Introduction 25% of Stage III colon cancer patients relapse within 5 years due to minimal residual disease (MRD) not eliminated by surgery and chemotherapy. We hypothesise that sub-types of MRD, defined by circulating tumour cells (CTCs) and bone marrow micro-metastasis (mM) have different types and kinetics of relapse. Patients and Methods One month of curative surgery and 1 month after completing six cycles of FOLFOX chemotherapy blood and bone marrow samples were taken to detect CTCs and mM using immunocytochemistry with anti-carcino-embryonic antigen (CEA). Follow up was up to 5 years or disease progression defined as new images on CT scanning. Survival curves using Kaplan–Meier (KM) and Restricted Mean Survival Time (RMST) were calculated for three prognostic groups: CTC and mM negative, CTC negative mM positive, and CTC positive. Results 76 patients (39 men) participated, mean age 67 years, median follow-up 3.6 years. The response to chemotherapy was heterogeneous and MRD pre-treatment did not predict response to therapy. Of 21 patients MRD (−), 20 remained MRD negative and one patient became mM (+); of 21 patients mM (+), 10 became MRD (−), 8 remained the same and 3 became CTC (+); of the 34 CTC positive, 8 became MRD (−), 8 with only mM, and 18 remained positive. After chemotherapy, 38 patients were negative for CTC and mM, 17 were positive for only mM, and 21 for CTCs. For the whole cohort, the 5 year KM was 58%, the median survival was not reached. For the three prognostic groups, the KM 5-year survivals were 87%, 58%, and 4%, respectively, the median survival for patients MRD negative and mM only was not reached. RMST for the whole cohort was 3.6 years, for the three prognostic groups the RMST was 4.6 years, 4.0 years, and 1.5 years, respectively. Serum CEA was significantly higher pre-surgery in the CTC positive group. There were no significant differences with respect to age or sex between the three groups. Conclusions MRD subtypes pre-chemotherapy did not predict treatment response. Post-chemotherapy MRD subtypes were associated with the pattern of failure and time to failure. MRD negative patients had an excellent prognosis with 87% disease-free survival at 5 years. Those with only mM had a similar outcome up to 2 years and then were at increasing risk of late failure. Patients who were CTC positive had a high risk of early failure. MRD subclassification may be useful to define the risk of relapse in Stage III colon cancer patients and warrants further studies with a larger number of patients.

Aim: Despite curative surgery, 25% of patients with Stage II colorectal cancer will relapse due to minimal residual disease (MRD). Markers of immune function, such as the neutrophil to lymphocyte ratio (NLR), may be associated with MRD defined by bone marrow micro-metastasis (mM) and circulating tumour cells (CTCs). Method: A prospective cohort study of consecutive patients with Stage II colon cancer patients attended at a single centre between 2007 and 2014. Blood and bone marrow samples were taken to detect CTCs and mM using immunocytochemistry with anticarcinoembryonic antigen 1 month after surgery. The NLR and absolute neutrophil and lymphocyte counts were determined immediately pre-surgery and 1 month post-surgery. These were compared with the sub-types of MRD: group I MRD(−); group II mM positive and group III CTC positive. Cut-off values of the NLR of >3.0 and >5.0 were used. Follow-up was for up to 5 years or relapse and disease-free survival (DFS) was calculated using Kaplan-Meier analysis. Results: In all, 181 patients (99 women) participated. Mean age was 68 years. Median follow-up was 4.04 years: I, N = 105; II, N = 36; III, N = 40. The NLR significantly decreased post-surgery only in group I patients. The frequency of NLR >3.0 and >5.0 was significantly higher in group III; between groups I and II there was no significant difference.5-year DFS was 98% in group I, 68% in group II and 7% in group III.Conclusions: Patients with a significantly higher immune dysfunction had a shorter time to disease progression, a worse DFS and the presence of CTCs.

Background: The aim of this study was to assess detection of circulating tumor cells (CTC) using anti-CEA pre and post surgery in Chilean patients with colo-rectal cancer. Materials and Methods: The presence of CTCs was evaluated in 80 colorectal cancer patients pre and post surgery using standard immunocytochemistry and the results were compared with findings for standard clinico-pathological parameters. Results: In patients presurgery CEA (+) CTCs were frequently found, with no relation to tumor size or nodal status. After surgery, the presence of CTCs was associated with such clinico-pathological parameters. The frequency of CTC detection in node positive patients did not change after surgery. In patients with metastasis there was also no change in the frequency of CTC detection, and clusters of 3 or more CTCs were evident. Conclusions: Secondary CTCs are associated with clinico-pathological parameters only after surgical removal of the primary tumor, and might be important in identifying patients at high risk of relapse. Primary CTCs detected before surgical removal are frequently found, are not associated with the clinico-pathological parameters and might have a role in cancer screening. These findings suggest the need for studies with a larger population of patients.

No abstract

Introduction: Minimal residual disease (MRD) is the net result of the biological properties of disseminated tumour cells and the effect of the immune system and treatment to eliminate them. The aim of this study was to analyse the effect of combined chemotherapy on the immune function as determined by the neutrophil-lymphocyte ratio (NLR) and if it was associated with changes in the subtype of minimal residual disease and outcome in stage III colon cancer. Methods and Patients: A prospective, single centre observational study; the NLR was determined immediately prior to and one, two and three months after completing chemotherapy. Circulating tumour cells (CTCs) and bone marrow micro-metastasis (mM) using immunocytochemistry with anti-CEA were determined prior to and one month after chemotherapy. The association of changes in the NLR with MRD subtypes classified as Group I (negative for CTCs and mM), Group II (positive for mM) and Group III (positive for CTCs) as a result of chemotherapy and five-year disease free progression (DFS) analysed. Results: One hundred and eighty eight patients participated of whom 83 (44.9%) relapsed. In non-relapsing patients the NLR significantly increased and was higher after chemotherapy compared with relapsing patients. Significant increases in the NLR were associated with changes to a better MRD prognostic subtype and decreases with a worse MRD subtype. Neither baseline NLR nor MRD subtype predicted response to chemotherapy. DFS for MRD subgroups were 88%, 56% and 6% for Groups I to III respectively. Conclusions: Immune function as measured by the NLR is associated with MRD prognostic subtypes, improvements in the NLR are associated with improvements in MRD post chemotherapy but neither baseline NLR or MRD predicted outcome.

Aim: Minimal residual disease (MRD) is the net result of the biological properties of disseminated tumour cells and the effect of the immune system and treatment to eliminate them. The aim of this work is to report the changes in MRD status and immune function (lymphocyte count) after FOLFOX chemotherapy, and the outcome in Stage III colon cancer patients.Method: This study is a prospective, single-centre observational study. Lymphocyte counts were determined prior to and 1, 2 and 3 months after the completion of chemotherapy. Circulating tumour cells (CTCs) and bone marrow micrometastases were determined using immunocytochemistry with anticarcinoembryonic antigen prior to and 1 month after chemotherapy. MRD was classified as negative (Group I), micrometastasis positive only (Group II) and CTC positive (Group III). Changes in lymphocyte counts and MRD subtype following chemotherapy and relapse-free progression were analysed.Results: Of the total of 185 patients, 83 (44.9%) relapsed. The risk of relapse significantly increased from Groups I to III (p < 0.001) and with decreasing lymphocyte count (p < 0.01). The lymphocyte count significantly decreased from Groups I to III (p < 0.001).Multivariance Cox regression analysis showed hazard ratios of 3.58 (Group II), 17.43 (Group III) and 0.39 (lymphocyte count) in predicting relapse. Following chemotherapy, improved lymphocyte count was associated with improved MRD subtype (p < 0.0001).Neither baseline lymphocyte count nor MRD subtype predicted response to chemotherapy. Five-year relapse-free survival for combined lymphocyte-MRD subtypes was 95%, 57% and 5% for Groups I to III, respectively (p < 0.001). Conclusion:Following chemotherapy, improvements in immune function were associated with improved MRD subtype and a better relapse-free survival.

healthcare budget restrictions leads to the controversial model of procedural justice. The objective was to describe the characteristics of the current decision-making scenario in Brazil using Health Technology Assessment (HTA), its main actors, consequences and future opportunities. METHODS: A review of HTA regulation in Brazil and the published literature on the topic was conducted. The Brazilian HTA model was discussed and strengths and weaknesses highlighted. RESULTS: Over the years, drug expenditures and healthcare demand have grown exponentially in Brazil. In 2006, the Brazilian Ministry of Health (MoH) created a HTA process (Regulation #152). The main objective was to align the dynamics of health technology decisions with population social needs, epidemiological profile, and healthcare system financing characteristics. The principal components are a clinical review and economic analysis of technologies under evaluation. Multiple government players are involved, but no reference to external involvement. Health technology decisions take into consideration: a) the relevance/impact of the technology within the system, and b) the safety, effectiveness, and cost-effectiveness of the appraised technologies. No reference was found to what is considered cost-effective/efficient for the system. Proposed HTA regulation changes are underway and include: rapid response, societal engagement (i.e., public consultation of MoH decisions), and changes in decision determinants (i.e., economic impact to be least important). CONCLUSIONS: Currently, Brazil holds an informed health technology decisionmaking process. However, clear/objective parameters for aiding decisions have not been described or yet proposed. Uncertainty still remains with regards to efficient health technology decisions. Current initiatives to improve HTA process are controversial. In the future, HTA could serve as a mediator between constitutional obligations and current budgetary restrictions in the country.

No abstract