Effects of azacitidine in 93 patients with IDH1/2 mutated acute myeloid leukemia/myelodysplastic syndromes: a French retrospective multicenter study.

Isocitrate dehydrogenase 1 (IDH1) and 2 (IDH2) mutations in Myeloid Neoplams (MNs) exhibit DNA hypermethylation via 2-hydroxyglutarate (2HG) over-production. Clinical impact of azacitidine (AZA) remains inconsistent in IDH1/2-mutated MNs and the potential of serum 2HG as a suitable marker of response to AZA is unknown. To address these questions, we retrospectively analyzed 93 MNs patients (78 AML, 11 MDS, 4 CMML) with IDH1/2 mutations treated with AZA. After a median of 5 cycles of AZA, overall response rate was 28% (including 15% complete remission) and median OS was 12.3 months (significantly shorter in AML compared to MDS/CMML patients). In multivariate analysis of AML patients, DNMT3A mutation was associated with shorter OS while IDH1/2 mutation subtypes had no independent impact. No difference was observed in serum 2HG levels upon AZA treatment between responding and refractory patients suggesting that serum 2HG cannot be used as a surrogate marker of AZA response.

Prodrugs as drug delivery system in oncology.

The use of conventional chemotherapy in the treatment of cancer has been restricted by the lack of cell specificity, which causes toxicity regarding healthy cells resulting in limiting side effects responsible for low therapeutic efficiency. To overcome these drawbacks, the design of prodrugs has evolved and improved by covalently linking the drug through a degradable spacer. The use of these prodrugs as drug delivery systems, which are able to inactivate the drug during its biodistribution to specifically deliver the drug to its target, is an important breakthrough in cancer therapy. This strategy consisting in the covalent binding of a promoiety to daily used therapeutic compounds has been clinically proven in the design of targeted prodrugs leading enhanced therapeutic efficacy and increase of the therapeutic index. This review summarizes and compares several strategies that improve the therapeutic index of chemotherapy (i.e. conventional drugs) by their chemical transformation into prodrugs improving pharmacokinetic profiles and optimizing administration routes in comparison to the initial drug. This review provides an overview of the methods used to control the structure and function of prodrugs and, ultimately, their current and future potential in increasing the therapeutic index of daily used anticancer drugs. First, prodrugs' design and their activation within the tumor microenvironment or within the tumor cell will be exposed. Then, the different strategies used leading to these prodrugs will be presented.

[An apperture effect in hypochondria]. / A la recherche d'un effet d'ouverture chez l'hypocondriaque

It is usual to consider hypocondriac patients as jailed in their own bodies; of course, this jail may be a protection against declared paranoiac or paranoid states. However, our experience has shown us that in certain cases, there are some possibilities of aperture if we feel ourself free enough with our medical identity and if we keep silent as long as the patient is not able to hear us. A step is then allowed to him. Our prudent remark concerns the story which is then gradually revealed: it is often the story of the secret of maternal suffering which is enclosed in his own body.

[Anticholinergics during neuroleptic treatment. Value and withdrawal]. / Les anti-cholinergiques au cours des traitements neuroleptiques. Intérêt et sevrage.

In a study on 144 chronic psychotic patients treated with neuroleptics, the authors tried to define a therapeutic schedule for anti-cholinergic drugs use to control parkinsonism induced by anti-psychotic drugs. Systematic treatment by anti-cholinergic drugs seems to be useless, even dangerous, and, if they have to be employed, the treatment must not exceed six months. The authors emphasize and analyse through the literature, the problems of drug abuse, withdrawal and psychological dependence with anti-parkinsonian drugs and their neurochemical effects.

[A four-dimensional model of chronic schizophrenia based on the factorial structure of the Positive and Negative Syndrome Scale (PANSS). A study of a group of 153 chronic schizophrenic patients and comparison with the factorial structure of the BPRS]. / Modèle quadridimensionnel des schizophrénies chroniques issu de la structure factorielle de l'échelle des syndromes positif et négatif (PANSS). Etude chez un groupe de 153 schizophrènes chroniques et comparaison avec la structure factorielle de la BPRS.

The aim of the study is to explore the latent dimensions in chronic schizophrenia using factorial analysis methods. 153 subjects (89 males, 64 females) with a mean age of 38.83 years (sd = 10.15) meet the RDC criteria for chronic schizophrenia and were included in the study. They were 127 inpatients and 26 outpatients and the mean duration of the illness since the first psychotic episode was 14.69 years (sd = 9.64). The majority of the schizophrenics received antipsychotic treatment with a mean dose (in chlorpromazine-equivalent) of 401.86 mg (sd = 368.13). The schizophrenics were rated using the French versions of the Positive and Negative Syndrome Scale (PANSS) and the Brief Psychiatric Rating Scale (BPRS). Two successive principal components analyses (PCA) were carried out on the correlation matrix of the 30 PANSS and 18 BPRS items. The numbers of factors were limited using several guidelines : eigenvalues higher than 1, screen test and the parallel analysis of Horn. Then an orthogonal equamax rotation was made and the saturation value was chosen using and ad-hoc paradigm. The results have shown a four-factors solution for the PANSS with the following factors : negative, positive-hostility, disorganization-impulsivity, depressive-anxious. The composition of the four preceding factors was respectively : negative [N1, N2, N3, N4, N6, N7, G7, P4 (-)]; positive-hostility (P1, P2, P3, P5, P6, P7, G8, G9, G12, G15, G16); disorganization-impulsivity (G5, G10, G11, G13, G14, N5); depressive-anxious (G1, G2, G3, G4, G6). The ACP of the BPRS have shown a three factors solution (positive-disorganization, negative, depressive-anxious). The factorial structure of the PANSS was discussed with the different studies. Our results confirm the division of the productive symptomatology into two components, delusions-hallucinations and cognitive (disorganization). Moreover depressive and negative symptomatology constitute two separate dimensions. Contrary to the others studies we did not find an excited component, the corresponding items were found in the positive and disorganization factors. The inclusion of solely chronic schizophrenics could explain the lack of the excited component. Our data in chronic schizophrenia allow us to propose a four-dimensional model explaining the symptomatology of this disease.

[Capacity to experience pleasure and displeasure by Cloninger and von Knorring in type I and II alcoholism]. / Capacité à éprouver du plaisir et du déplaisir et alcoolisme de types I et II selon Cloninger et von Knorring.

The aim of the present study is to test the hypothesis that Cloninger and von Knorring's type II alcoholics are more hedonic and experience less displeasure than type I alcoholics. 55 inpatients filled out the DSM III-R criteria for abuse or alcoholic dependence. The alcoholics were dichotomized into type I or type II using the onset of their alcoholism (type II < 25 years, type I > or = 25 years). In the few days of their hospitalization, the subjects filled out the Fawcett Clark Pleasure Capacity Scale-Physical Pleasure (FCPCS-PP), the Hardy Displeasure Capacity Scale-Physical Displeasure (HDCS-PD) and the abridged form of the Beck Depression inventory (BDI). The sociodemographic characteristics, the proportions of "abusers" and "dependents" and the scales scores were compared between the two groups. The sex-ratio and the educative level were not different between the two groups; the values of the chi 2 were respectively 1.36 (df = 1), p = 0.24 and 1.03 (df = 2), p = 0.59. The ratio "abusers" /"dependents" was not different (chi 2 = 1.115, p = 0.291). The mean age of the type I alcoholics was higher (m = 46.7, sd = 11.2) than that of the type II (m = 38.9, sd = 7.9) (U = 218.5, p = 0.013). Using covariance analyses (ANCOVA) to control the age, the results have shown that the FCPCS-PP and HDCS-PD scores of the type II alcoholics were not different than these of the type I alcoholics [respectively F (1.52) = 1.5, p = 0.23 and F (1.52) = 0.14, p = 0.7]. In conclusion, we failed to confirm the hypothesis that type II alcoholics would experience more pleasure and less displeasure than type I alcoholics. These negative results were discussed and the potential factors that could explain them are detailed.

[Anhedonia in schizophrenia]. / L'anhédonie dans les schizophrénies.

A study on 61 subjects who meet Spitzer's Research Diagnosis Criteria of schizophrenia and on 56 normal subjects has been conducted to explore anhedonia. Anhedonia was evaluated by two rating scales, the Physical Anhedonia Scale (PAS) and a sub-scale of physical pleasure (FCPCS-PP) extracted from the pleasure scale of Fawcett. The reliabilities of the scales were studied in the schizophrenic group by the Cronbach alpha and the Kuder Richardson (KR 20) coefficient and by the correlation between the two scales (concurrent validity). The Cronbach alpha was 0.77 for the FCPCS-PP and the KR 20 was 0.82 for the PAS. The correlation between the two scales was -0.37 (p < 0.01). The schizophrenics were significantly more anhedonic than normals with higher score on the PAS and with a lower score on the FCPCS-PP. Using the Beck Depression Inventory to rate depression in the schizophrenic group and to dichotomize these subjects into depressed schizophrenics and no depressed schizophrenics, we failed to find significantly differences concerning anhedonia scales between these two sub-groups of schizophrenics. There was no difference between in and outpatients concerning the anhedonia scales. Our results suggest that anhedonia would be a possible marker of schizophrenic disease. The distribution of the anhedonia scales in the schizophrenic group is normal or unimodal and it doesn't support the hypothesis of a qualitative sub-group of schizophrenics characterised by severe anhedonia.

[Locus of control in alcoholics: comparative study of 64 alcoholics vs 50 hospitalized patients and 50 normal controls]. / Le lieu de contrôle chez les alcooliques: étude comparative de 64 alcooliques versus 50 témoins hospitalisés et 57 sujets sains.

The locus of control is a construct that consists of factors that influence and contribute to a person's belief concerning the extent and degree to which he or others can influence life events. The study had four purposes. They were to examine differences between psychiatric inpatients alcoholics and non alcoholics on the internal, chance and powerful others subscales of the French version of Levenson's scale, to evaluate differences on these scores between the alcoholics who accepted the alcohol program treatment proposed at the admission (hospitalization of 15 days with a directive and structured context) and those who refused this treatment, to assess the impact of treatment on the Levenson scale scores of the alcoholics, and finally to determine whether the Levenson scale scores differentiate between treatment successes and failures (evaluated at three months). 171 subjects were divided into three groups: 64 patients hospitalized in psychiatry for chronic alcoholism (ICD-10 criteria for alcohol dependency), 50 patients hospitalized in psychiatry for an other pathology (control group) and 57 healthy subjects (normal group). These subjects filled out the IPC (Internal, Powerful others, Chance) scale of Levenson, different from the I-E (Internal-External) Rotter's scale because it distinguishes two types of externality: one imprevisible, the chance, and the other previsible, the powerful others. The results showed that the alcoholics as the controls are more external than the healthy subjects (Chance and Powerful others subscales). They also showed that the alcoholics who refused the alcohol treatment program proposed at the admission were more internal than those who accepted. We also found that, during the treatment, the alcoholics' scores of Internality increased while their scores of externality (Chance and Powerful others) decreased. This decreasing was also found with the check inpatients. So these changes would have connections with an "hospitalization factor" and wouldn't be due to the alcohol treatment. As for the last purpose, there were no significant differences between the initial locus of control scores of the successes and those of the failures.

[Clinical characteristics of chronic schizophrenic patients presenting with severe anhedonia]. / Etude des caractéristiques cliniques des schizophrénies chroniques présentant une sévère anhédonie.

The aim of the present study is first to test the existence of a sub-group of chronic schizophrenics characterized by a severe anhedonia and secondly to determine the characteristics of that sub-group. 150 patients meet the DSM III-R and RDC criteria for chronic schizophrenia and 151 healthy subjects constituted the control group. The subjects filled out the Physical Anhedonia Scale of Chapman (PAS), the Fawcett Clark Pleasure Capacity Scale-Physical Pleasure (FCPCS-PP) and the abridged form of the Beck Depression Inventory (BDI). The distributions of the PAS and FCPCS-PP were studied using a test of normality. In the normal group the distributions of the anhedonia scales were unimodal and in the schizophrenic group the distributions were not. The schizophrenics were dichotomized into anhedonic schizophrenics (PAS scores higher or equal to 29) and hedonic schizophrenics (PAS scores lower than 29) and these subgroups were compared on socio-clinical variables and PANSS, BPRS and BDI scores using chi 2 square tests or Mann and Whitney tests. They were 32 subjects in the anhedonic sub-group and 128 subjects in the hedonic sub-group. They were not significant differences between the sub-groups concerning the sex-ratio, educative level, age, mean duration of the illness, mean number of hospitalization and the mean dose of antipsychotics. The proportions of depressive and deficit syndromes did not differ between the two sub-groups but the proportion of "negatives" (using the composite score of the PANSS) was greater in the anhedonic sub-group. A discriminant analysis has been done on the items of the BPRS, PANSS and BDI and the results have shown that the anhedonic schizophrenics had more hallucinatory behavior, disorientation, blunted affect, social withdrawal, cognitive distorsions and less anxiety and displeasure than hedonic schizophrenics. Our results allow to identify a sub-group of chronic schizophrenia characterized by a severe anhedonia and will be confirmed by others studies using prospective methodology.

[External validity, reliability and basic score determination of the Toronto Alexithymia Scales (TAS and TAS-20) in a group of alcoholic patients]. / Etude de la validité externe, de la fidélité et détermination des notes seuils des échelles d'alexithymie de Toronto (TAS et TAS-20) chez un groupe de malades alcooliques.

The criterion validity of the Toronto Alexithymia Scales (TAS and TAS-20) was assessed by administering the scales to 47 alcoholic inpatients. The 47 subjects were inpatients meeting the Research Diagnostic Criteria for alcoholism. The subjects were assessed by two raters using the Beth Israël Questionnaire in the first week following their hospitalization. They filled out the TAS and one week later the TAS-20. Among the 47 alcoholics, 31 were alexithymic and 16 were non-alexithymic. The TAS and the TAS-20 scores of the alexithymics were significantly higher than that of the non alexithymics. The mean (sd) of the TAS in the alexithymics and the non alexithymics were respectively (m = 76.13, sd = 9.56; m = 64.2, sd = 13.88; t = 3.38, df = 45, p = 0.0015). The mean (sd) of the TAS-20 in the alexithymics and the non alexithymics were respectively (m = 54.1, sd = 8.81; m = 43.18, sd = 11.5; t = 3.62, df = 45, p = 0.0007). The one-week test-retest was r = 0.17, p < 0.001. On the basis of these findings, TAS and TAS-20 cutoff scores were suggested. A range of potential cutoff scores around the mean TAS or TAS-20 score were tested using four methods to assess the goodness of a diagnostic test (sensitivity, specificity, Younden's coefficient, positive predictive value). The best scores that maximizes the diagnostic validity of the TAS and TAS-20 in identifying alexithymic subjects were respectively 73 and 56. On the basis of the mean TAS and TAS-20 score for the non alexithymic group and the means that we have obtained with normal groups, scores of 64 and 44 were respectively selected as the cutoff level for the identification of non alexithymic subjects.

[The "lethality" of attempted suicide]. / La "léthalité" des tentatives de suicide.

It is possible to quantify medical severity of a suicide attempt ("lethality") and its relationships with other components of the suicidal gesture have to be analysed. Our study about 758 suicide attempts aims to define psychiatric and psychological factors which are linked to "lethality" as measured by Weisman and Worden scale. Results of factorial analysis show a strong relation between "lethality" and some variables proving the intensity of psychological difficulties. Those results suggest the existence of relationship between "high lethality" on one hand, and diagnosis of psychosis, depressive symptomatology, high suicidal intent, some conceptions of death, on the other hand. A "low lethality" is associated with hedonistic conception of death, lack of positive signs of depression, existence of impulsiveness, psychopathic behaviors or lack of established mental disorder. These results reinforce the hypothesis of a relation between severity of patients psychological difficulties and medical severity of suicide attempt.

[Affective dependency and primary alcoholism]. / Dépendance affective et alcoolisme primaire.

The relationships between dependency and alcoholism have been studied in two groups of male subjects. In the first group 41 subjects met Spitzer's criteria for primary alcoholism and the 50 subjects of the second group were healthy. All the subjects filled out two rating scales, the Interpersonal Dependency Inventory (IDI) and the Beck Depression Inventory (BDI) (shortened version). The alcoholics were divided into depressives vs non depressives by the means of the score of the BDI. Comparing to controls the alcoholics scored significantly higher on the IDI, but there were no differences for this scale between the two sub-groups of alcoholics (depressed alcoholics, non depressed alcoholics). Interpersonal dependency seems to be a characteristic of the alcoholic personality without influence of secondary depression.