Self-reported suicidal ideation among individuals with first episode psychosis and healthy controls: Findings from the international multicentre EU-GEI study.

INTRODUCTION: Suicidal ideation is common among individuals with first episode psychosis (FEP), with prevalence estimates up to 56.5 %. Despite its high prevalence, relatively little is known about how sociodemographic, clinical and/or developmental characteristics contribute to the experience of suicidal ideation in individuals with FEP. METHODS: In this cross-sectional study (FEP n = 551 and controls n = 857), univariate logistic regression analyses were performed to study the associations of sociodemographic, clinical, and developmental factors with suicidal ideation in individuals with FEP as well as controls. Suicidal ideation was assessed using the Community Assessment of Psychic Experiences (CAPE). In addition, multivariate logistic regression analyses were conducted based on a stepwise approach. RESULTS: In FEP, only depressive symptoms remained significantly associated with suicidal ideation when all correlates were integrated into one model. In the multivariate model in controls, depressive symptoms, positive symptoms, and traumatic childhood experiences were significantly associated with suicidal ideation. CONCLUSIONS: This study showed that depressive symptoms are an important factor relating to suicidal ideation in individuals with FEP, over and above other clinical, sociodemographic, and developmental factors. This underscores the relevance of screening for suicidal ideation in individuals with FEP, and highlights the need for a better understanding of the diagnostic uncertainty and course of mood symptoms in early psychosis. LIMITATIONS: Cross-sectional study design, self-reported questionnaires.

Exploring the mechanisms underlying increased risk of depressive disorder in ethnic minority populations in Europe: A causal loop diagram.

BACKGROUND: Multiple ethnic minority populations in Europe show high risk of major depressive disorder (MDD), with ethnic discrimination and low socioeconomic position (SEP) as established risk factors. How this risk is shaped by the interactions between these, and other social factors, remains to be elucidated. We aimed to develop a causal-loop diagram (CLD) to gain a better understanding of how factors at the intersection of ethnic discrimination and SEP dynamically interact to drive MDD risk. METHODS: We iteratively mapped the interactions and feedback loops between factors at the intersection of ethnic discrimination and SEP, drawing input from (i) a series of two interviews with a range of MDD domain experts, (ii) an existing CLD mapping the onset of MDD across psychological, biological, and social dimensions at the level of the individual, and (iii) other relevant literature. RESULTS: Through tracing the feedback loops in the resulting CLD, we identified ten driving mechanisms for MDD onset in ethnic minorities (two related to ethnic discrimination, SEP, social network and support, and acculturation, as well as one relating to the living environment and self-stigma towards MDD); and four factors that modulate these mechanisms (recent migration, religious affiliation, neighborhood social environment, and public stigma towards MDD). The intersecting nature of ethnic discrimination and SEP, combined with the reinforcing dynamics of the identified driving mechanisms across time- and spatial scales, underscores the excess exposure to circumstances that increase MDD risk in ethnic minorities. CONCLUSIONS: While this CLD requires validation through future studies, the intersecting and reinforcing nature of the identified driving mechanisms highlights that tackling the high risk of MDD in ethnic minorities may require intervening at multiple targets, from the individual (e.g., psychological interventions targeting negative beliefs or reducing stress) to the societal level (e.g., addressing labor market discrimination).

Neural effects of deep brain stimulation on reward and loss anticipation and food viewing in anorexia nervosa: a pilot study.

BACKGROUND: Anorexia nervosa (AN) is a severe and life-threatening psychiatric disorder. Initial studies on deep brain stimulation (DBS) in severe, treatment-refractory AN have shown clinical effects. However, the working mechanisms of DBS in AN remain largely unknown. Here, we used a task-based functional MRI approach to understand the pathophysiology of AN. METHODS: We performed functional MRI on four AN patients that participated in a pilot study on the efficacy, safety, and functional effects of DBS targeted at the ventral limb of the capsula interna (vALIC). The patients and six gender-matched healthy controls (HC) were investigated at three different time points. We used an adapted version of the monetary incentive delay task to probe generic reward processing in patients and controls, and a food-specific task in patients only. RESULTS: At baseline, no significant differences for reward anticipation were found between AN and HC. Significant group (AN and HC) by time (pre- and post-DBS) interactions were found in the right precuneus, right putamen, right ventral and medial orbitofrontal cortex (mOFC). No significant interactions were found in the food viewing task, neither between the conditions high-calorie and low-calorie food images nor between the different time points. This could possibly be due to the small sample size and the lack of a control group. CONCLUSION: The results showed a difference in the response of reward-related brain areas post-DBS. This supports the hypotheses that the reward circuitry is involved in the pathogenesis of AN and that DBS affects responsivity of reward-related brain areas. Trial registration Registered in the Netherlands Trial Register ( https://www.trialregister.nl/trial/3322 ): NL3322 (NTR3469).

Anorexia Nervosa (An) is a severe eating disorder with many, sometimes life-threatening, complications. A substantial number of AN patients do not respond to the available treatment options and remain chronically ill or even die as a consequence of the AN. Because part of the causes of AN may reside in the brain, we studied the efficacy and safety of a potential new treatment option for AN, namely deep brain stimulation (DBS). DBS has proven to be an effective treatment option for movements disorders like Parkinson's Disease and other psychiatric disorders such as obsessive compulsive disorder. Our previous pilot study and other research have shown that DBS leads to improvements in weight, mood, anxiety, and eating disorder symptoms. In this substudy, we examined the effects of DBS on specific brain circuitries that are implicated in AN. We conducted brain scans (fMRI) to measure brain activity while patients performed tasks. We observed a difference in brain response when we compared scans taken before and after the DBS, which supports our thoughts on the involvement of specific parts of the brain in AN.

The association between child maltreatment and problematic alcohol use in adulthood in a large multi-ethnic cohort: the HELIUS study.

AIMS: There is evidence that child maltreatment is associated with problematic alcohol use later in life. However, previous epidemiological studies that have examined the link between child maltreatment and adult problematic alcohol use have not considered ethnic differences. Therefore, the purpose of the current study was to investigate the relationship between child maltreatment and adult problematic alcohol use among six ethnic groups in the Netherlands, in a large, urban sample. METHODS: This study used baseline data from the Healthy Life in an Urban Setting (HELIUS) study: a large-scale, multi-ethnic prospective cohort study conducted in Amsterdam, the Netherlands. Child maltreatment, current problematic alcohol use and several potential confounders (e.g. parental alcohol use) were assessed in participants (N = 23 356) of Dutch, South-Asian Surinamese, African Surinamese, Ghanaian, Turkish and Moroccan origin. With logistic regression analyses, we examined effect modification by ethnicity on the association between child maltreatment and problematic alcohol use. Furthermore, we explored effect modification by ethnicity for specific types of child maltreatment, namely: physical, sexual and psychological abuse and emotional neglect. RESULTS: Effect modification by ethnicity was present. Stronger associations between child maltreatment and problematic alcohol use were found in all ethnic minority groups compared to the Dutch reference group. Particularly strong associations between all four types of child maltreatment and alcohol use problems were found for the Moroccan origin group. CONCLUSIONS: This study adds to a growing body of evidence that child maltreatment is associated with problematic alcohol use in adulthood. In addition, our findings indicate that ethnicity impacts this relationship. Although problematic alcohol use was more prevalent in the Dutch origin group, associations with child maltreatment were stronger in ethnic minority groups. Future studies on child maltreatment and alcohol use problems should also examine ethnic disparities and should further unravel how these disparities can be explained.

Duodenal Permeability Is Associated With Mucosal Microbiota in Compensated Cirrhosis.

INTRODUCTION: Several complications of decompensated cirrhosis are believed to result from increased intestinal permeability. However, little is known about the relationship between mucosal bacteria and epithelial permeability in cirrhosis. We aimed to assess epithelial permeability and associations with mucosal bacteria in patients with compensated cirrhosis. METHODS: We obtained duodenal tissue biopsies from patients with compensated cirrhosis and controls. Patients were excluded if they used antibiotics or immunosuppression. The composition of mucosal microbiota was determined by 16S rRNA gene sequencing and epithelial permeability by transepithelial electrical resistance (TEER) and tight junction protein expression. RESULTS: We studied 24 patients with compensated cirrhosis and 20 controls. Patients with cirrhosis were older than controls (62 vs 52 years, P = 0.02) but had a similar number of extrahepatic comorbidities (2.2 vs 1.4, P = 0.13). Patients with compensated cirrhosis had lower duodenal TEER (i.e., increased epithelial permeability; 13.3 Ω/cm 2 ± 3.4 vs 18.9 Ω/cm 2 ± 7.1; P = 0.004). Patients with compensated cirrhosis trended toward a distinct mucosal microbiota community structure relative to controls ( P = 0.09). Clustering analysis identified two unique enterotypes. These enterotypes differed in bacterial composition and also TEER. A beta-binomial model found 13 individual bacteria associated with TEER, including Lactobacillus and Bifidobacterium taxa. Thirty-six taxa were associated with tight junction protein expression, including Lactobacillus and Bifidobacterium. DISCUSSION: Compensated cirrhosis is characterized by increased duodenal epithelial permeability with a distinct mucosal microbial community. Intriguingly, bacteria previously associated with health were protective of duodenal permeability.

'Rapid speed of response to ECT in bipolar depression: A chart review.

OBJECTIVE: To validate a faster speed of response to electroconvulsive therapy (ECT) for bipolar depression (BPD) compared to major depressive disorder (MDD) METHOD: Retrospective chart review on an ECT cohort in an academic hospital setting. Speed of response was defined by the number of ECT treatments needed for response or remission. RESULTS: Sixty-four depressed patients were included, of whom 53 (MDD: 40, BPD: 13) could be analyzed. The bipolar group responded faster with a mean difference of 3.3 fewer ECT treatments to meet response criteria (MDD 10.4 vs. BPD 7.1, p = 0.054). When using mixed effects regression models for the response/remitter group (n = 35), a faster response for the bipolar group (AIC 252.83 vs 258.55, χ2 = 11.72, p = 0.008) was shown. Other factors, such as psychotic features or comorbidity, did not influence the speed of response. CONCLUSION: This chart review of an ECT cohort in an naturalistic academic hospital setting shows an evident and clinically relevant faster speed of response in bipolar depression.

[Mental disorders in a dental practice. Psychomood disorders]. / Serie: Psychische stoornissen in de mondzorgpraktijk. Stemmings­stoornissen.

Individuals with a depressive or bipolar mood disorder have a higher prevalence of somatic comorbidities, including dental problems. This is partly due to impaired self-care, smoking, alcohol use, and an unhealthy diet, and partly due to the often long-term use of medication. Depression has a negative impact on concentration and motivation and increases anxiety and avoidant behavior. In addition, there are indications for an interaction between stress, psychopathology, neuro-inflammatory processes and somatic health. These (temporary) factors must be taken into consideration in dental care for persons suffering from depression. Also, one must be alert for interactions between psychiatric medications and medications used in dental care. Especially in chronic psychiatric disorders, a coordinated care between dentist, general practitioner, and psychiatrist is of importance.

Exploring the impact of work-related potential traumatic events among Dutch psychiatrists.

Psychiatrists are frequently exposed to work-related potential traumatic events (PTEs). A survey was sent to the members of the Dutch Society of Psychiatrists of which 250 questionnaires were eligible for analysis. At least one work-related PTE was reported by 196 (78.4%) of the respondents, of which 177 described the PTE. Witnessing or experiencing verbal aggression (29.2%), physical violence (29.2%) or completed suicide (26.8%) were the most common PTEs. This survey implies that psychiatrists frequently experience work-related PTEs, often with a significant emotional impact. The majority of respondents considered current support as insufficient.

Fatty acids and recurrence of major depressive disorder: combined analysis of two Dutch clinical cohorts.

OBJECTIVE: Omega-3 (n-3) and omega-6 (n-6) polyunsaturated fatty acid (PUFA) alterations in patients with major depressive disorder (MDD) have been shown to persist after remission. Whether these alterations are risk factors for MDD recurrence remains unknown. Here, we examined whether fatty acids predict time until MDD recurrence in remitted MDD patients. METHODS: Data were used from remitted MDD patients of the Netherlands Study of Depression and Anxiety (n = 356) and the Depression Evaluation Longitudinal Therapy Assessment studies (n = 118). Associations of FAs with time until MDD recurrence up to 8-year follow-up were analyzed using Cox regression analyses. Study-specific estimates were pooled using mega- and meta-analysis techniques. RESULTS: 27.5% (NESDA) and 56.8% (DELTA) participants had an MDD recurrence. Pooled results showed that no FA was significantly associated with time until MDD recurrence (n-3 PUFAs: hazard ratio (HR) = 1.17, 95% confidence interval (CI) = 0.98-1.41, P = 0.082; n-6 PUFAs: HR = 1.08, 95% CI = 0.84-1.38, P = 0.55). CONCLUSION: In remitted MDD patients, circulating PUFAs were not associated with prospective risk of MDD recurrence. Consequently, circulating PUFAs are unlikely to reflect a vulnerability marker for recurrence, so correcting n-3 PUFA 'deficits' through supplementation does not seem a promising option to prevent MDD recurrence.

[Reaction on 'Persistant underuse of ECT for persistant depressive disorder?'] / Reactie op 'Persisterend ondergebruik van ECT bij persisterende depressieve stoornis?'.

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[Electroconvulsion therapy for persistent depression in the Netherlands; very low application rate]. / Elektroconvulsietherapie bij persisterende depressie in Nederland; zeer lage toepassingsgraad.

BACKGROUND: Of all depressive disorders, 20% has a persistent course. For persistent depressive patients, electroconvulsive therapy (ect) is recommended for this patient population, since it is the most potent treatment for depression. The Dutch depression guideline advises the use of ect for persistent depressive disorder at approximately 12 months after inadequate efficacy of psychotherapy and/or pharmacological treatment.
AIM: To quantify the use of electroconvulsive therapy in persistent depressive patients in the Netherlands.
METHOD: Quantitative research using the Dutch registration system (diagnosis-treatment-combination; dbc) information system (dis) of the Dutch Healthcare Authority (nza).
RESULTS: Of the patients within the dbc system (in 2014) with the main diagnosis of unipolar depression, 23,597 (26%) were registered for more than two years and could be classified as having a persistent depressive episode. Of these latter patients, only 278 (1.2%) received ect.
CONCLUSION: In the Netherlands, only 1.2% of patients with a persistent depression received ect, whereas this treatment could have been considered for 26% of this group. The low application rate might be caused by professionals' inadequate knowledge about ect and the premature use of the handicap model.

Cortisol, dehydroepiandrosterone sulfate, fatty acids, and their relation in recurrent depression.

BACKGROUND: Alterations in hypothalamic-pituitary-adrenal (HPA)-axis activity, fatty acid metabolism, and their relation have been associated with (recurrent) major depressive disorder (MDD), although conflicting findings exist. AIMS: To determine whether alterations in HPA-axis activity and fatty acids in recurrent MDD remain during remission (i.e. reflect a potential trait factor). Furthermore, to test the association between HPA-axis activity and fatty acids in patients versus controls. METHODS: We cross-sectionally compared 73 remitted unmedicated recurrent MDD patients with 46 matched never-depressed controls. Measurements included salivary cortisol and dehydroepiandrosterone sulfate (DHEAS) (awakening, evening, and after sad mood induction) and erythrocyte fatty acid parameters: (I) three main fatty acids [omega-3 docosahexaenoic acid (DHA), and the omega-3 eicosapentaenoic acid/omega-6 arachidonic acid (EPA/AA)-ratio], and (II) structural fatty acid indices [chain length, unsaturation and peroxidation]. RESULTS: Patients showed higher cortisol awakening responses (p = 0.006) and lower evening cortisol/DHEAS ratios (p = 0.044) compared to matched controls. Fatty acids did not differ between patients and controls, but HPA-axis indicators were significantly associated with fatty acid parameters in both groups (0.001 ≤ p ≤ 0.043). Patients and controls significantly differed in the relations between awakening DHEAS or cortisol/DHEAS ratios and fatty acid parameters, including unsaturation and peroxidation indices (0.001≤ p ≤ 0.034). Significance remained after correction for confounders. CONCLUSIONS: Our results further support alterations in HPA-axis activity, i.e. a lower baseline, but higher responsiveness of awakening cortisol, in remitted medication-free recurrent MDD patients. Furthermore, the relationship between HPA-axis and fatty acids showed significant differences in recurrent MDD patients versus controls. Prospective research is needed to determine the predictive value of this relationship for MDD recurrence.

[Posttraumatic stress disorder: current insights in diagnostics, treatment and prevention]. / Posttraumatische stressstoornis.

- Posttraumatic stress disorder (PTSD) is a psychiatric disorder that may develop after traumatic events.- PTSD is one of the most prevalent psychiatric disorders in the Netherlands, with an estimated lifetime prevalence of 7%.- Recurrent re-experiencing of the traumatic event is the most characteristic PTSD symptom.- Recognition of PTSD may be hampered by the heterogeneous symptomatology, avoidance to talk about the trauma and highly frequent comorbid psychiatric and somatic comorbidity.- Feelings of guilt and shame may also influence reported trauma history.- First choice treatment for PTSD is trauma-focused psychotherapy, which may be combined with pharmacotherapy.- In case of severe acute posttraumatic stress symptoms after a recent trauma, it is recommended to start early trauma-focused psychotherapy.- Neurobiological findings are increasingly applied in novel interventions to improve the treatment and prevention of PTSD.

Psychometric properties of the PROMIS short form measures in a U.S. cohort of 961 patients with chronic hepatitis C prescribed direct acting antiviral therapy.

BACKGROUND: To better understand symptoms experienced by patients infected with chronic hepatitis C virus (HCV), valid and reliable patient-reported outcome (PRO) measures are needed. AIM: To assess the reliability and validity of 10 patient-reported outcomes measurement information system (PROMIS) measures and the Headache Impact Test-6 (HIT-6) in a large national sample of patients with HCV. METHODS: Pre-treatment data from 961 patients with HCV starting direct acting antiviral therapy at 11 U.S. liver centers were analyzed. Internal reliability was evaluated using Cronbach's alpha coefficient; frequency distributions were examined for floor and ceiling effects; structural validity was investigated via item-response-theory models; convergent validity was evaluated using correlations with theoretically-similar items from the HCV-PRO and memorial symptom assessment scale (MSAS); and known-groups validity was investigated by observing PRO differences by liver disease status and number of comorbidities. RESULTS: The HIT-6 and the majority of the PROMIS measures yielded excellent reliability (alphas ≥ 0.87). Ceiling effects were infrequent ( < 4%), while 30%-59% of patients reported no symptoms (floor effects). The data supported structural validity of the HIT-6 and most PROMIS measures. The PROMIS measures showed moderate to strong correlations with theoretically-similar items from the HCV-PRO and MSAS (0.39-0.77). Trends were observed between worse PRO scores and advanced cirrhosis and greater number of comorbidities, lending support for known-groups validity. CONCLUSIONS: The psychometric properties of the HIT-6 and PROMIS measures performed satisfactorily in this large cohort of patients with HCV starting direct acting antiviral therapy. Opportunities exist for further refinement of these PROs. Evaluation of performance over time and in under-represented subgroups is needed.

[Proper patient education improves hepatitis C patients' disease-related knowledge and antiviral treatment acceptance in rural China].

Objective: To evaluate the affect of hepatitis C virus (HCV) education in chronic hepatitis C patients' disease related knowledge and antiviral treatment acceptance in rural china. Methods: Rural HCV patients of attended CHC project of HCV education. Doctor delivered subsequent interactive lecture, and patients completed pre- and post-education questionnaires before and after taking the lectures. Results: 151 CHC patients were included. Mean age was 57.3 years old, 50.3% were male, 51.0% of the students had primary school education or illiterate, and 76.2% had a monthly income below RMB 3,000. 98.0% of patients defined their baseline HCV knowledge as "nothing" or "a little bit". A multivariate analysis reveled baseline knowledge scores were associated with age and household income. After education, mean knowledge score (range: 0-28) increased from 13.1 to 23.0 (P < 0.001) and average percent of patients with correct answers from the topic rose from 46.8% to 82.1% (P < 0.001), and patients' antiviral treatment acceptance increased from 33.9% to 65.6% (P < 0.001). Conclusion: A rural Chinese patients had less education, HCV education delivered on the preferred format of patients substantially improved hepatitis C patients' disease-related knowledge and antiviral treatment acceptance in rural china.

The higher prevalence of truncal obesity and diabetes in American than Chinese patients with chronic hepatitis C might contribute to more rapid progression to advanced liver disease.

BACKGROUND: Chronic hepatitis C virus (HCV) infection is the leading cause of cirrhosis and hepatocellular carcinoma (HCC) in the United States (US) and an emerging cause in China. AIM: To compare the clinical characteristics of hepatitis C patients in the US and China, and factors influencing disease stage. METHODS: Prospective study of 2 cohorts of HCV patients recruited at 1 site in the US and 3 sites in China. Standardised questionnaire on risk factors and medical history were used and diagnosis of cirrhosis and HCC was based on pre-defined criteria. RESULTS: One thousand nine hundred and fifty seven patients (1000 US and 957 China) were enrolled. US patients were more likely to be men (61.4% vs 48.5%), older (median age 57 vs 53 years), obese (38.4% vs 16.8%) and diabetic (21.8% vs 10.8%). A significantly higher per cent of US patients had cirrhosis (38.2% vs 16.0%) and HCC (14.1% vs 2.7%). Investigator estimated time at infection in US was 10 years earlier than in Chinese patients but US patients were more likely to have advanced disease even after stratifying for duration of infection. Study site in the US, older age, truncal obesity, diabetes and prior HCV treatment were significant predictors of advanced disease on multivariate analysis. CONCLUSIONS: HCV patients in the US had more advanced liver disease than those in China. We speculate that underlying fatty liver disease may be a major contributor to this difference, and management of glycometabolic abnormalities should occur in parallel with anti-viral therapy to achieve optimal outcomes.

Prevalence of hepatitis B antiviral drug resistance variants in North American patients with chronic hepatitis B not receiving antiviral treatment.

Antiviral drug resistance hepatitis B virus (HBV) variants (HBV-DR) occur spontaneously in chronic hepatitis B (CHB) patients and after exposure to nucleos(t)ide analogues (NUCs). We determined the prevalence of HBV-DR variants among participants of the Hepatitis B Research Network (HBRN) Cohort Study conducted at 21 sites in the United States (US) and Canada. Samples obtained from 1342 CHB participants aged ≥18 years, and who were currently not receiving NUCs, were tested for HBV-DR variants by Sanger sequencing. In addition, next generation sequencing (NGS) was used to characterize HBV-DR variants from 66 participants with and 66 participants with no prior NUC exposure matched for HBV genotype and HBV DNA level. Half the participants were men, 75% Asian, 26% HBeAg positive. Primary HBV-DR variants were detected by Sanger sequencing in 16 (1.2%) participants: 2/142 (1.4%) with and 14/1200 (1.2%) without prior NUC exposure; only 1 of these 16 had a secondary variant. In total, 23 (1.7%) participants had secondary variants, including 1 with prior NUC experience. In the subset of 132 participants, NGS detected HBV-DR variants in a higher proportion of participants: primary variants in 18 (13.6%) (8 [12.1%] with, and 10 [15.2%] without prior NUC therapy) and secondary variants in 10 (7.6%) participants. Based on Sanger sequencing, prevalence of primary HBV-DR variants is low (1.2%) among adults with CHB in US/Canada. The similar low prevalence of HBV-DR variants in participants with and without NUC treatment suggests transmission of these variants is uncommon.

Carboplatin instead of cisplatin in combination with dexamethasone, high-dose cytarabine with or without rituximab (DHAC+/-R) is an effective treatment with low toxicity in Hodgkin's and non-Hodgkin's lymphomas.

The DHAP regimen (high-dose cytarabine in combination with dexamethasone and cisplatin) with or without rituximab (DHAP+/-R) is one of the most common regimens in daily practice. It is considered the standard treatment for relapse or refractory Hodgkin's and non-Hodgkin's lymphoma (NHL). Cisplatin nephrotoxicity is a major concern, and other platinum compounds are being tried. We performed a monocentric retrospective analysis to evaluate the use of carboplatin, so-called DHAC+/-R regimen. The purpose was to assess the toxicity of the DHAC+/-R regimen in real-life. The Dexamethasone, Cytarabine, Carboplatin (DHAC) regimen consisted of carboplatin AUC = 5 mg/ml/min (targeted area under the curve with Calvert's formula) on day 1, cytarabine 2 g/m2 twice a day on day 2 and IV dexamethasone 40 mg from days 1 to 4. Rituximab was administrated at 375 mg/m2 on day 1 for CD20+ NHL. The interval between courses was 21 days. During the period considered, 199 patients received DHAC+/-R. For the entire cohort, median follow-up is 24 months (range, 2-82), median OS is not reached (NR), estimated 2-year OS is 75% (95% CI, 69-83) and median progression-free survival (PFS) is 46 months (95% CI, 22-NA). Of 144 patients scheduled for autologous stem cell transplantation (ASCT), 102 (71%, NA = 2) were in response after DHAC+/-R and all except 4 underwent ASCT. Grade ≥ 3 haematological toxicities were mainly thrombocytopenia (n = 101) and anaemia (n = 95). Grade ≥ 3 neutropenia occurred in 10 patients. No grade ≥ 3 renal and one grade 3 neurological toxicity were reported. DHAC+/-R is feasible in daily practice, provides good response rates and jeopardises neither stem cell collection nor ASCT.

p53 dysregulation in B-cell malignancies: More than a single gene in the pathway to hell.

TP53 deletion or mutation is frequent in B-cell malignancies and is associated with a low response rate. We describe here the p53 landscape in B-cell malignancies, from B-Acute Lymphoblastic Leukemia to Plasma Cell Leukemia, by analyzing incidence of gain or loss of function of actors both upstream and within the p53 pathway, namely MYC, RAS, ARF, MDM2, ATM and TP53. Abnormalities are not equally distributed and their incidence is highly variable among malignancies. Deletion and mutation, usually associated, of ATM or TP53 are frequent in Diffuse Large B-Cell Lymphoma and Mantle Cell Lymphoma. MYC gain, absent in post-GC malignancies, is frequent in B-Prolymphocytic-Leukemia, Multiple Myeloma and Plasma Cell Leukemias. RAS mutations are rare except in MM and PCL. Multiple Factorial Analysis notes that MYC deregulation is closely related to TP53 status. Moreover, MYC gain, TP53 deletion and RAS mutations are inversely correlated with survival. Based on this landscape, we further propose targeted therapeutic approaches for the different B-cell malignancies.