Serum uric acid as a surrogate marker of favorable response to bevacizumab treatment in patients with metastatic colon cancer

Bevacizumab is a monoclonal antibody which is a vascular endothelial growth factor inhibitor. It obscures vascularization of tumor tissue and damages intratumoral microcirculation. The damaged intratumoral microcirculation leads to tissue hypoxia and results in increase of uric acid level. The main aim of our study was to investigate the relationship between uric acid change and response to bevacizumab therapy. This study included a total of 158 patients with metastatic colorectal cancer who had received bevacizumab therapy. The number of male patients was 100 (63.3 %) while female patients number was 58 (37.7 %). The median age was 61 (29-83). There was relationship between increase of uric acid level of third month uric acid level and stable disease (p < 0.001). There was a significant overall survival increased in the group with increased uric acid level (p < 0.001). The decline of CEA level was related to uric acid level (p < 0.022). In conclusion, this study is the first showing significant increases of serum uric acid in patients with metastatic colorectal cancer who favorably responded to chemotherapy with bevacizumab. But further studies are justified to test whether monitoring uric acid levels might predict clinical outcomes of patients with metastatic colorectal cancer (AU)

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Serum uric acid as a surrogate marker of favorable response to bevacizumab treatment in patients with metastatic colon cancer.

Bevacizumab is a monoclonal antibody which is a vascular endothelial growth factor inhibitor. It obscures vascularization of tumor tissue and damages intratumoral microcirculation. The damaged intratumoral microcirculation leads to tissue hypoxia and results in increase of uric acid level. The main aim of our study was to investigate the relationship between uric acid change and response to bevacizumab therapy. This study included a total of 158 patients with metastatic colorectal cancer who had received bevacizumab therapy. The number of male patients was 100 (63.3 %) while female patients number was 58 (37.7 %). The median age was 61 (29-83). There was relationship between increase of uric acid level of third month uric acid level and stable disease (p < 0.001). There was a significant overall survival increased in the group with increased uric acid level (p < 0.001). The decline of CEA level was related to uric acid level (p < 0.022). In conclusion, this study is the first showing significant increases of serum uric acid in patients with metastatic colorectal cancer who favorably responded to chemotherapy with bevacizumab. But further studies are justified to test whether monitoring uric acid levels might predict clinical outcomes of patients with metastatic colorectal cancer.

Preoperative chemoradiotherapy improves local recurrence free survival in locally advanced rectal cancer.

PURPOSE: Preoperative chemoradiotherapy (pre-CRT) followed by total mesorectal excision (TME) is the recommended therapy for patients with locally advanced rectal cancer (LARC). The primary aim of this study was to compare the rates of local and distant recurrence and overall survival (OS) in LARC patients who received pre-CRT vs postoperative (post) CRT. METHODS: The medical records of 158 rectal cancer patients with clinical stage T3, T4 or N positive disease who received either pre-CRT or post-CRT between 2000-2009 were retrospectively analysed. Pre-CRT employed protracted 5-fluorouracil (5FU) infusion, whereas post-CRT included bolus 5FU and leucovorin concurrently with radiation therapy (RT). Radiation dose was 50.4 Gy in 82% and 45 Gy in 18% of the patients. RESULTS: 158 patients (65 females, 93 males) were analysed. Median age was 56.5 years (range 19-78). Fifty-three (34%) patients received pre-CRT and 105 (66%) post-CRT. Median follow-up was 43.3 months (range 8-182) and 47.6 months (range 9-194) in pre-CRT and post-CRT patients, respectively. After pre-CRT, significant downstaging was achieved. However, the type of surgical resection was not influenced by the administration of pre-CRT in tumors ≥5 cm distant from the anal verge (p=0.3). Pathologic complete response was achieved in 20% of the patients in the pre-CRT group. Local recurrence free survival (LRFS) at 5-years was 89.2% in the pre-CRT and 74.8% in the post-CRT group (p=0.04). Distant recurrence free survival (DRFS) at 5-years was 81.7% and 68.5 % in pre-CRT and post-CRT groups, respectively (p=0.1). OS was similar in the two groups (71.4 vs 64.4%, p=0.9). CONCLUSION: Treatment of LARC with pre-CRT followed by surgery improved LRFS as compared to surgery followed by post-CRT, but failed to improve DRFS or OS in our patient population.

The role of K-RAS and B-RAF mutations as biomarkers in metastatic colorectal cancer.

PURPOSE: Unlike cetuximab, there is a paucity of biomarkers for bevacizumab as predictors of outcome in metastatic colorectal cancer (mCRC) patients. Obviously exploring the worth of some potential markers in this setting is warranted. The purpose of this study was to investigate the predictive value of the presence of K-RAS and B-RAF mutations on the outcome of patients with mCRC treated with FOLFIRI and bevacizumab combination therapy. METHODS: A total of 172 patients with mCRC were evaluated. K-RAS and B-RAF mutations were analyzed by quantitative PCR. Median progression-free survival (PFS) and overall survival (OS) were compared utilizing chi-square and Mann-Whitney U tests, respectively. RESULTS: Forty-four percent (N=77) of the patients were found to harbor K-RAS mutations and 6 (7.5%) were positive for B-RAF mutations. In baseline no difference in PFS and OS was observed between the groups with or without K-RAS mutation. No relationship was established between K-RAS and B-RAF mutation status and baseline CEA and CA19-9 tumor markers levels. CONCLUSION: K-RAS and B-RAF mutations do not seem to be predictive of treatment outcome as potential biomarkers for bevacizumab therapy in mCRC. However, not only the presence of K-RAS and B-RAF mutations but also the different biological behavior of the various subtypes of mutations should be considered as potential determinants in the final outcome of this disease.

Prognostic factors in patients with papillary thyroid carcinoma.

BACKGROUND: Papillary thyroid carcinomas are associated with metastases and decreased survival in a small group of patients. AIM: The aim of this study is to determine the factors associated with recurrences/metastases in papillary thyroid carcinoma patients. SUBJECTS AND METHODS: One hundred and thirty-one patients with papillary thyroid carcinoma were evaluated retrospectively. The diagnosis was papillary microcarcinoma (PMC) in 48 patients. All patients had undergone near-total/total thyroidectomy. Radioactive iodine was given to 103 patients. Age at diagnosis, gender, previous history of thyroid disease, tumor stage, histopathological characteristics of tumor and initial treatment strategies were evaluated. RESULTS: Recurrences/metastases developed in 17 patients during follow-up. Recurrences developed at a significantly higher percentage in patients with a tumor stage >T1 and patients with lymph node metastasis at presentation. No significant difference was observed in recurrence ratio between patients with PMC and patients with a tumor diameter > or =1cm. In the Cox-regression analysis only the advanced tumor stage (>T1) and presence of lymph node metastases were found to be significant predictors for recurrence (univariate analysis, odds ratio =4.02 and 3.15, respectively). However, multivariate analysis did not reveal any significant independent predictors. According to the Kaplan- Meier survival analysis, lymph node metastases at presentation were associated with a decrease in recurrence-free survival at statistical significance (p=0.05). No mortality was observed during follow-up. CONCLUSION: Papillary thyroid carcinoma leads to recurrences/metastases in a small group of patients. Initial characteristics of the patients--i.e. presence of lymph node metastases--may predict recurrences/metastases in these patients.

Impaired brachial endothelial function in patients with primary anti-phospholipid syndrome.

Although the precise pathophysiology of thrombosis is unknown in primary anti-phospholipid syndrome (PAPS), it is assumed that autoantibodies developed against endothelial cells and platelets might be one of the primary mechanisms. However, whether interaction between autoantibodies and endothelium leads to an impaired vasodilator response has not been investigated yet. In this study, we aimed to investigate the endothelial functions in patients with PAPS. Thirty-one patients with PAPS (22 female, nine male, mean age: 34.6+/-8.9 years) and 27 age- and sex-matched, healthy controls were included in the study. Brachial artery responses to reactive hyperaemia (endothelium-dependent dilatation) [EDD] and sublingual nitroglycerine (endothelium-independent dilatation) [EID] were measured by using high-resolution vascular ultrasound both in patients with PAPS and in the controls. The results were expressed as percentage of change in baseline values. Regarding cardiovascular risk factors, there was no significant difference between the two groups. EDD in patients with PAPS was significantly lower than those of controls (6.9+/-4.9 vs. 14.8+/-4.1%; p<0.0001). EID measurements were not significantly different between the groups. In the PAPS group, EDD in patients with arterial involvement (17 patients) was significantly lower than those of patients with venous involvement (12 patients) (4.6+/-3.9 vs. 7.4+/-4.1%; p = 0.02). This study showed that endothelial functions determined by using brachial artery ultrasound were impaired in patients with PAPS, and this was more prominent in the subgroup of patients with arterial involvement compared to patients with venous involvement.

Endothelial dysfunction in renal transplant patients is closely related to serum cyclosporine levels.

BACKGROUND: Cyclosporine (CsA), one of the standard agents used in renal transplant recipients, has been considered to cause endothelial dysfunction and to contribute to arterial complications posttransplant. Since concentration-dependent effects of CsA on endothelial functions in humans have not been examined, this study was performed to investigate this relationship. METHODS: Fifteen renal transplant patient and 20 healthy subjects (controls) were evaluated for brachial artery endothelial function using high-resolution vascular ultrasound just before the CsA dosage (baseline) and at the second hour after the administration. Endothelium-dependent and -independent vasodilatations (EDD and EID, respectively) were assessed by establishing of the responses to reactive hyperemia and by using sublingual nitroglycerine, respectively. CsA levels were assessed at baseline and at second hour, times when performing brachial artery measurements. RESULTS: There were no significant differences between recipients and controls with respect to atherosclerosis risk factors. Mean EDD of recipients at baseline times were significantly less than those in controls (9.1% +/- 5.5% vs 15.2% +/- 7.2%, respectively; P < .001). CsA levels at trough and at second hour were 153.9 +/- 74.8 ng/mL and 646.8 +/- 163.2 ng/mL, respectively (P < .0001). Recipient, EDD at second hour was significantly reduced compared to baseline values (5.3% +/- 3.6% vs 9.1% +/- 5.5% respectively; P = .014) while changes in EID and in the diameter of the brachial artery between baseline and second hour were insignificant. CONCLUSION: Endothelial dysfunction evaluated by brachial ultrasound in renal transplant recipients is closely related to CsA levels. It is more pronounced at 2 hours after CsA dosage, at the time of peak drug levels.

Is there a relation between duration of cyclosporine usage and right and left ventricular function in renal transplant patients? Tissue Doppler Echocardiography study.

BACKGROUND: Our aim was to investigate the effect of cyclosporine (CsA), which is commonly used in renal transplant patients and causes myocardial fibrosis and elevated arterial tension, on cardiac function. METHODS: Sixty-six renal transplant patients (RTPs) and 25 healthy controls were included in the study. Renal transplantation patients were divided according to time of CsA exposure: group 1 (0 to 36 months); group 2 (36 to 72 months) and group 3 (> 72 months). Systolic peak velocity (Sm, mitral; St, tricuspid) and mitral early (e)/late (a) (Me/a) and tricuspid e/a (Te/a) waves of the right and the left ventricles were measured by pulse-wave (PW) Doppler used for tissue Doppler imaging of both ventricles as well as the ventricle free wall near to the lateral tricuspid and the posterior mitral leaflets. The measurements included conventional diastolic early (E) and late (A) waves and deceleration time (DT) of the E wave, isovolumetric relaxation time (IVRT) of both ventricles, as well as left ventricular systolic ejection fraction (EF). RESULTS: There were no statistically significant differences between the groups with regard to demographic, clinical, and most biochemical characteristics. Left ventricular EF was normal in all groups; there were no statistically significant differences. IVRT and DT of left ventricle and right ventricle DT values were similar among RTPs. On the other hand, values were found to be increased in RTP groups compared with the control group. E/A ratio, Me/a Te/a of both ventricles were similar among RTPs. However, these values were found to be decreased in RTP groups compared with the control group. CONCLUSIONS: Although left ventricular systolic functions were normal in all groups, there were statistically significant impairments of biventricular diastolic function parameters among renal transplant recipients compared with the control group.