2f6a77c548e9f1f64e8cd95c5656d48f 236711.pdf 96590fd825143666208e8cc45f64b4c26224380d 236711.pdf ad1b36b1df8b612310b5544b71a30178674cfe44e117511f95a57fbf63b10efc 236711.pdf Title: Pembrolizumab as Consolidation Strategy in Patients with Multiple Myeloma: Results of the GEM-Pembresid Clinical Trial Subject: PD1 expression in CD4+ and CD8+ T cells is increased after treatment in multiple myeloma patients with persistent disease. The GEM-Pembresid trial analyzed the efficacy and safety of pembrolizumab as consolidation in patients achieving at least very good partial response but with persistent measurable disease after first- or second-line treatment. Moreover, the characteristics of the immune system were investigated to identify potential biomarkers of response to pembrolizumab. One out of the 17 evaluable patients showed a decrease in the amount of M-protein, although a potential late effect of high-dose melphalan could not be ruled out. Fourteen adverse events were considered related to pembrolizumab, two of which (G3 diarrhea and G2 pneumonitis) prompted treatment discontinuation and all resolving without sequelae. Interestingly, pembrolizumab induced a decrease in the percentage of NK cells at cycle 3, due to the reduction of the circulating and adaptive subsets (0.615 vs. 0.43, p = 0.007; 1.12 vs. 0.86, p = 0.02). In the early progressors, a significantly lower expression of PD1 in CD8+ effector memory T cells (MFI 1327 vs. 926, p = 0.03) was observed. In conclusion, pembrolizumab used as consolidation monotherapy shows an acceptable toxicity profile but did not improve responses in this MM patient population. The trial was registered at clinicaltrials.gov with identifier NCT02636010 and with EUDRACT number 2015-003359-23. Keywords: pembrolizumab; immunotherapy; myeloma; consolidation Author: Noemí Puig, Luis A. Corchete-Sánchez, José J. Pérez-Morán, Julio Dávila, Teresa Paíno, Javier de la Rubia, Albert Oriol, Jesús Martín-Sánchez, Felipe de Arriba, Joan Bladé, María-Jesús Blanchard, Verónica González-Calle, Ramón García-Sanz, Bruno Paiva, Juan-José Lahuerta, Jesús F. San-Miguel, María-Victoria Mateos and Enrique M. Ocio Creator: LaTeX with hyperref package Producer: pdfTeX-1.40.18 CreationDate: Thu Dec 3 09:20:35 2020 CET ModDate: Thu Dec 3 09:20:35 2020 CET Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 13 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 1668393 bytes Optimized: no PDF version: 1.5 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- ATWXPC+URWPalladioL-Ital Type 1 Custom yes yes no 88 0 PCVIDS+URWPalladioL-Bold Type 1 Custom yes yes no 89 0 DGBDNV+VnURWPalladioL-Bold Type 1 Custom yes yes no 90 0 OMSYNX+URWPalladioL-Roma Type 1 Custom yes yes no 91 0 SVVJCD+Rpxr Type 1 Builtin yes yes no 92 0 KPKHYQ+VnURWPalladioL Type 1 Custom yes yes no 93 0 LCJEVJ+TimesNewRomanPS-BoldItalicMT Type 1C WinAnsi yes yes no 99 0 MCBCCI+SourceSansRoman-Regular Type 1C Custom yes yes no 116 0 MCBCCM+SourceSansRoman.613wght Type 1C Custom yes yes no 117 0 MCBCCO+SourceSansRoman-Bold Type 1C Custom yes yes no 118 0 KNELVT+Pxsy Type 1 Builtin yes yes no 167 0 UWYRVX+EURM10 Type 1 Builtin yes yes no 175 0 STNZGY+Rpxb Type 1 Builtin yes yes no 184 0 URYLRZ+URWPalladioL-BoldItal Type 1 Custom yes yes no 185 0 LGZKLX+Rpxi Type 1 Builtin yes yes no 186 0 NEEOOG+PalatinoLinotype TrueType WinAnsi yes yes no 198 0 NEEPBH+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 199 0 NEEPCI+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 200 0 NEFAGC+TimesNewRoman CID TrueType Identity-H yes yes yes 201 0 NEEOOG+PalatinoLinotype TrueType WinAnsi yes yes no 230 0 NEEPBH+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 231 0 NEEPCI+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 232 0 NEFAGC+TimesNewRoman CID TrueType Identity-H yes yes yes 233 0 NEEOOG+PalatinoLinotype TrueType WinAnsi yes yes no 264 0 NEEPBH+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 265 0 NEEPCI+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 266 0 NEFAGC+TimesNewRoman CID TrueType Identity-H yes yes yes 267 0 NEEOOG+PalatinoLinotype TrueType WinAnsi yes yes no 292 0 NEEPBH+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 293 0 NEEPCI+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 294 0 NEFAGC+TimesNewRoman CID TrueType Identity-H yes yes yes 295 0 VSHNAE+Rpcxr Type 1 Builtin yes yes no 406 0 Jhove (Rel. 1.22.1, 2019-04-17) Date: 2021-02-18 02:20:55 CET RepresentationInformation: 236711.pdf ReportingModule: PDF-hul, Rel. 1.12.1 (2019-04-17) LastModified: 2021-02-12 19:40:48 CET Size: 1668393 Format: PDF Version: 1.5 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 0 FreeObjects: 1 IncrementalUpdates: 0 DocumentCatalog: ViewerPreferences: HideToolbar: false HideMenubar: false HideWindowUI: false FitWindow: true CenterWindow: false DisplayDocTitle: false NonFullScreenPageMode: UseNone Direction: L2R ViewArea: CropBox ViewClip: CropBox PrintArea: CropBox PageClip: CropBox PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: ぉのぴひはつふっぴどはのぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸲ Item: Title: きづぴとはつびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮ㄩ‾㸊⡜㌷㙜㌷㝜〰こぴふつべぜ〴ぜ〰いづびどでのぜ〴ぜ〰ちのつぜ〴ぜ〰ぐちぴどづのぴぜ〴ぜ〰ぐはばふぬちぴどはのぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㈩‾㸊⡜㌷㙜㌷㝜〰ぅのつばはどのぴびぜ〴ぜ〰ちのつぜ〴ぜ〰こぴふつべぜ〴ぜ〰ぁびびづびびねづのぴびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㌩‾㸊⡜㌷㙜㌷㝜〰ぅぶちぬふちぴどはのぜ〴ぜ〰はてぜ〴ぜ〰ぴとづぜ〴ぜ〰ぉねねふのづぜ〴ぜ〰こべびぴづねぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㐩‾㸊⡜㌷㙜㌷㝜〰こぴちぴどびぴどっちぬぜ〴ぜ〰ぁのちぬべびどびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㔩‾㸊⡜㌷㙜㌷㝜〰いちぴちぜ〴ぜ〰ことちひどのでぜ〴ぜ〰こぴちぴづねづのぴぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸳ Children: Item: Title: こぴふつべぜ〴ぜ〰いづびどでのぜ〴ぜ〰ちのつぜ〴ぜ〰ぐちぴどづのぴぜ〴ぜ〰ぐはばふぬちぴどはのぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㈩‾㸊⡜㌷㙜㌷㝜〰ぅのつばはどのぴびぜ〴ぜ〰ちのつぜ〴ぜ〰こぴふつべぜ〴ぜ〰ぁびびづびびねづのぴびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㌩‾㸊⡜㌷㙜㌷㝜〰ぅぶちぬふちぴどはのぜ〴ぜ〰はてぜ〴ぜ〰ぴとづぜ〴ぜ〰ぉねねふのづぜ〴ぜ〰こべびぴづねぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㐩‾㸊⡜㌷㙜㌷㝜〰こぴちぴどびぴどっちぬぜ〴ぜ〰ぁのちぬべびどびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㔩‾㸊⡜㌷㙜㌷㝜〰いちぴちぜ〴ぜ〰ことちひどのでぜ〴ぜ〰こぴちぴづねづのぴぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸳ Item: Title: ぅのつばはどのぴびぜ〴ぜ〰ちのつぜ〴ぜ〰こぴふつべぜ〴ぜ〰ぁびびづびびねづのぴびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㌩‾㸊⡜㌷㙜㌷㝜〰ぅぶちぬふちぴどはのぜ〴ぜ〰はてぜ〴ぜ〰ぴとづぜ〴ぜ〰ぉねねふのづぜ〴ぜ〰こべびぴづねぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㐩‾㸊⡜㌷㙜㌷㝜〰こぴちぴどびぴどっちぬぜ〴ぜ〰ぁのちぬべびどびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㔩‾㸊⡜㌷㙜㌷㝜〰いちぴちぜ〴ぜ〰ことちひどのでぜ〴ぜ〰こぴちぴづねづのぴぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸳ Item: Title: ぅぶちぬふちぴどはのぜ〴ぜ〰はてぜ〴ぜ〰ぴとづぜ〴ぜ〰ぉねねふのづぜ〴ぜ〰こべびぴづねぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㐩‾㸊⡜㌷㙜㌷㝜〰こぴちぴどびぴどっちぬぜ〴ぜ〰ぁのちぬべびどびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㔩‾㸊⡜㌷㙜㌷㝜〰いちぴちぜ〴ぜ〰ことちひどのでぜ〴ぜ〰こぴちぴづねづのぴぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸳ Item: Title: こぴちぴどびぴどっちぬぜ〴ぜ〰ぁのちぬべびどびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㈮㔩‾㸊⡜㌷㙜㌷㝜〰いちぴちぜ〴ぜ〰ことちひどのでぜ〴ぜ〰こぴちぴづねづのぴぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸳ Item: Title: いちぴちぜ〴ぜ〰ことちひどのでぜ〴ぜ〰こぴちぴづねづのぴぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸳ Item: Title: げづびふぬぴびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㌮ㄩ‾㸊⡜㌷㙜㌷㝜〰ぐちぴどづのぴぜ〴ぜ〰ぐはばふぬちぴどはのぜ〴ぜ〰ちのつぜ〴ぜ〰ぃとちひちっぴづひどびぴどっびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㌮㈩‾㸊⡜㌷㙜㌷㝜〰ぅててどっちっべぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㌮㌩‾㸊⡜㌷㙜㌷㝜〰こちてづぴべぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㌮㐩‾㸊⡜㌷㙜㌷㝜〰あどはねちひにづひびぜ〴ぜ〰はてぜ〴ぜ〰げづびばはのびづぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸴ Children: Item: Title: ぐちぴどづのぴぜ〴ぜ〰ぐはばふぬちぴどはのぜ〴ぜ〰ちのつぜ〴ぜ〰ぃとちひちっぴづひどびぴどっびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㌮㈩‾㸊⡜㌷㙜㌷㝜〰ぅててどっちっべぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㌮㌩‾㸊⡜㌷㙜㌷㝜〰こちてづぴべぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㌮㐩‾㸊⡜㌷㙜㌷㝜〰あどはねちひにづひびぜ〴ぜ〰はてぜ〴ぜ〰げづびばはのびづぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸴ Item: Title: ぅててどっちっべぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㌮㌩‾㸊⡜㌷㙜㌷㝜〰こちてづぴべぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㌮㐩‾㸊⡜㌷㙜㌷㝜〰あどはねちひにづひびぜ〴ぜ〰はてぜ〴ぜ〰げづびばはのびづぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸴ Item: Title: こちてづぴべぜ〴〩਼㰠⽓ 䝯呯 䐠⡳畢獥捴楯渮㌮㐩‾㸊⡜㌷㙜㌷㝜〰あどはねちひにづひびぜ〴ぜ〰はてぜ〴ぜ〰げづびばはのびづぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸴ Item: Title: あどはねちひにづひびぜ〴ぜ〰はてぜ〴ぜ〰げづびばはのびづぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸴ Item: Title: いどびっふびびどはのぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸵ Item: Title: ぃはのっぬふびどはのびぜ〴〩਼㰠⽓ 䝯呯 䐠⡳散瑩潮⸵ Item: Title: げづてづひづのっづび Filters: FilterPipeline: FlateDecode Fonts: Type1: Font: BaseFont: VSHNAE+Rpcxr FontSubset: true FirstChar: 169 LastChar: 169 FontDescriptor: FontName: VSHNAE+Rpcxr Flags: Symbolic FontBBox: -212, -286, 1344, 973 FontFile: true Font: BaseFont: KNELVT+Pxsy FontSubset: true FirstChar: 0 LastChar: 21 FontDescriptor: FontName: KNELVT+Pxsy Flags: Symbolic FontBBox: -21, -994, 1292, 912 FontFile: true Font: BaseFont: ATWXPC+URWPalladioL-Ital FontSubset: true FirstChar: 3 LastChar: 122 FontDescriptor: FontName: ATWXPC+URWPalladioL-Ital Flags: Symbolic FontBBox: -170, -305, 1010, 941 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: STNZGY+Rpxb FontSubset: true FirstChar: 14 LastChar: 61 FontDescriptor: FontName: STNZGY+Rpxb Flags: Symbolic FontBBox: -57, -266, 932, 729 FontFile: true Font: BaseFont: PCVIDS+URWPalladioL-Bold FontSubset: true FirstChar: 3 LastChar: 122 FontDescriptor: FontName: PCVIDS+URWPalladioL-Bold Flags: Symbolic FontBBox: -152, -301, 1000, 935 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: URYLRZ+URWPalladioL-BoldItal FontSubset: true FirstChar: 110 LastChar: 110 FontDescriptor: FontName: URYLRZ+URWPalladioL-BoldItal Flags: Symbolic FontBBox: -170, -300, 1073, 935 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: DGBDNV+VnURWPalladioL-Bold FontSubset: true FirstChar: 161 LastChar: 243 FontDescriptor: FontName: DGBDNV+VnURWPalladioL-Bold Flags: Symbolic FontBBox: -152, -301, 1000, 935 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: LGZKLX+Rpxi FontSubset: true FirstChar: 14 LastChar: 14 FontDescriptor: FontName: LGZKLX+Rpxi Flags: Symbolic FontBBox: -162, -280, 856, 733 FontFile: true Font: BaseFont: OMSYNX+URWPalladioL-Roma FontSubset: true FirstChar: 2 LastChar: 246 FontDescriptor: FontName: OMSYNX+URWPalladioL-Roma Flags: Symbolic FontBBox: -166, -283, 1021, 943 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: SVVJCD+Rpxr FontSubset: true FirstChar: 11 LastChar: 61 FontDescriptor: FontName: SVVJCD+Rpxr Flags: Symbolic FontBBox: -40, -283, 904, 728 FontFile: true Font: BaseFont: KPKHYQ+VnURWPalladioL FontSubset: true FirstChar: 128 LastChar: 243 FontDescriptor: FontName: KPKHYQ+VnURWPalladioL Flags: Symbolic FontBBox: -166, -283, 1021, 943 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: UWYRVX+EURM10 FontSubset: true FirstChar: 13 LastChar: 34 FontDescriptor: FontName: UWYRVX+EURM10 Flags: Symbolic FontBBox: -32, -243, 1060, 720 FontFile: true Pages: Page: Sequence: 1 Annotations: Annotation: Subtype: Link Rect: 75, 757, 193, 793 Annotation: Subtype: Link Rect: 474, 757, 519, 793 Annotation: Subtype: Link Rect: 265, 641, 276, 655 Annotation: Subtype: Link Rect: 441, 641, 452, 655 Annotation: Subtype: Link Rect: 139, 628, 150, 641 Annotation: Subtype: Link Rect: 241, 628, 252, 641 Annotation: Subtype: Link Rect: 318, 628, 329, 641 Annotation: Subtype: Link Rect: 456, 614, 467, 628 Annotation: Subtype: Link Rect: 172, 601, 183, 614 Annotation: Subtype: Link Rect: 184, 587, 195, 601 Annotation: Subtype: Link Rect: 308, 587, 319, 601 Annotation: Subtype: Link Rect: 466, 255, 518, 274 Annotation: Subtype: Link Rect: 168, 38, 256, 50 Annotation: Subtype: Link Rect: 404, 38, 519, 50 Page: Sequence: 2 Annotations: Annotation: Subtype: Link Rect: 111, 430, 118, 440 ActionDest: 367 Annotation: Subtype: Link Rect: 342, 403, 349, 413 ActionDest: 367 Annotation: Subtype: Link Rect: 354, 390, 361, 399 ActionDest: 367 Annotation: Subtype: Link Rect: 444, 390, 451, 399 ActionDest: 367 Annotation: Subtype: Link Rect: 501, 363, 508, 372 ActionDest: 367 Annotation: Subtype: Link Rect: 509, 363, 516, 372 ActionDest: 367 Annotation: Subtype: Link Rect: 192, 268, 199, 277 ActionDest: 367 Annotation: Subtype: Link Rect: 199, 268, 206, 277 ActionDest: 367 Annotation: Subtype: Link Rect: 340, 268, 347, 277 ActionDest: 367 Annotation: Subtype: Link Rect: 348, 268, 355, 277 ActionDest: 367 Annotation: Subtype: Link Rect: 207, 228, 214, 237 ActionDest: 367 Annotation: Subtype: Link Rect: 217, 228, 229, 237 ActionDest: 367 Annotation: Subtype: Link Rect: 189, 214, 201, 223 ActionDest: 367 Annotation: Subtype: Link Rect: 454, 174, 466, 183 ActionDest: 392 Annotation: Subtype: Link Rect: 182, 106, 194, 115 ActionDest: 392 Page: Sequence: 3 Annotations: Annotation: Subtype: Link Rect: 113, 337, 125, 346 ActionDest: 392 Annotation: Subtype: Link Rect: 356, 228, 368, 238 ActionDest: 392 Page: Sequence: 4 Annotations: Annotation: Subtype: Link Rect: 512, 241, 518, 253 ActionDest: 181 Page: Sequence: 5 Annotations: Annotation: Subtype: Link Rect: 171, 360, 178, 372 ActionDest: 191 Page: Sequence: 6 Page: Sequence: 7 Annotations: Annotation: Subtype: Link Rect: 287, 672, 294, 684 ActionDest: 221 Annotation: Subtype: Link Rect: 383, 308, 390, 319 ActionDest: 255 Annotation: Subtype: Link Rect: 376, 281, 383, 292 ActionDest: 255 Annotation: Subtype: Link Rect: 347, 213, 354, 225 ActionDest: 255 Page: Sequence: 8 Page: Sequence: 9 Annotations: Annotation: Subtype: Link Rect: 503, 715, 515, 725 ActionDest: 392 Annotation: Subtype: Link Rect: 465, 661, 472, 671 ActionDest: 367 Annotation: Subtype: Link Rect: 297, 540, 309, 549 ActionDest: 392 Annotation: Subtype: Link Rect: 266, 445, 273, 454 ActionDest: 367 Annotation: Subtype: Link Rect: 273, 445, 280, 454 ActionDest: 367 Annotation: Subtype: Link Rect: 488, 351, 500, 360 ActionDest: 392 Annotation: Subtype: Link Rect: 503, 351, 515, 360 ActionDest: 392 Annotation: Subtype: Link Rect: 341, 270, 353, 279 ActionDest: 392 Annotation: Subtype: Link Rect: 217, 175, 229, 184 ActionDest: 392 Page: Sequence: 10 Annotations: Annotation: Subtype: Link Rect: 218, 675, 230, 684 ActionDest: 392 Annotation: Subtype: Link Rect: 188, 580, 200, 590 ActionDest: 392 Annotation: Subtype: Link Rect: 203, 580, 215, 590 ActionDest: 392 Annotation: Subtype: Link Rect: 159, 526, 171, 535 ActionDest: 392 Annotation: Subtype: Link Rect: 188, 486, 200, 495 ActionDest: 392 Annotation: Subtype: Link Rect: 343, 472, 355, 481 ActionDest: 403 Annotation: Subtype: Link Rect: 355, 472, 367, 481 ActionDest: 403 Page: Sequence: 11 Annotations: Annotation: Subtype: Link Rect: 406, 537, 443, 548 Annotation: Subtype: Link Rect: 450, 537, 486, 548 Annotation: Subtype: Link Rect: 287, 499, 324, 509 Annotation: Subtype: Link Rect: 330, 499, 367, 509 Annotation: Subtype: Link Rect: 176, 448, 214, 458 Annotation: Subtype: Link Rect: 243, 396, 280, 406 Annotation: Subtype: Link Rect: 347, 357, 385, 367 Annotation: Subtype: Link Rect: 435, 318, 473, 329 Annotation: Subtype: Link Rect: 288, 279, 325, 290 Annotation: Subtype: Link Rect: 397, 240, 435, 251 Annotation: Subtype: Link Rect: 307, 215, 344, 225 Annotation: Subtype: Link Rect: 225, 164, 263, 174 Annotation: Subtype: Link Rect: 439, 124, 475, 135 Annotation: Subtype: Link Rect: 481, 124, 516, 135 Annotation: Subtype: Link Rect: 190, 86, 228, 96 Annotation: Subtype: Link Rect: 234, 86, 270, 96 Page: Sequence: 12 Annotations: Annotation: Subtype: Link Rect: 479, 714, 516, 725 Annotation: Subtype: Link Rect: 100, 702, 136, 712 Annotation: Subtype: Link Rect: 366, 663, 404, 673 Annotation: Subtype: Link Rect: 410, 663, 446, 673 Annotation: Subtype: Link Rect: 449, 624, 486, 635 Annotation: Subtype: Link Rect: 478, 585, 516, 596 Annotation: Subtype: Link Rect: 100, 573, 136, 583 Annotation: Subtype: Link Rect: 452, 546, 490, 557 Annotation: Subtype: Link Rect: 345, 521, 382, 531 Annotation: Subtype: Link Rect: 330, 495, 367, 506 Annotation: Subtype: Link Rect: 309, 456, 346, 467 Annotation: Subtype: Link Rect: 450, 404, 487, 415 Annotation: Subtype: Link Rect: 204, 315, 241, 325 Annotation: Subtype: Link Rect: 247, 315, 283, 325 Annotation: Subtype: Link Rect: 379, 275, 416, 286 Annotation: Subtype: Link Rect: 422, 275, 459, 286 Annotation: Subtype: Link Rect: 480, 236, 516, 247 Annotation: Subtype: Link Rect: 100, 224, 136, 234 Annotation: Subtype: Link Rect: 163, 173, 201, 183 Annotation: Subtype: Link Rect: 207, 173, 243, 183 Annotation: Subtype: Link Rect: 100, 134, 137, 144 Annotation: Subtype: Link Rect: 443, 94, 480, 105 Page: Sequence: 13 Annotations: Annotation: Subtype: Link Rect: 145, 702, 183, 712 Annotation: Subtype: Link Rect: 109, 651, 146, 661 Annotation: Subtype: Link Rect: 76, 578, 166, 609 Annotation: Subtype: Link Rect: 234, 572, 407, 583 Checksum: 6a97f169 Type: CRC32 Checksum: 2f6a77c548e9f1f64e8cd95c5656d48f Type: MD5 Checksum: 96590fd825143666208e8cc45f64b4c26224380d Type: SHA-1