f68970895c96b44de77f4466f911b140 pmc_9497128.pdf 59d8f698ea5a57c231701658bfd37375183cd419 pmc_9497128.pdf bd778b48439f92d30058b929af55a5b6bcc9150caad30a0ced42329d5cad8d75 pmc_9497128.pdf Title: Multicenter Real-World Data of Subsequent Chemotherapy after Progression to PARP Inhibitors in a Maintenance Relapse Setting Subject: Background: Despite impressive progression-free survival (PFS) results from PARP inhibitors (PARPi) in ovarian cancer, concerns about their effect on post-progression treatment outcomes have recently arisen, particularly when administered in the relapsed setting. Overlapping mechanisms of resistance between PARPi and platinum have been described, and optimal therapies upon progression to PARPi are unknown. We communicate real-world data (RWD) on outcomes of subsequent chemotherapy upon progression to PARPi used as maintenance in ovarian cancer relapses, particularly focusing on platinum rechallenge, according to BRCA status. Methods: Data from high-grade serous or endometrioid ovarian cancer patients who received subsequent chemotherapy after progression to maintenance PARPi in the relapsed setting, in 16 Catalan hospitals between August 2016 and April 2021, and who were followed-up until July 2021, were included. Endpoints were overall response rate (ORR), and PFS and overall survival (OS) measured from the subsequent chemotherapy starting date. Results: 111 patients were included [46 (41.4%) presented pathological BRCA1/2 mutations, 8 (7.5%) in other homologous recombination-related genes]. Sixty-four patients (57.7%) had received two prior chemotherapy lines, including the one immediately prior to PARPi. PARPi were niraparib (n = 60, 54.1%), olaparib (n = 49, 44.1%), and rucaparib (n = 2, 1.8%). A total of 81 patients remained platinum-sensitive (PS population) after progression to PARPi (when progression-free interval [PFI] was >6 months after the last cycle of prior platinum) [median PFI 12.0 months (interquartile range, IQR, 8.8–17.1)]. Of those, 74 were treated with subsequent platinum regimens, with the following results: ORR of 41.9%, median PFS (mPFS) of 6.6 months (95% CI 6–9.2), and median OS (mOS) of 20.6 months (95% CI 13.6–28.9). Analysis of these 74 patients according to BRCA status showed that PFIs for BRCA mutant and non BRCA-mutant patients were 13.6 [IQR11.2–22.2] and 10.3 [IQR 7.4–14.9] months, respectively (p = 0.010); ORR were 40.0% versus 43.6%, respectively; Rates of progression (as best response) to subsequent platinum were 45.7% versus 17.9%, respectively (p = 0.004); mPFS and mOS were 3.5 (95% CI 2.5–8.6) versus 7.5 months (95% CI 6.5–10.1, p = 0.03), and 16.4 (95% CI 9.3–27.5) versus 24.2 months (95% CI 17.2–NR, p = 0.036), respectively. Conclusion: This is the largest series of real-world data on ovarian cancer patients retreated with platinum in the post-PARPi scenario, separately analyzing BRCA mutant and non-mutant patients, to our knowledge. In our platinum-sensitive population, rechallenge with platinum after progression upon PARPi in the 3rd or later lines for ovarian cancer relapses shows relevant ORR and similar PFS outcomes to historical series of the prePARPi era. However, BRCA mutant patients presented significantly higher rates of progression under subsequent platinum and worse survival outcomes associated with subsequent platinum than non-BRCA-mutant patients. Keywords: ovarian cancer; PARP inhibitors; platinum sensitivity; platinum rechallenge; mechanisms of resistance Author: Margarita Romeo, Marta Gil-Martín, Lydia Gaba, Iris Teruel, Álvaro Taus, Claudia Fina, Maria Masvidal, Paola Murata, Julen Fernández-Plana, Alejandro Martínez, Cristina Pérez, Yolanda García, Valerie Rodriguez, Sara Cros, Marta Parera, Montserrat Zanui, Silvia Catot, Beatriz Pardo, Andrea Plaja, Anna Esteve and Maria Pilar Barretina-Ginesta Creator: LaTeX with hyperref Producer: pdfTeX-1.40.21 CreationDate: Sun Sep 11 10:49:29 2022 CEST ModDate: Sun Sep 11 10:56:38 2022 CEST Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 17 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 933679 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- ILUGHX+VnURWPalladioL-Bold Type 1 Custom yes yes no 10 0 CMFVHJ+VnURWPalladioL Type 1 Custom yes yes no 15 0 WWNCCM+URWPalladioL-Bold Type 1 Custom yes yes no 19 0 HEKNDT+URWPalladioL-Roma Type 1 Custom yes yes no 24 0 HLKCOY+URWPalladioL-Ital Type 1 Custom yes yes no 28 0 LCJEVJ+TimesNewRomanPS-BoldItalicMT Type 1C WinAnsi yes yes no 47 0 BCDEEE+PalatinoLinotype-Bold TrueType WinAnsi yes yes no 83 0 BCDFEE+PalatinoLinotype-Roman TrueType WinAnsi yes yes no 87 0 BCDGEE+PalatinoLinotype-Italic TrueType WinAnsi yes yes no 91 0 BCDIEE+PalatinoLinotype-Roman CID TrueType Identity-H yes yes yes 95 0 QLBIEB+URWPalladioL-BoldItal Type 1 Custom yes yes no 106 0 BCDEEE+PalatinoLinotype-Bold TrueType WinAnsi yes yes no 127 0 BCDFEE+PalatinoLinotype-Roman TrueType WinAnsi yes yes no 131 0 BCDGEE+PalatinoLinotype-Italic TrueType WinAnsi yes yes no 135 0 BCDIEE+PalatinoLinotype-Roman CID TrueType Identity-H yes yes yes 139 0 FXXUVH+CMSY10 Type 1 Builtin yes yes no 150 0 Jhove (Rel. 1.22.1, 2019-04-17) Date: 2023-09-09 02:41:10 CEST RepresentationInformation: pmc_9497128.pdf ReportingModule: PDF-hul, Rel. 1.12.1 (2019-04-17) LastModified: 2023-09-08 02:18:39 CEST Size: 933679 Format: PDF Version: 1.7 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 322 FreeObjects: 1 IncrementalUpdates: 0 DocumentCatalog: PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: Introduction Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@44c8afef Item: Title: Materials and Methods Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@7b69c6ba Children: Item: Title: Study Design Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@46daef40 Item: Title: Outcomes Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@12f41634 Item: Title: Statistical Analysis Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@13c27452 Item: Title: Results Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@262b2c86 Children: Item: Title: Patients’ Characteristics and General Description of the Populations of Study Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@371a67ec Item: Title: Outcomes in the PS Population Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@5ed828d Item: Title: Outcomes in the PR Relapsed Population Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@50d0686 Item: Title: Discussion Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@7a3d45bd Item: Title: Conclusions Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1e7c7811 Item: Title: References Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@77ec78b9 Info: Title: Multicenter Real-World Data of Subsequent Chemotherapy after Progression to PARP Inhibitors in a Maintenance Relapse Setting Author: Margarita Romeo, Marta Gil-Martín, Lydia Gaba, Iris Teruel, Álvaro Taus, Claudia Fina, Maria Masvidal, Paola Murata, Julen Fernández-Plana, Alejandro Martínez, Cristina Pérez, Yolanda García, Valerie Rodriguez, Sara Cros, Marta Parera, Montserrat Zanui, Silvia Catot, Beatriz Pardo, Andrea Plaja, Anna Esteve and Maria Pilar Barretina-Ginesta Subject: Background: Despite impressive progression-free survival (PFS) results from PARP inhibitors (PARPi) in ovarian cancer, concerns about their effect on post-progression treatment outcomes have recently arisen, particularly when administered in the relapsed setting. Overlapping mechanisms of resistance between PARPi and platinum have been described, and optimal therapies upon progression to PARPi are unknown. We communicate real-world data (RWD) on outcomes of subsequent chemotherapy upon progression to PARPi used as maintenance in ovarian cancer relapses, particularly focusing on platinum rechallenge, according to BRCA status. Methods: Data from high-grade serous or endometrioid ovarian cancer patients who received subsequent chemotherapy after progression to maintenance PARPi in the relapsed setting, in 16 Catalan hospitals between August 2016 and April 2021, and who were followed-up until July 2021, were included. Endpoints were overall response rate (ORR), and PFS and overall survival (OS) measured from the subsequent chemotherapy starting date. Results: 111 patients were included [46 (41.4%) presented pathological BRCA1/2 mutations, 8 (7.5%) in other homologous recombination-related genes]. Sixty-four patients (57.7%) had received two prior chemotherapy lines, including the one immediately prior to PARPi. PARPi were niraparib (n = 60, 54.1%), olaparib (n = 49, 44.1%), and rucaparib (n = 2, 1.8%). A total of 81 patients remained platinum-sensitive (PS population) after progression to PARPi (when progression-free interval [PFI] was >6 months after the last cycle of prior platinum) [median PFI 12.0 months (interquartile range, IQR, 8.8 17.1)]. Of those, 74 were treated with subsequent platinum regimens, with the following results: ORR of 41.9%, median PFS (mPFS) of 6.6 months (95% CI 6 9.2), and median OS (mOS) of 20.6 months (95% CI 13.6 28.9). Analysis of these 74 patients according to BRCA status showed that PFIs for BRCA mutant and non BRCA-mutant patients were 13.6 [IQR11.2 22.2] and 10.3 [IQR 7.4 14.9] months, respectively (p = 0.010); ORR were 40.0% versus 43.6%, respectively; Rates of progression (as best response) to subsequent platinum were 45.7% versus 17.9%, respectively (p = 0.004); mPFS and mOS were 3.5 (95% CI 2.5 8.6) versus 7.5 months (95% CI 6.5 10.1, p = 0.03), and 16.4 (95% CI 9.3 27.5) versus 24.2 months (95% CI 17.2 NR, p = 0.036), respectively. Conclusion: This is the largest series of real-world data on ovarian cancer patients retreated with platinum in the post-PARPi scenario, separately analyzing BRCA mutant and non-mutant patients, to our knowledge. In our platinum-sensitive population, rechallenge with platinum after progression upon PARPi in the 3rd or later lines for ovarian cancer relapses shows relevant ORR and similar PFS outcomes to historical series of the prePARPi era. However, BRCA mutant patients presented significantly higher rates of progression under subsequent platinum and worse survival outcomes associated with subsequent platinum than non-BRCA-mutant patients. Keywords: ovarian cancer; PARP inhibitors; platinum sensitivity; platinum rechallenge; mechanisms of resistance Creator: LaTeX with hyperref Producer: pdfTeX-1.40.21 CreationDate: Sun Sep 11 10:49:29 CEST 2022 ModDate: Sun Sep 11 10:56:38 CEST 2022 ID: 0x1f5b9fe50c9617a5e9ad4cab8260e0ca, 0x1f5b9fe50c9617a5e9ad4cab8260e0ca Filters: FilterPipeline: FlateDecode Fonts: Type1: Font: BaseFont: WWNCCM+URWPalladioL-Bold FontSubset: true FirstChar: 3 LastChar: 135 FontDescriptor: FontName: WWNCCM+URWPalladioL-Bold Flags: Symbolic FontBBox: -152, -301, 1000, 935 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: HEKNDT+URWPalladioL-Roma FontSubset: true FirstChar: 2 LastChar: 237 FontDescriptor: FontName: HEKNDT+URWPalladioL-Roma Flags: Symbolic FontBBox: -166, -283, 1021, 943 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: ILUGHX+VnURWPalladioL-Bold FontSubset: true FirstChar: 129 LastChar: 189 FontDescriptor: FontName: ILUGHX+VnURWPalladioL-Bold Flags: Symbolic FontBBox: -152, -301, 1000, 935 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: HLKCOY+URWPalladioL-Ital FontSubset: true FirstChar: 39 LastChar: 121 FontDescriptor: FontName: HLKCOY+URWPalladioL-Ital Flags: Symbolic FontBBox: -170, -305, 1010, 941 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: CMFVHJ+VnURWPalladioL FontSubset: true FirstChar: 129 LastChar: 226 FontDescriptor: FontName: CMFVHJ+VnURWPalladioL Flags: Symbolic FontBBox: -166, -283, 1021, 943 FontFile: true EncodingDictionary: Differences: true Pages: Page: Sequence: 1 Annotations: Annotation: Subtype: Link Rect: 82, 323, 152, 332 Annotation: Subtype: Link Rect: 34, 312, 113, 320 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: 134, 641, 145, 655 Annotation: Subtype: Link Rect: 430, 641, 441, 655 Annotation: Subtype: Link Rect: 173, 604, 184, 617 Annotation: Subtype: Link Rect: 261, 604, 272, 617 Annotation: Subtype: Link Rect: 114, 17, 265, 28 Annotation: Subtype: Link Rect: 410, 17, 560, 28 Annotation: Subtype: Link Rect: 34, 432, 87, 451 Page: Sequence: 2 Annotations: Annotation: Subtype: Link Rect: 549, 169, 556, 178 ActionDest: 164 Annotation: Subtype: Link Rect: 303, 81, 310, 90 ActionDest: 164 Annotation: Subtype: Link Rect: 310, 81, 317, 90 ActionDest: 164 Page: Sequence: 3 Annotations: Annotation: Subtype: Link Rect: 279, 698, 286, 707 ActionDest: 164 Annotation: Subtype: Link Rect: 286, 698, 293, 707 ActionDest: 164 Annotation: Subtype: Link Rect: 286, 685, 293, 694 ActionDest: 164 Annotation: Subtype: Link Rect: 499, 635, 506, 644 ActionDest: 167 Annotation: Subtype: Link Rect: 337, 572, 344, 581 ActionDest: 167 Annotation: Subtype: Link Rect: 292, 560, 299, 569 ActionDest: 167 Annotation: Subtype: Link Rect: 349, 560, 361, 569 ActionDest: 167 Annotation: Subtype: Link Rect: 421, 560, 433, 569 ActionDest: 167 Annotation: Subtype: Link Rect: 491, 560, 503, 569 ActionDest: 167 Annotation: Subtype: Link Rect: 291, 497, 303, 506 ActionDest: 167 Annotation: Subtype: Link Rect: 406, 459, 418, 468 ActionDest: 167 Annotation: Subtype: Link Rect: 414, 422, 426, 431 ActionDest: 167 Annotation: Subtype: Link Rect: 229, 384, 241, 393 ActionDest: 167 Annotation: Subtype: Link Rect: 368, 372, 380, 380 ActionDest: 167 Annotation: Subtype: Link Rect: 405, 346, 417, 355 ActionDest: 167 Annotation: Subtype: Link Rect: 417, 346, 429, 355 ActionDest: 167 Annotation: Subtype: Link Rect: 467, 246, 479, 255 ActionDest: 167 Annotation: Subtype: Link Rect: 363, 233, 375, 242 ActionDest: 167 Annotation: Subtype: Link Rect: 448, 233, 460, 242 ActionDest: 167 Annotation: Subtype: Link Rect: 409, 196, 421, 205 ActionDest: 167 Annotation: Subtype: Link Rect: 544, 158, 556, 167 ActionDest: 167 Annotation: Subtype: Link Rect: 234, 120, 246, 129 ActionDest: 167 Annotation: Subtype: Link Rect: 246, 120, 258, 129 ActionDest: 167 Annotation: Subtype: Link Rect: 259, 120, 271, 129 ActionDest: 167 Page: Sequence: 4 Annotations: Annotation: Subtype: Link Rect: 477, 735, 484, 744 ActionDest: 164 Annotation: Subtype: Link Rect: 377, 698, 389, 707 ActionDest: 167 Annotation: Subtype: Link Rect: 318, 257, 325, 266 ActionDest: 164 Annotation: Subtype: Link Rect: 326, 257, 332, 266 ActionDest: 164 Annotation: Subtype: Link Rect: 228, 192, 235, 204 ActionDest: 75 Page: Sequence: 5 Annotations: Annotation: Subtype: Link Rect: 521, 157, 533, 166 ActionDest: 170 Page: Sequence: 6 Annotations: Annotation: Subtype: Link Rect: 549, 708, 556, 720 ActionDest: 75 Annotation: Subtype: Link Rect: 388, 670, 395, 682 ActionDest: 103 Page: Sequence: 7 Annotations: Annotation: Subtype: Link Rect: 457, 107, 464, 119 ActionDest: 75 Page: Sequence: 8 Annotations: Annotation: Subtype: Link Rect: 190, 708, 197, 720 ActionDest: 113 Annotation: Subtype: Link Rect: 505, 398, 511, 410 ActionDest: 116 Annotation: Subtype: Link Rect: 202, 385, 209, 397 ActionDest: 113 Annotation: Subtype: Link Rect: 247, 310, 254, 322 ActionDest: 119 Page: Sequence: 9 Page: Sequence: 10 Annotations: Annotation: Subtype: Link Rect: 510, 62, 517, 74 ActionDest: 75 Page: Sequence: 11 Page: Sequence: 12 Annotations: Annotation: Subtype: Link Rect: 545, 710, 557, 719 ActionDest: 167 Annotation: Subtype: Link Rect: 314, 698, 326, 707 ActionDest: 167 Annotation: Subtype: Link Rect: 399, 647, 411, 657 ActionDest: 170 Annotation: Subtype: Link Rect: 228, 585, 240, 594 ActionDest: 170 Annotation: Subtype: Link Rect: 193, 547, 205, 556 ActionDest: 170 Annotation: Subtype: Link Rect: 269, 509, 281, 519 ActionDest: 167 Annotation: Subtype: Link Rect: 501, 384, 508, 393 ActionDest: 164 Annotation: Subtype: Link Rect: 477, 158, 489, 167 ActionDest: 170 Page: Sequence: 13 Annotations: Annotation: Subtype: Link Rect: 452, 723, 464, 732 ActionDest: 170 Annotation: Subtype: Link Rect: 262, 560, 274, 569 ActionDest: 170 Annotation: Subtype: Link Rect: 226, 522, 238, 531 ActionDest: 170 Annotation: Subtype: Link Rect: 246, 296, 258, 305 ActionDest: 167 Annotation: Subtype: Link Rect: 454, 146, 466, 154 ActionDest: 170 Annotation: Subtype: Link Rect: 467, 120, 479, 129 ActionDest: 170 Annotation: Subtype: Link Rect: 236, 108, 248, 117 ActionDest: 167 Annotation: Subtype: Link Rect: 395, 108, 407, 117 ActionDest: 170 Annotation: Subtype: Link Rect: 401, 70, 413, 79 ActionDest: 167 Page: Sequence: 14 Annotations: Annotation: Subtype: Link Rect: 295, 535, 302, 544 ActionDest: 167 Annotation: Subtype: Link Rect: 416, 522, 423, 531 ActionDest: 167 Annotation: Subtype: Link Rect: 424, 522, 436, 531 ActionDest: 170 Annotation: Subtype: Link Rect: 332, 497, 344, 506 ActionDest: 170 Annotation: Subtype: Link Rect: 524, 409, 531, 418 ActionDest: 167 Annotation: Subtype: Link Rect: 531, 409, 543, 418 ActionDest: 167 Annotation: Subtype: Link Rect: 544, 409, 556, 418 ActionDest: 170 Annotation: Subtype: Link Rect: 525, 182, 560, 193 Annotation: Subtype: Link Rect: 165, 170, 375, 181 Page: Sequence: 15 Annotations: Annotation: Subtype: Link Rect: 366, 213, 404, 224 Annotation: Subtype: Link Rect: 410, 213, 446, 224 Annotation: Subtype: Link Rect: 101, 180, 139, 190 Annotation: Subtype: Link Rect: 145, 180, 181, 190 Annotation: Subtype: Link Rect: 332, 144, 370, 155 Annotation: Subtype: Link Rect: 376, 144, 412, 155 Annotation: Subtype: Link Rect: 59, 122, 96, 132 Annotation: Subtype: Link Rect: 331, 99, 368, 109 Annotation: Subtype: Link Rect: 476, 64, 513, 75 Page: Sequence: 16 Annotations: Annotation: Subtype: Link Rect: 508, 710, 545, 721 Annotation: Subtype: Link Rect: 104, 665, 141, 675 Annotation: Subtype: Link Rect: 457, 629, 495, 640 Annotation: Subtype: Link Rect: 59, 584, 96, 594 Annotation: Subtype: Link Rect: 457, 549, 494, 560 Annotation: Subtype: Link Rect: 501, 549, 537, 560 Annotation: Subtype: Link Rect: 440, 537, 560, 548 Annotation: Subtype: Link Rect: 56, 526, 334, 537 Annotation: Subtype: Link Rect: 365, 503, 402, 514 Annotation: Subtype: Link Rect: 409, 503, 445, 514 Annotation: Subtype: Link Rect: 122, 469, 160, 479 Annotation: Subtype: Link Rect: 131, 423, 168, 433 Annotation: Subtype: Link Rect: 59, 389, 96, 399 Annotation: Subtype: Link Rect: 102, 389, 138, 399 Annotation: Subtype: Link Rect: 408, 353, 445, 364 Annotation: Subtype: Link Rect: 104, 320, 142, 330 Annotation: Subtype: Link Rect: 520, 296, 557, 307 Annotation: Subtype: Link Rect: 247, 273, 285, 284 Annotation: Subtype: Link Rect: 59, 239, 96, 249 Annotation: Subtype: Link Rect: 336, 215, 373, 226 Annotation: Subtype: Link Rect: 380, 215, 416, 226 Annotation: Subtype: Link Rect: 512, 181, 549, 192 Annotation: Subtype: Link Rect: 95, 147, 132, 157 Annotation: Subtype: Link Rect: 464, 123, 502, 134 Annotation: Subtype: Link Rect: 508, 123, 544, 134 Annotation: Subtype: Link Rect: 519, 89, 557, 100 Annotation: Subtype: Link Rect: 59, 78, 95, 88 Page: Sequence: 17 Annotations: Annotation: Subtype: Link Rect: 425, 711, 462, 721 Annotation: Subtype: Link Rect: 498, 676, 535, 687 Annotation: Subtype: Link Rect: 56, 629, 365, 640 Annotation: Subtype: Link Rect: 477, 629, 515, 640 Annotation: Subtype: Link Rect: 82, 596, 119, 606 Annotation: Subtype: Link Rect: 333, 560, 370, 571 Annotation: Subtype: Link Rect: 414, 526, 452, 537 Annotation: Subtype: Link Rect: 458, 526, 494, 537 Annotation: Subtype: Link Rect: 273, 491, 310, 502 Annotation: Subtype: Link Rect: 316, 491, 353, 502 Annotation: Subtype: Link Rect: 196, 458, 234, 468 Annotation: Subtype: Link Rect: 134, 411, 172, 422 Annotation: Subtype: Link Rect: 374, 376, 411, 387 Annotation: Subtype: Link Rect: 411, 342, 448, 353 Annotation: Subtype: Link Rect: 266, 296, 303, 307 Checksum: 2ce7bcc5 Type: CRC32 Checksum: f68970895c96b44de77f4466f911b140 Type: MD5 Checksum: 59d8f698ea5a57c231701658bfd37375183cd419 Type: SHA-1