title: Tailoring heated intraperitoneal mitomycin C for peritoneal metastases originating from colorectal carcinoma: a translational approach to improve survival.
abstract: BACKGROUND
  Patients with peritoneal metastases (PMs) originating from colorectal carcinoma (CRC) are curatively treated by cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) with mitomycin C (MMC). We aim to improve patient selection for HIPEC by predicting MMC sensitivity.
  
  
  METHODS
  The MMC sensitivity was determined for 12 CRC cell lines and correlated to mRNA expression of 37 genes related to the Fanconi anaemia (FA)-BRCA pathway, ATM-ATR pathway and enzymatic activation of MMC. Functionality of the FA-BRCA pathway in cell lines was assessed using a chromosomal breakage assay and western blot for key protein FANCD2. Bloom syndrome protein (BLM) was further analysed by staining for the corresponding protein with immunohistochemistry (IHC) on both CRC cell lines (n=12) and patient material (n=20).
  
  
  RESULTS
  High sensitivity correlated with a low BLM (P=0.01) and BRCA2 (P=0.02) at mRNA expression level. However, FA-BRCA pathway functionality demonstrated no correlation to MMC sensitivity. In cell lines, weak intensity staining of BLM by IHC correlated to high sensitivity (P=0.04) to MMC. Low BLM protein expression was significantly associated with an improved survival in patients after CRS and HIPEC (P=0.04).
  
  
  CONCLUSIONS
  Low BLM levels are associated with high MMC sensitivity and an improved survival after HIPEC.
authors: Department of Surgical Oncology, Cancer Center Amsterdam and VU University Medical Center, De Boelelaan 1117, Amsterdam 1081 HV, The Netherlands.
authors: R
authors: R
authors: Kwakman
authors: Department of Surgical Oncology, Cancer Center Amsterdam and VU University Medical Center, De Boelelaan 1117, Amsterdam 1081 HV, The Netherlands.
authors: E M V
authors: EM
authors: de Cuba
authors: Department of Clinical Genetics, Cancer Center Amsterdam and VU University Medical Center, De Boelelaan 1117, Amsterdam 1081 HV, The Netherlands.
authors: J P
authors: JP
authors: de Winter
authors: Department of Surgery, Catharina Ziekenhuis Eindhoven, Eindhoven, The Netherlands.
authors: I H J T
authors: IH
authors: de Hingh
authors: Department of Pathology and Tumour Profiling Unit, Cancer Center Amsterdam and VU University Medical Center, De Boelelaan 1117, Amsterdam 1081 HV, The Netherlands.
authors: P M
authors: PM
authors: Delis-van Diemen
authors: Department of Pathology and Tumour Profiling Unit, Cancer Center Amsterdam and VU University Medical Center, De Boelelaan 1117, Amsterdam 1081 HV, The Netherlands.
authors: M
authors: M
authors: Tijssen
authors: Department of Clinical Genetics, Cancer Center Amsterdam and VU University Medical Center, De Boelelaan 1117, Amsterdam 1081 HV, The Netherlands.
authors: M A
authors: MA
authors: Rooimans
authors: Department of Pathology and Tumour Profiling Unit, Cancer Center Amsterdam and VU University Medical Center, De Boelelaan 1117, Amsterdam 1081 HV, The Netherlands.
authors: O
authors: O
authors: Krijgsman
authors: Department of Pathology and Tumour Profiling Unit, Cancer Center Amsterdam and VU University Medical Center, De Boelelaan 1117, Amsterdam 1081 HV, The Netherlands.
authors: B
authors: B
authors: Carvalho
authors: Department of Oncology, Cancer Center Amsterdam and VU University Medical Center, De Boelelaan 1117, Amsterdam 1081 HV, The Netherlands.
authors: G J
authors: GJ
authors: Peters
authors: Department of Surgical Oncology, Cancer Center Amsterdam and VU University Medical Center, De Boelelaan 1117, Amsterdam 1081 HV, The Netherlands.
authors: H J
authors: HJ
authors: Bonjer
authors: Department of Pathology and Tumour Profiling Unit, Cancer Center Amsterdam and VU University Medical Center, De Boelelaan 1117, Amsterdam 1081 HV, The Netherlands.
authors: G A
authors: GA
authors: Meijer
authors: Department of Surgical Oncology, Cancer Center Amsterdam and VU University Medical Center, De Boelelaan 1117, Amsterdam 1081 HV, The Netherlands.
authors: E A
authors: EA
authors: Te Velde
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000494:pharmacology* / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000378:metabolism*; D018938:Caco-2 Cells; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000401:mortality / Q000628:therapy*; D052236:Fanconi Anemia Complementation Group D2 Protein / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D006979:Hyperthermia, Induced / Q000379:methods*; D016685:Mitomycin / Q000494:pharmacology* / Q000627:therapeutic use; D010534:Peritoneal Neoplasms / Q000401:mortality / Q000556:secondary* / Q000628:therapy*; D053484:RecQ Helicases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D016019:Survival Analysis; D057170:Translational Research, Biomedical
chemical_list: D000903:Antibiotics, Antineoplastic; D014408:Biomarkers, Tumor; C499905:FANCD2 protein, human; D052236:Fanconi Anemia Complementation Group D2 Protein; D016685:Mitomycin; C097151:Bloom syndrome protein; D053484:RecQ Helicases