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Background: To reduce the occurrence of medication errors, a systemic approach was developed combining anti-neoplastic medication error reviews and morbidity and mortality conferences (M&MCs). We report the first experience of implementing this strategy in oncology. Methods: The case reports submitted to combined reviews were prepared by physicians and pharmacists, and medication error(s) were described and chronological and root-cause analyses were performed. Results: Ten combined reviews were conducted, which involved the departments of haematology, medical oncology, pneumology, gastroenterology and clinical oncology pharmacy. A total of 91 errors were analysed, of which 3 had reached the patient. Thirty-four corrective actions were proposed; 53% consisted of changes in practice, 35% in procedural reminders and 12% in on-ward education sessions. Conclusions: The combination of medication error reviews and M&MCs appears to be an efficient means of improving cancer patient safety and personnel proficiency. This multidisciplinary work is indispensable to improve future patient management through the critical analysis of past medical errors. © 2014 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

These studies investigated the role of substance P (SP) in the regulation of the hypothalamic-pituitary-ovarian axis in cynomolgus monkeys with normal menstrual cycles. Plasma concentrations of SP were determined in blood samples taken every morning in normally menstruating cynomolgus monkeys throughout the menstrual cycle. There was a significant decreasing linear trend of SP during the follicular phase (cycle day –13 to day 0) and a significant inverse relationship between SP plasma values and plasma 17β-estradiol (E[sub 2] ) values from day –13 to day 0 of the adjusted cycle. Correspondingly, SP area under the curve was significantly greater during the follicular phase than the luteal phase. In a second experiment, plasma concentrations of E[sub 2] , luteinizing hormone (LH), follicle-stimulating hormone (FSH) and progesterone and length of cycles were measured after five daily intragastric administrations (10 mg/kg) of an NK[sub 1] receptor (SP receptor) antagonist (RPR 100893; 10 mg/kg) initiated after serum E[sub 2] concentrations had exceeded 125 pg/ml. There was a statistically significant reduction in the amplitude (41% of control) and the area under the curve (37% of control) of the preovulatory LH surge. In addition, there was a reduction of the duration of the LH surge (3 ± 0.1 days in controls vs. 2.1 ± 0.2 days in treated animals). The present results show for the first time that there are significant variations in plasma levels of SP, with a strong negative correlation with serum levels of E[sub 2] during the follicular phase of the cynomolgus monkey, and that endogenous SP has a potentiating role in the interactive hypothalamo-anterior-pituitary mechanisms which lead to the preovulatory LH and FSH surges during the menstrual cycle in the monkey.Copyright © 2000 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Impaired skeletal muscle mitochondrial fatty acid oxidation (mFAO) has been implicated in the etiology of insulin resistance. Carnitine palmitoyltransferase-1 (CPT1) is a key regulatory enzyme of mFAO whose activity is inhibited by malonyl-CoA, a lipogenic intermediate. Whereas increasing CPT1 activity in vitro has been shown to exert a protective effect against lipid-induced insulin resistance in skeletal muscle cells, only a few studies have addressed this issue in vivo. We thus examined whether a direct modulation of muscle CPT1/malonyl-CoA partnership is detrimental or beneficial for insulin sensitivity in the context of diet-induced obesity. By using a Cre-LoxP recombination approach, we generated mice with skeletal muscle-specific and inducible expression of a mutated CPT1 form (CPT1mt) that is active but insensitive to malonyl-CoA inhibition. When fed control chow, homozygous CPT1mt transgenic (dbTg) mice exhibited decreased CPT1 sensitivity to malonyl-CoA inhibition in isolated muscle mitochondria, which was sufficient to substantially increase ex vivo muscle mFAO capacity and whole body fatty acid utilization in vivo. Moreover, dbTg mice were less prone to high-fat/high-sucrose (HFHS) diet-induced insulin resistance and muscle lipotoxicity despite similar body weight gain, adiposity, and muscle malonyl-CoA content. Interestingly, these CPT1mt-protective effects in dbTg-HFHS mice were associated with preserved muscle insulin signaling, increased muscle glycogen content, and upregulation of key genes involved in muscle glucose metabolism. These beneficial effects of muscle CPT1mt expression suggest that a direct modulation of the malonyl-CoA/CPT1 partnership in skeletal muscle could represent a potential strategy to prevent obesity-induced insulin resistance., (Copyright © 2016 the American Physiological Society.)

Hydrogen sulfide (H2S) is the third gasotransmitter described in mammals. These gasotransmitters (H2S, CO, and NO) are small molecules able to diffuse freely across membranes and thus susceptible to reach easily intracellular targets, one of which is the respiratory enzyme cytochrome oxidase subject to complete inhibition by low micromolar concentrations of these gases. However in contrast to NO or CO, H2S can be metabolized by a sulfide quinone reductase feeding the mitochondrial respiratory chain with the hydrogen atoms of sulfide. Sulfide is thus a two-sided molecule: substrate or poison according to the concentration. The aim of this chapter is to present a mean to monitor sulfide oxidation by isolated mitochondria or cells and to summarize how the properties of this amazing couple (mitochondria and sulfide) translate into practical and conceptual consequences., (© 2015 Elsevier Inc. All rights reserved.)

Aim: To determine the prognostic value of microtubule component expression in tumors of patients with carcinomas of unknown primary site (CUP)., Patients and Methods: Class III beta-tubulin, Delta2-alpha-tubulin and tau protein were examined immunohistochemically in 51 CUP tumors from patients receiving paclitaxel and compared with their response to treatment., Results: The overall response rate was 18.4% among 49 evaluable patients. Delta2-alpha-Tubulin and tau were not correlated with response or patient outcome. High class III beta-tubulin expression was correlated with both resistance to chemotherapy and shorter overall survival, while there was no relation with progression-free survival. In multivariate analysis taking into account clinical factors, class III beta-tubulin expression was independently correlated with overall survival., Conclusion: These findings show that in tumor cells a high level of expression of class III beta-tubulin, but not Delta2-alpha-tubulin or tau, is associated with resistance to paclitaxel and a poor prognosis in CUP patients receiving paclitaxel.

The development of anticancer targeted therapies is the result of a knowledge transfer from biology research to clinical practice. Indeed these drugs act on proliferation signal pathways involved in oncogenesis. Monoclonal antibodies (antiHER1 or cetuximab, antiHER2 or trastuzimab, antiVEGF or bevacizumab...) or inhibitor proteins (antiHER1 or cetuximab, antityrosine kinase c-Kit or imatinib...) are used in the treatment of several cancers types (breast, colon-rectum, lung, kidney...) alone or in association with chemotherapies since they improve patients' prognosis and survival. However additional clinical studies are still required to optimize their administration.

This study is intended to describe the cancer-related hospitalisations in the thirty French University and Regional Hospitals (CHR&U). The analysis is carried out on the years 2001 and 2002 databases and uses a relevant PMSI (Medicalisation Program Information System, the French DRG) data analysis program, which is an adapted version of the DAC (Cancer Activity Description) analysis program. Cases are selected from cancer-related diagnoses and procedures. The results provided have been classified according to paediatric and adult populations, to the organ anatomical localisations and to the different types of care : one-day hospitalisations or hospitalisations of more than one day, medical or surgical care, cares which include chemotherapy, radiation therapy or palliative procedures. Cancer-related hospitalisations amount to almost 25 % of the total CHR&U hospitalisations and add up to over a million stays per year. One-day hospitalisations amount to 25% of the cancer-related stays and essentially consist in radiation therapy (50% within the adult category) and for chemotherapy (30%). 26% of the hospitalisations of more than one day are surgical. This study is a first descriptive analysis of cancer-related hospital activity in CHR&U. The next stage will see this analysis applied to patients, using the anonymous patient identification number contained in the PMSI coding.

Objectives: In order to determine the exact pattern of plasma Substance P (SP) concentration during the LH preovulatory surge and the functional correlates which could exist between plasma SP, LH, 17 beta-estradiol (E2) and Progesterone, we performed a detailed analysis of changes in plasma SP concentration, during the critical phases of the LH preovulatory surge in the Human., Methods: The experimental study was performed in 21 women between the ages of 26 and 35 years. For each subject, blood samples were taken every 15 min, between 07:00 a.m. and 09:00 a.m. for 3 consecutive days when E2 plasma values reached at last 125 pg/ml. Then, each subject, according to the mean LH value of each day, was classified into one of the following groups: 1) the day before the day of the ascending phase, 2) the day of the ascending phase, 3) The day of the LH surge, 4) the day of the descending phase, 5) the day after the day of the descending phase., Results: Mean SP plasma values for the day of the LH peak, the day of the descending phase and the day after the day of the descending phase were all significantly higher than the values of the day of the ascending phase. Overall, there was an almost linear increase for plasma SP values between the day before the day of the ascending phase and the day after the day of the descending phase Also,this linear increase in plasma SP concentration exhibited a positive correlation (p = 0.016) with plasma progesterone concentrations which also started to increase on the day of the ascending phase of the LH surge., Conclusions: Taken together with previous results which have shown that the administration of a SP antagonist reduces both the amplitude and the duration of the preovulatory LH surge in the monkey, the increase in plasma SP concentrations, possibly driven by the rise in serum progesterone concentration, which take place at the time of the preovulatory LH surge, is certainly an important element of the Hypothalamo-Pituitary-Gonadal interactive network necessary for the full development of the preovulatory LH surge in the Human.

Objectives: A strong positive coupling has been already documented between the adrenocortical axis and the gonadal axis at the time of the initiation of the preovulatory LH surge of the menstrual cycle in the human. The LH preovulatory surge starts in the morning at the time of the acrophase (maximal plasma cortisol values) of the cortisol circadian rhythm. Also, it was shown that morning maximal plasma cortisol values were higher during the follicular phase than during the luteal phase. The objective of the present study was designed to determine the exact day of the fall of morning maximal plasma cortisol values and the functional correlates which could exist between plasma 17beta-Estradiol, LH, ACTH and Cortisol at the time of the preovulatory LH surge., Methods: We performed a detailed analysis of variations of plasma ACTH and cortisol concentrations during the various phases of the LH surge: 1) the day before the ascending phase, 2) the day of the ascending phase, 3) the day of the LH peak, 4) the day of the descending phase, 5) the day after the descending phase. 17beta-Estradiol, LH and FSH were determined by microparticle enzyme immunoassays kits and Progesterone determination was made using a radioimmunoassay kit. ACTH determination was made using a RIA kit and Cortisol was assayed by a RIA method., Results: Plasma ACTH concentrations were at their highest the day before the day of the ascending phase of the LH surge and significantly higher than the day of the descending phase and the day after the day of the descending phase (p < 0.02). Plasma cortisol concentrations were at their highest, with almost similar values, the day before the day of the ascending phase, the day of the ascending phase and the day of the LH peak; then, plasma cortisol concentrations were significantly lower than those of the preceding days, the day of the descending phase (p = 0.0001) and the day after the day of the descending phase (p = 0.02), when plasma 17beta-Estradiol starts to decrease., Conclusion: Overall, these results suggest that the positive ACTH-Cortisol-Estrogen dependency, well documented in the female rat, is also operating at midcycle during the menstrual cycle in the human.

Objective: To assess the physicians' use of clinical practice guidelines (CPG) for gastrointestinal oncology., Method: Quantitative study with semistructured individual interviews of 17 physicians treating patients with gastrointestinal cancer in the Rhone district of France., Results: The interviews identified 7 major themes: issues associated with development of the CPG; their usefulness in the physician-patient relationship; their ease of application; relevance of the specific topic; the procedures used for their development; the methods for disseminating them; and monitoring of their impact., Conclusion: The physicians were relatively favorable to the CPG but stressed the need for greater transparency about related issues and effects, economic and legal, in particular, for dissemination through multiple and novel communication tools, and for assessment of their impact.

Recently, to answer patients, caregivers and professionals needs, the "Plan Cancer" has been presented by the French Government. This plan is intended to improve quality of care in cancer patients and finally, patients' survival and quality of life. This planned strategy stresses the importance of organized interactions between hospitals and between the various health professionals. Measuring the number of patients with cancer and the activity related to cancer in large networks of multidisciplinary hospitals has became a real challenge in France for organizational, quality of care and economic reasons. Many University Hospitals in France have chosen to face this question by using the French DRG based information system called PMSI. It allows estimating the proportion of hospital stays concerned by cancers that are identified with algorithms based on ICD 10. However, French databases of hospital discharges do not allow patients identification. We collected data on hospital stays and patients in a subset of an organized network focused on cancer care and composed of 55 public or private hospitals in the Rhone-Alpes area. We used these data to estimate the number of patients who had been hospitalized within the network in 2000. Approximately 110,000 hospital stays were related with a diagnostic of cancer, corresponding to a number of patients within a range of 30345 to 35700. In absence of communicating files between hospitals, claims databases are an interesting source of information for cancer burden. The recent implementation of a procedure allowing the linkage of data concerning each patient should permit better estimates in the future. The main limitation will remain the possibility of a hospital to participate to more than one network.

In an era where health care expenditure control is a necessity, weighing a new treatment's cost against its added benefits is of crucial importance. These medico-economic analyses may be planned for the evaluation of new molecules in their daily use. Different methods may be used. The medico-economic evaluation of a drug can be performed with the use of clinical studies or modelization techniques. "Clinical studies" include the following methods: randomized trials, so-called "experimental", non-randomized studies, and observational studies. This classification follows a downward evolution of both the investigator's intervention power and the level of proof. Finally, modelization is becoming a commonly used tool. Randomized trials are the "gold standard" but the other, more pragmatic study types, providing a lesser degree of proof can complete the evaluation of a new molecule. One must find the best compromise between the study's objectives and the study type.

The increasing costs of care make it important to identify those strategies of greatest value from both an effectiveness and cost perspective. Economic analysis is characterized by a simultaneous consideration of alternatives costs and outcomes, and can provide useful data for managerial decision making. In this paper, methods of economic evaluations in general and in cancer in particular is reviewed. In cancer treatment, preventive, curative or palliative strategies can be concerned. Economic evaluation have become increasingly important in oncology because of the proliferation of expensive new treatments. Furthermore, considering quality of life effects is particularly important in oncology, where many treatments obtain modest improvements in response or survival. Quality of life measurements are also reviewed.

A single intragastric administration of 7,12-dimethylbenz(a)anthracene (DMBA) has been shown to induce mammary tumors in young cycling female Sprague-Dawley rats. The appearance of the tumors is preceded by a series of neuroendocrine disturbances, including attenuation of the preovulatory Luteinizing Hormone surge and Gonadotropin-Releasing Hormone release and amplification of the preovulatory 17beta-Estradiol (E2) surge. In this study, we examined the hypothesis that a single administration of DMBA increases the E2 and Progesterone inhibition of the spontaneous and Isoproterenol-induced Melatonin (MT) secretion from the pineal gland, during the latency phase. Also, the incidence of mammary tumors, as well as the possible preventive effect of various doses of Melatonin, were recorded up to 6 months after daily administration. For all studies, Sprague-Dawley rats, 55-60 days of age, received, on the Estrous day of the Estrous cycle, a single dose of 15 mg DMBA delivered by intragastric intubation. For the study on ovarian steroids, they were ovariectomized 5 days later and then sacrificed by decapitation at 10 a.m., one month later. Pineal glands were removed and placed in perifusion chambers containing Hanks 199 medium. The medium was saturated with O2/CO2 (95%/5%) and its pH was 7.4. Ten independent chambers were immersed in a water bath at 37 degrees C. Each pineal gland received medium (flow rate: 0.16 ml/min) through a system of input lines. The fractions were collected every 10 min, and immediately frozen at -20 degrees C until Melatonin RIA. Experiments were repeated to obtain up to five experimental points for each treatment. E2 (10(-11)-10(-9) M) and Progesterone (10(-9)-10(-7) M) were applied during the entire perifusion period (7 h). Isoproterenol (10(-6) M) was applied for 20 min after 2.5 h in perifusion. Melatonin concentrations and Areas Under the Curves were compared using two-factor ANOVA as well as parametric or nonparametric two-sample methods after testing sample normality. For the study on the possible preventive effect of Melatonin, they were daily treated, by the intragastric route, with increasing doses of Melatonin for 6 months. The percentage of female rats having at least one mammary carcinoma were compared using the Fischer exact t-test. During the latency phase, in vehicle-treated rats, E2 and Progesterone treatments lead an almost significant inhibition of the Isoproterenol-induced stimulation of Melatonin secretion. In DMBA-treated rats, E2 treatment leads to a complete blunting of the Isoproterenol-induced stimulation of Melatonin and Progesterone treatment leads to a cyclic inhibition of the Isoproterenol-induced Melatonin secretion. During the promotion phase, there was a dose-dependent inhibitory effect (up to 65% inhibition) of the daily administration of Melatonin, on mammary tumors occurrence. In conclusion, the long term inhibition of DMBA upon Melatonin secretion from the pineal gland might accelerate the promotion of mammary tumors induced by the mammary carcinogen. Inversely, the daily administration of Melatonin for 6 months induces a long lasting protective effect against the formation of mammary tumors.

Measuring the burden of cancer activity in big teaching multidisciplinary hospitals becomes a real challenge in France for organizational, quality of care and economic reasons. At the "Hospices Civils de Lyon" University Hospital in France, we have chosen to face this question by using the french DRG based information system called PMSI. It allows to identify hospital stays related to cancer care through the use of an algorithm based on selected ICD 10 codes for hospital stay. We then estimate the proportion of patients concerned by cancer and classify hospital stays and patients according to various epidemiological and clinical parameters. The results for the year 1999 taken as an example showed that 43,883 out of 293,827 (15%) of hospital stays were related with a diagnostic of cancer, corresponding to 12,777 different patients. The concordance study on 154 patients between the data from the electronic PMSI files and medical paper records showed a 97% concordance for cancer diagnosis and 93% for the precise type of tumor. In absence of hospital based cancer registries, the PMSI data base gives an accurate source of information for cancer burden and provides many potential applications in defining hospital policies for cancer management and resource allocations.

The therapeutic interest of gemcitabine both as a single drug and in combination is now well known and applied in various malignant diseases. However, it would be worth being further explored in two tumor models for which its efficacy has been suspected and which have been somehow "abandoned" by modern oncology after the demonstration of their high sensitivity to platinum derivatives, namely epidermoid tumours of the upper aero-digestive tract and uterine cervix. Combination studies should be encouraged in this setting.

Primary peritoneal tumors are rare and yet not well-known malignancies. We report here the clinical cases of 8 patients who were referred to our institution with a primary peritoneal tumor, 4 serous carcinomas (PSC) and 4 malignant mesotheliomas (PMM). Diagnosis was available in all cases and reviewed by two pathologists. A battery of various immunomarkers contributed to confirm the morphological diagnosis. All patients underwent initial surgery with or without optimal debulking. All of them received a platinum-based systemic chemotherapy. Intraperitoneal treatment with cisplatin and hyperthermia was performed in two cases. Four patients are dead (3 PSC, 1 PMM), two are alive (one in partial remission (1 PSC) and one is having treatment (1 PMM)), one is in complete remission (1 PMM) and one is lost to follow up (1 MMP). PSC and PMM are difficult to distinguish since they share the embryonic cOElomic epithelium as a common origin. The clinical presentations are similar and usually include the detection of a pelvic mass and/or diffuse peritoneal carcinomatosis with or without malignant ascites. Therefore, the accuracy and reliability of the initial histological examination is of crucial importance. Further attempts will be required to better identify the most active therapeutic post-surgical combinations, especially for PMM.