The correlation between the levels of tissue inhibitor of metalloproteinases 1 in plasma and tumour response and survival after preoperative radiochemotherapy in patients with rectal cancer.

BACKGROUND: The aim of this study was to analyse whether the level of tissue inhibitor of metalloproteinases (TIMP) 1 is associated with the tumour response and survival to preoperative radiochemotherapy in rectal cancer patients. PATIENTS AND METHODS: Ninety-two patients with histologically confirmed non-metastatic rectal cancer of clinical stage I- III were treated with preoperative radiochemotherapy, surgery and postoperative chemotherapy. Plasma TIMP-1 concentrations were measured prior to the start of the treatment with an enzyme-linked immunosorbent assay (ELISA). RESULTS: Median follow-up time was 68 months (range: 3-93 months) while in survivors it was 80 months (range: 68-93 months). The 5-year locoregional control (LRC), disease-free survival (DFS), disease-specific survival (DSS) and overall survival (OS) rates for all patients were 80.2%, 56.4%, 63.7% and 52.2%, respectively. The median TIMP-1 level was 185 ng/mL (range: 22-523 ng/mL) and the mean level (±standard deviation) was 192 (±87) ng/mL. Serum TIMP-1 levels were found to be significantly increased in patients with preoperative CRP>12 mg/L and in those who died from rectal cancer or had cT4 tumours. No correlation was established for age, gender, carcinoembriogenic antigene (CEA) level, platelets count, histopathological grade, response to preoperative therapy, resectability and disease reappearance. On univariate analysis, various parameters favourably influenced one or more survival endpoints: TIMP-1 <170 ng/mL, CRP <12 mg/L, platelets count <290 10E9/L, CEA <3.4mg/L, age <69 years, male gender, early stage disease (cN0 and/or cT2-3), radical surgery (R0) and response to preoperative radiochemotherapy. In multivariate model, LRC was favourably influenced by N-downstage, DFS by lower CRP and N-downstage, DSS by lower CRP and N-downstage and OS by lower TIMP-1 level, lower CRP and N-downstage. CONCLUSIONS: Although we did not find any association between pretreatment serum TIMP-1 levels and primary tumour response to preoperative radiochemotherapy in our cohort of patients with rectal cancer, TIMP-1 levels were recognized as an independent prognostic factor for OS in these patients.

Oral glutamine supplementation during preoperative radiochemotherapy in patients with rectal cancer: a randomised double blinded, placebo controlled pilot study.

BACKGROUND & AIMS: Enteral glutamine may have protective effects on gut function and reduce metabolic stress in patients receiving radiochemotherapy. The aim of our study was to evaluate its influence in patients with rectal cancer undergoing preoperative radiochemotherapy. METHODS: We performed a randomized double blind, placebo controlled pilot study in 33 patients. 30 g of glutamine, average dose 0.41 g/kg (SD = 0.07) g/kg/day was administered orally in three doses per day for five weeks during preoperative radiochemotherapy of rectal cancer. 30 g of maltodextrin was given as placebo. Body weight was measured and NRS 2002 screening was performed before and after treatment. Bowel function was evaluated by stool consistency and frequency. Plasma levels of inflammatory parameters and hormones were measured. RESULTS: There was no difference between groups in frequency and severity of diarrhoea during radiochemotherapy (p = 0.5 and p = 0.39 respectively), insulin levels significantly increased in both groups, IL-6 only in glutamine group. CONCLUSION: Results of this small pilot study in rectal cancer patients receiving preoperative radiochemotherapy, showed that ingestion of larger quantities of glutamine given more often as previously reported did not diminish the incidence and severity of diarrhoea and did not affect inflammatory and metabolic activity compared to the placebo treatment with maltodextrin.

Triple negative breast cancer - prognostic factors and survival.

BACKGROUND: Triple negative breast cancer (TNBC) is defined by a lack of expression of both estrogen (ER) and progesteron (PgR) receptors as well as human epidermal growth factor receptor 2 (HER2). Our retrospective analysis addressed prognostic factors for short- and long-term outcomes of patients (pts) with TNBC pts treated in routine clinical practice. PATIENT AND METHODS.: Our retrospective study included 269 TNBC treated at Institute of Oncology Ljubljana between March 2000 and December 2006. The collected data included patients', tumours' and treatments' characteristics. The survival analyses were performed using the Kaplan-Meier method. The Cox proportional hazard model was used in the multivariate analysis. RESULTS: The median age of our patients was 55.3 yrs (23-88.5) and the median follow-up was 5.9 yrs (0.3-9.6). Six (2%) pts experienced local only, 79 (92%) pts distal recurrence and 66 (24%) died. The predominant localisation of the first relapse was in visceral organs (70.4%). The 5-year disease-free survival (DFS) for the entire group was 68.2% and the 5-year overall survival (OS) was 74.5%. We found a pattern of high recurrence rate in the first 3 years following the diagnosis and a clear decline in recurrence rate over the next 3 years. In the univariate analysis age, nodal status, size and lymphovascular invasion (LVI) were found to have a significant impact on DFS as well as on OS. In the multivariate analysis only age (HR=1.79; 95%CI=1.14-2.82; p=0.012) and nodal status (HR=2.71; 95%CI=1.64-4.46; p<0.001) retained their independent prognostic value for DFS and for OS only the nodal status (HR=2.96; 95%CI=1.51-5.82; p=0.002). CONCLUSIONS: In our series of TNBC pts nodal status and age (older than 65 yrs) were found to be independent prognostic factors for DFS, whereas for OS only the nodal status. We found a pattern of a high recurrence rate in the first 3 years following the diagnosis and a decline in the recurrence rate over the next 3 yrs with higher rate of distal versus local recurrence and a predominant localization of distal metastases in visceral organs.

Differences in plasma TIMP-1 levels between healthy people and patients with rectal cancer stage II or III.

BACKGROUND: The purpose of the study was to analyse whether the levels of the tissue inhibitor of matrix metalloproteinases-1 (TIMP-1) are higher in patients with rectal cancer as compared with healthy blood donors. PATIENTS AND METHODS.: Two hundred and seventeen patients (147 male, 70 female) with histologically confirmed non-metastatic rectal cancer (clinical stage II-III) and 45 healthy blood donors (15 male, 30 female) were included in analysis. Patient's mean age was 66 years (range: 34-87 years) and healthy blood donor's mean age was 35 years (range: 18-64 years). Plasma TIMP-1 concentrations were measured with an enzyme-linked immunosorbent assay (ELISA) using commercially available TIMP-1 ELISA kit. Mann-Whitney-test for independent groups was used to assess the differences of plasma TIMP-1 levels and clinicopathological parameters. Two-sided tests were used and the differences at P<0.05 were considered as statistically significant. RESULTS: Median patients TIMP-1 level was 180 ng/mL (range: 22-538 ng/mL); the mean (±SD) level was 193.7 (79.5) ng/mL. The median healthy blood donors TIMP-1 level was 112 ng/mL (range: 48-211 ng/mL); the mean (±SD) level was 115 (35.7) ng/mL. TIMP-1 levels in patients with rectal cancer were statistically significantly higher than TIMP-1 levels in healthy blood donors (P<0.0001). Significant differences in TIMP-1 levels were not found comparing gender (P=0.43), but in both groups TIMP-1 levels were increased with higher age (P=0.007). CONCLUSIONS: Patients with rectal cancer had statistically significantly higher mean and median TIMP-1 level than healthy blood donors which is in accordance with the results published in other publications. These findings suggest possibility that plasma TIMP-1 levels could be used as new biological markers for early cancer detection.

Report on isoelectric focusing trial of erythropoietin profiling in two cancer patients during chemotherapy and darbepoetin treatment.

The level of erythropoietin, main regulator of erythropoiesis, is affected by hypoxia, anaemia, application of recombinant erythropoietin, chemotherapy and others. Isoelectric focusing (IEF) combined with double immunobloting is a method that enables distinct analysis of endogenous and recombinant erythropoietin isoforms. Aim of our study was to set up analysis of treatment effects on the pattern of endogenous erythropoietin in anaemic breast cancer patient. Urine and blood samples were collected during and after termination of the treatment and analysed by isoelectric focusing. Endogenous erythropoietin was found lower, but still detectable during darbepoetin treatment. Normal shift of erythropoietin isoforms between serum vs. urine, ordinary seen in healthy volunteers, was not observed indicating kidney damage. The patient was suffering from heavy proteinuria and had low Glomerular filtration rate indicating acute renal failure, probably caused by clinical status or cisplatin chemotherapy. IEF has not yet been used for follow up of erythropoietin profile in cancer patients. It enables to monitor the effects of treatment on the level of endogenous erythropoietin and indirectly indicates kidney function.

High levels of uPA and PAI-1 predict a good response to anthracyclines.

Urokinase-type plasminogen activator (uPA) and its main inhibitor (PAI-1) were shown with level 1 evidence to be prognostic factors for primary breast cancer. Our preliminary retrospective study on a cohort of 1,220 consecutive patients hinted that uPA and PAI-1 could also serve as predictive factors for systemic therapy, namely that patients with high levels of the two markers benefit much more from anthracycline-based chemotherapy than patients with low levels of the two markers. The latter could equally well be treated with less toxic CMF-based chemotherapy (cyclophosphamide, methotrexate, and fluorouracil). The retrospective study, however, suffered from severely uneven patient and tumor characteristics as the patients were treated per institutional guidelines valid at the time and were not randomized between the anthracycline and CMF arms. In the present paper, we attempted to remedy this shortcoming and recheck our previous observations on more balanced data. To this end we employed a custom-made computer algorithm that selected 180 patients out of a total of 1,220 patients such that we obtained very well balanced anthracycline and CMF arms according to patient and tumor characteristics. Moreover, the low and high uPA/PAI-1 subgroups within both arms were also completely balanced. The algorithm in a way created a similar setting to that of a randomized study at the expense of greatly reducing the number of patients included into the study. In this setting, we observed the 3-year disease-free survival (DFS) in all four subgroups (according to treatment and levels of markers: both uPA and PAI-1 low versus one or both high). We report that the 3-year DFS in the CMF arm differed significantly: 87.1% for patients with low levels of markers versus 77.0% for patients with high levels of markers (P = 0.044, HR = 2.81, 95% CI = 0.98-8.04). On the other hand, the 3-year DFS in the anthracycline arm did not differ much between the two marker level subgroups: 85.2% for patients with low levels of markers versus 81.8% for patients with high levels of markers. Our observation points out that worse prognosis correlated to high uPA and PAI-1 levels can be reversed by treatment efficacy achieved through anthracycline-based chemotherapy. Based on this observation, we hypothesize that uPA/PAI-1 combination could be predictive for response to systemic therapy.