**6. References**

Allegra, C. J., Jessup, J. M., Somerfield, M. R., Hamilton, S. R., Hammond, E. H., Hayes, D. F., McAllister, P. K., Morton, R. F. & Schilsky, R. L. (2009). American Society of Clinical Oncology provisional clinical opinion: testing for KRAS gene mutations in

Biomarkers in Gastrointestinal Cancer: Focus on Colon, Pancreatic and Gastric Cancer 69

Croxtall, J. D. & McKeage, K. (2010). Trastuzumab: in HER2-positive metastatic gastric

Dasari, A. & Messersmith, W. A. (2010). New strategies in colorectal cancer: biomarkers of

De Roock, W., Biesmans, B., De Schutter, J. & Tejpar, S. (2009). Clinical biomarkers in oncology: focus on colorectal cancer. *Molecular diagnosis & therapy* 13(2), 103–114. De Roock, W., Jonker, D. J., Di Nicolantonio, F., Sartore-Bianchi, A., Tu, D., Siena, S., Lamba,

*JAMA : the journal of the American Medical Association* 304(16), 1812–1820. De Roock, W., Claes, B., Bernasconi, D., De Schutter, J., Biesmans, B., Fountzilas, G.,

De Roock, W., De Vriendt, V., Normanno, N., Ciardiello, F. & Tejpar, S. (2011). KRAS, BRAF,

De Vita, F., Giuliani, F., Silvestris, N., Catalano, G., Ciardiello, F. & Orditura, M. (2010).

Deschoolmeester, V., Baay, M., Specenier, P., Lardon, F. & Vermorken, J. B. (2010). A review

Di Nicolantonio, F., Martini, M., Molinari, F., Sartore-Bianchi, A., Arena, S., Saletti, P., De

Duffy, M. J. & Crown, J. (2008). A personalized approach to cancer treatment: how

Farrell, J. J., Elsaleh, H., Garcia, M., Lai, R., Ammar, A., Regine, W. F., Abrams, R., Benson,

PIK3CA, and PTEN mutations: implications for targeted therapies in metastatic

Human epidermal growth factor receptor 2 (HER2) in gastric cancer: a new

of the most promising biomarkers in colorectal cancer: one step closer to targeted

Dosso, S., Mazzucchelli, L., Frattini, M., Siena, S. & Bardelli, A. (2008). Wild-type BRAF is required for response to panitumumab or cetuximab in metastatic colorectal cancer. *Journal of clinical oncology : official journal of the American Society of* 

A. B., Macdonald, J., Cass, C. E., Dicker, A. P. & Mackey, J. R. (2009). Human equilibrative nucleoside transporter 1 levels predict response to gemcitabine in

response to epidermal growth factor receptor monoclonal antibodies and potential therapeutic targets in phosphoinositide 3-kinase and mitogen-activated protein kinase pathways. *Clinical cancer research : an official journal of the American Association* 

S., Arena, S., Frattini, M., Piessevaux, H., Van Cutsem, E., O'Callaghan, C. J., Khambata-Ford, S., Zalcberg, J. R., Simes, J., Karapetis, C. S., Bardelli, A. & Tejpar, S. (2010a). Association of KRAS p.G13D mutation with outcome in patients with chemotherapy-refractory metastatic colorectal cancer treated with cetuximab.

Kalogeras, K. T., Kotoula, V., Papamichael, D., Laurent-Puig, P., Penault-Llorca, F., Rougier, P., Vincenzi, B., Santini, D., Tonini, G., Cappuzzo, F., Frattini, M., Molinari, F., Saletti, P., De Dosso, S., Martini, M., Bardelli, A., Siena, S., Sartore-Bianchi, A., Tabernero, J., Macarulla, T., Di Fiore, F., Gangloff, A. O., Ciardiello, F., Pfeiffer, P., Qvortrup, C., Hansen, T. P., Van Cutsem, E., Piessevaux, H., Lambrechts, D., Delorenzi, M. & Tejpar, S. (2010b). Effects of KRAS, BRAF, NRAS, and PIK3CA mutations on the efficacy of cetuximab plus chemotherapy in chemotherapy-refractory metastatic colorectal cancer: a retrospective consortium

cancer. *Drugs* 70(17), 2259–2267.

*for Cancer Research* 16(15), 3811–3818.

analysis. *The lancet oncology* 11(8), 753–762.

therapy. *The oncologist* 15(7), 699–731.

*Clinical Oncology* 26(35), 5705–5712.

colorectal cancer. *The lancet oncology* 12(6), 594–603.

therapeutic target. *Cancer treatment reviews* 36 Suppl 3, S11–5.

biomarkers can help. *Clinical chemistry* 54(11), 1770–1779.

patients with pancreatic cancer. *Gastroenterology* 136(1), 187–195.

patients with metastatic colorectal carcinoma to predict response to anti-epidermal growth factor receptor monoclonal antibody therapy. *Journal of clinical oncology : official journal of the American Society of Clinical Oncology* 27(12), 2091–2096.


*official journal of the American Society of Clinical Oncology* 27(12), 2091–2096. Ananiev, J., Gulubova, M., Manolova, I. & Tchernev, G. (2011). Prognostic significance of

Ansari, D., Rosendahl, A., Elebro, J. & Andersson, R. (2011). Systematic review of

Barault, L., Veyrie, N., Jooste, V., Lecorre, D., Chapusot, C., Ferraz, J.-M., Lièvre, A., Cortet,

Basturk, O., Singh, R., Kaygusuz, E., Balci, S., Dursun, N., Culhaci, N. & Adsay, N. V. (2011).

Bellon, E., Ligtenberg, M. J. L., Tejpar, S., Cox, K., de Hertogh, G., de Stricker, K., Edsjö, A.,

Bloomston, M., Frankel, W. L., Petrocca, F., Volinia, S., Alder, H., Hagan, J. P., Liu, C.-G.,

Buxbaum, J. L. & Eloubeidi, M. A. (2010). Molecular and clinical markers of pancreas cancer.

Bünger, S., Laubert, T., Roblick, U. J. & Habermann, J. K. (2011). Serum biomarkers for

Chen, Y. F., Mai, C. R., Tie, Z. J., Feng, Z. T., Zhang, J., Lu, X. H., Lu, G. J., Xue, Y. H. & Pan,

Chua, T. C. & Merrett, N. D. (2011). Clinicopathologic factors associated with HER2-Positive

with pancreatic cancer. *The British journal of surgery* 98(8), 1041–1055. Bang, Y.-J., Van Cutsem, E., Feyereislova, A., Chung, H. C., Shen, L., Sawaki, A., Lordick, F.,

label, randomised controlled trial. *Lancet* 376(9742), 687–697.

diagnosis, and prognosis. *Pancreas* 40(2), 187–192.

*JOP : Journal of the pancreas* 11(6), 536–544.

*research and clinical oncology* 137(3), 375–389.

450–454.

2255–2259.

1908.

*oncologist* 16(4), 467–478.

patients with metastatic colorectal carcinoma to predict response to anti-epidermal growth factor receptor monoclonal antibody therapy. *Journal of clinical oncology :* 

HER2/neu expression in gastric cancer. *Wiener klinische Wochenschrift* 123(13-14),

immunohistochemical biomarkers to identify prognostic subgroups of patients

Ohtsu, A., Omuro, Y., Satoh, T., Aprile, G., Kulikov, E., Hill, J., Lehle, M., Rüschoff, J., Kang, Y.-K.ToGA Trial Investigators (2010). Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-

M., Bouvier, A.-M., Rat, P., Roignot, P., Faivre, J., Laurent-Puig, P. & Piard, F. (2008). Mutations in the RAS-MAPK, PI(3)K (phosphatidylinositol-3-OH kinase) signaling network correlate with poor survival in a population-based series of colon cancers. *International journal of cancer. Journal international du cancer* 122(10),

GLUT-1 expression in pancreatic neoplasia: implications in pathogenesis,

Gorgoulis, V., Höfler, G., Jung, A., Kotsinas, A., Laurent-Puig, P., López-Ríos, F., Hansen, T. P., Rouleau, E., Vandenberghe, P., van Krieken, J. J. M. & Dequeker, E. (2011). External quality assessment for KRAS testing is needed: setup of a European program and report of the first joined regional quality assessment rounds. *The* 

Bhatt, D., Taccioli, C. & Croce, C. M. (2007). MicroRNA expression patterns to differentiate pancreatic adenocarcinoma from normal pancreas and chronic pancreatitis. *JAMA : the journal of the American Medical Association* 297(17), 1901–

improved diagnostic of pancreatic cancer: a current overview. *Journal of cancer* 

G. Z. (1989). The diagnostic significance of carbohydrate antigen CA 19-9 in serum and pancreatic juice in pancreatic carcinoma. *Chinese medical journal* 102(5), 333–337.

gastric cancer and its impact on survival outcomes - a systematic review. *International journal of cancer. Journal international du cancer, DOI: 10.1002/ijc26292*.


Biomarkers in Gastrointestinal Cancer: Focus on Colon, Pancreatic and Gastric Cancer 71

Kato, S., Iida, S., Higuchi, T., Ishikawa, T., Takagi, Y., Yasuno, M., Enomoto, M., Uetake, H.

Kim, K. C., Koh, Y. W., Chang, H.-M., Kim, T. H., Yook, J. H., Kim, B. S., Jang, S. J. & Park, Y.

Kim, R., Tan, A., Lai, K. K., Jiang, J., Wang, Y., Rybicki, L. A. & Liu, X. (2011b). Prognostic

subunit M1 (RRM1) in resected pancreatic cancer. *Cancer* 117(14), 3126–3134. Kim, S. Y., Kim, H. P., Kim, Y. J., Oh, D.-Y., Im, S.-A., Lee, D., Jong, H.-S., Kim, T.-Y. & Bang,

Koch, C., Zeuzem, S. & Trojan, J. (2011). The KRAS p.G13D Mutation in Patients With

Laurent-Puig, P., Cayre, A., Manceau, G., Buc, E., Bachet, J.-B., Lecomte, T., Rougier, P.,

Lee, E. J., Gusev, Y., Jiang, J., Nuovo, G. J., Lerner, M. R., Frankel, W. L., Morgan, D. L.,

Lièvre, A., Bachet, J.-B., Le Corre, D., Boige, V., Landi, B., Emile, J.-F., Côté, J.-F., Tomasic, G.,

Lockhart, A. C., Lockhart, C. & Berlin, J. D. (2005). The epidermal growth factor receptor as a target for colorectal cancer therapy. *Seminars in oncology* 32(1), 52–60. Lorenzen, S. & Lordick, F. (2011). How will human epidermal growth factor receptor 2-neu

Loupakis, F., Ruzzo, A., Cremolini, C., Vincenzi, B., Salvatore, L., Santini, D., Masi, G., Stasi,

Loupakis, F., Pollina, L., Stasi, I., Ruzzo, A., Scartozzi, M., Santini, D., Masi, G., Graziano, F.,

microarrays. *Annals of surgical oncology* 18(10), 2833–2840.

121(8), 1771–1778.

*oncology* 32(1), 89–95.

*Gastroenterology* 141(4), 1527–1528.

*Society of Clinical Oncology* 27(35), 5924–5930.

*Journal international du cancer* 120(5), 1046–1054.

cancer. *Cancer research* 66(8), 3992–3995.

*British journal of cancer* 101(4), 715–721.

396–402.

& Sugihara, K. (2007). PIK3CA mutation is predictive of poor survival in patients with colorectal cancer. *International journal of cancer. Journal international du cancer*

S. (2011a). Evaluation of HER2 protein expression in gastric carcinomas: comparative analysis of 1,414 cases of whole-tissue sections and 595 cases of tissue

roles of human equilibrative transporter 1 (hENT-1) and ribonucleoside reductase

Y.-J. (2008). Trastuzumab inhibits the growth of human gastric cancer cell lines with HER2 amplification synergistically with cisplatin. *International journal of* 

Metastatic Colorectal Cancer: A Cheat in the Orchestra of Predictive Biomarkers?

Lièvre, A., Landi, B., Boige, V., Ducreux, M., Ychou, M., Bibeau, F., Bouché, O., Reid, J., Stone, S. & Penault-Llorca, F. (2009). Analysis of PTEN, BRAF, and EGFR status in determining benefit from cetuximab therapy in wild-type KRAS metastatic colon cancer. *Journal of clinical oncology : official journal of the American* 

Postier, R. G., Brackett, D. J. & Schmittgen, T. D. (2007). Expression profiling identifies microRNA signature in pancreatic cancer. *International journal of cancer.* 

Penna, C., Ducreux, M., Rougier, P., Penault-Llorca, F. & Laurent-Puig, P. (2006). KRAS mutation status is predictive of response to cetuximab therapy in colorectal

data impact clinical management of gastric cancer? *Current opinion in oncology* 23(4),

I., Canestrari, E., Rulli, E., Floriani, I., Bencardino, K., Galluccio, N., Catalano, V., Tonini, G., Magnani, M., Fontanini, G., Basolo, F., Falcone, A. & Graziano, F. (2009a). KRAS codon 61, 146 and BRAF mutations predict resistance to cetuximab plus irinotecan in KRAS codon 12 and 13 wild-type metastatic colorectal cancer.

Cremolini, C., Rulli, E., Canestrari, E., Funel, N., Schiavon, G., Petrini, I., Magnani, M., Tonini, G., Campani, D., Floriani, I., Cascinu, S. & Falcone, A. (2009b). PTEN


Fornaro, L., Lucchesi, M., Caparello, C., Vasile, E., Caponi, S., Ginocchi, L., Masi, G. &

Fujimoto-Ouchi, K., Sekiguchi, F., Yasuno, H., Moriya, Y., Mori, K. & Tanaka, Y. (2007).

Gentiloni, N., Caradonna, P., Costamagna, G., D'Ostilio, N., Perri, V., Mutignani, M.,

Goel, A., Arnold, C. N., Niedzwiecki, D., Carethers, J. M., Dowell, J. M., Wasserman, L.,

Grabsch, H., Sivakumar, S., Gray, S., Gabbert, H. E. & Müller, W. (2010). HER2 expression in

Gravalos, C. & Jimeno, A. (2008). HER2 in gastric cancer: a new prognostic factor and a

Hamada, S. & Shimosegawa, T. (2011). Biomarkers of pancreatic cancer. *Pancreatology :* 

Harding, J. & Burtness, B. (2005). Cetuximab: an epidermal growth factor receptor chemeric

Hayes, D. F., Bast, R. C., Desch, C. E., Fritsche, H., Kemeny, N. E., Jessup, J. M., Locker, G.

pancreatic adenocarcinoma. *Annals of surgical oncology* 17(12), 3120–3128. Im, S.-A., Lee, K. E., Nam, E., Kim, D. Y., Lee, J.-H., Han, H.-S., Seoh, J.-Y., Park, H.-Y., Cho,

Ito, H., Duxbury, M., Zinner, M. J., Ashley, S. W. & Whang, E. E. (2004). Glucose transporter-

Jang, K.-S., Song, Y. S., Jang, S.-H., Min, K.-W., Na, W., Jang, S. M., Jun, Y. J., Lee, K. H.,

expression in colorectal adenocarcinoma. *Histopathology* 56(2), 229–239.

high sporadic colorectal cancers. *Cancer research* 64(9), 3014–3021.

*International Society for Cellular Oncology* 32(1-2), 57–65.

*Medical Oncology / ESMO* 19(9), 1523–1529.

*Nature reviews. Gastroenterology & hepatology* 8(7), 369–383.

805.

1072.

2, 14–19.

107–127.

*Tumori* 91(6), 513–521.

activity. *Surgery* 136(3), 548–556.

Falcone, A. (2011). Anti-HER agents in gastric cancer: from bench to bedside.

Antitumor activity of trastuzumab in combination with chemotherapy in human gastric cancer xenograft models. *Cancer chemotherapy and pharmacology* 59(6), 795–

Febbraro, S., Tinari, N., Iacobelli, S. & Natoli, C. (1995). Pancreatic juice 90K and serum CA 19-9 combined determination can discriminate between pancreatic cancer and chronic pancreatitis. *The American journal of gastroenterology* 90(7), 1069–

Compton, C., Mayer, R. J., Bertagnolli, M. M. & Boland, C. R. (2004). Frequent inactivation of PTEN by promoter hypermethylation in microsatellite instability-

gastric cancer: Rare, heterogeneous and of no prognostic value - conclusions from 924 cases of two independent series. *Cellular oncology : the official journal of the* 

novel therapeutic target. *Annals of oncology : official journal of the European Society for* 

*official journal of the International Association of Pancreatology (IAP) ... [et al.]* 11 Suppl

human-murine monoclonal antibody. *Drugs of today (Barcelona, Spain : 1998)* 41(2),

Y., Macdonald, J. S., Mennel, R. G., Norton, L., Ravdin, P., Taube, S. & Winn, R. J. (1996). Tumor marker utility grading system: a framework to evaluate clinical utility of tumor markers. *Journal of the National Cancer Institute* 88(20), 1456–1466. Ikenaga, N., Ohuchida, K., Mizumoto, K., Yu, J., Kayashima, T., Sakai, H., Fujita, H., Nakata,

K. & Tanaka, M. (2010). MicroRNA-203 expression as a new prognostic marker of

M.-S., Han, W. S. & Lee, S. N. (2005). Potential prognostic significance of p185(HER2) overexpression with loss of PTEN expression in gastric carcinomas.

1 gene expression is associated with pancreatic cancer invasiveness and MMP-2

Choi, D. & Paik, S. S. (2010). Clinicopathological significance of nuclear PTEN


Biomarkers in Gastrointestinal Cancer: Focus on Colon, Pancreatic and Gastric Cancer 73

Nakaizumi, A., Uehara, H., Takenaka, A., Uedo, N., Sakai, N., Yano, H., Ohigashi, H.,

Neumann, J., Zeindl-Eberhart, E., Kirchner, T. & Jung, A. (2009). Frequency and type of

Ng, K. & Zhu, A. X. (2008). Targeting the epidermal growth factor receptor in metastatic

Nishida, K., Tasaki, N., Miyagawa, H., Yoshikawa, T. & Kondo, M. (1988). Estimation of

Oliveira, C., Westra, J. L., Arango, D., Ollikainen, M., Domingo, E., Ferreira, A., Velho, S.,

Overman, M. J. & Hoff, P. M. (2007). EGFR-targeted therapies in colorectal cancer. *Diseases of* 

Park, J. H., Han, S.-W., Oh, D.-Y., Im, S.-A., Jeong, S.-Y., Park, K. J., Kim, T.-Y., Bang, Y.-J. &

Perrone, F., Lampis, A., Orsenigo, M., Di Bartolomeo, M., Gevorgyan, A., Losa, M., Frattini,

Park, J.-G. (2011). Analysis of KRAS, BRAF, PTEN, IGF1R, EGFR intron 1 CA status in both primary tumors and paired metastases in determining benefit from cetuximab therapy in colon cancer. *Cancer chemotherapy and pharmacology* 68(4),

M., Riva, C., Andreola, S., Bajetta, E., Bertario, L., Leo, E., Pierotti, M. A. & Pilotti, S. (2009). PI3KCA/PTEN deregulation contributes to impaired responses to

pancreatic cancer. *The American journal of gastroenterology* 83(2), 126–129. Ogino, S., Nosho, K., Kirkner, G. J., Kawasaki, T., Meyerhardt, J. A., Loda, M., Giovannucci,

colorectal cancer. *Critical reviews in oncology/hematology* 65(1), 8–20.

*Pathology, research and practice* 205(12), 858–862.

*Society of Clinical Oncology* 27(9), 1477–1484.

*the colon and rectum* 50(8), 1259–1270.

10.1007/S00534-011-0440-3

17(2), 572–578.

13(19), 2303–2311.

1045–1055.

nucleoside transporter 1 expression is a strong independent prognostic factor in UICC T3-T4 pancreatic cancer patients treated with preoperative gemcitabinebased chemoradiotherapy. *Journal of hepato-biliary-pancreatic sciences,* DOI:

Ishikawa, O., Ishiguro, S., Sugano, K. & Tatsuta, M. (1999). Diagnosis of pancreatic cancer by cytology and measurement of oncogene and tumor markers in pure pancreatic juice aspirated by endoscopy. *Hepato-gastroenterology* 46(25), 31–37. Nash, G. M., Gimbel, M., Shia, J., Nathanson, D. R., Ndubuisi, M. I., Zeng, Z.-S., Kemeny, N.

& Paty, P. B. (2010). KRAS mutation correlates with accelerated metastatic progression in patients with colorectal liver metastases. *Annals of surgical oncology*

KRAS mutations in routine diagnostic analysis of metastatic colorectal cancer.

carbohydrate antigen (CA) 19-9 levels in pure pancreatic juice of patients with

E. L. & Fuchs, C. S. (2009a). CpG island methylator phenotype, microsatellite instability, BRAF mutation and clinical outcome in colon cancer. *Gut* 58(1), 90–96. Ogino, S., Nosho, K., Kirkner, G. J., Shima, K., Irahara, N., Kure, S., Chan, A. T., Engelman, J.

A., Kraft, P., Cantley, L. C., Giovannucci, E. L. & Fuchs, C. S. (2009b). PIK3CA mutation is associated with poor prognosis among patients with curatively resected colon cancer. *Journal of clinical oncology : official journal of the American* 

Niessen, R., Lagerstedt, K., Alhopuro, P., Laiho, P., Veiga, I., Teixeira, M. R., Ligtenberg, M., Kleibeuker, J. H., Sijmons, R. H., Plukker, J. T., Imai, K., Lage, P., Hamelin, R., Albuquerque, C., Schwartz, S., Lindblom, A., Peltomaki, P., Yamamoto, H., Aaltonen, L. A., Seruca, R. & Hofstra, R. M. W. (2004). Distinct patterns of KRAS mutations in colorectal carcinomas according to germline mismatch repair defects and hMLH1 methylation status. *Human molecular genetics*

expression and KRAS mutations on primary tumors and metastases in the prediction of benefit from cetuximab plus irinotecan for patients with metastatic colorectal cancer. *Journal of clinical oncology : official journal of the American Society of Clinical Oncology* 27(16), 2622–2629.


Lyshchik, A., Higashi, T., Hara, T., Nakamoto, Y., Fujimoto, K., Doi, R., Imamura, M., Saga,

Malesci, A., Tommasini, M. A., Bonato, C., Bocchia, P., Bersani, M., Zerbi, A., Beretta, E. & Di

Maréchal, R., Mackey, J. R., Lai, R., Demetter, P., Peeters, M., Polus, M., Cass, C. E., Young,

Matsui, Y., Inomata, M., Tojigamori, M., Sonoda, K., Shiraishi, N. & Kitano, S. (2005).

Matsumoto, S., Harada, H., Tanaka, J., Ochi, K., Seno, T., Tsurumi, T. & Kunichika, K. (1994).

Melstrom, L. G., Salabat, M. R., Ding, X.-Z., Milam, B. M., Strouch, M., Pelling, J. C. &

Meriggi, F., Di Biasi, B., Abeni, C. & Zaniboni, A. (2009). Anti-EGFR therapy in colorectal cancer: how to choose the right patient. *Current drug targets* 10(10), 1033–1040. Molinari, F., Martin, V., Saletti, P., De Dosso, S., Spitale, A., Camponovo, A., Bordoni, A.,

may be clinically relevant. *British journal of cancer* 100(7), 1087–1094. Morinaga, S., Nakamura, Y., Watanabe, T., Mikayama, H., Tamagawa, H., Yamamoto, N.,

Adjuvant Gemcitabine Monotherapy. *Annals of surgical oncology*.

Murata, Y., Hamada, T., Kishiwada, M., Ohsawa, I., Mizuno, S., Usui, M., Sakurai, H.,

diagnosis of pancreatic cancer at early stages. *Pancreas* 9(6), 741–747. Mees, S. T., Mardin, W. A., Wendel, C., Baeumer, N., Willscher, E., Senninger, N., Schleicher,

*journal of cancer. Journal international du cancer* 126(1), 114–124.

*Clinical Oncology* 27(16), 2622–2629.

*Cancer investigation* 25(3), 154–162.

*for Cancer Research* 15(8), 2913–2919.

*Gastroenterology* 92(1), 60–67.

681–685.

37(4), 426–431.

expression and KRAS mutations on primary tumors and metastases in the prediction of benefit from cetuximab plus irinotecan for patients with metastatic colorectal cancer. *Journal of clinical oncology : official journal of the American Society of* 

T. & Togashi, K. (2007). Expression of glucose transporter-1, hexokinase-II, proliferating cell nuclear antigen and survival of patients with pancreatic cancer.

Carlo, V. (1987). Determination of CA 19-9 antigen in serum and pancreatic juice for differential diagnosis of pancreatic adenocarcinoma from chronic pancreatitis.

J., Salmon, I., Devière, J. & Van Laethem, J.-L. (2009). Human equilibrative nucleoside transporter 1 and human concentrative nucleoside transporter 3 predict survival after adjuvant gemcitabine therapy in resected pancreatic adenocarcinoma. *Clinical cancer research : an official journal of the American Association* 

Suppression of tumor growth in human gastric cancer with HER2 overexpression by an anti-HER2 antibody in a murine model. *International journal of oncology* 27(3),

Evaluation of cytology and tumor markers of pure pancreatic juice for the

C., Colombo-Benkmann, M. & Haier, J. (2010). EP300--a miRNA-regulated metastasis suppressor gene in ductal adenocarcinomas of the pancreas. *International* 

Bentrem, D. J. (2008). Apigenin inhibits the GLUT-1 glucose transporter and the phosphoinositide 3-kinase/Akt pathway in human pancreatic cancer cells. *Pancreas*

Crippa, S., Mazzucchelli, L. & Frattini, M. (2009). Differing deregulation of EGFR and downstream proteins in primary colorectal cancer and related metastatic sites

Shiozawa, M., Akaike, M., Ohkawa, S., Kameda, Y. & Miyagi, Y. (2011). Immunohistochemical Analysis of Human Equilibrative Nucleoside Transporter-1 (hENT1) Predicts Survival in Resected Pancreatic Cancer Patients Treated with

Tabata, M., Ii, N., Inoue, H., Shiraishi, T. & Isaji, S. (2011). Human equilibrative

nucleoside transporter 1 expression is a strong independent prognostic factor in UICC T3-T4 pancreatic cancer patients treated with preoperative gemcitabinebased chemoradiotherapy. *Journal of hepato-biliary-pancreatic sciences,* DOI: 10.1007/S00534-011-0440-3


Biomarkers in Gastrointestinal Cancer: Focus on Colon, Pancreatic and Gastric Cancer 75

Siena, S., Sartore-Bianchi, A., Di Nicolantonio, F., Balfour, J. & Bardelli, A. (2009).

Souglakos, J., Philips, J., Wang, R., Marwah, S., Silver, M., Tzardi, M., Silver, J., Ogino, S.,

Sun, H.-C., Qiu, Z.-J., Liu, J., Sun, J., Jiang, T., Huang, K.-J., Yao, M. & Huang, C. (2007).

Szafranska, A. E., Davison, T. S., John, J., Cannon, T., Sipos, B., Maghnouj, A., Labourier, E.

Szafranska, A. E., Davison, T. S., Shingara, J., Doleshal, M., Riggenbach, J. A., Morrison, C.

Tanner, M., Hollmén, M., Junttila, T. T., Kapanen, A. I., Tommola, S., Soini, Y., Helin, H.,

Tejpar, S., Bertagnolli, M., Bosman, F., Lenz, H.-J., Garraway, L., Waldman, F., Warren, R.,

Tol, J., Nagtegaal, I. D. & Punt, C. J. A. (2009). BRAF mutation in metastatic colorectal

US National Academy Press, Institute of Medicine (U.S.). Committee on Developing

*Cytology [and] American Society of Cytology* 28(2), 61–68.

*American Association for Cancer Research* 10(20), 6956–6961.

*Journal of molecular diagnostics : JMD* 10(5), 415–423.

biomarker discovery. *The oncologist* 15(4), 390–404.

cancer. *The New England journal of medicine* 361(1), 98–99.

*Institute* 101(19), 1308–1324.

*journal of oncology* 30(6), 1359–1367.

26(30), 4442–4452.

393–403.

cancer. *Analytical and quantitative cytology and histology / the International Academy of* 

Biomarkers predicting clinical outcome of epidermal growth factor receptortargeted therapy in metastatic colorectal cancer. *Journal of the National Cancer* 

Hooshmand, S., Kwak, E., Freed, E., Meyerhardt, J. A., Saridaki, Z., Georgoulias, V., Finkelstein, D., Fuchs, C. S., Kulke, M. H. & Shivdasani, R. A. (2009). Prognostic and predictive value of common mutations for treatment response and survival in patients with metastatic colorectal cancer. *British journal of cancer* 101(3), 465–472. Spratlin, J., Sangha, R., Glubrecht, D., Dabbagh, L., Young, J. D., Dumontet, C., Cass, C., Lai,

R. & Mackey, J. R. (2004). The absence of human equilibrative nucleoside transporter 1 is associated with reduced survival in patients with gemcitabinetreated pancreas adenocarcinoma. *Clinical cancer research : an official journal of the* 

Expression of hypoxia-inducible factor-1 alpha and associated proteins in pancreatic ductal adenocarcinoma and their impact on prognosis. *International* 

& Hahn, S. A. (2007). MicroRNA expression alterations are linked to tumorigenesis and non-neoplastic processes in pancreatic ductal adenocarcinoma. *Oncogene*

D., Jewell, S. & Labourier, E. (2008). Accurate molecular characterization of formalin-fixed, paraffin-embedded tissues by microRNA expression profiling. *The* 

Salo, J., Joensuu, H., Sihvo, E., Elenius, K. & Isola, J. (2005). Amplification of HER-2 in gastric carcinoma: association with Topoisomerase IIalpha gene amplification, intestinal type, poor prognosis and sensitivity to trastuzumab. *Annals of oncology : official journal of the European Society for Medical Oncology / ESMO* 16(2), 273–278. Tedesco, K. L., Lockhart, A. C. & Berlin, J. D. (2004). The epidermal growth factor receptor as

a target for gastrointestinal cancer therapy. *Current treatment options in oncology* 5(5),

Bild, A., Collins-Brennan, D., Hahn, H., Harkin, D. P., Kennedy, R., Ilyas, M., Morreau, H., Proutski, V., Swanton, C., Tomlinson, I., Delorenzi, M., Fiocca, R., Van Cutsem, E. & Roth, A. (2010). Prognostic and predictive biomarkers in resected colon cancer: current status and future perspectives for integrating genomics into

Biomarker-Based Tools for Cancer Screening, Diagnosis, and Treatment (2007).

cetuximab in metastatic colorectal cancer patients. *Annals of oncology : official journal of the European Society for Medical Oncology / ESMO* 20(1), 84–90.


Pizzi, S., Porzionato, A., Pasquali, C., Guidolin, D., Sperti, C., Fogar, P., Macchi, V., De Caro,

Prenen, H., De Schutter, J., Jacobs, B., De Roock, W., Biesmans, B., Claes, B., Lambrechts, D.,

Rachagani, S., Kumar, S. & Batra, S. K. (2010). MicroRNA in pancreatic cancer: pathological,

Rivera, F., Vega-Villegas, M. E. & López-Brea, M. F. (2008). Cetuximab, its clinical use and

Roth, A. D., Tejpar, S., Delorenzi, M., Yan, P., Fiocca, R., Klingbiel, D., Dietrich, D.,

Samowitz, W. S., Sweeney, C., Herrick, J., Albertsen, H., Levin, T. R., Murtaugh, M. A.,

Sartore-Bianchi, A., Martini, M., Molinari, F., Veronese, S., Nichelatti, M., Artale, S., Di

Sawai, H., Yasuda, A., Ochi, N., Ma, J., Matsuo, Y., Wakasugi, T., Takahashi, H., Funahashi,

Scartozzi, M., Pierantoni, C., Berardi, R., Squadroni, M. & Cascinu, S. (2006a). Anti-EGFR

Scartozzi, M., Pierantoni, C., Berardi, R., Antognoli, S., Bearzi, I. & Cascinu, S. (2006b).

Biesmans, B., Bodoky, G., Barone, C., Aranda, E., Nordlinger, B., Cisar, L., Labianca, R., Cunningham, D., Van Cutsem, E. & Bosman, F. (2010). Prognostic role of KRAS and BRAF in stage II and III resected colon cancer: results of the translational study on the PETACC-3, EORTC 40993, SAKK 60-00 trial. *Journal of clinical oncology : official journal of the American Society of Clinical Oncology* 28(3), 466–

Wolff, R. K. & Slattery, M. L. (2005). Poor survival associated with the BRAF V600E mutation in microsatellite-stable colon cancers. *Cancer research* 65(14), 6063–6069. Sartore-Bianchi, A., Di Nicolantonio, F., Nichelatti, M., Molinari, F., De Dosso, S., Saletti, P.,

Martini, M., Cipani, T., Marrapese, G., Mazzucchelli, L., Lamba, S., Veronese, S., Frattini, M., Bardelli, A. & Siena, S. (2009a). Multi-determinants analysis of molecular alterations for predicting clinical benefit to EGFR-targeted monoclonal

Nicolantonio, F., Saletti, P., De Dosso, S., Mazzucchelli, L., Frattini, M., Siena, S. & Bardelli, A. (2009b). PIK3CA mutations in colorectal cancer are associated with clinical resistance to EGFR-targeted monoclonal antibodies. *Cancer research* 69(5),

H., Sato, M. & Takeyama, H. (2008). Loss of PTEN expression is associated with colorectal cancer liver metastasis and poor patient survival. *BMC gastroenterology* 8,

strategies as an incremental step for the treatment of colorectal cancer patients: moving from scientific evidence to clinical practice. *Expert opinion on therapeutic* 

Epidermal growth factor receptor: a promising therapeutic target for colorectal

diagnostic and therapeutic implications. *Cancer letters* 292(1), 8–16.

*of the European Society for Medical Oncology / ESMO* 20(1), 84–90.

*Association for Cancer Research* 15(9), 3184–3188.

future perspectives. *Anti-cancer drugs* 19(2), 99–113.

antibodies in colorectal cancer. *PloS one* 4(10), e7287.

24(2), 175–185.

474.

1851–1857.

*targets* 10(2), 281–287.

56.

cetuximab in metastatic colorectal cancer patients. *Annals of oncology : official journal* 

R., Pedrazzoli, S. & Parenti, A. (2009). Glucose transporter-1 expression and prognostic significance in pancreatic carcinogenesis. *Histology and histopathology*

Van Cutsem, E. & Tejpar, S. (2009). PIK3CA mutations are not a major determinant of resistance to the epidermal growth factor receptor inhibitor cetuximab in metastatic colorectal cancer. *Clinical cancer research : an official journal of the American*  cancer. *Analytical and quantitative cytology and histology / the International Academy of Cytology [and] American Society of Cytology* 28(2), 61–68.


**4** 

Lydia Finney

*USA* 

*Advanced Photon Source, Argonne National Laboratory,* 

**Inorganic Signatures of Physiology:** 

**The X-Ray Fluorescence Microscopy Revolution** 

Metals are vital to nearly all the life processes within the cell. It is estimated that nearly a third of cellular proteins bind metals. Yet, the very same properties of these metal ions which make them so useful, also makes them potentially hazardous within the cell. Endogenous metals, such as copper, zinc, and iron are also potentially toxic, performing deleterious redox chemistry if not carefully controlled and regulated(Finney and O'Halloran 2003). The intricate cellular machinery that manages these metals are collectively known as the metal homeostasis and trafficking proteins of the cell. While we have learned much with respect to how the cell partitions and allocates metals, and at times attempted to define the 'concentration' in various compartments of the cell, instead we have begun to see how illdefined a 'resting' condition really is, and how much the partitioning of cellular metals can

What is it about metals which make them so critical, and so useful? Unlike other elements, biological metals, and particularly the first row of transition metals in the periodic table, have a partially filled d-shell of orbitals. This gives them multiple semi-stable oxidation states under ambient conditions. And the changes between these states provide reduction and oxidation potential for the chemistry of the cell (Bertini, Gray et al. 2007). For example, iron, as part of hemoglobin, shuffles between a (II) and (III) oxidation state to perform the vital act of delivering oxygen throughout the body. However, the same element, iron, if it were a 'free' aquo- ion in the cytoplasm of the cell would likely undergo Fenton chemistry, and these same changes in oxidation state would give rise to the generation of radicals that

Still, biology manages, most of the time, to work. The efficient chemistry of these life processes often exceeds our own ability to accomplish their work synthetically. Unraveling the ways in which the chemistry of these metals is controlled promises not only to improve what we know about chemistry, accomplishing important reactions such as the oxidation of methane or the fixation of nitrogen in new and more efficient ways, but also to remarkably

improve our understanding of biology, and our ability to manipulate it as well.

**1.1 Metals as an essential, yet potentially toxic part of cellular chemistry**

change (Dodani, Leary et al. 2011; Qin, Dittmer et al. 2011).

**1. Introduction** 

would damage the cell.

*Cancer biomarkers*. p 236 Natl Academy Pr. (the promises and challenges of improving detection and treatment).

