ERCC2 2251A>C genetic polymorphism was highly correlated with early relapse in high-risk stage II and stage III colorectal cancer patients: A preliminary study

<p>Abstract</p> <p>Background</p> <p>Early relapse in colorectal cancer (CRC) patients is attributed mainly to the higher malignant entity (such as an unfavorable genotype, deeper tumor invasion, lymph node metastasis and advance cancer stage) and poor response to chemotherapy. Several investigations have demonstrated that genetic polymorphisms in drug-targeted genes, metabolizing enzymes, and DNA-repairing enzymes are all strongly correlated with inter-individual differences in the efficacy and toxicity of many treatment regimens. This preliminary study attempts to identify the correlation between genetic polymorphisms and clinicopathological features of CRC, and evaluates the relationship between genetic polymorphisms and chemotherapeutic susceptibility of Taiwanese CRC patients. To our knowledge, this study discusses, for the first time, early cancer relapse and its indication by multiple genes.</p> <p>Methods</p> <p>Six gene polymorphisms functional in drug-metabolism – <it>GSTP1 </it>Ile105Val, <it>ABCB1 </it>Ile1145Ile, <it>MTHFR </it>Ala222Val, <it>TYMS </it>double (2R) or triple (3R) tandem repeat – and DNA-repair genes – <it>ERCC2 </it>Lys751Gln and <it>XRCC1 A</it>rg399Gln – were assessed in 201 CRC patients using a polymerase chain reaction-restriction fragment-length polymorphism (PCR-RFLP) technique and DNA sequencing. Patients were diagnosed as either high-risk stage II (T2 and 3 N0 M0) or III (any T N1 and 2 M0) and were administered adjuvant chemotherapy regimens that included 5-fluorouracil (5FU) and leucovorin (LV). The correlations between genetic polymorphisms and patient clinicopathological features and relapses were investigated.</p> <p>Results</p> <p>In this study, the distributions of <it>GSTP1 </it>(<it>P </it>= 0.003), <it>ABCB1 </it>(<it>P </it>= 0.001), <it>TYMS </it>(<it>P </it>< 0.0001), <it>ERCC2 </it>(<it>P </it>< 0.0001) and <it>XRCC1 </it>(<it>P </it>= 0.006) genotypes in the Asian population, with the exception of <it>MTHFR </it>(<it>P </it>= 0.081), differed significantly from their distributions in a Caucasian population. However, the unfavorable genotype <it>ERCC2 </it>2251A>C (<it>P </it>= 0.006), tumor invasion depth (<it>P </it>= 0.025), lymph node metastasis (<it>P </it>= 0.011) and cancer stage (<it>P </it>= 0.008) were significantly correlated with early relapse. Patients carrying the <it>ERCC2 </it>2251AC or2251CC genotypes had a significantly increased risk of early relapse (OR = 3.294, 95% CI, 1.272–8.532).</p> <p>Conclusion</p> <p>We suggest that <it>ERCC2 </it>2251A>C alleles may be genetic predictors of early CRC relapse.</p

RECOMBINANT-HUMAN-ERYTHROPOIETIN IN PATIENTS WITH MYELODYSPLASTIC SYNDROMES

As anemia is frequently the main problem in myelodysplastic syndromes (MDS), we studied the efficacy of human erythropoietin (rhEpo) in stimulating the erythroid lineage in 14 patients, starting with 40 U/kg three times a week and doubling the dose every 6 weeks until a response was observed. The highest doses administered were 80 (n = 1), 160 (n = 4), 320 (n = 8) and 640 U/kg (n = 1). One patient (refractory anemia with an excess of blasts, RAEB) showed an increase of hemoglobin, white blood cells and platelets with 80 U/kg rhEpo. However, this patient developed acute leukemia while on therapy. Two other patients (RAEB and RAEB in transformation) also transformed to acute leukemia. In the other 11 patients no response was observed. There was no correlation between in vitro culture data and in vivo responsiveness. The treatment was well tolerated and no non-hematological side effects were observed. From this study we conclude that rhEpo, even when given at high doses, has a low response rate in patients with MDS. Further investigation is needed in order to clarify whether rhEpo increases the potential risk of transformation to acute leukemia

Phase II study of intensive chemotherapy with autologous bone marrow transplantation in patients in complete remission of disseminated breast cancer

Background: This trial studied the disease-free survival after high-dose chemotherapy in patients in complete remission of metastatic breast cancer. Patients and methods: Thirty women, mean age 42.2 years (range 33-55) with metastatic breast cancer, received high-dose chemotherapy in a phase II study. Patients were eligible if they were less than or equal to 55 years of age, had achieved complete remission within 6 months of the initiation of chemotherapy, and had a WHO performance scale of 0 or 1. The high-dose regimen consisted of melphalan 180 mg/m(2) and mitoxantrone 60 mg/m(2) both divided over 3 days. On day 7 bone marrow and/or peripheral stem cells were infused. After bone marrow recovery, external beam radiation was administered to sites of previous metastatic disease in 15 patients. Results: Apart from leuko- and thrombocytopenia, mucositis was the major side effect. One patient died during the bone marrow transplant period due to an aspergillus infection. The median follow-up since high-dose chemotherapy is 25 months (range 13 to 56 months). The median disease-free survival since high-dose chemotherapy is 27 months and the disease free survival is still 43% with an overall survival of 53% at 3 years. In two patients tumor relapse occurred only in the brain; in one patient the only relapse sign was a meningeal carcinosis. At the moment 17 patients are disease-free (13+-56+) months after high-dose chemotherapy. Conclusion: Until now this high-dose regimen in selected patients with complete remission after induction chemotherapy for metastatic breast cancer has a promising disease free survival