Factors associated with prolonged COVID-related PTSD-like symptoms among adults diagnosed with mild COVID-19 in Poland.

COVID-19 has been considered a possible cause of post-traumatic stress disorder (PTSD) or similar conditions. However, what specific disease symptoms may contribute most to prolonged PTSD-like symptoms in COVID-19 survivors is unclear. The study aimed to present the factor structure of COVID-19 symptoms and identify which symptoms of COVID-19 best explain the subsequent presence of PTSD-like symptoms in mild COVID-19 survivors. COVID-positive adults (n = 341) completed online self-report scales at the baseline assessment (T1) and after approximately 4 months (T2), including The Patient Health Questionnaire Anxiety-Depression Scale; The Scale of Psychosocial Experience Related to COVID-19, The Primary Care PTSD Screen for DSM-5; and self-designed questionnaires evaluating the severity of COVID-related medical and neurocognitive symptoms and pre-pandemic variables. Exploratory factor analysis revealed five factors of COVID-19 symptoms: flu-like, respiratory, cold, neurological, and neurocognitive. Hierarchical logistic regression showed that besides selected control variables (anxiety and depression, presence of PTSD-like symptoms, COVID-related stigma in T1), neurocognitive symptoms of COVID-19 in T1 but not other symptoms of the disease were a significant predictor of the presence of PTSD-like symptom in T2. Findings suggest a need for a comprehensive neurocognitive assessment of people diagnosed with COVID-19 and prompt interventions targeting the prevention of potential risks for long-term PTSD-like states at the community level.

Incidence, risk factors, and outcomes of second neoplasms in patients with acute promyelocytic leukemia: the PETHEMA-PALG experience.

The most important challenges in acute promyelocytic leukemia (APL) is preventing early death and reducing long-term events, such as second neoplasms (s-NPLs). We performed a retrospective analysis of 2670 unselected APL patients, treated with PETHEMA "chemotherapy based" and "chemotherapy free" protocols. Only de novo APL patients who achieved complete remission (CR) and completed the three consolidation cycles were enrolled into the analysis. Out of 2670 APL patients, there were 118 (4.4%) who developed s-NPLs with the median latency period (between first CR and diagnosis of s-NPL) of 48.0 months (range 2.8-231.1): 43.3 (range: 2.8-113.9) for s-MDS/AML and 61.7 (range: 7.1-231.1) for solid tumour. The 5-year CI of all s-NPLs was of 4.43% and 10 years of 7.92%. Among s-NPLs, there were 58 cases of s-MDS/AML, 3 cases of other hematological neoplasms, 57 solid tumours and 1 non-identified neoplasm. The most frequent solid tumour was colorectal, lung and breast cancer. Overall, the 2-year OS from diagnosis of s-NPLs was 40.6%, with a median OS of 11.1 months. Multivariate analysis identified age of 35 years (hazard ratio = 0.2584; p < 0.0001) as an independent prognostic factor for s-NPLs. There were no significant differences in CI of s-NPLs at 5 years between chemotherapy-based vs chemotherapy-free regimens (hazard ratio = 1.09; p = 0.932). Larger series with longer follow-up are required to confirm the potential impact of ATO+ATRA regimens to reduce the incidence of s-NPLs after front-line therapy for APL.

Research on the Pathogenesis of Cognitive and Neurofunctional Impairments in Patients with Noonan Syndrome: The Role of Rat Sarcoma-Mitogen Activated Protein Kinase Signaling Pathway Gene Disturbances.

Noonan syndrome (NS) is one of the most common genetic conditions inherited mostly in an autosomal dominant manner with vast heterogeneity in clinical and genetic features. Patients with NS might have speech disturbances, memory and attention deficits, limitations in daily functioning, and decreased overall intelligence. Here, 34 patients with Noonan syndrome and 23 healthy controls were enrolled in a study involving gray and white matter volume evaluation using voxel-based morphometry (VBM), white matter connectivity measurements using diffusion tensor imaging (DTI), and resting-state functional magnetic resonance imaging (rs-fMRI). Fractional anisotropy (FA) and mean diffusivity (MD) probability distributions were calculated. Cognitive abilities were assessed using the Stanford Binet Intelligence Scales. Reductions in white matter connectivity were detected using DTI in NS patients. The rs-fMRI revealed hyper-connectivity in NS patients between the sensorimotor network and language network and between the sensorimotor network and salience network in comparison to healthy controls. NS patients exhibited decreased verbal and nonverbal IQ compared to healthy controls. The assessment of the microstructural alterations of white matter as well as the resting-state functional connectivity (rsFC) analysis in patients with NS may shed light on the mechanisms responsible for cognitive and neurofunctional impairments.

Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) in Poland: analysis of patient series and practical guidelines for breast surgeons.

Introduction: Although breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is infrequent, with less than 1000 noted cases worldwide, patients consenting for breast implant surgery should be aware of its risk. We describe the first Polish multicenter case-series data on BIA-ALCL patients and present diagnostic and treatment recommendation for breast surgeons. Material and methods: In cooperation with the Polish Society of Surgical Oncology and Polish Lymphoma Research Group, we collected BIA-ALCL cases in Poland. Results: We retrospectively reviewed clinical data of seven BIA-ALCL patients, diagnosed between July 2013 and November 2019. The median time from implant placement to the first BIA-ALCL symptoms was 65 months (range: 33-96 months). All the patients were exposed to textured implants at presentation. Capsulectomy with implant removal was performed in all the patients with immediate reimplantation in 2 cases. In a median follow-up of 19 months (range 5-81 months), there was no recurrence and all the patients stayed alive. Between 2013 and 2019, the incidence of BIA-ALCL in Polish female population age 30 and above ranged from 0 to 0.021/100 000/year. Conclusions: BIA-ALCL is scarce in the Polish population. In a short-term follow-up, patients' prognosis remains excellent. Due to the withdrawal of roughly textured implants from the market and the exclusion of likely the most potent etiologic factor, it might be expected that the incidence of BIA-ALCL will become even rarer.

Watching talking faces: The development of cortical representation of visual syllables in infancy.

From birth, we perceive speech by hearing and seeing people talk. In adults cortical representations of visual speech are processed in the putative temporal visual speech area (TVSA), but it remains unknown how these representations develop. We measured infants' cortical responses to silent visual syllables and non-communicative mouth movements using functional Near-Infrared Spectroscopy. Our results indicate that cortical specialisation for visual speech may emerge during infancy. The putative TVSA was active to both visual syllables and gurning around 5 months of age, and more active to gurning than to visual syllables around 10 months of age. Multivariate pattern analysis classification of distinct cortical responses to visual speech and gurning was successful at 10, but not at 5 months of age. These findings imply that cortical representations of visual speech change between 5 and 10 months of age, showing that the putative TVSA is initially broadly tuned and becomes selective with age.

The Development of Cortical Responses to the Integration of Audiovisual Speech in Infancy.

In adults, the integration of audiovisual speech elicits specific higher (super-additive) or lower (sub-additive) cortical responses when compared to the responses to unisensory stimuli. Although there is evidence that the fronto-temporal network is active during perception of audiovisual speech in infancy, the development of fronto-temporal responses to audiovisual integration remains unknown. In the current study, 5-month-olds and 10-month-olds watched bimodal (audiovisual) and alternating unimodal (auditory + visual) syllables. In this context we use alternating unimodal to denote alternating auditory and visual syllables that are perceived as separate syllables by adults. Using fNIRS we measured responses over large cortical areas including the inferior frontal and superior temporal regions. We identified channels showing different responses to bimodal than alternating unimodal condition and used multivariate pattern analysis (MVPA) to decode patterns of cortical responses to bimodal (audiovisual) and alternating unimodal (auditory + visual) speech. Results showed that in both age groups integration elicits cortical responses consistent with both super- and sub-additive responses in the fronto-temporal cortex. The univariate analyses revealed that between 5 and 10 months spatial distribution of these responses becomes increasingly focal. MVPA correctly classified responses at 5 months, with key input from channels located in the inferior frontal and superior temporal channels of the right hemisphere. However, MVPA classification was not successful at 10 months, suggesting a potential cortical re-organisation of audiovisual speech perception at this age. These results show the complex and non-gradual development of the cortical responses to integration of congruent audiovisual speech in infancy.

Prognostic value of XIAP and survivin expression in locally advanced breast cancer patients treated with anthracycline-based neoadjuvant chemotherapy.

Introduction: Neoadjuvant treatment in locally advanced breast cancer (LABC) is intended to decrease the cancer mass, increase the likelihood of radical resection and improve survival. Resistance to chemotherapy may depend on cellular expression of anti-apoptotic proteins. XIAP and survivin are the most potent inhibitors of apoptosis (IAP), but their role in drug-induced cancer cell apoptosis remains unclear. This study was designed to evaluate the impact of pre-treatment expression of XIAP and survivin on pathological complete response and survival in LABC patients. Material and methods: The study included 60 LABC patients treated with anthracycline-based chemotherapy. XIAP and survivin expression was assessed immunohistochemically in pre-treatment core biopsy specimens. Results: Pathological complete response was achieved in 33% of the LABC patients. Low/intermediate expression of both XIAP and survivin was significantly associated with pathological complete response (p ≤ 0.04 and p < 0.001, respectively) and positively correlated with disease-free survival (p = 0.017 and p < 0.001) and overall survival (p = 0.052 and p < 0.001). The area under receiver operating characteristics curves (AUC) revealed predictive value of survivin expression for relapse and death in breast cancer patients (AUC = 0.63, p = 0.001 and AUC = 0.8, p < 0.001, respectively). Conclusions: Our findings suggest that downregulation of XIAP and survivin in LABC patients might predict better treatment outcomes after anthracycline-based chemotherapy. This, in turn, may indicate XIAP and survivin proteins as potential targets for innovative anticancer therapies.

Theory of Mind and Parental Mental-State Talk in Children with CIs.

Previous studies have suggested that parents may support the development of theory of mind (ToM) in their child by talking about mental states (mental state talk; MST). However, MST has not been sufficiently explored in deaf children with cochlear implants (CIs). This study investigated ToM and availability of parental MST in deaf children with CIs (n = 39, Mage = 62.92, SD = 15.23) in comparison with their peers with typical hearing (TH; n = 52, Mage = 52.48, SD = 1.07). MST was measured during shared storybook reading. Parents' narratives were coded for cognitive, emotional, literal, and non-mental references. ToM was measured with a parental questionnaire. Children with CIs had lower ToM scores than their peers with TH, and their parents used more literal references during shared storybook reading. There were no significant differences in the frequencies of cognitive and emotional references between groups. Parental emotional references contributed positively to children's ToM scores when controlling for the child's age and receptive grammar only in the CI group. These results indicated some distinctive features in parents of deaf children with CIs' MST and highlighted the role of MST in the development of ToM abilities in this group.

Exposure to hate speech deteriorates neurocognitive mechanisms of the ability to understand others' pain.

The widespread ubiquity of hate speech affects people's attitudes and behavior. Exposure to hate speech can lead to prejudice, dehumanization, and lack of empathy towards members of outgroups. However, the impact of exposure to hate speech on empathy and propensity to attribute mental states to others has never been directly tested empirically. In this fMRI study, we examine the effects of exposure to hate speech on neural mechanisms of empathy towards ingroup (Poles) versus outgroup members (Arabs). Thirty healthy young adults were randomly assigned to 2 groups: hateful and neutral. During the fMRI study, they were initially exposed to hateful or neutral comments and subsequently to narratives depicting Poles and Arabs in pain. Using whole-brain and region of interest analysis, we showed that exposure to derogatory language about migrants attenuates the brain response to someone else's pain in the right temporal parietal junction (rTPJ), irrespective of group membership (Poles or Arabs). Given that rTPJ is associated with processes relevant to perspective-taking, its reduced activity might be related to a decreased propensity to take the psychological perspective of others. This finding suggests that hate speech affects human functioning beyond intergroup relations.

Does the TPJ fit it all? Representational similarity analysis of different forms of mentalizing.

Mentalizing is the key socio-cognitive ability. Its heterogeneous structure may result from a variety of forms of mental state inference, which may be based on lower-level processing of cues encoded in the observable behavior of others, or rather involve higher-level computations aimed at understanding another person's perspective. Here we aimed to investigate the representational content of the brain regions engaged in mentalizing. To this end, 61 healthy adults took part in an fMRI study. We explored ROI activity patterns associated with five well-recognized ToM tasks that induce either decoding of mental states from motion kinematics or belief-reasoning. By using multivariate representational similarity analysis, we examined whether these examples of lower- and higher-level forms of social inference induced common or distinct patterns of brain activity. Distinct patterns of brain activity related to decoding of mental states from motion kinematics and belief-reasoning were found in lTPJp and the left IFG, but not the rTPJp. This may indicate that rTPJp supports a general mechanism for the representation of mental states. The divergent patterns of activation in lTPJp and frontal areas likely reflect differences in the degree of involvement of cognitive functions which support the basic mentalizing processes engaged by the two task groups.

Targeting Apoptosis in AML: Where Do We Stand?

More than 97% of patients with acute myeloid leukemia (AML) demonstrate genetic mutations leading to excessive proliferation combined with the evasion of regulated cell death (RCD). The most prominent and well-defined form of RCD is apoptosis, which serves as a defense mechanism against the emergence of cancer cells. Apoptosis is regulated in part by the BCL-2 family of pro- and anti-apoptotic proteins, whose balance can significantly determine cell survival. Apoptosis evasion plays a key role in tumorigenesis and drug resistance, and thus in the development and progression of AML. Research on the structural and biochemical aspects of apoptosis proteins and their regulators offers promise for new classes of targeted therapies and strategies for therapeutic intervention. This review provides a comprehensive overview of current AML treatment options related to the mechanism of apoptosis, particularly its mitochondrial pathway, and other promising concepts such as neddylation. It pays particular attention to clinically-relevant aspects of current and future AML treatment approaches, highlighting the molecular basis of individual therapies.

Main Aspects of Preparing Diabetic Patients in Poland for Self-Care.

Diabetes is a lifestyle disease which can cause many complications and organ-related disorders. The aim of the study was to analyze selected aspects of preparing patients with diabetes for self-care. The study group consisted of 190 people diagnosed with type 1 and type 2 diabetes, including 101 women and 89 men. The mean age of the respondents was 42.2 ± 13.4 years. The study was conducted using an anonymous self-designed questionnaire containing 50 questions. Among the respondents, 23.2% did not control their glucose levels at home. The respondents most often measured glucose once a day (33.6%) or three times a day (26.7%). A total of 64.7% of the respondents declared that they kept a self-monitoring diary. The knowledge of the symptoms of hypoglycemia and the ability to properly manage it was declared by 64.8% of the respondents. A total of 52.1% of the patients did not undertake any activity lasting more than 30 min at least 3 times a week, and 75.2% described their condition as very good and good. Independent participation in therapy, i.e., taking hypoglycemic drugs or insulin, was declared by 63.7% of the respondents. Despite undergoing therapeutic education, the study population diagnosed with diabetes still shows deficiencies in terms of awareness of proper health behaviors. Objective results showed that the patients had insufficient knowledge and skills in terms of self-care and self-observation, blood glucose and blood pressure measurements, physical activity, diet therapy as well as adherence to pharmacotherapy recommendations. Despite the good general preparation for self-care as declared by the respondents, these patients require further systematic, individual educational activities. The results of the present study have implications for nursing practice, patient therapeutic education, and the functioning of the public health and healthcare systems. The number of diabetic patients is constantly increasing. Patients require coordinated care and individualized therapeutic education in order to be prepared for self-care and self-management, thus reducing the risk of complications. Delaying the occurrence of potential complications provides patients with a chance to live an active private and professional life, and protects the health care system from carrying the cost burden of expensive highly specialized services.

Stronger connectivity and higher extraversion protect against stress-related deterioration of cognitive functions.

Here we attempted to define the relationship between: EEG activity, personality and coping during lockdown. We were in a unique situation since the COVID-19 outbreak interrupted our independent longitudinal study. We already collected a significant amount of data before lockdown. During lockdown, a subgroup of participants willingly continued their engagement in the study. These circumstances provided us with an opportunity to examine the relationship between personality/cognition and brain rhythms in individuals who continued their engagement during lockdown compared to control data collected well before pandemic. The testing consisted of a one-time assessment of personality dimensions and two sessions of EEG recording and deductive reasoning task. Participants were divided into groups based on the time they completed the second session: before or during the COVID-19 outbreak 'Pre-pandemic Controls' and 'Pandemics', respectively. The Pandemics were characterized by a higher extraversion and stronger connectivity, compared to Pre-pandemic Controls. Furthermore, the Pandemics improved their cognitive performance under long-term stress as compared to the Pre-Pandemic Controls matched for personality traits to the Pandemics. The Pandemics were also characterized by increased EEG connectivity during lockdown. We posit that stronger EEG connectivity and higher extraversion could act as a defense mechanism against stress-related deterioration of cognitive functions.

Alterations in microRNA Expression during Hematopoietic Stem Cell Mobilization.

microRNAs play an important role in the regulation of gene expression, cell fate, hematopoiesis, and may influence the efficacy of CD34+ cell mobilization. The present study examines the role of hsa-miR-15a-5p, hsa-miR-16-5p, hsa-miR-34a-5p, hsa-miR-126-3p, hsa-miR-146a-5p, hsa-miR-155-5p, and hsa-miR-223-3p in the course of hematopoietic stem cell mobilization. The numbers of CD34+ cells collected in patients with hematological malignancies (39 multiple myelomas, 11 lymphomas) were determined during mobilization for an autologous hematopoietic stem cell transplantation. The miRNA level was evaluated by RT-PCR. Compared to baseline, a significant decline in hsa-miR-15a-5p, hsa-miR-16-5p, hsa-miR-126-3p, hsa-miR-146a-5p, and hsa-miR-155-5p was observed on the day of the first apheresis (day A). An increase was observed only in the expression of hsa-miR-34a-5p. On day A, a negative correlation was found between hsa-miR-15a-5p and hsa-miR-146a-5p levels and the number of CD34+ cells in peripheral blood. A negative correlation was observed between hsa-miR-146a-5p and the number of collected CD34+ cells after the first apheresis. Good mobilizers, defined according to GITMO criteria, demonstrated a lower hsa-miR-146a-5p level on day A than poor mobilizers. Patients from the hsa-miR-146a-5p "low expressors" collected more CD34+ cells than "high expressors". Our results suggest that the investigated miRNAs, especially hsa-miR-146a-5p, may influence the efficacy of HSC mobilization.

Aberrant orbitofrontal cortex reactivity to erotic cues in Compulsive Sexual Behavior Disorder.

BACKGROUND AND AIMS: Compulsive Sexual Behavior Disorder (CSBD) is characterized by increased reactivity to erotic reward cues. Cue-encoded reward parameters, such as type (e.g. erotic or monetary) or probability of anticipated reward, shape reward-related motivational processes, increase the attractiveness of cues and therefore might enhance maladaptive behavioral patterns in CSBD. Studies on the neural patterns of cue processing in individuals with CSBD have been limited mainly to ventral striatal responses. Therefore, here we aimed to examine the cue reactivity of multiple key structures in the brain's reward system, taking into account not only the type of predicted reward but also its probability. METHODS: Twenty Nine men seeking professional help due to CSBD and 24 healthy volunteers took part in an fMRI study with a modified Incentive Delay Task with erotic and monetary rewards preceded by cues indicating a 25%, 50%, or 75% chance of reward. Analyses of functional patterns of activity related to cue type and probability were conducted on the whole-brain and ROI levels. RESULTS: Increased anticipatory response to cues predictive of erotic rewards was observed among CSBD participants when compared to controls, in the ventral striatum and anterior orbitofrontal cortex (aOFC). The activity in aOFC was modulated by reward probability. DISCUSSION AND CONCLUSIONS: Type of anticipated reward (erotic vs monetary) affects reward-related behavioral motivation in CSBD more strongly than reward probability. We present evidence of abnormal aOFC function in CSBD by demonstrating the recruitment of additional subsections of this region by erotic reward cues.

Cladribine Combined with Low-Dose Cytarabine as Frontline Treatment for Unfit Elderly Acute Myeloid Leukemia Patients: Results from a Prospective Multicenter Study of Polish Adult Leukemia Group (PALG).

Acute myeloid leukemia (AML) in older unfit patients is a therapeutic challenge for clinical hematologists. We evaluated the efficacy and safety of a novel low-intensity regimen consisting of low-dose cytarabine and cladribine (LD-AC+cladribine) in first-line treatment of elderly (≥60 years) AML patients not eligible for intensive chemotherapy (IC) who had either the Eastern Cooperative Oncology Group performance status (ECOG PS) ≥2 or the hematopoietic cell transplantation comorbidity index (HCT-CI) score ≥3. The induction phase included two cycles of LD-AC+cladribine. Patients who achieved at least partial remission (PR) received maintenance treatment with LD-AC alone. Overall, 117 patients with a median age of 70 years were enrolled. Adverse cytogenetics, ECOG PS ≥2 and HCT-CI score ≥3 was observed in 43.5%, 60%, and 58% of patients, respectively. The response rate (≥PR) was 54% (complete remission [CR], 32%; CR with incomplete hematologic recovery [CRi], 5%). A median overall survival (OS) was 21 and 8.8 months in CR/CRi and PR group, respectively. Advanced age (≥75 years) and adverse cytogenetics had a negative impact on OS. The 56-day mortality rate was 20.5%. In conclusion, LD-AC+cladribine is a beneficial therapeutic option with a predictable safety profile in elderly AML patients not eligible for IC.

False Belief Understanding in Deaf Children With Cochlear Implants.

Theory of mind (ToM) is crucial for social interactions. Previous research has indicated that deaf and hard-of-hearing children born into hearing families (DoH) are at risk of delayed ToM development. However, it is unclear whether this is the case for DoH children who receive cochlear implants (CIs) before and around the second year of life. The present study aimed to investigate false belief understanding (FBU) in DoH children with CIs. The relationships between false belief task (FBT) performance, sentence comprehension, age at implantation, duration of CI use, and Speech Recognition Threshold were explored. A total of 94 children with typical levels of hearing (TH) and 45 DoH children (age range: 3-8), who received their first CI between 6 and 27 months of age, were tested on the FBT and a sentence comprehension test. Results showed that 4- and 5-year-old children with CIs performed significantly worse than their peers with TH on the FBT; 6- to 8-year-old children with CIs performed similarly to age-matched children with TH. Age at implantation and duration of CI use were correlated with sentence comprehension but not with the FBT. The results indicated that FBU was delayed until the age of 6 years in most of children with CIs.

Risk of Developing Post-traumatic Stress Disorder in Severe COVID-19 Survivors, Their Families and Frontline Healthcare Workers: What Should Mental Health Specialists Prepare For?

Given the high mortality of the coronavirus disease 2019 (COVID-19), having severe COVID-19 may be a life-threatening event, especially for individuals at high risk of complications. Therefore, in the article we try to answer two questions that are relevant to public mental health: Can we define groups who are at higher risk of developing pandemic-related PTSD? How can health specialists prepare for it? Given the results of previous research on PTSD in epidemic (e.g., SARS) survivors, we suggest that mental health professionals in countries touched by the pandemic should prepare for an increase in the PTSD prevalence, specifically in: individuals who have had severe COVID-19; family members of these patients and of patients who have died; and frontline healthcare workers witnessing COVID-19 patients' sudden deaths, or numerous life-threatening situations. We postulate that these groups at risk should be routinely screened for PTSD in primary medical and pediatric care. Mental health services should prepare for providing therapeutic interventions for individuals with PTSD in the vulnerable groups, and support to their families, especially children.

The role of NF-κB and Smac/DIABLO proteins in the treatment response and survival of acute myeloid leukemia patients.

INTRODUCTION: The misbalance between a family of inhibitor of apoptosis proteins (IAP), regulated by the nuclear factor kappa B (NF-κB) and their natural antagonist second mitochondrial-derived activator of caspases/direct IAP binding protein with low pI (Smac/DIABLO) are important to biology of acute myeloid leukemia (AML). MATERIAL AND METHODS: The aim of the study was to assess NF-κB and Smac/DIABLO proteins expression in blasts of 109 newly diagnosed AML patients using the multicolor flow cytometry and evaluate their influence on AML patients outcome. RESULTS: Expression of NF-κB and of Smac/DIABLO proteins were found in 95% and 98% of the patients, respectively. A negative correlation between Smac/DIABLO and NF-κB was observed. Age < 60 years old as well as higher Smac/DIABLO expression were associated with a higher probability of complete response achievement in the multivariate analysis. Longer overall survival (OS) in the univariate and multivariate analyses was influenced by age < 60 years old, a favorable or intermediate-risk karyotype and high Smac/DIABLO expression. Additionally, in the survival analysis of the subgroups, the patients aged < 60 years old, with high Smac/DIABLO expression, lower NF-κB expression and < 50% of bone marrow blasts who were treated with standard treatment had better OS. CONCLUSIONS: Lower NF-κB and higher Smac/DIABLO expression may influence AML patients outcome.

IDH2 mutations in patients with normal karyotype AML predict favorable responses to daunorubicin, cytarabine and cladribine regimen.

Mutations in isocitrate dehydrogenase 1 and 2 (IDH1/2) genes occur in about 20% patients with acute myeloid leukemia (AML), leading to DNA hypermethylation and epigenetic deregulation. We assessed the prognostic significance of IDH1/2 mutations (IDH1/2+) in 398 AML patients with normal karyotype (NK-AML), treated with daunorubicine + cytarabine (DA), DA + cladribine (DAC), or DA + fludarabine. IDH2 mutation was an independent favorable prognostic factor for 4-year overall survival (OS) in total NK-AML population (p = 0.03, censoring at allotransplant). We next evaluated the effect of addition of cladribine to induction regimen on the patients' outcome according to IDH1/2 mutation status. In DAC group, 4-year OS was increased in IDH2+ patients, compared to IDH-wild type group (54% vs 33%; p = 0.0087, censoring at allotransplant), while no difference was observed for DA-treated subjects. In multivariate analysis, DAC independently improved the survival of IDH2+ patients (HR = 0.6 [0.37-0.93]; p = 0.024; censored at transplant), indicating that this group specifically benefits from cladribine-containing therapy. In AML cells with R140Q or R172K IDH2 mutations, cladribine restrained mutations-related DNA hypermethylation. Altogether, DAC regimen produces better outcomes in IDH2+ NK-AML patients than DA, and this likely results from the hypomethylating activity of cladribine. Our observations warrant further investigations of induction protocols combining cladribine with IDH1/2 inhibitors in IDH2-mutant.