Estimation of the incidence for non-terminal events in presence of a terminal event and evaluation of covariate effects: Sub-distribution and marginal distributions based on copulas. An application to disease progression on a breast cancer trial dataset

In clinical studies, during follow-up several kinds of events related to disease progression may be observed. In the semi-competing risks setting, some events, such as death, may prevent the observation of disease progression, thus acting as competitor for the event of interest. Methods of analysis specific for semi-competing risks data referring to marginal distribution of the non-competing events constitute a recent area of methodological research which has received a great impulse in latest years. However in clinical applications the analysis is traditionally based on crude cumulative incidences, and inference on marginal distributions is seldom considered, even when the principal aim concerns the probability of observing disease progression and death occurred without progression is a \u201cnuisance\u201d. Aim of this work is making a comparative review of semi-parametric marginal and sub-distribution methods of analysis, with particular reference to marginal regression models based on copulas. More specifically, two structures were considered for marginal models: in the first one all parameters are time-dependent, while in the second one parameters vary with covariates but does not depend on time. Applications to breast cancer clinical trial data and to a simulated dataset are reported, to show the differences and the similarities among marginal and sub-distribution approaches. Results highlight that, when the competing event acts during the whole follow-up, the marginal approach became essential for the correct estimation of marginal incidences and covariate effects. Regression methods based on copulas are promising, however there is a need of refinements concerning model building strategies, and, of standardised software routine for the practical application of these methods

Contribution of 3H-thymidine labelling index and flow cytometric S-phase in predicting survival of patients with non-Hodgkin's lymphoma.

The 3H-thymidine labelling index (3H-dT LI) of cell suspensions from fresh material and the flow cytometric S-phase (FCM-S) of nuclei recovered from paraffin blocks were determined on the same pathologic lymph node specimen for 190 non-Hodgkin's lymphomas (NHLs). FCM-S was defined by a planimetric method and by an optimization procedure. Poor correlation coefficients were observed among the three cell kinetic variables. All three cell kinetic variables were significant indicators of 8-year survival and median survival time. The life-regression procedure evidenced a significant relative contribution of 3H-dT LI and FCM-S, thus suggesting a different biologic meaning of the two cell kinetic variables. This finding was further supported by evidence that simultaneous use of 3H-dT LI and FCM-S can identify groups of patients with different survival better than when either modality is used alone. Multivariate analysis indicated that the risk groups as defined by cell kinetic variables are predictors of survival even in the presence of established factors such as histology and stage

Value of epidermal growth factor receptor status compared with growth fraction and other factors for prognosis in early breast cancer.

The epidermal growth factor receptor (EGFR) is a transmembrane glycoprotein whose expression is important in the regulation of breast cancer cell growth. The relationship between EGFR status (determined by an immunocytochemical assay) and various prognostic factors was investigated in 164 primary breast cancers. Overall 56% of tumours were EGFR-positive and the expression of EGFR was unrelated to axillary node status, tumour size and histological grade; and it was poorly associated with the tumour proliferative activity measured by Ki-67 immuno-cytochemistry. The relapse-free survival (RFS) probability at 3-years was significantly worse for patients with EGFR positive tumours (P = 0.003) and for those whose Ki-67 score was > 7.5% (P = 0.0027), as well as in patients with axillary node involvement (P = 0.01) and with poorly differentiated tumours (P = 0.04). Immunocytochemical determination of EGFR and cell kinetics gave superimposable prognostic information for predicting RFS with odds ratios of 3.51, when evaluated singly. In our series of patients EGFR, Ki-67 and node status retain their prognostic value concerning RFS in multivariate analysis. The 3-year probability of overall survival (OS) was significantly better in node-negative patients (P = 0.04) and was similar in EGFR-positive and negative patients. In conclusion, EGFR status appears to be a significant and independent indicator of recurrence in human breast cancer and the concomitant measurement of the tumour proliferative activity seems to improve the selection of patients with different risks of recurrence

Long-term follow-up of elderly patients with operable breast cancer treated with surgery without axillary dissection plus adjuvant tamoxifen.

Between 1982 and 1990, 321 elderly patients (range 70-92 years, median age 77) with operable breast cancer (T1 in 219, T2 in 77, T3 in one and T4b in 24 patients) and clinically uninvolved axillary nodes underwent surgery without axillary dissection and received adjuvant tamoxifen. All patients had surgery performed under local anaesthesia. Tamoxifen was given after surgery at the dose of 20 mg daily, indefinitely. With a median follow-up of 67 months (range 42-141), 17 patients developed local relapse, 14 ipsilateral axillary recurrence, five ipsilateral breast cancer, five contralateral breast cancer, 13 second primary and 23 developed distant metastases. The cumulative probability of developing a local, axillary and distant recurrence at 72 months was estimated to be 5.4%, 4.3% and 6.2%, respectively. Out of 244 patients who did not develop any relapse, 83 (25.8%) died from intercurrent disease. The 72 month relapse-free survival rate was 76%. This experience suggests that elderly patients with small tumours without clinical axillary involvement may be satisfactorily treated with conservative surgery and tamoxifen. The importance of axillary dissection is controversial owing to a high response rate to hormonal therapy and an increased death rate due to concomitant diseases

Contribution of vascular endothelial growth factor to the Nottingham prognostic index in node-negative breast cancer

The prognostic contribution of intratumour VEGF, the most important factor in tumour-induced angiogenesis, to NPI was evaluated by using flexible modelling in a series of 226 N-primary breast cancer patients in which steroid receptors and cell proliferation were also accounted for. VEGF provided an additional prognostic contribution to NPI mainly within ER-poor tumours. © 2001 Cancer Research Campaignhttp://www.bjcancer.co

Investigation on Dabigatran Etexilate and Worsening of Renal Function in Patients with Atrial fibrillation : the IDEA Study

BACKGROUND AND OBJECTIVES: Warfarin-related nephropathy is an unexplained acute kidney injury, and may occur in patients with supratherapeutic INR, in the absence of overt bleeding. Similar findings have been observed in rats treated with dabigatran etexilate. We conducted a prospective study in dabigatran etexilate-treated patients to assess the incidence of dabigatran-related nephropathy and to investigate the possible correlation between dabigatran plasma concentration (DPC) and worsening renal function. METHOD: One hundred and seven patients treated long term with dabigatran etexilate for non-valvular atrial fibrillation (NVAF) were followed up for 90 days. DPC, serum creatinine (SCr) and serum cystatin C were prospectively measured. Ninety five patients had complete follow-up data and were evaluable for primary endpoint. RESULTS: Eleven patients had supratherapeutic DPC, defined as DPC higher than 200 ng/ml at study enrolment, but at the end of follow-up no patient showed a persistent increase in SCr. No patients experienced acute kidney injury. CONCLUSIONS: Our study shows that no persistent renal detrimental effect is associated with dabigatran treatment. An increase in SCr during dabigatran treatment is reversible and it seems to be unrelated to dabigatran itself

Tissue carcinoembryonic antigen and oestrogen receptor status in breast carcinoma: an immunohistochemical study of clinical outcome in a series of 252 patients with long-term follow-up.

Carcinoembryonic antigen (CEA) is a well-known tumour marker whose immunohistochemical expression could be prognostically relevant in breast carcinomas. We evaluated CEA immunohistochemical expression, using the specific T84.66 monoclonal antibody, in a series of 252 consecutive cases of infiltrating breast carcinomas (104 N0, 148 N1/2) with median follow-up of 84 months. Oestrogen receptor (ER) status has been evaluated with the immunohistochemical method (ER1D5 antibody, 10% cut-off value): 121 cases were ER negative, 128 cases were ER positive and in three cases ER status was unknown. CEA staining was cytoplasmic; staining intensity and percentage of reacting cells were combined to obtain a final score (CEA score). The difference between the distribution of CEA score within the modalities of the other variables was not statistically significant. Univariate survival analysis has been performed on the series of node-negative and node-positive patients. In the latter subgroup, this has been performed separately for patients treated with systemic adjuvant hormonal therapy or chemotherapy. A multivariate analysis was only performed for node-positive patients treated with adjuvant therapy. CEA immunoreactivity was not prognostically relevant in any subset of analysed patients. The most important prognostic markers were nodal status and tumour size