.8 Tf  [(Pillai R, Deeter R, Rigl CT, Nystrom JS, Miller MH, et al. \(2011\) Validation and Reproducibility of a Microarray-Based Gene )] TJ ET
BT 26.250 517.000 Td /F1 9.8 Tf  [(Expression Test for Tumor Identification in Formalin-Fixed, Paraffin-Embedded Specimens. Journal of Molecular Diagnostics )] TJ ET
BT 26.250 505.095 Td /F1 9.8 Tf  [(13: 48-56.)] TJ ET
BT 26.250 485.691 Td /F1 9.8 Tf  [(16.)] TJ ET
BT 43.553 485.691 Td /F1 9.8 Tf  [(National Comprehensvie Cancer Network. Bladder cancer including upper tract tumors and urothelial carcinoma of the )] TJ ET
BT 26.250 473.786 Td /F1 9.8 Tf  [(prostate. Accessed April 25. https://www.nccn.org/professionals/physician_gls/f_guidelines.asp [subscription required])] TJ ET
BT 26.250 454.381 Td /F1 9.8 Tf  [(17.)] TJ ET
BT 43.553 454.381 Td /F1 9.8 Tf  [(Smith SC, Baras AS, Dancik G, Ru Y, Ding KF, et al. \(2011\) A 20-gene model for molecular nodal staging of bladder )] TJ ET
BT 26.250 442.476 Td /F1 9.8 Tf  [(cancer: development and prospective assessment. Lancet Oncol 12: 137-143.)] TJ ET
BT 26.250 423.072 Td /F1 9.8 Tf  [(18.)] TJ ET
BT 43.553 423.072 Td /F1 9.8 Tf  [(Shi LM, Reid LH, Jones WD, Shippy R, Warrington JA, et al. \(2006\) The MicroArray Quality Control \(MAQC\) project shows )] TJ ET
BT 26.250 411.167 Td /F1 9.8 Tf  [(inter- and intraplatform reproducibility of gene expression measurements. Nature Biotechnology 24: 1151-1161.)] TJ ET
BT 26.250 391.762 Td /F1 9.8 Tf  [(19.)] TJ ET
BT 43.553 391.762 Td /F1 9.8 Tf  [(Sanchez-Carbayo M, Socci ND, Lozano J, Saint F, Cordon-Cardo C \(2006\) Defining molecular profiles of poor outcome in )] TJ ET
BT 26.250 379.857 Td /F1 9.8 Tf  [(patients with invasive bladder cancer using oligonucleotide microarrays. J Clin Oncol 24: 778-789.)] TJ ET
BT 26.250 360.453 Td /F1 9.8 Tf  [(20.)] TJ ET
BT 43.553 360.453 Td /F1 9.8 Tf  [(Lehmann J, Retz M, Wiemers C, Beck J, Thuroff J, et al. \(2005\) Adjuvant cisplatin plus methotrexate versus methotrexate, )] TJ ET
BT 26.250 348.548 Td /F1 9.8 Tf  [(vinblastine, epirubicin, and cisplatin in locally advanced bladder cancer: results of a randomized, multicenter, phase III trial )] TJ ET
BT 26.250 336.643 Td /F1 9.8 Tf  [(\(AUO-AB 05/95\). J Clin Oncol 23: 4963-4974.)] TJ ET
BT 26.250 317.238 Td /F1 9.8 Tf  [(21.)] TJ ET
BT 43.553 317.238 Td /F1 9.8 Tf  [(Pillai R, Deeter R, Rigl CT, Nystrom JS, Miller MH, et al. \(2011\) Validation and Reproducibility of a Microarray-Based Gene )] TJ ET
BT 26.250 305.334 Td /F1 9.8 Tf  [(Expression Test for Tumor Identification in Formalin-Fixed, Paraffin-Embedded Specimens. Journal of Molecular Diagnostics )] TJ ET
BT 26.250 293.429 Td /F1 9.8 Tf  [(13: 48-56.)] TJ ET
Q
q
0.000 0.000 0.000 rg
BT 291.710 19.825 Td /F1 11.0 Tf  [(5)] TJ ET
BT 25.000 19.825 Td /F1 11.0 Tf  [(PLOS Currents Evidence on Genomic Tests)] TJ ET

Q
endstream
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