TYMS/KRAS/BRAF molecular profiling predicts survival following adjuvant chemotherapy in colorectal cancer

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 (mKRAS) and BRAF (mBRAF). 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). mBRAF (3.8% of patients) was associated with increased risk of death (HR 4.500, P = 0.022) whereas mKRAS (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.

Integrating TYMS, KRAS and BRAF testing in patients with metastatic colorectal cancer

AIM To investigate the impact of thymidylate synthase(TYMS), KRAS and BRAF in the survival of metastatic colorectal cancer(m CRC) patients treated with chemotherapy. METHODS Clinical data were collected retrospectively from records of consecutive patients with m CRC 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.RESULTS The analysis recovered 89 patients with m CRC(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).CONCLUSION The TYMS genotypes ins/ins and ins/LOH associate with worst prognosis in m CRC patients under fluoropyrimidine-based chemotherapy. Large prospective studies are needed for validation of our findings.

结肠的腺癌和麦芽淋巴瘤的同时的出现: 一系列三个盒子

Simultaneous development of adenocarcinoma and primary B cell lymphoma of mucosa-associated lymphoid tissue(MALT) lymphoma of the colon is rare;only one case has so far been reported out of 13 cases with the coexistence of colonic adenocarcinoma with involvement of the colon by lymphoma.We hereby present three more cases,two females(aged 75 and 71 years) and a male(aged 72 years).All three underwent colectomy based on a preoperative biopsy revealing colonic carcinoma.Histological examination of the resection specimens disclosed a colonic adenocarcinoma in two cases,whereas a tubulovillous adenoma with superficial foci of intraepithelial adenocarcinoma was seen in the thirdcase.Moreover,in all three cases,a coexisting MALT lymphoma was diagnosed in the colon(1 case),in both colon and adjacent lymph nodes(1 case) or in colonic lymph nodes and omentum(1 case).In the last case,a post-operative bone marrow biopsy revealed extensive infiltration of the bone marrow,due to which the patient received postoperative chemotherapy.Diagnostic and treatment issues are briefly discussed.

Management of primary retroperitoneal synovial sarcoma: A case report and review of literature

BACKGROUND Synovial sarcoma(SS) is a rare type of soft tissue sarcoma that is usually developed from areas where synovial tissue exists, especially at the extremities.Nevertheless, several cases of retroperitoneal SS(RSS) have been described. We herein report a case of RSS presented in our institution.CASE SUMMARY A 69-year-old female patient was admitted with a large, palpable, firm mass in the right abdominal space SS. Computerized tomography scan depicted a concentric, sharply marinated retro-peritoneal lesion which was displacing the right kidney and the lower edge of the liver. Subsequently, the patient underwent surgical excision of the mass with additional right nephrectomy and resection of the right adrenal gland and a part of the diaphragm. The final histological diagnosis of the tumour was grade II monophasic RSS.CONCLUSION RSS is encountered in the biphasic type, the monophasic fibrous, and the monophasic epithelial category as well. Relevant clinical manifestations are not always documented at early stages. Therefore, the final diagnosis is posed after complete histological examination taking into consideration the results of immunochemistry and genetic analysis. Therapeutic approach happens often late when metastases at the lungs and the liver are apparent. Thus, 5-year survival rates remain low.

Laparoscopic liver surgery: yesterday, today and tomorrow

Laparoscopic liver surgery(LLS)is currently considered as a standard of care approach for selected patients in an increasing number of centers worldwide(1).In his review article entitled"Laparoscopic liver resection:the current status and the future",Professor Cai aimed to present how LLS has evolved over time,current concepts and what is expected for the future(2).

Simultaneous resection of synchronous colorectal liver metastases:a promising alternative to staged resections

Management of patients with synchronous colorectal liver metastases(SCRLM)has transformed dramatically over the past 2 decades(1-3).A step-by-step,patient tailored approach as orchestrated by a multidisciplinary tumor board(MDT),combined with advances in surgical techniques,perioperative care and the evolution of systemic therapies have led to remarkable long-term outcomes(2,4).In particular,selected patients with resectable SCRLM undergoing surgery have been reported to enjoy 5-year survival rates as high as 76%(1).However,the optimal surgical strategy for these patients remains elusive with multiple retrospective studies presenting conflicting outcomes(4).In their up-to-date review of the literature Lillemoe and Vauthey sought to evaluate and critically appraise currently available surgical treatment strategies for patients presenting with SCRLM.