levoleucovorin and Adenoma

NR4A2, an orphan nuclear receptor essential in neuron generation, has been recently linked to inflammatory and metabolic pathways of colorectal carcinoma (CRC). However, the effects of NR4A2 on chemo-resistance and postoperative prognosis of CRC remain unknown.. NR4A2 was transfected into CRC cells to investigate its effects on chemo-resistance to 5-fluorouracil and oxaliplatin and chemotherapeutics-induced apoptosis. We also investigated prostaglandin E2 (PGE2)-induced NR4A2 expression and its effect on chemo-resistance. Tissue microarrays including 51 adenoma, 14 familial adenomatous polyposis with CRC, 17 stage IV CRC with adjacent mucosa and 682 stage I-III CRC specimens were examined immunohistochemically for NR4A2 expression. Median follow-up time for stage I-III CRC patients was 53 months.. Ectopic expression of NR4A2 increased the chemo-resistance, and attenuated the chemotherapeutics-induced apoptosis. Transient treatment of PGE2 significantly up-regulated NR4A2 expression via protein kinase A pathway and increased the chemo-resistance. NR4A2 expression in epithelials consecutively increased from adenoma, adjacent mucosa to CRC (P(trend)<0.001). In multivariate Cox regression analyses, high NR4A2 expression in cancer nuclei (immunoreactive score ≥ 4) significantly predicted a shorter disease-specific survival (DSS) of CRC patients (hazard ratio [HR]=1.88, P=0.024). High NR4A2 expression specifically predicted a shorter DSS of colon cancer patients (dichotomisation, HR=2.55, log-rank test P=0.011), especially for those who received postoperative 5-fluorouracil/leucovorin plus oxaliplatin (FOLFOX) chemotherapy (3-score range, HR=1.86, log-rank test P=0.020).. High expression of NR4A2 in CRC cells confers chemo-resistance, attenuates chemotherapeutics-induced apoptosis, and predicts unfavorable prognosis of colon cancer patients, especially for those who received postoperative chemotherapy. NR4A2 may be prognostic and predictive for colon cancer.

Topics: Adenoma; Adenomatous Polyposis Coli; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Biomarkers, Tumor; Chemotherapy, Adjuvant; Chi-Square Distribution; Colorectal Neoplasms; Dinoprostone; Disease-Free Survival; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Fluorouracil; HCT116 Cells; Humans; Intestinal Polyps; Kaplan-Meier Estimate; Leucovorin; Multivariate Analysis; Neoplasm Staging; Nuclear Receptor Subfamily 4, Group A, Member 2; Organoplatinum Compounds; Proportional Hazards Models; Time Factors; Transfection; Treatment Outcome; Up-Regulation

Differential diagnosis of liver lesion in the absence of proven primary tumor is still a challenge. We experienced a case of an asymptomatic 14 cm lesion of right hemiliver in a 67 year-old man submitted to right hepatectomy in December 2010. One year before the patient underwent to endoscopic removal of a tubular adenoma of the right colon. Preoperative diagnosis was supported by ultrasound, CT scan, PET and liver biopsy. The patient received 6 cycles of preoperative chemotherapy (FOLFOX) with down-staging of the lesion diameter. Immunohistochemistry on the surgical specimen showed positivity for cytokeratins 19 and 20, CEA, MUC-2, negativity for cytokeratin 7 and a-fetoprotein. Moreover, the neoplastic cells showed a focal positivity with lower intensity for MUC-1 and MUC-5AC. The immunohistochemical profile suggested the possibility of a metastatic tumour from the large bowel, without excluding a primitive mucinous cholangiocarcinoma with intestinal phenotype. At 6 months after intervention, the patient was submitted to chemotherapy (FOLFOX). At present he is in good condition, without radiological signs of recurrence. Oncologists must evaluate the possible benefits of further adjuvant treatments based on the differential diagnosis between a primitive or metastatic liver tumour. In conclusion, correct diagnosis of liver masses is mandatory and remains a challenge that can differentiate either follow-up or surgical and adjuvant treatment. Histology and immunohistochemistry must be related to clinical findings as they may not always be sufficient to reach a correct final diagnosis, and can even be confusing. At present, molecular biology cannot be considered a helpful for diagnosis in these cases.

Topics: Adenoma; Aged; Antineoplastic Combined Chemotherapy Protocols; Bile Duct Neoplasms; Bile Ducts, Intrahepatic; Biomarkers, Tumor; Cholangiocarcinoma; Diagnosis, Differential; Fluorouracil; Humans; Immunohistochemistry; Intestinal Neoplasms; Leucovorin; Male; Neoplasms, Second Primary; Neoplasms, Unknown Primary; Organoplatinum Compounds

Laparoscopic left lateral sectionectomy (LLS) has gained popularity in its use for benign and malignant tumors. This report describes the evolution of the authors' experience using laparoscopic LLS for different indications including living liver donation.. Between January 2004 and January 2009, 37 consecutive patients underwent laparoscopic LLS for benign, primary, and metastatic liver diseases, and for one case of living liver donation. Resection of malignant tumors was indicated for 19 (51%) of the 37 patients.. All but three patients (deceased due to metastatic cancer disease) are alive and well after a median follow-up period of 20 months (range, 8-46 months). Liver cell adenomas (72%) were the main indication among benign tumors, and colorectal liver metastases (84%) were the first indication of malignancy. One case of live liver donation was performed. Whereas 16 patients (43%) had undergone a previous abdominal surgery, 3 patients (8%) had LLS combined with bowel resection. The median operation time was of 195 min (range, 115-300 min), and the median blood loss was of 50 ml (range, 0-500 ml). Mild to severe steatosis was noted in 7 patients (19%) and aspecific portal inflammation in 11 patients (30%). A median free margin of 5 mm (range, 5-27 mm) was achieved for all cancer patients. The overall recurrence rate for colorectal liver metastases was of 44% (7 patients), but none recurred at the surgical margin. No conversion to laparotomy was recorded, and the overall morbidity rate was 8.1% (1 grade 1 and 2 grade 2 complications). The median hospital stay was 6 days (range, 2-10 days).. Laparoscopic LLS without portal clamping can be performed safely for cases of benign and malignant liver disease with minimal blood loss and overall morbidity, free resection margins, and a favorable outcome. As the ultimate step of the learning curve, laparoscopic LLS could be routinely proposed, potentially increasing the donor pool for living-related liver transplantation.

Topics: Adenocarcinoma; Adenoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Blood Loss, Surgical; Camptothecin; Carcinoma, Hepatocellular; Combined Modality Therapy; Disease-Free Survival; Female; Fluorouracil; Follow-Up Studies; Gastrointestinal Stromal Tumors; Hepatectomy; Humans; Laparoscopy; Length of Stay; Leucovorin; Liver Neoplasms; Liver Transplantation; Living Donors; Male; Melanoma; Middle Aged; Organoplatinum Compounds; Postoperative Complications; Retrospective Studies; Tissue and Organ Harvesting

Mutations in the DNA mismatch repair (MMR) gene MSH2 cause Lynch syndromes I and II and sporadic colorectal cancers. Msh2(null) mice predominantly develop lymphoma and do not accurately recapitulate the colorectal cancer phenotype.. We generated and examined mice with a conditional Msh2 disruption (Msh2(LoxP)), permitting tissue-specific gene inactivation. ECMsh2(LoxP/LoxP) mice carried an EIIa-Cre transgene, and VCMsh2(LoxP/LoxP) mice carried a Villin-Cre transgene. We combined the VCMsh2(LoxP) allele with either Msh2(Delta7null) (VCMsh2(LoxP/null)) or Msh2(G674D) mutations (VCMsh2(LoxP/G674D)) to create allelic phase mutants. These mice were given cisplatin or 5-fluorouracil/leucovorin and oxaliplatin (FOLFOX), and their tumors were measured by magnetic resonance imaging.. Embryonic fibroblasts from ECMsh2(LoxP/LoxP) mice do not express MSH2 and are MMR deficient. Reverse transcription, polymerase chain reaction, and immunohistochemistry from VCMsh2(LoxP/LoxP) mice demonstrated specific loss of Msh2 messenger RNA and protein from epithelial cells of the intestinal tract. Microsatellite instability was observed in all VCMsh2 strains and limited to the intestinal mucosa. Resulting adenomas and adenocarcinomas had somatic truncation mutations to the adenomatous polyposis coli (Apc) gene. VCMsh2(LoxP/LoxP) mice did not develop lymphoma. Comparison of allelic phase tumors revealed significant differences in multiplicity and size. When treated with cisplatin or FOLFOX, tumor size was reduced in VCMsh2(LoxP/G674D) but not VCMsh2(LoxP/null) tumors. The apoptotic response to FOLFOX was partially sustained in the intestinal mucosa of VCMsh2(LoxP/G674D) animals.. Msh2(LoxP/LoxP) mice in combination with appropriate Cre recombinase transgenes have excellent potential for preclinical modeling of Lynch syndrome, MMR-deficient tumors of other tissue types, and use in drug development.

Topics: Adenocarcinoma; Adenoma; Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Cisplatin; Colorectal Neoplasms, Hereditary Nonpolyposis; Disease Models, Animal; Drug Resistance, Neoplasm; Fluorouracil; Gene Expression Regulation, Neoplastic; Gene Silencing; Genes, APC; Genotype; Immunohistochemistry; Integrases; Intestinal Neoplasms; Leucovorin; Magnetic Resonance Imaging; Mice; Mice, Inbred C57BL; Mice, Knockout; Microfilament Proteins; Microsatellite Instability; Mutation; MutS Homolog 2 Protein; Organoplatinum Compounds; Phenotype; Reverse Transcriptase Polymerase Chain Reaction; Time Factors; Tumor Burden

Although modern chemotherapy of stage IV advanced colorectal cancer (CRC) has impressively improved overall survival, the response of the primary tumor has not been studied because surgical resection of the primary continues to be the standard procedure in stage IV CRC.. Long-term follow-up of the primary in patients with stage IV CRC under chemotherapy.. Here we report on the histological changes in the primary tumor in four patients suffering from stage IV CRC. Systemic chemotherapy was started immediately after endoscopic tumor debulking in three cases. In one case no endoscopic intervention was performed before chemotherapy. Neither macroscopic nor histological evidence for malignant tumor growth was found at the former site of the primary after 6, 23, 26 or 48 months, respectively. Two patients had a complete suppression of the primary, two patients had an adenoma at the former site of the primary. To date, three patients have died because of progression of liver metastases and one patient is still alive with no signs of tumor growth.. The four cases illustrate that today's chemotherapy may effectively induces suppression of the primary in CRC. The development of CRC may follow different pathways.

Topics: Adenocarcinoma; Adenoma; Aged; Antineoplastic Agents; Colon; Colonic Polyps; Colonoscopy; Colorectal Neoplasms; Combined Modality Therapy; Female; Fluorouracil; Humans; Leucovorin; Liver Neoplasms; Male; Middle Aged; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Remission Induction; Tomography, X-Ray Computed

Topics: Adenoma; Adenomatous Polyposis Coli; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Colonic Neoplasms; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Liver Neoplasms; Middle Aged; Treatment Outcome