INFLUENCE OF PRE-OPERATIVE CHEMOTHERAPY ON HEPATIC MORPHO-PATHOLOGY

September 5, 2017

INFLUENCE OF PRE-OPERATIVE CHEMOTHERAPY ON HEPATIC MORPHO-PATHOLOGY

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Title:	INFLUENCE OF PRE-OPERATIVE CHEMOTHERAPY ON HEPATIC MORPHO-PATHOLOGY
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Article_Title:	INFLUENCE OF PRE-OPERATIVE CHEMOTHERAPY ON HEPATIC MORPHO-PATHOLOGY
Authors:	Carolina Negrei1, George Traian Alexandru Burcea Dragomiroiu2, Octav Ginghină3*, Daniel Boda4, Bianca Galateanu5, Miriana Stan1, Cristian Balalau6, Claudia Gutu1, Corina Dalia Toderescu7, Geoge Ciprian Pribac8,9, Ion Dina10
Affiliation:	1 Department of Toxicology, “Carol Davila” University of Medicine and Pharmacy, 6, Traian Vuia Street, 020956, Bucharest, Romania 2 Department of Drug Control, “Carol Davila” University of Medicine and Pharmacy, 6, Traian Vuia Street, 020956, Bucharest, Romanianj 78 3“Sf. Ioan” Emergency Hospital, Surgical Clinic, University of Medicine and Pharmacy “ Carol Davila”, 13, Vitan-Bârzesti Street, 042122, Bucharest, Romania 4Dermato-oncology Excellence Research Center “Carol Davila” University of Medicine and Pharmacy, 22-24, Gr. Manolescu Street, Bucharest, Romania 5Department of Biochemistry and Molecular Biology, University of Bucharest, Bucharest, Romania 6 “Sf. Pantelimon” Hospital Bucharest, Surgical Clinic, “Carol Davila” University of Medicine and Pharmacy, 340-342, Pantelimon Street, Bucharest, Romania 7 Faculty of Pharmacy, Department of Pharmaceutical Sciences, ”Vasile Goldis” Western University of Arad, 91-93, L. Rebreanu Street, Arad, Romania 8 Faculty of Medicine, Department of Cell and Molecular Biology, Life Sciences Institute, ”Vasile Goldis” Western University of Arad, 91-93, L. Rebreanu Street, Arad, Romania 9 Department of Histopathology, Clinical Emergency County Hospital Arad, Romania 10 “Sf. Ioan” Emergency Hospital, Gastroenterology Clinic, University of Medicine and Pharmacy “ Carol Davila”, 13, Vitan-Bârzesti Street, 042122, Bucharest, Romania
Abstract:	Pre-surgical chemotherapy in colorectal liver metastases may determine histological changes in tumour-free liver, potentially impacting operative outcomes. Our study involved 92 patients with liver resection, undergoing treatment for liver metastases of colorectal origin; they were assigned into two groups, A and B, after random selection. Group A had 68 patients with pre-operative chemotherapy (standard FOLFOX/FOLFIRI) and Group B consisted of 24 patients considered chemotherapy naive. Pre-surgery FOLFOX/FOLFIRI chemotherapy induced hepatic lesions, the most important of which is not steatosis but vascular lesion. In-depth pathologic analysis showed that most serious vascular lesions may be traced back to enhanced intra-surgery transfusion. The risk for post-surgical complications is associated with length of pre-surgery chemotherapy.
Keywords:	colorectal cancer, liver metastases, chemotherapy, liver resection
References:	Abdalla E.K., Vauthey J.N., Ellis L.M., et al., Recurrence and outcomes following hepatic resection, radiofrequencyablation, and combined resection/ablation for colorectal liver metastases. Ann Surg 239:818-825, 2004 Adam R, Delvart V, Pascal G, et al., Rescue surgery for unresectable colorectal liver metastases downstaged by chemotherapy: A model to predict long-term survival. Ann Surg 240:644-657, 2004 Alberts S.R., Horvath W.L., Sternfeld W.C., Goldberg R.M., Mahoney M.R., Dakhil S.R., Levitt R., Rowland K., Nair S., Sargent D.J., Donohue J.H., Oxaliplatin, fluorouracil and leucovorin for patients with unresectable liver-only metastases from colorectal cancer: a North Central Cancer Treatment Group phase II study. J Clin Oncol 2005;23:9243-9249 Auer R.C., White R.R., Kemeny N.E., Schwartz L.H., Shia J., Blumgart L.H., Dematteo R.P., Fong Y., Jarnagin W.R., D’Angelica M.I., Predictors of a true complete response among disappearing liver metastases from colorectal cancer after chemotherapy, Cancer. 2010 Mar 15;116(6):1502-9. doi: 10.1002/cncr.24912. Behrns K.E., Tsiotos G.G., DeSouza N.F. et al., Hepatic steatosis as a potential risk factor for major hepatic resection. J Gastrointest Surg 2:292-298, 1998 Belghiti J., Hiramatsu K., Benoist S., et al., Seven hundred forty-seven hepatectomies in the 1990’s: An update to evaluate the actual risk of liver resection. J Am Coll Surg 191:38-46, 2000 Choti M.A, Sitzmann J.V, Tiburi M.F, et al., Trends in long-term survival following liver resection for hepatic colorectal metastases. Ann Surg 235:759-766, 2002 Elias D, Lasser P, Rougier P, et al., Frequency, technical aspects, results, and indications of major hepatectomy after prolonged intra-arterial hepatic chemotherapy for initially unresectable hepatic tumors. J Am Coll Surg 180:213-219, 1995 Fernandez F.G, Drebin JA, Linehan DC, et al., Five-year survival after resection of hepatic metastases from colorectal cancer in patients screened by positron emission tomography with F-18 fluorodeoxyglucose (FDG-PET). Ann Surg 240:438-447, 2004 Fernandez F.G., Ritter J., Goodwin J.W., Linehan D.C., Hawkins W.G., Strasberg S.M., Effect of steatohepatitis associated with irinotecan or oxaliplatin pretreatment on resectability of hepatic colorectal metastases. J Am Coll Surg 2005;200:845-853 Fong Y., Fortner J., Sun R.L., Brennan M.F., Blumgart L.H., Clinical score for predicting recurrence after hepatic resection for metastatic colorectal cancer: analysis of 1001 consecutive cases. Ann Surg 1999; 230:309-318; discussion 318-321 Gabrilovich D.I., Nagaraj S., Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol 2009;9:162-174 Grothey A., Sargent D., Goldberg R.M. et al., Survival of patients with advanced colorectal cancer improves with the availability of fluorouracil-leucovorin, irinotecan and oxaliplatin in the course of treatment. J Clin Oncol 2004;22:1209–1214 Imamura H, Takayama T, Sugawara Y, et al., Pringle’s manoeuvre in living donors. Lancet 360: 2049-2050, 2002 Karakousis G., Fong Y., The case for selective use of preoperative chemotherapy for hepatic colorectal metastases: more is not always better. Ann Surg Oncol 2009;16:2086-2088 Karoui M, Penna C, Amin-Hashem M, et al., Influence of preoperative chemotherapy on the risk of major hepatectomy for colorectal liver metastases. Ann Surg 243:1-7, 2006 Masi G., Cupini S., Marcucci L., Cerri E., Loupakis F., Allegrini G., Brunetti I.M., Pfanner E., Viti M., Goletti O., Filipponi F., Falcone A., Treatment with 5-fluorouracil/folinic acid, oxaliplatin and irinotecan enables surgical resection of metastases in patients with initially unresectable metastatic colorectal cancer. Ann Surg Oncol 2006;13:58-65 Mazzaferro V., Coppa J., Carrabba M.G., Rivoltini L., Schiavo M., Regalia E., Mariani L., Camerini T., Marchianò A., Andreola S., Camerini R., Corsi M., Lewis J.J., Srivastava P.K., Parmiani G., Vaccination with autologous tumor-derived heat-shock protein gp96 after liver resection for metastatic colorectal cancer. Clin Cancer Res 2003;9:3235-3245 Nordlinger B., Guiguet M., Vaillant J.C., Balladur P, Boudjema K., Bachellier P., Jaeck D., Surgical resection of colorectal carcinoma metastases to the liver. A prognostic scoring system to improve case selection, based on 1568 patients. Association Française de Chirurgie. Cancer 1996;77:1254-1262 Nordlinger B, Sorbye M, Debois M, et al., Feasibility and risks of preoperative chemotherapy with FOLFOX 4 and surgery for resectable colorectal cancer liver metastases: Interim results of the EORTC Intergroup randomized phase III study 40983. J Clin Oncol 23:253s, 2005 (suppl, abstr 3528) Parikh AA, Gentner B, Wu TT, et al., Perioperative complications in patients undergoing major liver resection with or without neoadjuvant chemotherapy. J Gastrointest Surg 7:1082-1088, 2003 Pawlik TM, Scoggins CR, Zorzi D, et al., Effect of surgical margin status on survival and site of recurrence after hepatic resection for colorectal metastases. Ann Surg 241:715-722, 2005 Pocard M, Vincent-Salomon A, Girodet J, et al., Effects of preoperative chemotherapy on liver function tests after hepatectomy. Hepatogastroenterology 48:1406-1408, 2001 Reddy G.K., Gibson A.D., Price N., Evolution of FOLFOX regimens in the treatment of advanced colorectal cancer. Clin Colorectal Cancer 2005;4:296–299 Rubbia-Brandt L, Audard V, Sartoretti P, et al., Severe hepatic sinusoidal obstruction associated with oxaliplatin-based chemotherapy in patients with metastatic colorectal cancer. Ann Oncol 15:460-466, 2004 Sauer R., Becker H., Hohenberger W., Rödel C., Wittekind C., Fietkau R., Martus P., Tschmelitsch J., Hager E., Hess C.F., Karstens J.H., Liersch T., Schmidberger H., Raab R., Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med 2004;351:1731-1740 Topham C, Adam R., Oncosurgery: A new reality in metastatic colorectal carcinoma. Semin Oncol 29:3-10, 2002 Troester M.A., Lee M.H., Carter M., Fan C., Cowan D.W., Perez E.R., Pirone J.R., Perou C.M., Jerry D.J., Schneider S.S., Activation of host wound responses in breast cancer microenvironment. Clin Cancer Res 2009;15:7020-7028 Vauthey J.N, Pawlik T.M, Abdalla E.K, et al, Is extended hepatectomy for hepatobiliary malignancy justified? Ann Surg 239:722-730, 2004 Vauthey J.N., Pawlik T.M., Ribero D., Wu T.T., Zorzi D., Hoff P.M. et al., Chemotherapy regimen predicts steatohepatitis and an increase in 90-day mortality after surgery for hepatic colorectal metastases. J Clin Oncol 2006;24:2065–2072 We attest to the fact that all Authors listed on the title page have the same contribution to the work.
Read_full_article:	pdf/vol19/iss4/4 JMA 2016 – Negrei – Articol 2 Arad 22.06.2017.pdf
Correspondence:	Octav Ginghină, “Sf. Ioan” Emergency Hospital, Surgical Clinic, University of Medicine and Pharmacy “Carol Davila”, 13, Vitan-Bârzesti Street, 042122, Bucharest, Romania, +40213345170/+40213345970, e-mail: octavginghina@yahoo.com

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Article Title:	INFLUENCE OF PRE-OPERATIVE CHEMOTHERAPY ON HEPATIC MORPHO-PATHOLOGY
Authors:	Carolina Negrei1, George Traian Alexandru Burcea Dragomiroiu2, Octav Ginghină3*, Daniel Boda4, Bianca Galateanu5, Miriana Stan1, Cristian Balalau6, Claudia Gutu1, Corina Dalia Toderescu7, Geoge Ciprian Pribac8,9, Ion Dina10
Affiliation:	1 Department of Toxicology, “Carol Davila” University of Medicine and Pharmacy, 6, Traian Vuia Street, 020956, Bucharest, Romania 2 Department of Drug Control, “Carol Davila” University of Medicine and Pharmacy, 6, Traian Vuia Street, 020956, Bucharest, Romanianj 78 3“Sf. Ioan” Emergency Hospital, Surgical Clinic, University of Medicine and Pharmacy “ Carol Davila”, 13, Vitan-Bârzesti Street, 042122, Bucharest, Romania 4Dermato-oncology Excellence Research Center “Carol Davila” University of Medicine and Pharmacy, 22-24, Gr. Manolescu Street, Bucharest, Romania 5Department of Biochemistry and Molecular Biology, University of Bucharest, Bucharest, Romania 6 “Sf. Pantelimon” Hospital Bucharest, Surgical Clinic, “Carol Davila” University of Medicine and Pharmacy, 340-342, Pantelimon Street, Bucharest, Romania 7 Faculty of Pharmacy, Department of Pharmaceutical Sciences, ”Vasile Goldis” Western University of Arad, 91-93, L. Rebreanu Street, Arad, Romania 8 Faculty of Medicine, Department of Cell and Molecular Biology, Life Sciences Institute, ”Vasile Goldis” Western University of Arad, 91-93, L. Rebreanu Street, Arad, Romania 9 Department of Histopathology, Clinical Emergency County Hospital Arad, Romania 10 “Sf. Ioan” Emergency Hospital, Gastroenterology Clinic, University of Medicine and Pharmacy “ Carol Davila”, 13, Vitan-Bârzesti Street, 042122, Bucharest, Romania
Abstract:	Pre-surgical chemotherapy in colorectal liver metastases may determine histological changes in tumour-free liver, potentially impacting operative outcomes. Our study involved 92 patients with liver resection, undergoing treatment for liver metastases of colorectal origin; they were assigned into two groups, A and B, after random selection. Group A had 68 patients with pre-operative chemotherapy (standard FOLFOX/FOLFIRI) and Group B consisted of 24 patients considered chemotherapy naive. Pre-surgery FOLFOX/FOLFIRI chemotherapy induced hepatic lesions, the most important of which is not steatosis but vascular lesion. In-depth pathologic analysis showed that most serious vascular lesions may be traced back to enhanced intra-surgery transfusion. The risk for post-surgical complications is associated with length of pre-surgery chemotherapy.
Keywords:	colorectal cancer, liver metastases, chemotherapy, liver resection
References:	Abdalla E.K., Vauthey J.N., Ellis L.M., et al., Recurrence and outcomes following hepatic resection, radiofrequencyablation, and combined resection/ablation for colorectal liver metastases. Ann Surg 239:818-825, 2004 Adam R, Delvart V, Pascal G, et al., Rescue surgery for unresectable colorectal liver metastases downstaged by chemotherapy: A model to predict long-term survival. Ann Surg 240:644-657, 2004 Alberts S.R., Horvath W.L., Sternfeld W.C., Goldberg R.M., Mahoney M.R., Dakhil S.R., Levitt R., Rowland K., Nair S., Sargent D.J., Donohue J.H., Oxaliplatin, fluorouracil and leucovorin for patients with unresectable liver-only metastases from colorectal cancer: a North Central Cancer Treatment Group phase II study. J Clin Oncol 2005;23:9243-9249 Auer R.C., White R.R., Kemeny N.E., Schwartz L.H., Shia J., Blumgart L.H., Dematteo R.P., Fong Y., Jarnagin W.R., D’Angelica M.I., Predictors of a true complete response among disappearing liver metastases from colorectal cancer after chemotherapy, Cancer. 2010 Mar 15;116(6):1502-9. doi: 10.1002/cncr.24912. Behrns K.E., Tsiotos G.G., DeSouza N.F. et al., Hepatic steatosis as a potential risk factor for major hepatic resection. J Gastrointest Surg 2:292-298, 1998 Belghiti J., Hiramatsu K., Benoist S., et al., Seven hundred forty-seven hepatectomies in the 1990’s: An update to evaluate the actual risk of liver resection. J Am Coll Surg 191:38-46, 2000 Choti M.A, Sitzmann J.V, Tiburi M.F, et al., Trends in long-term survival following liver resection for hepatic colorectal metastases. Ann Surg 235:759-766, 2002 Elias D, Lasser P, Rougier P, et al., Frequency, technical aspects, results, and indications of major hepatectomy after prolonged intra-arterial hepatic chemotherapy for initially unresectable hepatic tumors. J Am Coll Surg 180:213-219, 1995 Fernandez F.G, Drebin JA, Linehan DC, et al., Five-year survival after resection of hepatic metastases from colorectal cancer in patients screened by positron emission tomography with F-18 fluorodeoxyglucose (FDG-PET). Ann Surg 240:438-447, 2004 Fernandez F.G., Ritter J., Goodwin J.W., Linehan D.C., Hawkins W.G., Strasberg S.M., Effect of steatohepatitis associated with irinotecan or oxaliplatin pretreatment on resectability of hepatic colorectal metastases. J Am Coll Surg 2005;200:845-853 Fong Y., Fortner J., Sun R.L., Brennan M.F., Blumgart L.H., Clinical score for predicting recurrence after hepatic resection for metastatic colorectal cancer: analysis of 1001 consecutive cases. Ann Surg 1999; 230:309-318; discussion 318-321 Gabrilovich D.I., Nagaraj S., Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol 2009;9:162-174 Grothey A., Sargent D., Goldberg R.M. et al., Survival of patients with advanced colorectal cancer improves with the availability of fluorouracil-leucovorin, irinotecan and oxaliplatin in the course of treatment. J Clin Oncol 2004;22:1209–1214 Imamura H, Takayama T, Sugawara Y, et al., Pringle’s manoeuvre in living donors. Lancet 360: 2049-2050, 2002 Karakousis G., Fong Y., The case for selective use of preoperative chemotherapy for hepatic colorectal metastases: more is not always better. Ann Surg Oncol 2009;16:2086-2088 Karoui M, Penna C, Amin-Hashem M, et al., Influence of preoperative chemotherapy on the risk of major hepatectomy for colorectal liver metastases. Ann Surg 243:1-7, 2006 Masi G., Cupini S., Marcucci L., Cerri E., Loupakis F., Allegrini G., Brunetti I.M., Pfanner E., Viti M., Goletti O., Filipponi F., Falcone A., Treatment with 5-fluorouracil/folinic acid, oxaliplatin and irinotecan enables surgical resection of metastases in patients with initially unresectable metastatic colorectal cancer. Ann Surg Oncol 2006;13:58-65 Mazzaferro V., Coppa J., Carrabba M.G., Rivoltini L., Schiavo M., Regalia E., Mariani L., Camerini T., Marchianò A., Andreola S., Camerini R., Corsi M., Lewis J.J., Srivastava P.K., Parmiani G., Vaccination with autologous tumor-derived heat-shock protein gp96 after liver resection for metastatic colorectal cancer. Clin Cancer Res 2003;9:3235-3245 Nordlinger B., Guiguet M., Vaillant J.C., Balladur P, Boudjema K., Bachellier P., Jaeck D., Surgical resection of colorectal carcinoma metastases to the liver. A prognostic scoring system to improve case selection, based on 1568 patients. Association Française de Chirurgie. Cancer 1996;77:1254-1262 Nordlinger B, Sorbye M, Debois M, et al., Feasibility and risks of preoperative chemotherapy with FOLFOX 4 and surgery for resectable colorectal cancer liver metastases: Interim results of the EORTC Intergroup randomized phase III study 40983. J Clin Oncol 23:253s, 2005 (suppl, abstr 3528) Parikh AA, Gentner B, Wu TT, et al., Perioperative complications in patients undergoing major liver resection with or without neoadjuvant chemotherapy. J Gastrointest Surg 7:1082-1088, 2003 Pawlik TM, Scoggins CR, Zorzi D, et al., Effect of surgical margin status on survival and site of recurrence after hepatic resection for colorectal metastases. Ann Surg 241:715-722, 2005 Pocard M, Vincent-Salomon A, Girodet J, et al., Effects of preoperative chemotherapy on liver function tests after hepatectomy. Hepatogastroenterology 48:1406-1408, 2001 Reddy G.K., Gibson A.D., Price N., Evolution of FOLFOX regimens in the treatment of advanced colorectal cancer. Clin Colorectal Cancer 2005;4:296–299 Rubbia-Brandt L, Audard V, Sartoretti P, et al., Severe hepatic sinusoidal obstruction associated with oxaliplatin-based chemotherapy in patients with metastatic colorectal cancer. Ann Oncol 15:460-466, 2004 Sauer R., Becker H., Hohenberger W., Rödel C., Wittekind C., Fietkau R., Martus P., Tschmelitsch J., Hager E., Hess C.F., Karstens J.H., Liersch T., Schmidberger H., Raab R., Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med 2004;351:1731-1740 Topham C, Adam R., Oncosurgery: A new reality in metastatic colorectal carcinoma. Semin Oncol 29:3-10, 2002 Troester M.A., Lee M.H., Carter M., Fan C., Cowan D.W., Perez E.R., Pirone J.R., Perou C.M., Jerry D.J., Schneider S.S., Activation of host wound responses in breast cancer microenvironment. Clin Cancer Res 2009;15:7020-7028 Vauthey J.N, Pawlik T.M, Abdalla E.K, et al, Is extended hepatectomy for hepatobiliary malignancy justified? Ann Surg 239:722-730, 2004 Vauthey J.N., Pawlik T.M., Ribero D., Wu T.T., Zorzi D., Hoff P.M. et al., Chemotherapy regimen predicts steatohepatitis and an increase in 90-day mortality after surgery for hepatic colorectal metastases. J Clin Oncol 2006;24:2065–2072 We attest to the fact that all Authors listed on the title page have the same contribution to the work.
*Correspondence:	Octav Ginghină, “Sf. Ioan” Emergency Hospital, Surgical Clinic, University of Medicine and Pharmacy “Carol Davila”, 13, Vitan-Bârzesti Street, 042122, Bucharest, Romania, +40213345170/+40213345970, e-mail: octavginghina@yahoo.com

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