bb5ec6153c8fcaaee74d72afd901f76a 289531.pdf 6a50edc17aa0507f7f6cc40bdc778b3f71dbdc38 289531.pdf 81968b8a535bcd9cd13735a994993379c9b7531dbe9636feab5f4e53d14bfe56 289531.pdf Title: The Secondary Myelodysplastic Neoplasms (MDS) Jigsaw Subject: There is a great deal of controversy in the hematologic community regarding the classification of secondary myelodysplastic neoplasms (MDSs). Current classifications are based on the presence of genetic predisposition and MDS post-cytotoxic therapy (MDS-pCT) etiologies. However, since these risk factors are not exclusive for secondary MDSs and there are multiple overlapping scenarios, a comprehensive and definitive classification is yet to come. In addition, a sporadic MDS might arise after a primary tumor fulfills the diagnostic criteria of MDS-pCT without a causative cytotoxicity. In this review, we describe the triggering pieces of a secondary MDS jigsaw: previous cytotoxic therapy, germline predisposition and clonal hematopoiesis. Epidemiological and translational efforts are needed to put these pieces together and ascertain the real weight of each of these pieces in each MDS patient. Future classifications must contribute to understanding the role of secondary MDS jigsaw pieces in different concomitant or independent clinical scenarios associated with the primary tumor. Keywords: myelodysplastic neoplasms (MDSs); secondary MDS; genetic predisposition; therapy-related myeloid neoplasm (TRMN); MDS post-cytotoxic therapy (MDS-pCT); MDS comorbidity; clonal hematopoiesis of indeterminate potential (CHIP) Author: Oriol Calvete, Julia Mestre, Andrés Jerez and Francesc Solé Creator: LaTeX with hyperref Producer: pdfTeX-1.40.21 CreationDate: Sun Feb 26 11:00:24 2023 CET ModDate: Sun Feb 26 11:01:27 2023 CET Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 12 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 820670 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- IWTZGU+VnURWPalladioL Type 1 Custom yes yes no 10 0 HAUWBM+URWPalladioL-Bold Type 1 Custom yes yes no 15 0 PXEWOM+URWPalladioL-Roma Type 1 Custom yes yes no 20 0 NIYDQJ+URWPalladioL-Ital Type 1 Custom yes yes no 24 0 BTFGED+VnURWPalladioL-Bold Type 1 Custom yes yes no 28 0 LCJEVJ+TimesNewRomanPS-BoldItalicMT Type 1C WinAnsi yes yes no 47 0 FXXUVH+CMSY10 Type 1 Builtin yes yes no 72 0 BNIMLM+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 92 0 BNIMLO+PalatinoLinotype TrueType WinAnsi yes yes no 95 0 BNIMMA+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 98 0 BNIMLM+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 115 0 BNIMLO+PalatinoLinotype TrueType WinAnsi yes yes no 118 0 BNIMMA+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 121 0 NJWNDJ+VnURWPalladioL-Italic Type 1 Custom yes yes no 134 0 Jhove (Rel. 1.28.0, 2023-05-18) Date: 2024-02-29 02:34:18 CET RepresentationInformation: 289531.pdf ReportingModule: PDF-hul, Rel. 1.12.4 (2023-03-16) LastModified: 2024-02-28 11:07:25 CET Size: 820670 Format: PDF Version: 1.7 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 386 FreeObjects: 1 IncrementalUpdates: 0 DocumentCatalog: PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: Introduction Destination: section.1 Item: Title: The Pieces of the Jigsaw Destination: section.2 Children: Item: Title: MDS Post-Cytotoxic Therapy Destination: subsection.2.1 Item: Title: Germline Predisposition Destination: subsection.2.2 Item: Title: Clonal Hematopoiesis Destination: subsection.2.3 Item: Title: Current Classifications and Secondary MDS Destination: subsection.2.4 Item: Title: Discussion: How to Put the Jigsaw Pieces Together Destination: section.3 Item: Title: Conclusions and Future Directions Destination: section.4 Item: Title: References Destination: section.4 Info: Title: The Secondary Myelodysplastic Neoplasms (MDS) Jigsaw Author: Oriol Calvete, Julia Mestre, Andrés Jerez and Francesc Solé Subject: There is a great deal of controversy in the hematologic community regarding the classification of secondary myelodysplastic neoplasms (MDSs). Current classifications are based on the presence of genetic predisposition and MDS post-cytotoxic therapy (MDS-pCT) etiologies. However, since these risk factors are not exclusive for secondary MDSs and there are multiple overlapping scenarios, a comprehensive and definitive classification is yet to come. In addition, a sporadic MDS might arise after a primary tumor fulfills the diagnostic criteria of MDS-pCT without a causative cytotoxicity. In this review, we describe the triggering pieces of a secondary MDS jigsaw: previous cytotoxic therapy, germline predisposition and clonal hematopoiesis. Epidemiological and translational efforts are needed to put these pieces together and ascertain the real weight of each of these pieces in each MDS patient. Future classifications must contribute to understanding the role of secondary MDS jigsaw pieces in different concomitant or independent clinical scenarios associated with the primary tumor. Keywords: myelodysplastic neoplasms (MDSs); secondary MDS; genetic predisposition; therapy-related myeloid neoplasm (TRMN); MDS post-cytotoxic therapy (MDS-pCT); MDS comorbidity; clonal hematopoiesis of indeterminate potential (CHIP) Creator: LaTeX with hyperref Producer: pdfTeX-1.40.21 CreationDate: Sun Feb 26 11:00:24 CET 2023 ModDate: Sun Feb 26 11:01:27 CET 2023 ID: 0x0c9e08b00deb0e1bdb1dc87be87c8870, 0x0c9e08b00deb0e1bdb1dc87be87c8870 Filters: FilterPipeline: FlateDecode Fonts: Type1: Font: BaseFont: PXEWOM+URWPalladioL-Roma FontSubset: true FirstChar: 2 LastChar: 252 FontDescriptor: FontName: PXEWOM+URWPalladioL-Roma Flags: Symbolic FontBBox: -166, -283, 1021, 943 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: NJWNDJ+VnURWPalladioL-Italic FontSubset: true FirstChar: 189 LastChar: 226 FontDescriptor: FontName: NJWNDJ+VnURWPalladioL-Italic Flags: Symbolic FontBBox: -170, -305, 1010, 941 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: NIYDQJ+URWPalladioL-Ital FontSubset: true FirstChar: 2 LastChar: 151 FontDescriptor: FontName: NIYDQJ+URWPalladioL-Ital Flags: Symbolic FontBBox: -170, -305, 1010, 941 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: FXXUVH+CMSY10 FontSubset: true FirstChar: 0 LastChar: 0 FontDescriptor: FontName: FXXUVH+CMSY10 Flags: Symbolic FontBBox: -29, -960, 1116, 775 FontFile: true Font: BaseFont: IWTZGU+VnURWPalladioL FontSubset: true FirstChar: 161 LastChar: 254 FontDescriptor: FontName: IWTZGU+VnURWPalladioL Flags: Symbolic FontBBox: -166, -283, 1021, 943 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: BTFGED+VnURWPalladioL-Bold FontSubset: true FirstChar: 178 LastChar: 178 FontDescriptor: FontName: BTFGED+VnURWPalladioL-Bold Flags: Symbolic FontBBox: -152, -301, 1000, 935 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: HAUWBM+URWPalladioL-Bold FontSubset: true FirstChar: 3 LastChar: 122 FontDescriptor: FontName: HAUWBM+URWPalladioL-Bold Flags: Symbolic FontBBox: -152, -301, 1000, 935 FontFile: true EncodingDictionary: Differences: true Pages: Page: Sequence: 1 Annotations: Annotation: Subtype: Link Rect: 34, 293, 152, 302 Annotation: Subtype: Link Rect: 34, 283, 87, 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: 176, 680, 187, 693 Annotation: Subtype: Link Rect: 346, 680, 357, 693 Annotation: Subtype: Link Rect: 265, 193, 272, 202 ActionDest: 125 Annotation: Subtype: Link Rect: 260, 155, 267, 164 ActionDest: 125 Annotation: Subtype: Link Rect: 325, 130, 332, 139 ActionDest: 125 Annotation: Subtype: Link Rect: 548, 130, 555, 139 ActionDest: 125 Annotation: Subtype: Link Rect: 266, 118, 273, 127 ActionDest: 125 Annotation: Subtype: Link Rect: 202, 105, 209, 114 ActionDest: 125 Annotation: Subtype: Link Rect: 313, 80, 320, 89 ActionDest: 125 Annotation: Subtype: Link Rect: 114, 17, 265, 28 Annotation: Subtype: Link Rect: 410, 17, 560, 28 Annotation: Subtype: Link Rect: 34, 354, 87, 373 Page: Sequence: 2 Annotations: Annotation: Subtype: Link Rect: 366, 723, 373, 732 ActionDest: 125 Annotation: Subtype: Link Rect: 209, 635, 216, 644 ActionDest: 125 Annotation: Subtype: Link Rect: 435, 635, 442, 644 ActionDest: 125 Annotation: Subtype: Link Rect: 232, 522, 244, 531 ActionDest: 125 Annotation: Subtype: Link Rect: 372, 484, 384, 493 ActionDest: 125 Annotation: Subtype: Link Rect: 462, 395, 474, 404 ActionDest: 125 Annotation: Subtype: Link Rect: 549, 370, 556, 379 ActionDest: 125 Annotation: Subtype: Link Rect: 399, 332, 411, 342 ActionDest: 125 Annotation: Subtype: Link Rect: 270, 308, 282, 316 ActionDest: 125 Annotation: Subtype: Link Rect: 238, 270, 250, 279 ActionDest: 125 Annotation: Subtype: Link Rect: 519, 257, 531, 266 ActionDest: 128 Annotation: Subtype: Link Rect: 383, 245, 395, 254 ActionDest: 128 Annotation: Subtype: Link Rect: 322, 232, 334, 241 ActionDest: 128 Annotation: Subtype: Link Rect: 283, 219, 295, 229 ActionDest: 128 Annotation: Subtype: Link Rect: 250, 207, 262, 216 ActionDest: 128 Annotation: Subtype: Link Rect: 327, 194, 339, 203 ActionDest: 128 Annotation: Subtype: Link Rect: 339, 195, 351, 203 ActionDest: 128 Annotation: Subtype: Link Rect: 230, 182, 242, 191 ActionDest: 128 Annotation: Subtype: Link Rect: 446, 169, 458, 178 ActionDest: 128 Annotation: Subtype: Link Rect: 458, 169, 470, 178 ActionDest: 128 Annotation: Subtype: Link Rect: 471, 169, 483, 178 ActionDest: 128 Annotation: Subtype: Link Rect: 516, 167, 523, 179 ActionDest: 66 Annotation: Subtype: Link Rect: 276, 100, 287, 109 ActionDest: 128 Annotation: Subtype: Link Rect: 391, 100, 401, 109 ActionDest: 128 Annotation: Subtype: Link Rect: 504, 100, 515, 109 ActionDest: 128 Annotation: Subtype: Link Rect: 515, 100, 526, 109 ActionDest: 128 Annotation: Subtype: Link Rect: 384, 74, 395, 82 ActionDest: 128 Annotation: Subtype: Link Rect: 504, 74, 515, 82 ActionDest: 125 Annotation: Subtype: Link Rect: 515, 74, 526, 82 ActionDest: 128 Page: Sequence: 3 Annotations: Annotation: Subtype: Link Rect: 182, 648, 193, 657 ActionDest: 128 Annotation: Subtype: Link Rect: 280, 654, 287, 662 ActionDest: 125 Annotation: Subtype: Link Rect: 287, 654, 298, 662 ActionDest: 125 Annotation: Subtype: Link Rect: 377, 659, 388, 668 ActionDest: 128 Annotation: Subtype: Link Rect: 388, 659, 399, 668 ActionDest: 128 Annotation: Subtype: Link Rect: 527, 687, 538, 695 ActionDest: 128 Annotation: Subtype: Link Rect: 539, 687, 549, 695 ActionDest: 128 Annotation: Subtype: Link Rect: 527, 632, 538, 640 ActionDest: 128 Annotation: Subtype: Link Rect: 397, 572, 408, 581 ActionDest: 128 Annotation: Subtype: Link Rect: 512, 572, 523, 581 ActionDest: 128 Annotation: Subtype: Link Rect: 544, 514, 556, 523 ActionDest: 128 Annotation: Subtype: Link Rect: 437, 476, 449, 485 ActionDest: 128 Annotation: Subtype: Link Rect: 464, 451, 476, 460 ActionDest: 128 Annotation: Subtype: Link Rect: 402, 414, 414, 423 ActionDest: 128 Annotation: Subtype: Link Rect: 415, 413, 427, 423 ActionDest: 128 Annotation: Subtype: Link Rect: 427, 414, 439, 423 ActionDest: 128 Annotation: Subtype: Link Rect: 472, 411, 479, 423 ActionDest: 66 Annotation: Subtype: Link Rect: 549, 401, 556, 410 ActionDest: 125 Annotation: Subtype: Link Rect: 383, 351, 395, 360 ActionDest: 128 Annotation: Subtype: Link Rect: 395, 351, 407, 360 ActionDest: 128 Annotation: Subtype: Link Rect: 524, 338, 531, 347 ActionDest: 125 Annotation: Subtype: Link Rect: 531, 338, 543, 347 ActionDest: 128 Annotation: Subtype: Link Rect: 544, 338, 556, 347 ActionDest: 128 Annotation: Subtype: Link Rect: 307, 300, 319, 310 ActionDest: 128 Annotation: Subtype: Link Rect: 320, 300, 332, 310 ActionDest: 128 Annotation: Subtype: Link Rect: 346, 263, 358, 272 ActionDest: 128 Annotation: Subtype: Link Rect: 298, 175, 310, 184 ActionDest: 128 Annotation: Subtype: Link Rect: 310, 62, 322, 71 ActionDest: 128 Page: Sequence: 4 Annotations: Annotation: Subtype: Link Rect: 218, 710, 230, 719 ActionDest: 128 Annotation: Subtype: Link Rect: 463, 685, 475, 694 ActionDest: 128 Annotation: Subtype: Link Rect: 291, 610, 303, 619 ActionDest: 125 Annotation: Subtype: Link Rect: 266, 597, 278, 606 ActionDest: 128 Annotation: Subtype: Link Rect: 229, 560, 241, 569 ActionDest: 131 Annotation: Subtype: Link Rect: 474, 535, 486, 544 ActionDest: 131 Annotation: Subtype: Link Rect: 205, 434, 217, 443 ActionDest: 131 Annotation: Subtype: Link Rect: 478, 421, 490, 430 ActionDest: 131 Annotation: Subtype: Link Rect: 220, 396, 232, 405 ActionDest: 131 Annotation: Subtype: Link Rect: 407, 384, 419, 393 ActionDest: 131 Annotation: Subtype: Link Rect: 457, 359, 469, 368 ActionDest: 128 Annotation: Subtype: Link Rect: 268, 333, 280, 342 ActionDest: 131 Annotation: Subtype: Link Rect: 281, 333, 293, 342 ActionDest: 131 Annotation: Subtype: Link Rect: 289, 321, 301, 330 ActionDest: 131 Annotation: Subtype: Link Rect: 302, 321, 314, 330 ActionDest: 131 Annotation: Subtype: Link Rect: 339, 283, 351, 292 ActionDest: 131 Annotation: Subtype: Link Rect: 544, 271, 556, 280 ActionDest: 131 Annotation: Subtype: Link Rect: 218, 245, 230, 255 ActionDest: 131 Annotation: Subtype: Link Rect: 252, 233, 264, 242 ActionDest: 131 Annotation: Subtype: Link Rect: 274, 208, 286, 217 ActionDest: 131 Annotation: Subtype: Link Rect: 198, 145, 210, 154 ActionDest: 131 Annotation: Subtype: Link Rect: 243, 143, 250, 154 ActionDest: 66 Annotation: Subtype: Link Rect: 505, 95, 517, 104 ActionDest: 131 Page: Sequence: 5 Annotations: Annotation: Subtype: Link Rect: 308, 735, 315, 744 ActionDest: 125 Annotation: Subtype: Link Rect: 315, 735, 327, 744 ActionDest: 131 Annotation: Subtype: Link Rect: 544, 723, 556, 732 ActionDest: 131 Annotation: Subtype: Link Rect: 464, 685, 471, 694 ActionDest: 125 Annotation: Subtype: Link Rect: 471, 685, 483, 694 ActionDest: 128 Annotation: Subtype: Link Rect: 517, 683, 524, 695 ActionDest: 66 Annotation: Subtype: Link Rect: 194, 660, 206, 669 ActionDest: 131 Annotation: Subtype: Link Rect: 544, 610, 556, 619 ActionDest: 131 Annotation: Subtype: Link Rect: 544, 534, 556, 543 ActionDest: 131 Annotation: Subtype: Link Rect: 405, 484, 412, 493 ActionDest: 125 Annotation: Subtype: Link Rect: 479, 434, 491, 443 ActionDest: 131 Annotation: Subtype: Link Rect: 495, 331, 502, 343 ActionDest: 82 Annotation: Subtype: Link Rect: 544, 208, 556, 217 ActionDest: 125 Annotation: Subtype: Link Rect: 192, 183, 204, 192 ActionDest: 131 Annotation: Subtype: Link Rect: 205, 183, 217, 192 ActionDest: 139 Annotation: Subtype: Link Rect: 442, 183, 454, 192 ActionDest: 139 Annotation: Subtype: Link Rect: 207, 120, 219, 129 ActionDest: 139 Annotation: Subtype: Link Rect: 478, 107, 490, 117 ActionDest: 139 Annotation: Subtype: Link Rect: 514, 95, 526, 104 ActionDest: 139 Page: Sequence: 6 Annotations: Annotation: Subtype: Link Rect: 418, 735, 430, 744 ActionDest: 131 Annotation: Subtype: Link Rect: 445, 698, 457, 707 ActionDest: 139 Page: Sequence: 7 Annotations: Annotation: Subtype: Link Rect: 216, 695, 228, 704 ActionDest: 128 Annotation: Subtype: Link Rect: 229, 695, 240, 704 ActionDest: 128 Annotation: Subtype: Link Rect: 241, 695, 253, 704 ActionDest: 128 Annotation: Subtype: Link Rect: 287, 692, 295, 704 ActionDest: 66 Annotation: Subtype: Link Rect: 470, 667, 477, 679 ActionDest: 66 Annotation: Subtype: Link Rect: 427, 632, 434, 641 ActionDest: 125 Annotation: Subtype: Link Rect: 489, 632, 501, 641 ActionDest: 131 Annotation: Subtype: Link Rect: 541, 629, 548, 641 ActionDest: 82 Annotation: Subtype: Link Rect: 237, 594, 249, 603 ActionDest: 128 Annotation: Subtype: Link Rect: 249, 594, 261, 603 ActionDest: 131 Annotation: Subtype: Link Rect: 262, 594, 273, 603 ActionDest: 139 Annotation: Subtype: Link Rect: 274, 594, 286, 603 ActionDest: 139 Annotation: Subtype: Link Rect: 324, 592, 331, 604 ActionDest: 82 Annotation: Subtype: Link Rect: 323, 582, 335, 591 ActionDest: 125 Annotation: Subtype: Link Rect: 308, 569, 320, 578 ActionDest: 139 Annotation: Subtype: Link Rect: 227, 532, 239, 541 ActionDest: 139 Annotation: Subtype: Link Rect: 424, 416, 431, 428 ActionDest: 105 Page: Sequence: 8 Page: Sequence: 9 Annotations: Annotation: Subtype: Link Rect: 226, 454, 264, 465 Annotation: Subtype: Link Rect: 270, 454, 306, 465 Annotation: Subtype: Link Rect: 313, 420, 350, 431 Annotation: Subtype: Link Rect: 356, 420, 393, 431 Annotation: Subtype: Link Rect: 415, 397, 452, 408 Annotation: Subtype: Link Rect: 458, 397, 494, 408 Annotation: Subtype: Link Rect: 465, 362, 502, 373 Annotation: Subtype: Link Rect: 59, 340, 96, 350 Annotation: Subtype: Link Rect: 102, 340, 138, 350 Annotation: Subtype: Link Rect: 455, 316, 492, 327 Annotation: Subtype: Link Rect: 148, 294, 185, 304 Annotation: Subtype: Link Rect: 192, 294, 228, 304 Annotation: Subtype: Link Rect: 286, 259, 324, 270 Annotation: Subtype: Link Rect: 59, 213, 96, 224 Annotation: Subtype: Link Rect: 324, 190, 361, 201 Annotation: Subtype: Link Rect: 255, 167, 293, 178 Annotation: Subtype: Link Rect: 196, 144, 234, 155 Annotation: Subtype: Link Rect: 240, 144, 276, 155 Annotation: Subtype: Link Rect: 256, 110, 293, 120 Annotation: Subtype: Link Rect: 153, 87, 191, 97 Annotation: Subtype: Link Rect: 197, 87, 233, 97 Annotation: Subtype: Link Rect: 131, 64, 168, 74 Annotation: Subtype: Link Rect: 175, 64, 211, 74 Page: Sequence: 10 Annotations: Annotation: Subtype: Link Rect: 388, 722, 425, 733 Annotation: Subtype: Link Rect: 431, 722, 468, 733 Annotation: Subtype: Link Rect: 104, 676, 142, 687 Annotation: Subtype: Link Rect: 232, 630, 269, 640 Annotation: Subtype: Link Rect: 131, 584, 168, 594 Annotation: Subtype: Link Rect: 108, 561, 146, 571 Annotation: Subtype: Link Rect: 152, 561, 188, 571 Annotation: Subtype: Link Rect: 366, 537, 403, 548 Annotation: Subtype: Link Rect: 409, 537, 445, 548 Annotation: Subtype: Link Rect: 381, 514, 417, 525 Annotation: Subtype: Link Rect: 222, 491, 260, 502 Annotation: Subtype: Link Rect: 266, 491, 302, 502 Annotation: Subtype: Link Rect: 519, 468, 557, 479 Annotation: Subtype: Link Rect: 59, 458, 95, 468 Annotation: Subtype: Link Rect: 392, 445, 430, 456 Annotation: Subtype: Link Rect: 354, 412, 392, 422 Annotation: Subtype: Link Rect: 86, 389, 124, 399 Annotation: Subtype: Link Rect: 95, 354, 133, 364 Annotation: Subtype: Link Rect: 175, 319, 212, 330 Annotation: Subtype: Link Rect: 219, 319, 255, 330 Annotation: Subtype: Link Rect: 149, 297, 186, 307 Annotation: Subtype: Link Rect: 241, 262, 278, 272 Annotation: Subtype: Link Rect: 104, 228, 141, 238 Annotation: Subtype: Link Rect: 147, 228, 183, 238 Annotation: Subtype: Link Rect: 117, 205, 155, 215 Annotation: Subtype: Link Rect: 161, 205, 197, 215 Annotation: Subtype: Link Rect: 122, 170, 159, 180 Annotation: Subtype: Link Rect: 165, 170, 201, 180 Annotation: Subtype: Link Rect: 135, 136, 173, 146 Annotation: Subtype: Link Rect: 387, 100, 424, 111 Annotation: Subtype: Link Rect: 275, 67, 313, 77 Page: Sequence: 11 Annotations: Annotation: Subtype: Link Rect: 240, 710, 278, 721 Annotation: Subtype: Link Rect: 284, 710, 320, 721 Annotation: Subtype: Link Rect: 240, 688, 277, 698 Annotation: Subtype: Link Rect: 372, 664, 410, 675 Annotation: Subtype: Link Rect: 104, 630, 142, 640 Annotation: Subtype: Link Rect: 519, 606, 557, 617 Annotation: Subtype: Link Rect: 59, 596, 95, 606 Annotation: Subtype: Link Rect: 238, 561, 275, 571 Annotation: Subtype: Link Rect: 282, 561, 318, 571 Annotation: Subtype: Link Rect: 402, 526, 439, 537 Annotation: Subtype: Link Rect: 445, 526, 481, 537 Annotation: Subtype: Link Rect: 404, 503, 441, 514 Annotation: Subtype: Link Rect: 447, 503, 483, 514 Annotation: Subtype: Link Rect: 59, 481, 96, 491 Annotation: Subtype: Link Rect: 158, 458, 195, 468 Annotation: Subtype: Link Rect: 311, 434, 348, 445 Annotation: Subtype: Link Rect: 59, 389, 96, 399 Annotation: Subtype: Link Rect: 316, 330, 353, 341 Annotation: Subtype: Link Rect: 225, 308, 263, 318 Annotation: Subtype: Link Rect: 495, 284, 533, 295 Annotation: Subtype: Link Rect: 118, 262, 155, 272 Annotation: Subtype: Link Rect: 161, 262, 197, 272 Annotation: Subtype: Link Rect: 100, 239, 137, 249 Annotation: Subtype: Link Rect: 143, 239, 179, 249 Annotation: Subtype: Link Rect: 90, 205, 128, 215 Annotation: Subtype: Link Rect: 59, 170, 96, 180 Annotation: Subtype: Link Rect: 104, 136, 142, 146 Annotation: Subtype: Link Rect: 229, 101, 266, 111 Annotation: Subtype: Link Rect: 272, 66, 309, 77 Annotation: Subtype: Link Rect: 315, 66, 351, 77 Page: Sequence: 12 Annotations: Annotation: Subtype: Link Rect: 333, 710, 371, 721 Annotation: Subtype: Link Rect: 460, 687, 498, 698 Annotation: Subtype: Link Rect: 443, 664, 481, 675 Annotation: Subtype: Link Rect: 487, 664, 523, 675 Annotation: Subtype: Link Rect: 158, 630, 195, 640 Annotation: Subtype: Link Rect: 59, 607, 96, 617 Annotation: Subtype: Link Rect: 102, 607, 138, 617 Annotation: Subtype: Link Rect: 519, 583, 557, 594 Annotation: Subtype: Link Rect: 59, 573, 95, 583 Checksum: 04852a13 Type: CRC32 Checksum: bb5ec6153c8fcaaee74d72afd901f76a Type: MD5 Checksum: 6a50edc17aa0507f7f6cc40bdc778b3f71dbdc38 Type: SHA-1 Checksum: 81968b8a535bcd9cd13735a994993379c9b7531dbe9636feab5f4e53d14bfe56 Type: SHA-256