Prognostic and predictive value of thymidine labelling index in breast cancer

In the last few decades, much effort has been directed towards identifying the phenotypic or functional aspect of tumor cells which can contribute to a biofunctional staging for improving the accuracy of pathologic staging used for identifying patients at different risk. Among known biologic factors, the proliferative capacity of the tumor cell population, a feature common to all tumors, has been widely investigated.Several approaches have been used to measure different aspects of the cell cycle. Among these, the thymidine labeling index (TLI) represents the fraction of cells in S-phase cell fraction and is based on the active incorporation of labelled thymidine into DNA. From basic studies conducted on several thousands of patients, the TLI of primary breast cancers appears closely related to steroid receptor status and generally unrelated to pathologic stage. Retrospective analyses performed on large series of patients treated with local regional therapy alone have consistently shown the relevance of TLI value to clinical aggressiveness in terms of relapse-free survival and overall survival. Moreover, TLI is a prognostic indicator which is independent of tumor size, steroid receptors, and p53 and bc12 protein expression, and which, together with patient age and tumor size, is able to identify patients at different risk of loco-regional or distant metastases. Recently, a direct relationship between TLI and response to polychemotherapy has been shown in patients with operable and advanced breast cancers.This finding, derived from retrospective and recently confirmed in prospective clinical studies, has led to the activation of cell kinetics based therapeutic protocols for patients with node-negative and one to three node-positive operable breast cancers.     

Cervical screening behavior of women with atypical squamous cells of undetermined significance (ASCUS)

Expectant follow-up based on early repeat Papanicolaou (Pap) smear(s) is the most commonly recommended management of patients with atypical squamous cells of undetermined significance (ASCUS). In a cervical cytology laboratory in northern Italy, a retrospective study of 1,087 ASCUS patients aged 25-64 was conducted. The primary aim was to assess the actual probability of early repeat Pap smear and associated factors. Univariate comparisons were based on the actuarial method. Multivariate associations were evaluated by Cox regression analysis. The cumulative probability of early repeat Pap smear was 0.11 at 6 mo, 0.29 at 12 mo, and 0.41 at 24 mo, with a multivariate association with screening sector (relative hazard, 3.0 for public offices and 2.8 for private offices vs. organized screening) and previous Pap smear history. Laboratory recommendation, patient age, place of birth, place of residence, marital status, and occupation exerted no independent effect. In conclusion, the probability of early repeat Pap smear was poor and independent of demographic and social factors. The frequency of follow-up failures emerged as a major problem with ASCUS management.     

An interlaboratory study of the use of PapNet in the quality control of cervico-vaginal cytology]

In this feasibility study of the utilization of the PapNet System (Neuromedical Systems, Suffern, NY) for computer-assisted cervical/vaginal cytology diagnosis, a random sample of 329 negative smears and a series of 68 positive smears reported as such by the Caltagirone laboratory, underwent PapNet review at the Imola laboratory. False-positive (FP) cases (smears originally classified as ASCUS, LGSIL, AGUS, e HGSIL and interpreted as negative on PapNet) and false-negative (FN) cases (reverse discrepancies) were further and conventionally re-evaluated by the staff of the originating laboratory. On PapNet review, there were 16/68 FP cases (23.5%) e 20/329 FN cases (6.1%) with a FP:FN rate ratio of 3.8 (95% confidence interval, 2.2-6.3). At final re-examination of these diagnostic errors, most FP cases (14/16) were confirmed as such whereas the FN cases significantly decreased from 20 to 9, with a final rate of 2.7%. As a consequence, the ratio of the FP rate (14/68) to the FN rate (9/329) rose to 7.5 (4.1-12.6). The study suggests one potential approach to the preliminary utilization of PapNet by those laboratories that are interested in this technology. The results are in accordance with those of the previous PapNet review studies which have generally shown a greater frequency of FP cases compared with FN cases.     

Inhibitory effect of heparin on skin reactivity to autologous serum in chronic idiopathic urticaria

BACKGROUND: Most patients with chronic idiopathic urticaria (CIU) show cutaneous reactivity to intradermal injection of autologous serum. In some cases this reactivity is associated with the presence of autoantibodies directed against IgE or IgE receptors expressed on mast cells, whereas in others no autoimmune mechanisms can be documented. OBJECTIVES: The aims of this study were to compare the cutaneous reactivity to serum and plasma samples in a series of patients with active CIU and to address the mechanisms of the inhibitory effect exerted by heparin on the cutaneous responsiveness to the histamine-releasing factors (HRFs) present in CIU serum. METHODS: Fourteen patients with CIU were injected intradermally with autologous serum, plasma (anticoagulated by either heparin or EDTA), or serum samples to which heparin had been added. The effects of heparin injection on cutaneous responsiveness to allergens was tested in 5 atopic patients. Moreover, in a set of experiments sera were also adsorbed with Sepharose-conjugated heparin. RESULTS: All the patients had positive cutaneous reactions to autologous serum injection. When heparinized plasma was injected, negative reactions were observed in 12 of 14 patients, and a sizable reduction in the wheal-and-flare reactions was recorded in the remaining 2. Compared with results obtained with serum, no substantial change was observed in 6 of 8 patients injected with EDTA-anticoagulated plasma. When heparin was added to serum, abrogation of skin reactivity was seen; nonetheless, no change in the cutaneous response to allergens was associated with locally administered heparin in 5 atopic patients with no history of CIU. Finally, adsorption of CIU sera with solid-phase heparin abrogated the ability to induce cutaneous reactions in 5 of 7 patients, whereas in the remaining 2 a sizable reduction was observed. CONCLUSIONS: These data indicate that heparin is able to profoundly inhibit the cutaneous response to HRFs present in the sera of patients with CIU. Although the precise level of action of this heparin-mediated effect is unclear from present data, preliminary evidence seems to indicate that heparin could directly interfere with HRFs present in CIU sera.     

Disease-free survival advantage of adjuvant cyclophosphamide, methotrexate, and fluorouracil in patients with node-negative, rapidly proliferating breast cancer: a randomized multicenter study.

PURPOSE: According to one of the most recent key scientific questions concerning the use of biomarkers in clinical trials, we investigated whether node-negative breast cancer patients, defined as high-risk cases on the basis of tumor cell proliferation, could benefit from cyclophosphamide, methotrexate, and fluorouracil (CMF) adjuvant therapy. PATIENTS AND METHODS: Two hundred eighty-one patients with negative nodes and rapidly proliferating tumors, defined according to thymidine labeling index (TLI), were randomized to receive six cycles of CMF or no further treatment after surgery +/- radiotherapy. RESULTS: The 5-year disease-free survival (DFS) was 83% for patients treated with CMF compared with 72% in the control group (P: =.028). Adjuvant treatment reduced both locoregional and distant metastases. When clinical outcome was analyzed in cell kinetic subgroups characterized according to tertile criteria, compared with patients in the control arm, 5-year DFS was significantly higher after adjuvant CMF in patients with TLI values in the second (78% v 88%, respectively; P: =.037) and third tertiles (58% v 78%, respectively; P: =.024). CONCLUSION: The results from this randomized clinical study indicate that patients with node-negative, rapidly proliferating tumors significantly benefit from adjuvant CMF.     

Accuracy comparison between PAPNET diagnoses and conventional diagnoses in an Italian cervical cytology laboratory

In a population-based cervical screening laboratory with a controlled workload, a retrospective PAPNET review of 1,654 Pap smears was performed. The series included a random sample of smears originally and conventionally classified as negative (no. 1,309) and unsatisfactory (no. 43), and 299 consecutive smears originally classified as abnormal. The PAPNET diagnoses and the original diagnoses were compared for accuracy. For smears with discordant classification, a majority diagnosis as obtained on manual review was used as a gold standard. The PAPNET testing showed a greater proportion of negative smears classified as unsatisfactory (3.7% vs. 0.2%; ratio, 16.7; 95% CI 12.4–22.0); a reduced proportion of ASCUS/LGSIL cases correctly identified as positive (i.e., a reduced sensitivity for such lesions) (76.3% vs. 97.9%; ratio, 0.78; 95% CI 0.66–0.91); an equal proportion (96.2%) of AGUS/HGSIL cases correctly identified as positive (i.e., an equal sensitivity for such lesions); and an equal proportion of negative smears correctly identified as such (i.e., an equal specificity). In conclusion, the PAPNET testing did not improve the diagnostic performance of the manual screening. Diagn. Cytopathol. 1998;19:279–283. © 1998 Wiley-Liss, Inc.