No abstract

BACKGROUND Patients with stage II-III colorectal cancer (CRC) treated with adjuvant chemotherapy, gain a 25% survival benefit. In the context of personalized medicine, there is a need to identify patients with CRC who may benefit from adjuvant chemotherapy. Molecular profiling could guide treatment decisions in these patients. Thymidylate synthase ( TYMS ) gene polymorphisms, KRAS and BRAF could be included in the molecular profile under consideration. AIM To investigate the association of TYMS gene polymorphisms, KRAS and BRAF mutations with survival of CRC patients treated with chemotherapy. METHODS A retrospective study studied formalin-fixed paraffin-embedded tissues (FFPEs) of consecutive patients treated with adjuvant chemotherapy during January/2005-January/2007. FFPEs were analysed with PCR for the detection of TYMS polymorphisms, mutated KRAS (m KRAS ) and BRAF (m BRAF ). Patients were classified into three groups (high, medium and low risk) according to 5’UTR TYMS polymorphisms Similarly, based on 3’UTR polymorphism ins/loss of heterozygosity (LOH) patients were allocated into two groups (high and low risk of relapse, respectively). Cox regression models examined the associated 5-year survival outcomes. RESULTS One hundred and thirty patients with early stage CRC (stage I-II: 55 patients; stage III 75 patients; colon: 70 patients; rectal: 60 patients) were treated with surgery and chemotherapy. The 5-year disease free survival and overall survival rate was 61.6% and 73.9% respectively. 5’UTR polymorphisms of intermediate TYMS polymorphisms (2RG/3RG, 2RG/LOH, 3RC/LOH) were associated with lower risk for relapse [hazard ratio (HR) 0.320, P = 0.02 and HR 0.343, P = 0.013 respectively] and death (HR 0.368, P = 0.031 and HR 0.394, P = 0.029 respectively). The 3’UTR polymorphism ins/LOH was independently associated with increased risk for disease recurrence ( P = 0.001) and death ( P = 0.005). m BRAF (3.8% of patients) was associated with increased risk of death (HR 4.500, P = 0.022) whereas m KRAS (39% of patients) not. CONCLUSION Prospective validating studies are required to confirm whether 2RG/3RG, 2RG/LOH, 3RC/LOH, absence of ins/LOH and wild type BRAF may indicate patients at lower risk of relapse following adjuvant chemotherapy.

Colorectal cancer (CRC) remains a major public health issue. The detection of parameters that affect CRC prognosis is of great significance. KRAS mutations, play a crucial role in tumorigenesis with a strong predictive value. KRAS-mutated stage-IV CRC patients gain no benefit of the anti-EGFR therapy. The KRAS G12C mutation subtype is under investigation for treatment regimens. The present study aimed to detect various RAS mutations in a cohort of 578 RAS-mutated CRC patients; 49% of them had de novo metastatic disease; 60% were male; 71.4% had left-sided tumors; and 94.6% had a good performance status. KRAS mutations were detected in 93.2% of patients, with KRAS G12D being the most common subtype (30.1%). KRAS mutations presented shorter progression-free (PFS) and overall survival (OS), compared with NRAS mutations, although not significantly (PFS: 13.8 vs. 18.5 months; p = 0.552; OS: 53.1 vs. 60.9 months; p = 0.249). KRAS G12D mutations presented better OS rates (p = 0.04). KRAS G12C mutation, even though not significantly, presented worse PFS and OS rates. KRAS exon 3 and 4 mutations presented different PFS and OS rates, although these were not significant. Concluding, KRAS G12D and G12C mutations lead to better and worst prognosis, respectively. Further studies are warranted to validate such findings and their possible therapeutic implication.

AIMTo investigate the impact of thymidylate synthase (TYMS), KRAS and BRAF in the survival of metastatic colorectal cancer (mCRC) patients treated with chemotherapy.METHODSClinical data were collected retrospectively from records of consecutive patients with mCRC treated with fluoropyrimidine-based chemotherapy from 1/2005 to 1/2007. Formalin-fixed paraffin-embedded tissues were retrieved for analysis. TYMS genotypes were identified with restriction fragment analysis PCR, while KRAS and BRAF mutation status was evaluated using real-time PCR assays. TYMS gene polymorphisms of each of the 3’ untranslated region (UTR) and 5’UTR were classified into three groups according to the probability they have for high, medium and low TYMS expression (and similar levels of risk) based on evidence from previous studies. Univariate and multivariate survival analyses were performed.RESULTSThe analysis recovered 89 patients with mCRC (46.1% de novo metastatic disease and 53.9% relapsed). Of these, 46 patients (51.7%) had colon cancer and 43 (48.3%) rectal cancer as primary. All patients were treated with fluoropyrimidine-based chemotherapy (5FU or capecitabine) as single-agent or in combination with irinotecan or/and oxaliplatin or/and bevacizumab. With a median follow-up time of 14.8 mo (range 0-119.8), 85 patients (95.5%) experienced disease progression, and 63 deaths (70.8%) were recorded. The 3-year and 5-year OS rate was 25.4% and 7.7% while the 3-year progression-free survival rate was 7.1%. Multivariate analysis of TYMS polymorphisms, KRAS and BRAF with clinicopathological parameters indicated that TYMS 3’UTR polymorphisms are associated with risk for disease progression and death (P < 0.05 and P < 0.03 respectively). When compared to tumors without any del allele (genotypes ins/ins and ins/loss of heterozygosity (LOH) linked with high TYMS expression) tumors with del/del genotype (low expression group) and tumors with ins/del or del/LOH (intermediate expression group) have lower risk for disease progression (HR = 0.432, 95%CI: 0.198-0.946, P < 0.04 and HR = 0.513, 95%CI: 0.287-0.919, P < 0.03 respectively) and death (HR = 0.366, 95%CI: 0.162-0.827, P < 0.02 and HR = 0.559, 95%CI: 0.309-1.113, P < 0.06 respectively). Additionally, KRAS mutation was associated independently with the risk of disease progression (HR = 1.600, 95%CI: 1.011-2.531, P < 0.05). The addition of irinotecan in 1st line chemotherapy was associated independently with lower risk for disease progression and death (HR = 0.600, 95%CI: 0.372-0.969, P < 0.04 and HR = 0.352, 95%CI: 0.164-0.757, P < 0.01 respectively).CONCLUSIONThe TYMS genotypes ins/ins and ins/LOH associate with worst prognosis in mCRC patients under fluoropyrimidine-based chemotherapy. Large prospective studies are needed for validation of our findings.

Tuberculous peritonitis is rare in most Western counties, and can cause significant diagnostic and therapeutic problems. A 28-year-old pregnant female presented with nausea and vomiting, right lower quadrant abdominal pain, fever and intra-abdominal fluid. During surgery for presumed complicated acute appendicitis, many small masses (considered to be 'implants') were found within the peritoneal cavity, with a larger mass in the pelvis, mainly on the right. The clinical intra-operative diagnosis was advanced ovarian cancer and multiple biopsies were taken. The histological diagnosis was peritoneal tuberculosis. The patient was successfully treated conservatively. Hasty decisions to undertake radical and irreversible surgery should be avoided; this type of surgery should be performed only after histological confirmation.