Pancreatic Cancer () The Lancet, vol378, August 13, 2011 Audrey Vincent, PhD, Johns Hopkins Sol Goldman Joseph Herman, Rich Schulick, Ralph H Hruban, Michael Goggins, H23.9 The Lancet 2011 8 13 Johns Hopkins Sol Goldman high volume http://pathology.jhu.edu/pc/ the Lancet NEJM 240 16 low volume center 16.3% 16 high volume center 3.8 http://www.nejm.org/doi/full/10.1056/nejmsa012337 Hospital volume and surgical mortality in the United States, NEJM,April11,2002 15 20 high volume center CT CT 16 16 Johns Hopkins 64 1/19
80 5 4 2 1 2 9 50 (sporadic) BRCA2breast cancer 2 PALB2 AKB48 Johns Hopikins BRCA2 Oxana Yablonskaya 3 Oxana 1 BRCA2 29 3000 BRCA2 DNA 1 BRCA2 1 BRCA2 80 5% 10 NHK Johns Hopkins 2/19
http://www.jewishgeneticscenter.org/ Chicago Center for Jewish Genetic Disorders BRCA2 http://www.falco-genetics.com/brca/medical/brca1_2/index.html BRCA1, BRCA2 O O 10 metastatic subclone 10 3 3 1 2540% CA19-9 CA19-9 ( 37 ) 100 200IU/ml 3 CT MRI 3/19
CT ERCP CT 2cm T1T2 2cm SMA 17 23 SMA 20 SMA 180 8 14 4 6 15 high volume center gemcitabine, fluorouracil gemcitabine () Gemcitabine () 2001 5 gemcitabine+fluorouracil fluorouracil TS1 CTCA19-9mutant DNA gemcitabine erlotinib, fluorouracil, capecitabine Erlotinib() EGFR(epidermal growth factor receptor) gemcitabinepaclitaxel Paclitaxel taxan http://ja.wikipedia.org/wiki/%e3%82%a4%e3%83%81%e3%82%a4 taxus Taxan supportive care CT ablasion 4/19
PEG The Lancet, 38 the Lancet, 1. 5 4 2. 80 3. O 4. metformin 5. 1 6. 2 9 7. BRCA2PALB2 8. 1 BRCA2 9. 10. 10 11. metastatic subclone 12. 13. 14. 15. 2540% 16. 17. 3 CT 18. MRI 19. CA19-9 37 100 200IU/ml 20. CT 21. ERCP 22. 1723 23. SMA 20 24. SMA 180 8 14 25. 46 26. T1 T2 2cm 5/19
27. 15 high volume 28. gemcitabinefluorouracil 29. 30. gemcitabine() 31. gemcitabinefluorouracil 32. gemcitabine fluorouracil, erlotinib, capecitabine 33. gemcitabine+paclitaxel 34. 35. CTCA19-9mutantDNA 36. CT ablasion 37. PEG 38. Pancreatic Cancer () The Lancet, vol378, August 13, 2011 H23.9 Audrey Vincent, PhD, Johns Hopkins Sol Goldman Joseph Herman, Rich Schulick, Ralph H Hruban, Michael Goggins, non-invasive precursors of malignant disease 5 4 80 85 6/19
pancreatic ductal adenocarcinoma 4 22 7000 0 chlorynated hydrocarbon solvents, nickel Helicobacter pylori Metformin 20 7 10familial pancreatic cancer 2 9 3 32 sporadic 50 BRCA2 517% 10% BRCA2 PALB2 (partner and localizer of BRCA2) 3% BRCA2 PALB2 Fanconi DNA BRCA2-PALB2-FanconiDNA PARP inhibitor alkylating agents CDKN2A familial atypical multiple-mole melanoma germline STK11 Peutz-Jeghers syndrome 7/19
PRSS1 Lynch syndrome (hereditary non-polyposis colon cancer) O BRCA2breast cancer susceptibility gene PALB2 chemoprevention BRCA2 Atypical multiple-mole melanoma CDKN2A ( pancreatic ductal adenocarcinoma) pancreatic intraepithelial neoplasia intraductal papillary mucinous neoplasm mucinous cystic neoplasms 24 exomes KRAS CDKN2A, TP53, SMAD4, BRCA2telomere KRAS telomere pancreatic intraepithelial neoplasia Telomere TP53, SMAD4, BRCA2 pancreatic intraepithelial neoplasia, BRAF, MYB, AKT2, EGFR 8/19
MAP2K4, STK11, TFFBR1, TGFBR2, ACVR1B, ACVR2A, FBXW7, EP300 PIK3CG, DGKA, STK33, TTK, PRKCG driver mutation Intraductal papillary mucinous neoplasm intraepithelial neoplasia SMAD4 driver gene epigenetic DNA methylation non-coding RNA RNA DNA MethylationCH3 gene silencing CDKN2A DNA gene silencing MLH1 CDH1 CDKN1C, RELN, SPARC,TFPI2 aberrant gene silencing promotor hypomethylation SFN, MSLN,S100A4 RNA micro RNA expression micro RNA mir-21, mir-34,mir155, mir-200 Micro RNA molecular clock 10 metastatic subclone driver gene 9/19
cancer-associated fibroblasts KRAS1, RB1, CDKN2A, TP53, SMAD4, TGB1 Hedgehog, NOTCH, AKT1-PI3K-MTOR, BRCA2-PALB2-Fanconi T regulatory lymphocytes () mesothelin tumor-initiating cell, cancer stem cell pancreatic intraepithelial neoplasia noninvasive intraductal papillary mucinous neoplasm mucinous cystic neoplasm CAPS2 3 1 50 10 intraductal papillary mucinous neoplasm 10/19
1cm CAP3 CT27% 93 MRI81% pancreatic intraepithelial neoplsasia fine-needle aspiration silent chachexia panniculitis 25 40 3 CTtri-phasic pancreatic-protocol CT 80 accuracy 3 CT CT MRI resectable borderline resectable locally advanced metastatic 11/19
X CT PET CT CT CA19-9 100 200U/ml unresectability CT fine-needle aspiration ERCP 20 nonneoplastic reactive cell local or resectable 10 median 1723 Stage 0 (Tis, N0, M0 : carcinoma in situ, ) Stage 1A (T1,N0, M0: 2cm ) Stage 1B (T2, N0, M0: 2cm ) Stage 2A (T3, N0,M0: celiac A, SMA ) Stage 2B T1,N1,M0. 2cm T2,N1,M0: 2cm T3,N1,M0: celiac A,SMA Borderline resectable: 10 median20 Stage3 (T4,anyN,M0: celiac A SMA ) celiac A SMA 180 Locally advanced or unresectable ( 30 median814 ) Stage3 (T4,anyN,M0: celiac A SMA ) celiac A SMA 180 12/19
Metastatic ( 60 median 4-6 ) Stage4 (anyt, anyn,m1 : T, N ) MSW a. low volume high volume 15 20 gastric emptying R0 negative resection SMV tattooing CA19-9 13/19
b. R0 (negative resection) R1 margin R2 resection SMV T3 pancreatic ductal adenocarcinoma variants colloid carcinoma (intestinal- type intraductal papillary mucinous neoplasm ) medullary cancer (microsatellite instability ) adenosquamous tumor hepatoid carcinoma signet-ring cell cancer undifferentiated carcinoma undifferentiated carcinoma with osteoclast-like giant cells ductal adenocarcinoma 5 20 25 SMAD4 SPARC c. Adjuvant and neoadjuvant treatment 12 CT CA19-9 GITSGCONKO-001RTOG-9704 GISTG flluorouracil chemoradiation ESPAC-1 RTOG-9704 fluorouracil chemoradiation gemcitabine fluorouracil ESPAC-3 Gemcitbine fluorouracil 14/19
CONKO-001 Gemcitabine median 22.8 20.2 chemoradiation R0 resectiion R0 R1() median 20-25 8-18 R1 resection 7020 4 6 R0 resection R1 resection neoadjuvant therapyr0 resection d. median 3-6 median 9-15 gemcitabine() gemcitabine locally advanced disease chemoradiation 30 resectable patient 15/19
The National Comprehensive Cancer Network Fluorouracil 50 60Gy 4 gemcitabine Fluorouracil gemcitabine radiosensitiser gemcitbine fluorouracil e. 6 45 60Gy 1.82.0Gy/ Fluorouracil capecitabine (oral fluoropyrimidine) radiosesnsitizer 45Gy 5 15Gy neoadjuvant chemoradiotherapy borderline 0.52.0ml 0.5 2.0ml intensity-modulated radiation therapystereotactic body radiation therapy f. gemcitabine() gemcitabine () fluorouracil (5FU) gemcitabine ()capecitabine () Gemcitabine gemcitabine+fluorouracil+folinic acid+irinotecan+oxaliplatin 11 gemcitabine 6.8 gemcitabine+erlotinib Erlotinib EGFR(epidermal growth factor receptor) gemcitabine FDA 16/19
erlotinib wild-type KRAS subgroup gemcitabine+erlotinib+bevacizmab gemcitabine+erlotinib progression-free survival gemcitabine+platinum- based drug/fluoropyrimidine 2 gemcitabine gemcitabine+paclitaxel Gemcitabine1000mg/m2 nanoparticle-formulated paclitaxel (125mg/m2) phase3 trial oxaliplatin+fluorouracil+folinic acid second-line treatment Gemcitabine fluorouracil+folinic acid CONKO-003 trial g. CT RECIST(response evaluation criteria in solid tumours) criteria CT 2 CA19-9 mutant DNA h. olaparib BRCA2-PALB2-Fanconi DNA Poly (ADP-ribose) polymerase (PARP) inhibitors olaparib PARP DNA poly(adp-ribose) DNA histone 17/19
DNA, olaparib GDC-0449 GDC-0449 hedgehog pathway inhibitor phase 2 cryotherapy, photodynamic therapy, radiofrequency ablasion i. supportive care CT plexus ablasion biliary stenting Plastic stent Metal stent 20 PEG the Lancet, 1. 5 4 2. 80 3. O 4. metformin 5. 1 6. 2 9 7. BRCA2PALB2 8. 1 BRCA2 9. 10. 10 18/19
11. metastatic subclone 12. 13. 14. 15. 2540% 16. 17. 3 CT 18. MRI 19. CA19-9 37 100 200IU/ml 20. CT 21. ERCP 22. 1723 23. SMA 20 24. SMA 180 8 14 25. 46 26. T1 T2 2cm 27. 15 high volume 28. gemcitabinefluorouracil 29. 30. gemcitabine() 31. gemcitabinefluorouracil 32. gemcitabine fluorouracil, erlotinib, capecitabine 33. gemcitabine+paclitaxel 34. 35. CTCA19-9mutantDNA 36. CT ablasion 37. PEG 38. 19/19