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LUNG CANCER 2006

LUNG CANCER 2006. Epidemiology : Women and lung cancer Restaging after neoadjuvant treatment of patients in stage IIIA cN2 NSCLC : Non-invasive restaging: CT or PET ? Invasive restaging: Remediastinoscopy or EUS-FNA ? Customizing Chemotherapy. LUNG CANCER 2006.

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LUNG CANCER 2006

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  1. LUNG CANCER 2006 • Epidemiology : Women and lung cancer • Restaging after neoadjuvant treatment of patients in stage IIIA cN2 NSCLC : • Non-invasive restaging: CT or PET ? • Invasive restaging: Remediastinoscopy or EUS-FNA ? • Customizing Chemotherapy

  2. LUNG CANCER 2006 • Epidemiology : Women and lung cancer

  3. Women and Lung Cancer : Epidemiology, tumor biology, and emerging trends in clinical researchChandraP.Belani, SherryMarts, JoanSchiller, MarkA.SocinskiLung Cancer 2007; 55: 15-23 • Sex chromosomes: In men : The presence of the SRY-g ene on the Y chromosome • Expression of differences in physiology and endocrine function, (childhood,adolescence, adulthood and post menopause) • Higher percentage of body fat in women than in men,smaller muscle mass, lower blood pressure, higher levels of estrogens and progestins and lower levels of androgen ,

  4. Women and Lung Cancer : Epidemiology, tumor biology, and emerging trends in clinical research • Hormonal fluctuations associated with reproduction (mensturation and pregnancy) influence numerous body systems. • Reduced estrogen levels in menopause not only affect ovaries, uterus and breast but also other tissues (Brain,skin,cardiovascular tissue and bones) • Sex: an important variable in research design. Gandhi M et al. Annu Rev Pharmacol Toxicol 2004, Turgeon JL et al. Science 2004

  5. Lung Cancer: Epidemiology and Risk Factors • Male gender is a poor prognostic factor in metastatic disease • Duration of smoking before diagnosis and smoking habit in women : determines survey • Risk of death: higher in former smoker or smoker women in comparison with non-smokers • Women with lung cancer have similar features with non-smoker male patients and they are younger Fu JB Chest 2005 O’Connell JP JCO 1986 Ferguson MK JCO 1990 Shinkai T Can Chemoth Phar 1992 Albain KS JCO 1991 Paesmans M JCO 1995 Johnson BE AJM 1988 Ebbert JO Lung Cancer 2005 Goodman MT Cancer 1990 De Perrot M JTh Card Surg 2000 Visbal AL Ann Th Surg 2004 Nordquist LT Chest 2004 Ringer G Cl Lung Cancer 2005

  6. Lung Cancer: Epidemiology and Risk Factors • While male patients used to be more than females previously ( 1975 M/F= 3.65), currently they are lower (in1999, M/F= 1.99) • While insidence is decreasing in men, the increase in women is going on, and this is primarily parallel to the increase in smoking • Lung cancer deaths in women :1960 ( 5/100.000 ) , 2000 (40/100.000 ) are increasing • Today, the most frequent cause of death due to cancer in women is (27 %) lung cancer. Fu JB Chest 2005 O’Connell JP JCO 1986 Ferguson MK JCO 1990 Shinkai T Can Chemoth Phar 1992 Albain KS JCO 1991 Paesmans M JCO 1995 Johnson BE AJM 1988 Ebbert JO Lung Cancer 2005 Goodman MT Cancer 1990 De Perrot M JTh Card Surg 2000 Visbal AL Ann Th Surg 2004 Nordquist LT Chest 2004 Ringer G Cl Lung Cancer 2005

  7. Lung Cancer: Epidemiology and Risk Factors • Rates of smoking in women have been decreased since 1960 • In 2004 • 19 % of women aged > 18 currently smoking • In men aged > 18 the same rate is 23 % • Smoking in adolescence : M=F • Depression and weight gain affect smoking in young women CDC 28 May 2006,Warren CW Lancet 2006 Simantov E Arch Pediat Adolesc Med 2000,Saules KK Addict Behav 2004

  8. Table 1A Rates of 5-years survival according to stages in men and women with SCLC and NSCLC

  9. Table 2A Distribution of patients with squamous cell Ca and adenocarcinoma

  10. Table 2B Distribution of gender, histologycal type and smoking status of patients with lung cancer ( Muscat and Wynder)

  11. Lung Cancer : Epidemiology and Risk Factors • Smoking is major risk factor , only a minority of smokers develop lung cancer. • Approximately 10-15% of patients diagnosed are non-smokers. • The ratio of women to men in patients with lung cancer who have never smoked is approximately 3:1. • Increased risk of lung cancer in smokers and non-smokers are related to certain carcinogenic polymorphisms in genes involved in the metabolism of carcinogens. • Genetic susceptibility comes from studies on family history of lung cancer.

  12. Lung Cancer : Epidemiology and Risk Factors • A positive family history has been defined as a risk factor in non-smokers; particularly in the development of adenocarcinoma, in younger women. • An epidemiologic link between estrogen exposure and incidence of NSCLC has been suggested in Japanese non-smoking women . • Younger, presumably pre-menopausal women appear to have shorter survival than older women:(assumed to be premenopausal) have lower 1-year survival rates than older women : in a analysis of patients with advanced NSCLC enrolled in SWOG trials, women over 70 had a 34% 1 year survival compared with 11% for those under 45 . Visbal AL Ann Th Surg 2004, Gorlova OY Int J Cancer 2006, Thun MJ JNC Inst 1997, Stellman SD Cancer 1997, Wenzlaff AS Carsinogenesis 2005, Miller DP İnt J Cancer 2003, Wu AH Am J Epid 1996, Schwartz AG Am J Epid 1996, Matakidou A Br J Cancer 2005, Li X Lung Cancer 2005, Liu Y İnt J Cancer 2005, Xu H Hum Genet 2005, Schwartz AG AJRCCM 2006

  13. Sex Differences inLung Tumor Biology • Smoking-related lung cancer is induced by the formation of DNA adducts in lung epitheliel cells. • Processing of these adducts by the cellular DNA repair machinery may lead to mutations in genes that initiate or facilitate tumor growth, such as the tumor suppressor gene p53. • PAH activation is catalyzed by the cytochrome P450 enzymes CYP1A1 and CYP1B1, and inactivated by glutathione S-transferases (GSTs). • The expression of CYP1A1 and CYP1B1 in lung tissue is significantly higher in current smokers compared to former and never-smokers.than in non- and never-smokers .

  14. Sex Differences inLung Tumor Biology • Levels of lung DNA adducts correlate with the level of CYP1A1 expression . • Among smokers, female patients had a 3.9-fold higher median level of CYP1A1 compared to males. • In non-smokers, CYP1A1 polymorphisms are associated with an increased lung cancer risk. • A variant genotype of CYP1A1 and GSTM1 contribute to an increased risk of lung cancer in women (6.54) compared to men (2.36) . DeMarini DM Mutat Res 2004, Smith LE J Natl Cancer Inst 2000, Mollerup S İnt J Cancer 2006, Ng DP Cancer Causes Control 2005, Hung RJ Carcinogenesis 2003, Dresler CM Lung Can 2000

  15. Sex Differences in Lung Tumor Biology • In lung cancers, these activating EGFR mutations are more common in women and non-smokers. • Mutations in K-RAS, a downstream signaling molecule in the EGFR pathway, may also be more common in women, but are significantly associated with smoking and levels of DNA adduct formation. • In hormone-dependent tissues, such as breast and ovary, estrogen regulates the transcription of target genes through interaction with estrogen receptors (ERs) alpha or beta. • While important for normal tissue physiology, estrogen receptor-mediated signaling also promotes tumorigenesis. • Estrogen plays a role in both normal pulmonary physiology and in the biology of NSCLC. In vitro studies confirm that NSCLC cells respond to estrogens and anti-estrogens by altering endogenous gene expression. • Expression of ER-beta is associated with improved survival, while expression of ER-alpha is a poor prognostic factor. Among non-smokers,higher ER-beta expression was observed significantly more frequently in female patients (58.3%) than in male patients (40.9%). Lynch TJ NEJM 2004, Hsieh RK Chest 2005, Paez JG Science 2004, Sugio K BJC 2006, Nelson HH J Natl Can İnst 1999, Soung YH Virchows Arch 2005, Levin ER Mol Endoc 2005, Pietras RJ Steroids 2005, Stabile LP Cancer Res 2005, Razandi M J Biol Chem 2003, Bunone G EMBO 1996, Massaro D Am JPhys Lung Cell Mol Physiol 2005, Wu CT JTCardiovas Surg 2005,

  16. Current Therapy Options • Initial treatment for patients with localized, early-stage NSCLC typically includes surgical resection. • Patients with limited pulmonary reserve are candidates for radiotherapy. • The treatment modality for early stage disease differs significantly between men and women. • Radiotherapy is more frequently administered to men. • The lower frequency of surgical resection in men does not explain the observed survival benefit for women as a comparison of patients who received surgery as their initial treatment showed that women have better survival than men. Schiller JH NEJM 2002, Fossella F JCO 2003, Smit EF JCO 2003, Georgoulias V Lancet 2001, Gridelli C JCO 2003, Hoang T JCO 2005.

  17. Table 3Differences in treatment modalities related with gender

  18. TREATMENT • The role of angiogenesis in tumour progression in lung cancer has been well understood. • Release of VEGF proangiogenic factor and high microvascular density is associated with metastasis and poor survival. • VEGF inhibition(Bevacizumab) inhibits new tumour revitalisation. • In ECOG E4599 study, metastatic or recurrent NSCLC (besides squamous cell) • Signicant increase in response in Beva+Carbo+Paklitax group (27%) compared with Beva (-) group (10%) (p<0.001) • Increase in progression – free and overall survival, • In male cases with + Beva treatment : 11.7 months, with Beva(-) 8.7 months, (p=0.001) • Similar survival rates in both arms in women Fontanini G Cl Can Res 1997, O’Byrne KJ BJC 2000, Willett CG Nat Med 2004, Sandler AB ASCO 2005 JCO 2005, Brahmer JR ECOG 4599 ASCO 2006 JCO 2006, Thatcher N Lancet 2005, Herbst RS INTACT 2 JCO 2004, Giaccone G INTACT 1 JCO 2004, Shepherd FA NEJM 2005, Herbst RS TRIBUTE JCO 2005, Bell DW IDEAL/INTACT JCO 2005

  19. TREATMENT EGFR inhibitors (Erlotinib/gefitinib) • They increase the survival alone or with 2. or 3.series of CT, (primarily in female, Japanese, non-smoker cases and in patients with adenocarcinoma) • Association of EGFR mutations with sensitivity to Gefitinib has been shown in studies and mutations have been found in 20 % of female cases, and in only 9% of males Fontanini G Cl Can Res 1997, O’Byrne KJ BJC 2000, Willett CG Nat Med 2004, Sandler AB ASCO 2005 JCO 2005, Brahmer JR ECOG 4599 ASCO 2006 JCO 2006, Thatcher N Lancet 2005, Herbst RS INTACT 2 JCO 2004, Giaccone G INTACT 1 JCO 2004, Shepherd FA NEJM 2005, Herbst RS TRIBUTE JCO 2005, Bell DW IDEAL/INTACT JCO 2005

  20. TREATMENT • Paclitaxel poliglumex (PPX) • A macromolecular taxane • Stabile in systemic circulation • Accumulates in tumor tissue • Changes lymphatic clearence and permeability • In NSCLC metastatic disease and in cases with PS 2 , and without previous CT, the efficiency with Carboplatin or as a single agent in 800 cases, Phase III 2 study, survival was evaluated, in women treated with PPX survival was better while it was similar in men, • Oestrogen provides the efficiency of PPX by increasing the distribution to the tissues with ER-b release. Singer JW J Control Release 2005, O’Byrne K EurJCan 2005, Langer CJ ASCO 2005 JCO 2005

  21. DISCUSSION • Lung cancer tumor histology and biology can change with the inhalation of cigarette smoke and gender. • Female gender and genetic susceptibility are risk factors for the development of lung cancer in both smokers and non-smokers. • In regard of differences due to gender in lung tumor biology ,some treatments may be more effective in women than men. Singer JW J Control Release 2005, O’Byrne K EurJCan 2005, Langer CJ ASCO 2005 JCO 2005

  22. LUNG CANCER 2006 • Restaging after neoadjuvant treatment of patients in stage IIIA cN2 NSCLC: • non-invasive restaging: CT or PET ?

  23. NACT/ NACRT • In NSCLC, N2 NACT and surgery : 5 -year survival 20-40 % • Without induction CT : 5 - 20 % • Operable IIIA cN2: Induction( NACRT> NAKT) • Evaluation of response following neoadjuvan therapy: how should be done and surgery for whom ??

  24. LUNG CANCER 2006 • Non-invasive restaging: CT or PET ?

  25. Staging • Standard approach is the detection of LAP >1cm on olanlar CT, pathological examination of samples obtained with invasive techniques and establishment of diagnosis; • CT is standard, but without sufficient sensitivity, • Dimension is a poor determinant for malignancy, Accuracy 60-80 %, • Misdiagnose of mediastinal malignant lymph nodes on CT: 21-33 %, in locally advanced disease : 11 % pN2 • However, CT can’t determine mediastinal metastatic lymph nodes in nearly 13 % (false negative), • In %50 of the cases : (false positive). Wang KP et al. Chest 1983, Line BR et al Curr Treat Options Oncol 2004 Herth F et al. Chest 2004, Yasafuku K et al. Chest 2004 Rintoul RC et al. Eur Respir J 2006., Eloubeidi MA et al. Ann Thorac Surg 2005 De Leyn et al J Clin Oncol 2006, Stamatis G et al Pneumologie 2005 Goldstraw P J Clin Oncol 2006, Bruzzi JF Lung Cancer 2006, Yamamoto Y Eur J Nucl Med Imagıng 2006

  26. RESTAGİNG IN SHORT TERM FOLLOWING NEOADJUVANT THERAPY-1 • Aim:Are CT measurements in the first month of therapy useful in the evaluation of treatment response in patients with NSCLC ? • Patients and Method: • Aprik 2001-June 2005 • CT within 31 days following only one cyclus of CT (mean 24, range 9-31 days) • Consensus of 2 radiologists in measurements,treatment response is evaluated according to RECİST criteriae • 30 male/ 27 female (57 patients) mean age 63 (37-85), Adeno(30),Squa (17) and others (10), stage: II(2), III(11) and IV(44) John F Bruzzi, Mylene Truong, Ralph Zinner et al. J Thorac Oncol 2006; 1: 425-29

  27. RESTAGİNG IN SHORT TERM FOLLOWING NEOADJUVANT THERAPY-2 • Results : • A significant change in tumor size 14 % (8) • Regression of > 30 % in total tumor size 3 % (2) • Progression of > 20 % in total tumor size 11 % (6) • Early insensitivity / resistance to CT in patients with progression or discontinuance of CT / a different protocol

  28. DISCUSSION Early restaging CT in NSCLC • In the evaluation of response to therapy in early stage • Useful in arrangement of more suitable treatments (2. or 3. series). (With a different CT rapid-early/ late response?, in different types ? Small size: metastasis?, large size: infection or scar tissue?)

  29. LUNG CANCER 2006 • Non-invasive restaging: CT or PET ?

  30. PET/ PET-CT RESTAGİNG FOLLOWING NEOADJUVANT THERAPY Ryu JS Lung Cancer 2002; 35(2): 179-87 • 26 pts, stage III • FDG PET: KRT pre and post • SUV: when it is 3, residue tumor or complete response: Sen: 88 %, Spec:67% • Mediastinal lymph node: sen 58 %, spec 93 % , accuracy 85 % Weber WA J Clin Oncol 2003; 21(14): 2651-2657 • Stage IIIB-IV 57 pts • FDG PET (Pretreatment and 21st day of the first KT cycle ) • Metabolic response: SUVs pre and post treatment difference 20%> decrease Sen 96 %, Spec 84 % • 1 year survival: ın metabolic responders 44 %, in nonresponders 10 % • PET response: % change = SUV(post—pre)X 100/ SUV pre

  31. FDG PET Post treatment prognostic value • The higher the post treatment PET (+) or max SUV , prognosis is so poor : • If 2 years survival= PET(+) is 23 %, or max SUV is 16.6> 37 %, if it is negative, 67 % or if max SUV is 0.4-6.4 61% Pandit N 2003, Davies A Lung Cancer 2007

  32. Repeat FDG-PET for neoadjuvant CT monitorization in patients with stage III NSCLC-1 Eschmann SM, G.Friedel, F.Paulsen et al. Lung Cancer 2007; 55: 165-171 Method • Stage III NSCLC 65 pts • 3 times FDG PET ( initial staging , after the 1st CT, pre RT after 15 days and RCT 15 days later ) • FDG uptake changes in primary tumour

  33. Repeat FDG-PET for neoadjuvant CT monitorization in patients with stage III NSCLC-2 • During NARCT significantly decreased mean maximum FDG uptake (standard uptake value, SUVmax), initial SUVmax PET1: 14.9+-4.0, induction CT 2 weeks later PET2: 8.7+-4.8 and 15 days after RCT PET3: 5.5+-2.4 • FDG PET SUVmax • If (PET1-PET2) decrease is >60 % , survival is long (5 years 60 %) • If < 60 % it is short 15 % (p=0.0007) • If the decrease is <25 %, survival is shorter <5 %

  34. DİSCUSSİON • FDG PET is useful in treatment monitorization of stage lll patients • FDG uptake decrease during induction therapy has a major role in determining and deciding treatment

  35. FDG PET (Results) • T stage: sensitivity 90 %, specifity 67 %, N stage: sensitivity 67 %, specifity 93 % , M stage: sensitivity 100 % , specifity100 % • For mediastinal lymph nodes, the rate of accuracy is low for restaging in patients who haven’t been treated previously • PET/PET-CT(=functional imaging, metabolic response evaluation)in the evaluation of treatment response determination of survival earlier and better than CT(anatomic imaging)(p<0.0001) • Post NACT • Tm central, N1 positive :Remediastinoscopy • Tm periferal, N1 negative: Remediastinoscopy is not required !! Eschmann SM Eur J Nucl Med Mol Imaging 2006, Akhurst T Ann Thorac Surg 2005 , Vansteenkiste J Lancet Oncology 2004

  36. LUNG CANCER 2006 İnvasive restaging: Remediastinoscopy or EUS-FNA ?

  37. Nodal status at repeat mediastinoscopy determines survival in non-small lung cancer with mediastinal nodal involvement, treated by induction therapy De Waele M, J Hendriks, P Lauwers et al. European Journal of Cardio-thoracic Sur 2006;29: 240-43 • Aim: Remediastinoscopy (reMS) is a useful procedure for the determination of the spread of mediastinal lymph nodes and pathological response to therapy following induction therapy , restaging and patient selection for thoracotomy in NSCLC. However, long term survival data following reMS are minimal. • Method: November1994-April 2003 , a total of 32 (29 male, 3 female), locally advanced NSCLC, reMS following induction CT, mean age 67.8 (47-83), 26 pts:NACT, 6 pts: CRT, followed till January 2005.

  38. REMEDİASTİNOSCOPY Results • 5 false negative reMS • Sensitivity 71 %, specifity 100 %, accuracy 84 % • Mean survival : 21 months • ReMS positivity : 7 months, negativity: 41 months (p=0.003) • False negative reMS : 24 months • Positive and false negative reMS : 8 months • Prognosis : age,gender, histology and lymph node status, lymph node statusis an important factor (p=0.015)

  39. ReMS Discussion • ReMS is a valuable “restaging” procedure following induction therapy. • Prognosis is poor in patients with persistant widespread mediastinal lymph nodes detected in ReMS

  40. LUNG CANCER 2006 • Invasive restaging: EUS-FNA ?

  41. Transoesophageal US-guided fine needle aspiration improves mediastinal staging in NSCLC patients with a normal mediastinum on CT Fernandez-Esparrach G, A.Gines, J.Belda et al. Lung Cancer 2006; 54: 35-40 • In NSCLC patients with negative mediastinal lymph nodes on CT • EUS-FNA in mediastinal staging, sen. 50%,spe. 100 %, PPV 100 %, NPV 88 %, accuracy 89 %, • EUS-FNA mediastinoscopy is more “cost-effective” than more invasive methods like surgery. • It should be known that lymph nodes can be small matastatic foci or micrometastases in NSCLC ( false negativity ) , and further new techniques are required to determine them!! Wallace MB et al. Ann Thorac Surg 2004, Leblanc JK et al. Am J Respir Crit Care Med 2005, Toloza EM et al. Chest 2003 Eloubeidi MA et al. Ann Thorac Surg 2005

  42. Molecular diagnostics of NSCLC using on mediastinal lymph nodes sampled by endoscopic US - guided needle aspiration M.Al-Haddad and M.B.Wallace Cytopathology 2006;17:3-9 • On the follow-up period after curative surgical resection, 5-year survival in stage l disease (No) is only 62 % , and in stage ll (N1), it is 42 %. • Metastatic disease in the majority of patients with NSCLC can be overlooked in spite of histologic examinations . • Recent studies have shown that serial sections and immunohistochemical stains increase sensitivity in the detection of metastatic disease. These techniques are time consuming, expensive and can’t be used routinely yet!!

  43. Molecular Staging • Molecular characterization of lymph node tissue is a new research field. • Early micrometastases in lymph nodes can’t be detected by standard cytologic or histologic methods. • The majority of tumour cells can be detected by the presence of proteins specific to pulmonary epithelium cell or mRNA analyses in lymph nodes. • Micrometastases are detected by the molecular techniques: “immunohistochemistry or reverse transcriptase-polymerase chain reaction (RT-PCR) ”. Various “markers’’ like telomeraz, and KS ¼ showing metastatic disease in cytopathologically negative lymph nodes using this method. • Micrometastases have been detected by molecular techniques in over 50 % of patients with histologically normal lymph nodes in this study. Presence of micrometastases in patients with histopathologically normal lymph nodes has significant effect on long term survival. Mori M et al. Cancer Res 1995 Wallace MB et al. Am J Respir Crit Care Med 2003 Wallace MB et al. Chest 2005

  44. Molecular Staging • RT-PCR and gene marker expression • Presence of malignant cells with epithelial derived mRNA transcripts in lymphoid cells which are normally absent in lymph nodes , for example : cytokeratine , mucopolysaccaride (MUC1 transcript), lunx, KS ¼ (Ber-EP4), EGFR and hTERT genes, p53 and K-ras positivity: Metastatic cells origined from the epithelium are present in lymph nodes and is associated with poor survival. • Presence of these markers is important for recurrence and survival!! Salerno CT et al. Chest 1998, Hashimoto T et al. Cancer Res 2000, Iwao K et al. Int J Cancer 2001, Perez MS et al. J Immunol 1989,Latza U et al. J Clin Pathol 1990. Saretzki G et al. Cancer Lett 2002. Han S-W et al. J Clin Oncol 2005

  45. LUNG CANCER 2006 • Customizing “Individual”Chemotherapy

  46. Pharmacogenomics : A reality or still a promise ? Gerold Bepler. Lung Cancer 2006: 54 (suppl 2): 3-7

  47. Genomic abnormalities in lung cancer • The most important types of genetic disorders in cancer : Structural disorders of the chromosomes formed during the repair of DNA double helical hybrid damage like “deletion, substitution and additions”. • Loss of Heterozygosity (LOH) analysis, is the most common used technique to measure genetic disorders. • Several chromosome ( 3, 5, 8, 9, 11 ve 17.chromosomes) loci with frequent LOH were determined by molecular geneticstudies. • Frequent allele loss at chromosome 11p15.5 in NSCLC, increased the investigations determining and characterizing the tumour suppressor genes associated with the development and progression of this disease. • Loss of Heterozygosityin this area in NSCLC affected the prognosis of the patient and was a highly effective determinant of poor survival.

  48. RRM1 • RRM1 is a tumour suppressor gene at 11p15.5 locus. • RRM1 (=ribonucleotide reductase M1) gene was shown • to inhibit the formation, migration and invasion of metastasis • to be a good prognostic factor in prediction of survival in NSCLC in invivo and invitro studies. • This hypothesis was investigated in resectedNSCLC patientswith retrospective/prospectivedata and low RRM1levels were found to be a significant biological and clinical determinator of malignantbehaviour. O’Briant K et al, Anticancer Res 1997;17:3243-52, Gautam A et al, Oncogene 2003; 22: 2135-42 Gautam A et al, Cancer Res 2006; 66: 6497-502,Bepler G et al, J Clin Oncol 2004; 22: 1878-85

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