A retrospective case series of 103 consecutive patients with leptomeningeal metastasis and breast cancer.

Approximately 2-5 % of patients with breast cancer (BC) develop leptomeningeal metastasis (LM). 103 consecutive patients with BC were diagnosed with LM and initially treated with intra-CSF liposomal cytarabine from 2007 to 2011 at a single institution. Correlations were determined with respect to patient characteristics and BC subtype with regard to overall survival (OS). At LM diagnosis, 61 % of patients had a 0-2 performance status (PS), the remaining 39 % were severely neurologically impaired. Regardless of PS, all patients received intra-cerebrospinal fluid (CSF) liposomal cytarabine as first-line treatment. Systemic treatment and radiotherapy were also given in 58 and 17 % of patients respectively as clinically appropriate. Second- (intra-CSF thiotepa) and third-line (intra-CSF methotrexate) treatment was administered in 24 and 6 patients respectively. Median OS was 3.8 months (range 1 day-2.8 years). In multivariate analysis, an initial combined treatment, a second-line treatment with intra-CSF thiotepa, an initial clinical response, and a non-'ER/PR/HER2 negative' BC were significantly associated with a better OS. Median OS in this heterogeneous retrospective case series was similar to that of previously observed BC patients treated with intra-CSF methotrexate suggesting intra-CSF liposomal cytarabine is a reasonable first choice therapy of BC-related LM.

Megestrol acetate versus metronomic cyclophosphamide in patients having exhausted all effective therapies under standard care.

BACKGROUND: To evaluate the antitumour activity and safety of metronomic cyclophosphamide vs megestrol acetate in progressive and advanced cancer patients having exhausted all effective therapies under standard care. METHODS: Patients were randomly assigned to receive orally metronomic cyclophosphamide (50 mg b.i.d) or megestrol acetate (160 mg only daily) until intolerance or progression (RECIST 1.0). The primary efficacy end point was a 2-month progression-free rate (PFR(2m)). According to Optimal Simon's design and the following assumptions, namely, P0=5%, P1=20%, alpha=beta=10%, the treatment is considered as effective if atleast 5 out of 44 patients achieved PFR(2m). RESULTS: Between September 2006 and January 2009, 88 patients were enrolled. Two patients experienced grade 3-4 toxicities in each arm (4%). One toxic death occurred in the megestrol acetate arm as a consequence of thrombosis. The metronomic cyclophosphamide arm reached the predefined level of efficacy with a PFR(2m) rate of 9 out of 44 and a PFR(4m) rate of 5 out of 44. The MA arm failed to achieve the level of efficacy with a PFR(2m) of 4 out of 44 and a PFR(4m) of 1 out of 44. The median overall survival was 195 and 144 days in the metronomic cyclophosphamide arm and megestrol acetate arm, respectively. CONCLUSION: Metronomic cyclophosphamide is well tolerated and provides stable disease in such vulnerable and poor-prognosis cancer patients. This regimen warrants further evaluations.

Additional direct medical costs associated with nosocomial infections after head and neck cancer surgery: a hospital-perspective analysis.

The clinical impact of surgical site infections (SSI) and postoperative pneumonia (PP) after head and neck cancer surgery has been assessed in the past, but little is known about their economic impact. The present study was designed to evaluate costs related to SSI and PP after head and neck cancer surgery with opening of mucosa. The incidence of SSI and PP was measured in a prospective cohort of 261 patients who had undergone head and neck cancer surgery. The additional direct medical costs related to these infections from the hospital perspective were determined based on postoperative length of stay. The mean direct hospital costs for patients with and without SSI or PP were compared. Of the 261 patients, 81 (31%), 21 (8%) and 13 (5%) developed SSI, PP or both, respectively. The additional lengths of stay attributable to SSI, PP or both were 16, 17 and 31 days, respectively, and additional direct medical costs related to these conditions were 17,000, 19,000 and 35,000 Euros. Nosocomial infections after head and neck cancer surgery significantly increase patients' length of stay and therefore generate additional direct medical costs. These results support the application of preventive interventions to reduce nosocomial infections in this setting.

[Analysis of the factors influencing the internal reporting of nosocomial infections. A review of 108 notifications]. / Analyse des facteurs influençant la démarche de signalement interne d'infection nosocomiale. A propos de 108 signalements.

INTRODUCTION: Since July 26, 2001, the external reporting to the regional office of health and social affairs (Direction départementale des affaires sanitaires et sociales--Ddass) and the coordination centre (Comité de lutte contre les infections nosocomiales--Cclin) for the fight against nosocomial infections (NI) is mandatory. However, the modalities of internal reporting to the Clin are unknown. METHOD: We performed a retrospective analysis of 108 cases of NI reported over 23 months in 4 medical-surgical departments (MSD) with 14 to 35 NI reported/MSD. The distribution of the bacteria responsible was compared with that of the local epidemiological state (chi2 test). A correlation analysis was performed between the number of NI reported in each MSD and the structural characteristics and activity index of these MSD (Spearmann's correlation test). RESULTS: The NI were predominantly infections related to a catheter (43), lower respiratory tract (25) and infection of the site of surgery (19). Ninety were documented biologically, among which 10 implied multi-resistant bacteria. Ninety-four NI were associated with the prescription of an antibiotic. Compared with the local epidemiological state, the NI reported generally implied multi-resistant bacteria (p=0.009). The other microbiological data had little implication. In each of the MSD, the number of cases reported was independent of: the global activity, the number of interventions, the mean duration of hospitalisation, the number of beds, the number of clinicians, the number of new patients managed and the chemotherapy outpatient activity. Conversely, there was a strong correlation between the global consumption of antibiotics (r=0.78), and the number of the Clin members in each MSD DMC (r=0.82). CONCLUSION: In each MSD, the internal reporting of NI relies on the discovery of multi-resistant bacteria, but above all on the implication of those involved in the fight against nosocomial infections.

Implementing a multiple-isolator unit for centralized preparation of cytotoxic drugs in a cancer center pharmacy.

Due to numerous reasons: assuring safety (technicians, patients, nurses, environment), preventing medication errors, cost, maintaining pharmaceutical quality, rules and regulations, it was decided to create a dedicated room within the pharmacy for the preparation of intravenous cytotoxic drugs. After a preliminary study, the following choices were made: isolator unit instead of a vertical laminar air-flow hood, rigid surface instead of flexible film, a multiple-unit structure (one half suit unit for storage and one isolator unit for passthrough, two preparation units, each with four double-gloving portals) instead of a single-unit structure. After the equipment was installed, the physical and microbiological processes were validated and a medical/pharmaceutical catalog of protocols was created. Then the technicians were trained and the standard operating procedures were written. Updated every six months, they describe the general organization, gaseous sterilization of the isolators, the drugs and the medical devices, prescription analysis and circuit, preparation of nominative forms and labels, double checking the preparations delivery, cleaning and maintenance, documentation and reports, waste disposal, safety and protection and instructions for emergency. The pharmacists, pharmacy staff, physicians and nurses were all included in a work group responsible for the isolator unit project. The unit was opened in January 1997.

Multicentric evaluation of the MDR phenotype in leukemia. French Network of the Drug Resistance Intergroup, and Drug Resistance Network of Assistance Publique-Hôpitaux de Paris.

The wide discrepancies in the frequency of 'positive' samples for multidrug resistance (MDR) phenotype within the same type of tumor observed in the literature justified the need for the definition of consensus recommendations. To define standard techniques of MDR phenotype measurement, we ran a large multicentric evaluation of the different methods available. Thirty-six French centers participated in the study, and 742 samples of 2-10 x 10(6) viable cells were sent by overnight express mail between December 1993 and February 1996. The same batches of MRK16, 4E3 and UIC2 were used. Nineteen samples of leukemia (12 AML, 1 ALL, 6 lymphoproliferative syndromes) and six leukemic cell lines with different levels of MDR expression were tested. Five meetings reached agreement concerning the guidelines for each technique, except immunocytochemistry. The 19 fresh samples were tested by each center using one to four techniques among cytofluorometry, immunocytochemistry, functional tests and RT-PCR. Five samples were diagnosed as 'negative' according to local criteria, with few discordant results (0 to 16% of 'positive' results). For all the 14 remaining samples, large discrepancies were observed from center to center, and from one technique to another. No correlations could be found between techniques. Flow cytometric analysis of cells already exposed to MRK16 or control IgG2A, fixed in paraformaldehyde and sent to centers did not reduce the discrepancies between centers in two of the four samples with moderate expression, emphasizing the role of histogram interpretation. The use of alternative monoclonal antibodies (4E3 and UIC2) did not reduce the discrepancies observed. In a second step, the K562 parental cell line, a low resistant subline (K562/HHT100, x7 resistance index to DNR) and a high resistant subline (K562/HHT300, x125 resistance index to DNR) were sent blindly three times, with an increasing level of recommendations for flow cytometry. Dramatic improvements were observed in cytometric results when the result was expressed as the ratio of arithmetic mean of fluorescence of antibody (10 microg of MRK16)/arithmetic mean of fluorescence of control (10 microg IgG2A): the proportion of expected results increased from 61 to 100% for K562, and from 37 to 85% for K562/HHT100. For uptake and drug efflux measurements, the use of 1 h uptake of 0.1 microM of rhodamine, followed by 1 h efflux +/-10 microM of verapamil, permitted an increased reproducibility of the technique from 71 to 100% for K562 and K562/HHT100. Whatever the technique used, concordant results were obtained for K562/HHT300. The immunocytochemistry, using several antibodies (MRK16, JSB1 and C219) gave many non-interpretable results (44%), due to a frequent high background and discordant results between antibodies in the same centers, and discordant conclusions between centers. The group does not recommend this technique for circulating tumoral cells.

[Lymphocyte hybridization and cancerology: diagnostic and therapeutic applications. Example of tumor markers]. / Hybridation lymphocytaire et cancérologie: applications diagnostiques et thérapeutiques. Cas particulier des marqueurs tumoraux.

First described in 1975 by Köhler and Milstein, monoclonal antibodies (Mabs) result from the fusion of a B lymphocyte and a myeloma cell. Among the many uses of Mabs, oncology constitute a privileged, but difficult, field of investigation: the antigen heterogeneity and difficulty of access to tumors are major obstacles. In diagnosis, the Mabs allow the identification and the quantification of tumor specific or tumor-associated antigens: the assay of circulating tumor markers is one of the largest applications. In situ localization of tumors is also possible, using radiolabelled Mabs. In therapeutics, Mabs are used alone or linked to radionuclides, toxins, anticancer drugs or enzymes. Ex vivo treatment of bone marrow is used in autologous and allergenic grafts. The use of mono (Fab,Fv) or bivalents (F(ab)'2) antibody fragments, chimeric or human Mabs, cocktails of Mabs, intended to improve sensitivity and specificity of the tests, are the main prospects of this research area.

An evaluation of CA 549, a circulating marker of breast cancer using a procedure for comparison with CA 15.3.

A serum assay of CA 549 (Hybri-BREScan CA 549 degrees, Hybritech), a new tumor marker, was performed in 129 patients with breast cancer and 35 healthy women, in parallel with CA 15.3 (ELSA-CA 15.3 degrees, CIS Biointernational). Comparing 95 women with primary breast carcinoma and 35 controls, Relative (or Receiver) Operating Characteristic (ROC) analysis revealed that the Area Under ROC Curve (AUC) of CA 15.3 was significantly higher than that of CA 549, indicating that, for our population, the first marker was more effective. Parallel and series analyses were also performed using ROC AUC and revealed that the combination of these two tests did not give more information than the CA 15.3 test alone; however, they did not in any way constitute diagnostic tools. In our experience, the best field of application for CA 549 seems to be the therapeutic monitoring and early detection of breast cancer recurrences. However, further investigations on a larger scale are necessary to assess more precisely the place of CA 549 in following the clinical course of breast cancer patients.

Drug resistance in oncology: from concepts to applications.

The complex problem of drug resistance is discussed with respect to host toxicity, to tumor characteristics (kinetic resistance, heterogeneity of cell subpopulations, hypoxia, mutation and gene amplification), and to the medication itself (pharmacokinetic and pharmacodynamic resistance: cell membrane, intracellular metabolism, intracellular target). After detailing each type of resistance, the possibilities of fighting against drug resistance are explored (dealing with host toxicity, tumor characteristics and drugs--intensifying therapy, multiple drug therapy, biochemical modulation, particular modalities of drug administration). Finally, perspectives of research and development of new drugs are summarized.

Thyrotropin binding inhibitory immunoglobulin (TBII) and thyroid diseases using ROC analysis.

At attempt to detect the auto-immune origin of hyperthyroidism may be made by measuring thyrotropin binding inhibitory immunoglobulin (TBII) which uses the antibodies ability to inhibit labelled TSH binding to the TSH receptor. This study was carried out on 196 patients of which 128 had autoimmune hyperthyroidism and 68 another thyroid disease. Construction of receiver operating characteristic (ROC) curves allowed us to show the quality of the assay. This method, according to the prevalence of the disease, helped to determine the ideal cut-off of the assay. This cut-off was between 13.5 and 7.5% for prevalences ranging between 10 and 80%. For a 9% cut-off, which corresponded to the group studied, we observed 87.5% sensitivity and 87% specificity. Existence of false positives and false negatives was linked to the assay method which only informed us about the occupation of the TSH binding site and not its physiological activity. However, we concluded this easy to perform assay is a good test for the diagnosis of autoimmune hyperthyroidism.

Rapid quantitative determination of epirubicin and its metabolites in plasma using high performance liquid chromatography and fluorescence detection.

A rapid sensitive and selective isocratic technique was developed for the analysis of plasma epirubicin and three of its known fluorescent metabolites epirubicinol, 4'-O-beta-D-glucuronyl-4'-epidoxorubicin and 4'-O-beta-D-glucuronyl 1,3-dihydro-4'-epidoxorubicin, with daunorubicin as an internal standard, by using high performance liquid chromatography (HPLC) with fluorescence detection and a 'Hypersil ODS' column. The drugs were easily and efficiently extracted with a Sep-Pak C18 cartridge and the mean recoveries were greater than 85%. Intraassay and Interassay coefficients of variation (plasma samples) were better than 8.25%. An example of pharmacokinetic study obtained in a cancer patient after intravenous injection of epirubicine is described.

[Diagnostic value of SCC-TA4 determination in 4 localizations of epidermoid cancers. An experience of the FNCLCC subgroup of radio-analysis]. / Intéret diagnostique du dosage du SCC-TA4 dans quatre localisations de cancers épidermoïdes. Expérience du sous-groupe de radio-analyse de la FNCLCC.

A multicenter and retrospective study of the diagnosis value of SCC-TA4 in squamous cell carcinomas of 4 localisations was made with the 2 thresholds of 2 and 2.5 ng/ml. However, 3.1% of controls have a SCC value above 2.5 ng/ml. Sixteen benign gynecologic pathologies had no positive level. The benign digestive (N = 73), bronchial (N = 345) pathologies and no squamous cell carcinomas (N = 93, N = 220 respectively), had SCC-TA4 mean levels significantly lower than corresponding squamous cell carcinomas (N = 153, N = 128 respectively). Sensitivity of the test varied from 40% in the squamous cell carcinomas of the lung, to 72% in the squamous cell carcinomas of the uterine cervix. Specificity was always very high and varied from 91% in the SCC of lung, to 100% in the SCC of uterine cervix. For the SCC of uterine cervix, oesophagus and head and neck, the mean values and incidence of positive levels increased significantly with increasing tumor size and advancing disease stage. For the SCC of uterine cervix, mean SCC-TA4 levels and percentages of positive levels above 2 ng/ml were significantly higher for the patients with recurrence (22.5 +/- 4.6 ng/ml; 76%) or with metastasis appearance (23.6 +/- 5.4 ng/ml; 77%) than for the patients in remission (less than 1.5 ng/ml; 0%). In the SCC of oesophagus, we report levels before treatment that are significantly higher for the patients with metastasis at the first attempt (4.2 +/- 5.1 ng/ml; 59%), and an elevated SCC level at the diagnosis evoked a SCC of lung already disseminated (8.8 +/- 12.1 ng/ml; 50%) that will fail to respond to treatment (4.0 +/- 4.2 ng/ml; 48%).

[The place of tumor markers in breast and gynecologic neoplasms]. / Place des marqueurs tumoraux dans les néoplasies mammaires et gynécologiques.

The main tumor markers used in breast and gynaecological neoplasias are reviewed with their individual characteristics: carcino-embryonic antigen (CEA), alpha-fetoprotein (AFP), chorionic gonadotropin hormone (CGH), CA 125, CA 15.3 and Squamous Cell Carcinoma Antigen (SCC). Their indications are specified according to the following cancer locations: breast, trophoblast, ovary, endometrium and cervix. The major clinical applications of the tumor markers routinely used are emphasized.

Significance of PSA and PAP in patients with or without prostatic cancer.

Coupled prostate-specific antigen (PSA) and prostatic acid phosphatase (PAP) measurements (using the radioimmunoassay method) were carried out on 220 controls, 33 patients with prostatic hyperplasia, and 71 with carcinoma. The mean PSA value was 3.70 +/- 3.31 ng in the controls. A level of 10 ng was adopted as the upper limit of normal. Four of the eight cases of prostatic hyperplasia with a high PSA level (between 10 and 25 ng) underwent surgery. Histological tests confirmed benign hyperplasia. In the localized cancers, the PSA level was normal. In the metastatic cancers, PSA proved to be more sensitive than PAP. Thus, PSA is of little use in the early diagnosis of cancer; its systematic measurement as a means of cancer screening for the general public may even be misleading.

[Value of the assay of squamous cell carcinoma in cancer of the uterine cervix]. / Intérêt du dosage de l'antigène "squamous cell carcinoma" dans le cancer du col utérin.

The squamous cell carcinoma (SCC) antigen was assayed by radioimmunoassay in patients with squamous cell carcinoma of the uterine cervix at different stages before any treatment and in patients under treatment. Low levels of SCC antigen were detected in the early stages of the disease, showing that this antigen cannot be considered an aid to diagnosis. In the more advanced cancers, an increase of SCC antigen levels proportional to the stage of the disease was observed. However, SCC antigen assays are mainly useful in the follow-up of patients to evaluate therapeutic effectiveness.

[Cancer of the ovary. Comparative value of serum CA-125, immunochemistry and biological tests of inflammation]. / Cancer de l'ovaire. Intérêt comparé du Ca-125 sérique de l'immunohistochimie et des tests biologiques de l'inflammation.

The marker CA-125 is not specific of malignant ovarian tumors but, when its titration is positive, its evolution permits to follow correctly the development of the tumor. The authors report their experience with 180 titrations coupled with the titration of inflammation markers.

Clinical pharmacokinetics of 6-hour infusion of high-dose methotrexate. Preliminary trial of monitoring high infusion doses.

Methotrexate (MTX) in serum was measured by RIA in 12 cancer patients receiving high doses of MTX (2 to 8 g/m2) in 6 hour infusions 69 treatments were studied. The peak serum level was proportional to the dose administered and was always greater than 10(-4) M. 2 elimination phases were seen: the first had a mean half-life of 2.36 h and the second a mean half-life of 16.14 h. 24 hours after beginning the infusions there were very large variations in individual serum concentrations of MTX, from 2.4 10(-6) M to 1.9 10(-5) M by 24 h after 8 g/m2. To control these variations, a mathematical model for prediction of the individual pharmacokinetic pattern of a 6 hour-infusion of high-dose MTX by kinetic analysis of a low-test dose is proposed. A program was created for an Apple III computer using toxic and therapeutic serum levels of MTX selected by the clinician. The computer program is adaptable to any infused substance for variable infusion times, thus introducing new advances over existing methods.