83fe65ec8aaac0a8ec52d7a478cb4803 pmc_10378094.pdf 8ea0a3f65734781eda40bd49cf61c8e40237956b pmc_10378094.pdf 4197d40f1fa4178ff53de96860a5493e8060c158927c2361f7ce779b44d06661 pmc_10378094.pdf Title: Xpert Bladder Cancer Monitor for the Early Detection of Non-Muscle Invasive Bladder Cancer Recurrences: Could Cystoscopy Be Substituted? Subject: XBM was prospectively assessed in spontaneous urine collected just before flexible cystoscopy and washing cytology carried out within the first 2 years follow-up of 337 patients with NMIBC. Recurrences were pathologically confirmed in 49 patients (14.5%), 22 of them being high-risk (6.5%). The XBM sensitivity for detecting any type of recurrence was 69.4% and 63.6% in the cases of high-risk NMIBC. Negative predictive value (NPV) for XBM was 93% for all recurrences and 96.2% for high-risk recurrences. XBM could have avoided 213 invasive controls but missed the detection of 15 recurrences (30.6%)–8 of them of high-risk (36.4%). XBM false positive elevations were detected in 90 patients (26.7%), whereas 10 patients with the invasive method had a false positive result (3%), p <0.001. However, early detection of recurrences during the first year’s follow-up after an XBM false positive result was observed in 18 patients (20%). On the other hand, 19 recurrences were detected during this period among the rest of the patients (7.7%)—p = 0.003, and odds ratio (OR) 3.0 (95% CI 1.5–6.0). Regarding one-year follow-up recurrences, 10% were high-risk recurrences in the XBM false positive group and 3.2% in the rest of the patients—p = 0.021, and OR 3.3 (95% CI 1.2–8.9). Additionally, 11.3% of the patients without false positive results developed a recurrence, p = 0.897, for any recurrence, being 10% and 5.2%, respectively, and high-risk and low-risk recurrences, p = 0.506. After searching for the best XBM cutoff for detecting the 38 high-risk initial recurrences and the early high-risk recurrences after a one-year follow-up, a linear discriminant analysis (LDA) of 0.13 could have avoided 11.3% of cystoscopies and bladder wash cytologies, as this cutoff missed only 1 high-risk recurrence (2.6%). More extensive and well-designed studies will confirm if XBM can improve the surveillance of NMIBC. Keywords: bladder cancer; biomarker; surveillance Author: Fernando Lozano, Carles X. Raventós, Albert Carrion, Carme Dinarés, Javier Hernández, Enrique Trilla and Juan Morote Creator: LaTeX with hyperref Producer: pdfTeX-1.40.21 CreationDate: Wed Jul 19 17:08:17 2023 CEST ModDate: Wed Jul 19 17:10:32 2023 CEST Custom Metadata: no Metadata Stream: no Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 16 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 1012450 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- WHADKM+URWPalladioL-Bold Type 1 Custom yes yes no 10 0 SHRRKQ+URWPalladioL-Roma Type 1 Custom yes yes no 15 0 VCVZPJ+URWPalladioL-Ital Type 1 Custom yes yes no 19 0 ZZTQUO+VnURWPalladioL-Bold Type 1 Custom yes yes no 23 0 LCJEVJ+TimesNewRomanPS-BoldItalicMT Type 1C WinAnsi yes yes no 43 0 AEIEME+CMSY10 Type 1 Builtin yes yes no 68 0 NLVTAT+VnURWPalladioL Type 1 Custom yes yes no 75 0 QLBIEB+URWPalladioL-BoldItal Type 1 Custom yes yes no 79 0 BCDJEE+PalatinoLinotype-Roman CID TrueType Identity-H yes yes yes 93 0 BCDHEE+PalatinoLinotype-Italic CID TrueType Identity-H yes yes yes 101 0 BCDIEE+PalatinoLinotype-Bold CID TrueType Identity-H yes yes yes 109 0 BCDGEE+PalatinoLinotype-Italic TrueType WinAnsi yes yes no 117 0 BCDEEE+PalatinoLinotype-Bold TrueType WinAnsi yes yes no 120 0 BCDFEE+PalatinoLinotype-Roman TrueType WinAnsi yes yes no 123 0 BCDIEE+PalatinoLinotype-Bold CID TrueType Identity-H yes yes yes 137 0 BCDJEE+PalatinoLinotype-Roman CID TrueType Identity-H yes yes yes 145 0 BCDGEE+PalatinoLinotype-Italic TrueType WinAnsi yes yes no 153 0 BCDEEE+PalatinoLinotype-Bold TrueType WinAnsi yes yes no 157 0 BCDFEE+PalatinoLinotype-Roman TrueType WinAnsi yes yes no 160 0 WABLSD+SFRM1000 Type 1 Custom yes yes no 173 0 BOLMEN+SFRM0900 Type 1 Custom yes yes no 191 0 Jhove (Rel. 1.28.0, 2023-05-18) Date: 2025-02-17 17:02:13 CET RepresentationInformation: pmc_10378094.pdf ReportingModule: PDF-hul, Rel. 1.12.4 (2023-03-16) LastModified: 2025-02-04 02:26:49 CET Size: 1012450 Format: PDF Version: 1.7 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 405 FreeObjects: 1 IncrementalUpdates: 0 DocumentCatalog: PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: Introduction Destination: section.1 Item: Title: Materials and Methods Destination: section.2 Children: Item: Title: Design, Setting, and Participants Destination: subsection.2.1 Item: Title: Diagnostic Procedure Destination: subsection.2.2 Item: Title: Adjuvant Preventive Treatment for Recurrences Destination: subsection.2.3 Item: Title: Follow-Up for Detection of Recurrences Destination: subsection.2.4 Item: Title: Recurrence Suspicion and Diagnosis Destination: subsection.2.5 Item: Title: XBM Assessment Destination: subsection.2.6 Item: Title: XBM “False Positives” Follow-Up Destination: subsection.2.7 Item: Title: Statistical Analyses Destination: subsection.2.8 Item: Title: Results Destination: section.3 Children: Item: Title: Characteristics of Analyzed Population Destination: subsection.3.1 Item: Title: Performance of XBM Destination: subsection.3.2 Item: Title: Prediction of Risk of Recurrence Destination: subsection.3.3 Item: Title: Follow Up on False Positives of XBM Destination: subsection.3.4 Item: Title: Searching for a Clinically Useful XBM Cutoff Destination: subsection.3.5 Item: Title: Discussion Destination: section.4 Item: Title: Conclusions Destination: section.5 Item: Title: References Destination: section.6 Info: Title: Xpert Bladder Cancer Monitor for the Early Detection of Non-Muscle Invasive Bladder Cancer Recurrences: Could Cystoscopy Be Substituted? Author: Fernando Lozano, Carles X. Raventós, Albert Carrion, Carme Dinarés, Javier Hernández, Enrique Trilla and Juan Morote Subject: XBM was prospectively assessed in spontaneous urine collected just before flexible cystoscopy and washing cytology carried out within the first 2 years follow-up of 337 patients with NMIBC. Recurrences were pathologically confirmed in 49 patients (14.5%), 22 of them being high-risk (6.5%). The XBM sensitivity for detecting any type of recurrence was 69.4% and 63.6% in the cases of high-risk NMIBC. Negative predictive value (NPV) for XBM was 93% for all recurrences and 96.2% for high-risk recurrences. XBM could have avoided 213 invasive controls but missed the detection of 15 recurrences (30.6%) 8 of them of high-risk (36.4%). XBM false positive elevations were detected in 90 patients (26.7%), whereas 10 patients with the invasive method had a false positive result (3%), p <0.001. However, early detection of recurrences during the first year’s follow-up after an XBM false positive result was observed in 18 patients (20%). On the other hand, 19 recurrences were detected during this period among the rest of the patients (7.7%) p = 0.003, and odds ratio (OR) 3.0 (95% CI 1.5 6.0). Regarding one-year follow-up recurrences, 10% were high-risk recurrences in the XBM false positive group and 3.2% in the rest of the patients p = 0.021, and OR 3.3 (95% CI 1.2 8.9). Additionally, 11.3% of the patients without false positive results developed a recurrence, p = 0.897, for any recurrence, being 10% and 5.2%, respectively, and high-risk and low-risk recurrences, p = 0.506. After searching for the best XBM cutoff for detecting the 38 high-risk initial recurrences and the early high-risk recurrences after a one-year follow-up, a linear discriminant analysis (LDA) of 0.13 could have avoided 11.3% of cystoscopies and bladder wash cytologies, as this cutoff missed only 1 high-risk recurrence (2.6%). More extensive and well-designed studies will confirm if XBM can improve the surveillance of NMIBC. Keywords: bladder cancer; biomarker; surveillance Creator: LaTeX with hyperref Producer: pdfTeX-1.40.21 CreationDate: Wed Jul 19 17:08:17 CEST 2023 ModDate: Wed Jul 19 17:10:32 CEST 2023 ID: 0x2b2c9c21c7519ef2dc1af2583f626ea1, 0x2b2c9c21c7519ef2dc1af2583f626ea1 Filters: FilterPipeline: FlateDecode Fonts: Type1: Font: BaseFont: VCVZPJ+URWPalladioL-Ital FontSubset: true FirstChar: 40 LastChar: 148 FontDescriptor: FontName: VCVZPJ+URWPalladioL-Ital Flags: Symbolic FontBBox: -170, -305, 1010, 941 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: AEIEME+CMSY10 FontSubset: true FirstChar: 21 LastChar: 48 FontDescriptor: FontName: AEIEME+CMSY10 Flags: Symbolic FontBBox: -29, -960, 1116, 775 FontFile: true Font: BaseFont: ZZTQUO+VnURWPalladioL-Bold FontSubset: true FirstChar: 161 LastChar: 226 FontDescriptor: FontName: ZZTQUO+VnURWPalladioL-Bold Flags: Symbolic FontBBox: -152, -301, 1000, 935 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: WHADKM+URWPalladioL-Bold FontSubset: true FirstChar: 2 LastChar: 134 FontDescriptor: FontName: WHADKM+URWPalladioL-Bold Flags: Symbolic FontBBox: -152, -301, 1000, 935 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: NLVTAT+VnURWPalladioL FontSubset: true FirstChar: 161 LastChar: 226 FontDescriptor: FontName: NLVTAT+VnURWPalladioL Flags: Symbolic FontBBox: -166, -283, 1021, 943 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: WABLSD+SFRM1000 FontSubset: true FirstChar: 180 LastChar: 180 FontDescriptor: FontName: WABLSD+SFRM1000 Flags: Symbolic FontBBox: -189, -321, 1456, 937 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: SHRRKQ+URWPalladioL-Roma FontSubset: true FirstChar: 2 LastChar: 246 FontDescriptor: FontName: SHRRKQ+URWPalladioL-Roma Flags: Symbolic FontBBox: -166, -283, 1021, 943 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: QLBIEB+URWPalladioL-BoldItal FontSubset: true FirstChar: 110 LastChar: 112 FontDescriptor: FontName: QLBIEB+URWPalladioL-BoldItal Flags: Symbolic FontBBox: -170, -300, 1073, 935 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: BOLMEN+SFRM0900 FontSubset: true FirstChar: 180 LastChar: 180 FontDescriptor: FontName: BOLMEN+SFRM0900 Flags: Symbolic FontBBox: -196, -322, 1502, 937 FontFile: true EncodingDictionary: Differences: true Pages: Page: Sequence: 1 Annotations: Annotation: Subtype: Link Rect: 82, 293, 152, 302 Annotation: Subtype: Link Rect: 34, 282, 113, 290 Annotation: Subtype: Link Rect: 34, 164, 96, 186 Annotation: Subtype: Link Rect: 126, 90, 154, 99 Annotation: Subtype: Link Rect: 34, 78, 147, 87 Annotation: Subtype: Link Rect: 34, 756, 152, 792 Annotation: Subtype: Link Rect: 515, 756, 560, 792 Annotation: Subtype: Link Rect: 127, 642, 138, 655 Annotation: Subtype: Link Rect: 311, 642, 322, 655 Annotation: Subtype: Link Rect: 491, 642, 502, 655 Annotation: Subtype: Link Rect: 114, 17, 265, 28 Annotation: Subtype: Link Rect: 410, 17, 560, 28 Annotation: Subtype: Link Rect: 34, 390, 87, 409 Page: Sequence: 2 Annotations: Annotation: Subtype: Link Rect: 316, 695, 323, 704 ActionDest: 182 Annotation: Subtype: Link Rect: 451, 670, 458, 679 ActionDest: 182 Annotation: Subtype: Link Rect: 458, 670, 465, 679 ActionDest: 182 Annotation: Subtype: Link Rect: 519, 645, 526, 654 ActionDest: 182 Annotation: Subtype: Link Rect: 527, 644, 534, 654 ActionDest: 182 Annotation: Subtype: Link Rect: 337, 607, 344, 616 ActionDest: 182 Annotation: Subtype: Link Rect: 220, 582, 227, 591 ActionDest: 182 Annotation: Subtype: Link Rect: 303, 544, 310, 553 ActionDest: 182 Annotation: Subtype: Link Rect: 487, 532, 494, 541 ActionDest: 182 Annotation: Subtype: Link Rect: 477, 519, 489, 528 ActionDest: 182 Annotation: Subtype: Link Rect: 490, 519, 502, 528 ActionDest: 182 Annotation: Subtype: Link Rect: 264, 494, 276, 503 ActionDest: 182 Annotation: Subtype: Link Rect: 544, 469, 556, 478 ActionDest: 182 Annotation: Subtype: Link Rect: 495, 444, 507, 453 ActionDest: 182 Annotation: Subtype: Link Rect: 338, 419, 350, 428 ActionDest: 182 Annotation: Subtype: Link Rect: 465, 393, 477, 403 ActionDest: 185 Annotation: Subtype: Link Rect: 478, 394, 490, 403 ActionDest: 185 Annotation: Subtype: Link Rect: 347, 381, 359, 390 ActionDest: 182 Annotation: Subtype: Link Rect: 482, 368, 494, 377 ActionDest: 185 Annotation: Subtype: Link Rect: 338, 293, 350, 302 ActionDest: 185 Annotation: Subtype: Link Rect: 447, 243, 459, 252 ActionDest: 185 Annotation: Subtype: Link Rect: 184, 205, 196, 214 ActionDest: 185 Annotation: Subtype: Link Rect: 217, 180, 229, 189 ActionDest: 185 Annotation: Subtype: Link Rect: 229, 180, 241, 189 ActionDest: 185 Annotation: Subtype: Link Rect: 238, 155, 250, 164 ActionDest: 185 Annotation: Subtype: Link Rect: 253, 155, 265, 164 ActionDest: 185 Annotation: Subtype: Link Rect: 226, 92, 238, 101 ActionDest: 185 Page: Sequence: 3 Annotations: Annotation: Subtype: Link Rect: 210, 685, 222, 694 ActionDest: 185 Annotation: Subtype: Link Rect: 316, 647, 328, 657 ActionDest: 185 Annotation: Subtype: Link Rect: 278, 622, 290, 631 ActionDest: 185 Annotation: Subtype: Link Rect: 349, 610, 361, 619 ActionDest: 185 Annotation: Subtype: Link Rect: 376, 597, 388, 606 ActionDest: 185 Annotation: Subtype: Link Rect: 526, 547, 538, 556 ActionDest: 185 Annotation: Subtype: Link Rect: 539, 547, 551, 556 ActionDest: 185 Annotation: Subtype: Link Rect: 187, 445, 199, 455 ActionDest: 185 Annotation: Subtype: Link Rect: 356, 420, 368, 429 ActionDest: 185 Annotation: Subtype: Link Rect: 443, 320, 455, 329 ActionDest: 185 Annotation: Subtype: Link Rect: 541, 282, 553, 291 ActionDest: 185 Annotation: Subtype: Link Rect: 451, 219, 463, 228 ActionDest: 185 Annotation: Subtype: Link Rect: 300, 194, 312, 203 ActionDest: 185 Annotation: Subtype: Link Rect: 302, 179, 308, 191 ActionDest: 72 Annotation: Subtype: Link Rect: 418, 118, 430, 127 ActionDest: 185 Annotation: Subtype: Link Rect: 543, 106, 555, 115 ActionDest: 185 Page: Sequence: 4 Annotations: Annotation: Subtype: Link Rect: 512, 75, 524, 84 ActionDest: 185 Page: Sequence: 5 Annotations: Annotation: Subtype: Link Rect: 488, 619, 500, 629 ActionDest: 188 Annotation: Subtype: Link Rect: 311, 594, 323, 603 ActionDest: 182 Page: Sequence: 6 Annotations: Annotation: Subtype: Link Rect: 247, 628, 254, 640 ActionDest: 72 Annotation: Subtype: Link Rect: 525, 628, 531, 640 ActionDest: 86 Page: Sequence: 7 Annotations: Annotation: Subtype: Link Rect: 362, 720, 369, 732 ActionDest: 127 Annotation: Subtype: Link Rect: 247, 460, 254, 471 ActionDest: 127 Annotation: Subtype: Link Rect: 231, 249, 238, 261 ActionDest: 127 Page: Sequence: 8 Annotations: Annotation: Subtype: Link Rect: 195, 529, 202, 541 ActionDest: 130 Annotation: Subtype: Link Rect: 231, 529, 238, 541 ActionDest: 164 Annotation: Subtype: Link Rect: 479, 112, 486, 124 ActionDest: 164 Page: Sequence: 9 Annotations: Annotation: Subtype: Link Rect: 434, 339, 441, 351 ActionDest: 164 Annotation: Subtype: Link Rect: 454, 74, 465, 83 ActionDest: 188 Annotation: Subtype: Link Rect: 191, 62, 203, 71 ActionDest: 188 Page: Sequence: 10 Annotations: Annotation: Subtype: Link Rect: 231, 698, 242, 707 ActionDest: 188 Annotation: Subtype: Link Rect: 387, 698, 399, 707 ActionDest: 185 Annotation: Subtype: Link Rect: 429, 685, 441, 694 ActionDest: 185 Annotation: Subtype: Link Rect: 514, 685, 526, 694 ActionDest: 188 Annotation: Subtype: Link Rect: 206, 673, 218, 682 ActionDest: 188 Annotation: Subtype: Link Rect: 292, 673, 304, 682 ActionDest: 188 Annotation: Subtype: Link Rect: 415, 673, 422, 682 ActionDest: 182 Annotation: Subtype: Link Rect: 288, 610, 300, 619 ActionDest: 188 Annotation: Subtype: Link Rect: 375, 560, 386, 569 ActionDest: 188 Annotation: Subtype: Link Rect: 391, 547, 403, 556 ActionDest: 188 Annotation: Subtype: Link Rect: 423, 509, 435, 519 ActionDest: 185 Annotation: Subtype: Link Rect: 287, 472, 299, 481 ActionDest: 185 Annotation: Subtype: Link Rect: 468, 459, 480, 468 ActionDest: 188 Annotation: Subtype: Link Rect: 297, 447, 309, 456 ActionDest: 185 Annotation: Subtype: Link Rect: 310, 447, 322, 456 ActionDest: 188 Annotation: Subtype: Link Rect: 325, 447, 337, 456 ActionDest: 188 Annotation: Subtype: Link Rect: 226, 409, 238, 418 ActionDest: 185 Annotation: Subtype: Link Rect: 318, 359, 330, 368 ActionDest: 188 Annotation: Subtype: Link Rect: 525, 334, 537, 343 ActionDest: 188 Annotation: Subtype: Link Rect: 391, 271, 403, 280 ActionDest: 188 Annotation: Subtype: Link Rect: 406, 271, 418, 280 ActionDest: 188 Annotation: Subtype: Link Rect: 468, 108, 480, 117 ActionDest: 188 Page: Sequence: 11 Annotations: Annotation: Subtype: Link Rect: 518, 710, 530, 719 ActionDest: 188 Annotation: Subtype: Link Rect: 306, 660, 318, 669 ActionDest: 188 Annotation: Subtype: Link Rect: 531, 484, 543, 493 ActionDest: 195 Annotation: Subtype: Link Rect: 544, 484, 556, 493 ActionDest: 195 Annotation: Subtype: Link Rect: 190, 459, 202, 468 ActionDest: 195 Annotation: Subtype: Link Rect: 391, 459, 403, 468 ActionDest: 195 Annotation: Subtype: Link Rect: 337, 422, 349, 431 ActionDest: 195 Annotation: Subtype: Link Rect: 208, 283, 220, 293 ActionDest: 185 Annotation: Subtype: Link Rect: 493, 258, 505, 267 ActionDest: 195 Annotation: Subtype: Link Rect: 544, 233, 556, 242 ActionDest: 195 Annotation: Subtype: Link Rect: 344, 221, 356, 230 ActionDest: 195 Annotation: Subtype: Link Rect: 233, 120, 245, 129 ActionDest: 195 Annotation: Subtype: Link Rect: 345, 120, 357, 129 ActionDest: 195 Page: Sequence: 12 Page: Sequence: 13 Annotations: Annotation: Subtype: Link Rect: 520, 485, 557, 496 Annotation: Subtype: Link Rect: 59, 474, 95, 484 Annotation: Subtype: Link Rect: 468, 450, 506, 461 Annotation: Subtype: Link Rect: 512, 450, 548, 461 Annotation: Subtype: Link Rect: 469, 427, 506, 438 Annotation: Subtype: Link Rect: 513, 427, 549, 438 Annotation: Subtype: Link Rect: 300, 404, 337, 415 Annotation: Subtype: Link Rect: 245, 382, 282, 392 Annotation: Subtype: Link Rect: 59, 348, 96, 358 Annotation: Subtype: Link Rect: 109, 313, 146, 323 Annotation: Subtype: Link Rect: 59, 290, 96, 300 Annotation: Subtype: Link Rect: 157, 267, 194, 277 Annotation: Subtype: Link Rect: 229, 232, 267, 243 Annotation: Subtype: Link Rect: 118, 209, 155, 220 Annotation: Subtype: Link Rect: 157, 175, 194, 185 Annotation: Subtype: Link Rect: 95, 140, 133, 151 Annotation: Subtype: Link Rect: 59, 94, 96, 105 Annotation: Subtype: Link Rect: 371, 70, 408, 81 Page: Sequence: 14 Annotations: Annotation: Subtype: Link Rect: 118, 665, 155, 675 Annotation: Subtype: Link Rect: 104, 607, 141, 617 Annotation: Subtype: Link Rect: 171, 584, 208, 594 Annotation: Subtype: Link Rect: 283, 561, 321, 571 Annotation: Subtype: Link Rect: 478, 526, 515, 537 Annotation: Subtype: Link Rect: 521, 526, 557, 537 Annotation: Subtype: Link Rect: 478, 503, 515, 514 Annotation: Subtype: Link Rect: 521, 503, 557, 514 Annotation: Subtype: Link Rect: 86, 469, 123, 479 Annotation: Subtype: Link Rect: 130, 469, 166, 479 Annotation: Subtype: Link Rect: 95, 435, 132, 445 Annotation: Subtype: Link Rect: 480, 411, 518, 422 Annotation: Subtype: Link Rect: 59, 389, 96, 399 Annotation: Subtype: Link Rect: 108, 354, 146, 364 Annotation: Subtype: Link Rect: 435, 342, 473, 353 Annotation: Subtype: Link Rect: 378, 331, 416, 341 Annotation: Subtype: Link Rect: 188, 296, 225, 307 Annotation: Subtype: Link Rect: 475, 273, 513, 284 Annotation: Subtype: Link Rect: 390, 250, 428, 261 Annotation: Subtype: Link Rect: 253, 215, 290, 226 Annotation: Subtype: Link Rect: 259, 181, 296, 192 Annotation: Subtype: Link Rect: 292, 146, 329, 157 Annotation: Subtype: Link Rect: 178, 112, 216, 123 Annotation: Subtype: Link Rect: 378, 77, 415, 88 Page: Sequence: 15 Annotations: Annotation: Subtype: Link Rect: 253, 710, 291, 721 Annotation: Subtype: Link Rect: 463, 676, 501, 687 Annotation: Subtype: Link Rect: 432, 618, 469, 629 Annotation: Subtype: Link Rect: 407, 583, 444, 594 Annotation: Subtype: Link Rect: 450, 583, 486, 594 Annotation: Subtype: Link Rect: 408, 561, 445, 571 Annotation: Subtype: Link Rect: 452, 561, 488, 571 Annotation: Subtype: Link Rect: 59, 515, 96, 525 Annotation: Subtype: Link Rect: 131, 481, 168, 491 Annotation: Subtype: Link Rect: 175, 481, 211, 491 Annotation: Subtype: Link Rect: 501, 457, 539, 468 Annotation: Subtype: Link Rect: 240, 434, 277, 445 Annotation: Subtype: Link Rect: 501, 411, 539, 422 Annotation: Subtype: Link Rect: 312, 376, 350, 387 Annotation: Subtype: Link Rect: 180, 343, 218, 353 Annotation: Subtype: Link Rect: 161, 308, 199, 318 Annotation: Subtype: Link Rect: 254, 261, 292, 272 Annotation: Subtype: Link Rect: 372, 204, 410, 215 Annotation: Subtype: Link Rect: 264, 169, 302, 180 Annotation: Subtype: Link Rect: 196, 136, 233, 146 Annotation: Subtype: Link Rect: 59, 101, 96, 111 Annotation: Subtype: Link Rect: 470, 77, 508, 88 Page: Sequence: 16 Annotations: Annotation: Subtype: Link Rect: 121, 711, 159, 721 Annotation: Subtype: Link Rect: 517, 687, 554, 698 Annotation: Subtype: Link Rect: 368, 653, 405, 664 Annotation: Subtype: Link Rect: 436, 629, 473, 640 Annotation: Subtype: Link Rect: 479, 629, 515, 640 Annotation: Subtype: Link Rect: 283, 596, 320, 606 Annotation: Subtype: Link Rect: 327, 596, 363, 606 Annotation: Subtype: Link Rect: 59, 538, 96, 548 Annotation: Subtype: Link Rect: 102, 538, 138, 548 Annotation: Subtype: Link Rect: 175, 515, 213, 525 Annotation: Subtype: Link Rect: 445, 480, 483, 491 Annotation: Subtype: Link Rect: 226, 446, 263, 456 Annotation: Subtype: Link Rect: 337, 422, 375, 433 Checksum: 10723b92 Type: CRC32 Checksum: 83fe65ec8aaac0a8ec52d7a478cb4803 Type: MD5 Checksum: 8ea0a3f65734781eda40bd49cf61c8e40237956b Type: SHA-1 Checksum: 4197d40f1fa4178ff53de96860a5493e8060c158927c2361f7ce779b44d06661 Type: SHA-256