Early kinetics of the human thyroid trap estimated with 99mTc and 131I

Kinetic parameters of ^99mTc and ¹³¹I thyroid trapping were compared in 13 patients (30 dynamic studies). The data were analyzed with a six-compartment model including three compartments for extrathyroid spaces. There was a good correlation between the estimates of the total iodide and pertechnetate pools (V₄+V₅). As expected, the ₁₄ loss rate constant for technetium was always higher than that for iodide.In five euthyroid patients, the unidirectional clearances (R₄₁) with TcO₄ ^– and I^– were generally of the same magnitude. The effect of TSH stimulation appears to be identical for both isotopes: an increase of R₄₁ and the total iodide and pertechnetate pool (V₄+V₅), a decrease of the isotope loss rate constant (₁₄).In two untreated thyrotoxic patients, the unidirectional clearance of ^99mTc was 2.5 times higher than that estimated with ¹³¹I. Under administration of antithyroid drug, unidirectional TcO₄ ^– clearance was lower than that of iodide in the six patients studied.A similar and greater discrepancy between early ¹³¹I and ^99mTc kinetics was observed in a patient with congenital goiter. The technetium thyroid trap was only slightly elevated, whereas unidirectional iodide clearance and (V₄+V₅) were clearly increased.This series of patients suggests that whereas there is a good correlation between early ¹³¹I and ^99mTc kinetics in euthyroid subjects, a discrepancy exists in patients with spontaneous or acquired dyshormonogenesis. This is confirmed by the segmentary study of a patient with a nodule appearing hot on the ^99mTc scintigram and cold on the ¹³¹I scan.Research supported by INSERM (CRL 7750943 B)     

Putative host resistance and long-term survival in breast cancer

Lymphocytic infiltration in and around the tumor together with sinus histiocytosis and follicular hyperplasia in regional nodes has been studied in a group of 310 patients with breast cancer treated by standard radical mastectomy. The semiquantitative grading of these particular changes made possible the division of patients into 3 classes of putative host resistance, namely, no or poor reaction, good reaction, and strong reaction. The grading was shown to have a close correlation with prognosis both 5 and 10 years after surgery. More interestingly, the incidence of metastases in the 3 classes was significantly different, i.e. much higher in the non-responder group, thus supporting the hypothesis that prognosis in breast cancer is closely related to a histological picture of cell-mediated immunity against the tumor, and that this resistance probably acts as a local barrier to the diffusion of the tumor.

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Résume Chez 310 malades atteintes de cancer du sein et traitées par mastectomie radicale, nous avons étudié l'infiltration lymphocytaire intra- et péritumorale et, dans les ganglions régionaux, l'histiocytose sinusale et l'hyperplasie folliculaire. Par une gradation semiquantitative, les malades ont été divisées en trois groupes de résistance potentielle: pas ou peu de réaction, réaction d'intensité moyenne, forte réaction. Cette gradation est en bonne corrélation avec le pronostic à 5 et 10 ans. De plus, la fréquence des métastases diffère dans les trois groupes; elle est beaucoup plus élevée dans le groupe à réaction nulle ou faible. Ces données confirment l'hypothèse qui admet que le pronostic du cancer du sein est en relation avec les aspects histologiques d'immunité cellulaire antitumorale et que celle-ci agit vraisemblablement comme un barrage local s'opposant à la diffusion de la tumeur.

     

Guidelines for routine assessment of cardiologic surgical risk: electrocardiogram

Cardiac complications are the main cause of perioperative mortality. A preoperative electrocardiogram and cardiologist's consultation are usually performed to get information about cardiac state of patients undergoing surgery and to prevent complications. In their study the Authors applied to 1715 patients undergoing surgery an evaluation schedule for the cardiac surgical risk, including an ECG as first-level test, performed systematically on the whole sample. The aim was to assess predictive value of this preoperative examination to verify its efficacy as routine test. Basing on results achieved, electrocardiogram is not routinely indicated before noncardiac elective surgery, but it should be requested for the patients having high risk of cardiac complications at an accurate clinical-anamnestic examination. Therefore, clinical judgement, that is the first level of any preoperative evaluation, should be the basis for ordering an ECG to be considered a second-level test.     

Schedule-dependent cytotoxic interaction between epidoxorubicin and gemcitabine in human bladder cancer cells in vitro.

PURPOSE: The aim of the study was to evaluate the activity of epidoxorubicin (EPI) and gemcitabine (GEM) and to define the most effective schedule in human bladder cancer cells. EXPERIMENTAL DESIGN: The study was performed on HT1376 and MCR cell lines. Cells were exposed for 1 and 24 h to drugs used in different schemes. Cytotoxic activity was evaluated by the sulforhodamine B assay, potential clinical activity was estimated by relative antitumor activity, and the type of drug interaction was assessed using the method of Chou and Talalay. Cell cycle perturbations and apoptosis were assessed by flow cytometry; BAX, BCL-2, and P53 expression was evaluated by Western blot; and DNA damage was assessed using the alkaline Comet assay. RESULTS: EPI and GEM produced a cytotoxic effect in both cell lines, with 50% inhibitory concentration and relative antitumor activity values suggestive of a high clinical activity. Simultaneous treatment with EPI and GEM and the sequence GEM-->EPI caused an antagonistic interaction (combination index > 1) after both 1- and 24-h treatments. Conversely, the inverse sequence, EPI-->GEM, produced a synergistic interaction that was more pronounced in MCR cells than in HT1376 cells. The increase in DNA-damaged cells from 10% to 20% after single-drug exposure to 40-60% at the end of EPI-->GEM treatment may explain the synergistic interaction produced by the anthracycline-antimetabolite sequence. CONCLUSIONS: Our findings show that the efficacy of the EPI and GEM combination is highly schedule dependent and indicate that the most active scheme is EPI followed by GEM, which is currently being validated in an ongoing intravesical Phase I-II clinical protocol.     

Phase I pharmacological and bioavailability study of oral diflomotecan (BN80915), a novel E-ring-modified camptothecin analogue in adults with solid tumors.

PURPOSE: Diflomotecan (BN80915) is an E-ring modified camptothecin analogue that possesses greater lactone stability in plasma compared with other topoisomerase I inhibitors, a potential advantage for antitumor activity. As with other camptothecins, oral administration has pharmacological and clinical advantages. This Phase I study was performed to assess the feasibility of the administration of oral diflomotecan, to determine the maximum-tolerated, dose its bioavailability, and to explore the pharmacokinetics. EXPERIMENTAL DESIGN: An initial i.v. bolus was administered to assess the bioavailability of diflomotecan. Fourteen days later, diflomotecan was administered p.o. once daily for 5 days to adult patients with solid malignant tumors and repeated every 3 weeks. BN80915 and its open lactone form BN80942 were measured. RESULTS: Twenty-two patients entered the study and received a total of 57 cycles of oral diflomotecan at flat dose levels of 0.10, 0.20, 0.27, and 0.35 mg. The main toxicity was hematological, but some patients experienced alopecia, mild gastrointestinal toxicity, and fatigue. At the 0.35-mg dose level, 2 of 4 patients experienced dose-limiting toxicity comprising grade 3 thrombocytopenia with epistaxis and febrile neutropenia in 1 patient and uncomplicated grade 4 neutropenia lasting for >7 days in another. Toxicity was acceptable at the 0.27-mg dose level at which dose-limiting toxicities were observed in 3 of 12 patients (grade 4 neutropenia > 7 days, complicated by fever in 1 patient but without other signs of infection). After two cycles of diflomotecan, 6 patients had disease stabilization, which was maintained in 2 patients for 9 months and >1 year, respectively. Diflomotecan pharmacokinetics were linear over the dose range studied. Systemic exposure correlated with the fall in WBC counts. The mean oral bioavailability (+/-SD) was 72.24 +/- 59.2% across all dose levels. Urinary excretion of BN80915 was very low. CONCLUSIONS: The recommended oral diflomotecan dose for Phase II studies is 0.27 mg/day x 5 every 3 weeks. This regimen is convenient and generally well tolerated with a favorable pharmacokinetic profile and high but variable bioavailability.     

High Serum Levels of Soluble IL-2 Receptor, Cytokines, and C Reactive Protein Correlate with Impairment of T Cell Response in Patients with Advanced Epithelial Ovarian Cancer

The serum levels of interleukin-(IL-)1α, IL-1β, IL-2, IL-6, TNFα, and sIL-2R and the proliferative response of peripheral blood mononuclear cells (PBMC) to phytohemagglutinin (PHA), anti-CD3 monoclonal antibody (mAb), recombinant IL-2 (rIL-2), and the combination of PHA or anti-CD3 mAb with rIL-2 were studied and correlated with serum levels of C-reactive protein (CRP) in women with advanced epithelial ovarian cancer. The expression of CD25 and CD122 subunities of membrane-bound IL-2R on PHA- or anti-CD3 mAb-stimulated PBMC was also studied. In comparisons with the controls, PBMC response to PHA, anti-CD3 mAb, and rIL-2 was significantly lower in the cancer patients. The addition of exogenous rIL-2 to the PBMC cultures increased response in both controls and patients but did not modify the significance of the differences. After stimulation with PHA or anti-CD3 mAb, the percentage of PBMC CD25⁺or CD122⁺was significantly lower in patients. The serum levels of IL-1α, IL-1β, IL-6, TNFα, sIL-2R, and CRP were significantly increased in patients compared to the controls. Instead, no differences were observed for serum levels of IL-2. A strong association was found between high serum levels of the above-mentioned cytokines, sIL-2R, and CRP. The results of our study on advanced stage (IIIb–IV) ovarian cancer patients are consistent with the previously reported hypothesis that high IL-6 and/or CRP serum levels may represent an important and independent prognostic factor of the likely outcome in cancer patients.     

Colonic Cell Proliferation in Normal Mucosa of Patients with Colon Cancer

Cell kinetics parameters have been analysed in colonic mucosa at different distances from a tumour in patients with colon carcinoma. Total cell number (TCN), H thymidine labelling index (TLI), mitotic index (MI), Goblet cell index (GCI) and the distribution of labelled cells along the crypt column (cell position frequency plot) were determined in well-aligned crypts. Total cell number, GCI and the labelled cell position frequency plots were similar in different samples from the same individual. A negative linear correlation between TCN and TLI was observed. The analysis of the cell position plots showed two patterns 1) with a high concentration in the bottom fifth of the crypt and 2) with frequent labelled cells at high positions. Whereas a negative correlation between overall TLI and the percent contribution to the TLI of the lowermost fifth was seen, the correlation was positive for the next 3 fifths and labelling was absent in the last part of the crypt.