Pre-BCR signaling in precursor B-cell acute lymphoblastic leukemia regulates PI3K/AKT, FOXO1 and MYC, and can be targeted by SYK inhibition.

Precursor-B-cell receptor (pre-BCR) signaling and spleen tyrosine kinase (SYK) recently were introduced as therapeutic targets for patients with B-cell acute lymphoblastic leukemia (B-ALL), but the importance of this pathway in B-ALL subsets and mechanism of downstream signaling have not fully been elucidated. Here, we provide new detailed insight into the mechanism of pre-BCR signaling in B-ALL. We compared the effects of pharmacological and genetic disruption of pre-BCR signaling in vitro and in mouse models for B-ALL, demonstrating exquisite dependency of pre-BCR(+) B-ALL, but not other B-ALL subsets, on this signaling pathway. We demonstrate that SYK, PI3K/AKT, FOXO1 and MYC are important downstream mediators of pre-BCR signaling in B-ALL. Furthermore, we define a characteristic immune phenotype and gene expression signature of pre-BCR(+) ALL to distinguish them from other B-ALL subsets. These data provide comprehensive new insight into pre-BCR signaling in B-ALL and corroborate pre-BCR signaling and SYK as promising new therapeutic targets in pre-BCR(+) B-ALL.

Alterations of CHEK2 forkhead-associated domain increase the risk of Hodgkin lymphoma.

Checkpoint kinase 2 gene (CHEK2) codes for an important mediator of DNA damage response pathway. Mutations in the CHEK2 gene increase the risk of several cancer types, however, their role in Hodgkin lymphoma (HL) has not been studied so far. The most frequent CHEK2 alterations (including c.470T>C; p.I157T) cluster into the forkhead-associated (FHA) domain-coding region of the CHEK2 gene. We performed mutation analysis of the CHEK2 gene segment coding for FHA domain using denaturing high-performance liquid chromatography in 298 HL patients and analyzed the impact of characterized CHEK2 gene variants on the risk of HL development and progression-free survival (PFS). The overall frequency of CHEK2 alterations was significantly higher in HL patients (17/298; 5.7%) compared to the previously analyzed non-cancer controls (19/683; 2.8%; p= 0.04). Presence of any alteration within the analyzed region of the CHEK2 gene was associated with increased risk of HL development (OR = 2.11; 95% CI = 1.08 - 4.13; p= 0.04). The most frequent I157T mutation was found in 4.0% of HL patients and 2.5% of controls (p = 0.22), however, the frequency of 5 other alterations (excluding I157T) was significantly higher in HL cases and associated with increased risk of HL development (OR = 5.81; 95% CI = 1.12 - 30.12; p= 0.03). PFS in HL patients did not differ between CHEK2 mutation carriers and non-carriers. The predominant I157T mutation together with other alterations in its proximity represent moderate genetic predisposition factor increasing the risk of HL development.

[Combination therapy with anticholinergics and alpha-blockers for the treatment of overactive bladder in female patients--pilot study]. / Kombinovaná lécba symptomu hyperaktivního mechýre anticholinergiky a alfalytiky u zen--pilotní studie.

INTRODUCTION: Overactive bladder (OAB) is one of the most common medical conditions with an estimated 16 percent of adult population being affected in Europe. The administration of anticholinergics is considered as the most frequent and most effective treatment. There is a evidence that alpha-blockers affect a detrusor function. The aim of the study is to investigate if the combinant therapy consisting of anticholinergics plus alpha-blockers could be beneficial for women suffering from OAB. MATERIAL AND METHODS: 28 female patients with OAB were included into the pilot study. Mean age of the patients was 54.8 (42-77) years. Patients have been randomised into two groups: one group of patients has been treated by propiverin 30 mg daily, another group of patients has been treated by combination of both propiverin 30 mg daily and tamsulosin 0.4 mg daily. Satisfaction with the treatment has been evaluated by I-QoL questionnaire. Semi-objective parameters have been obtained by analysis of 3-days voiding diaries (number of micturitions, number of urgency episodes, voided volume). Peak flow (Qmax) has been measured as a objective parameter. RESULTS: We observed a decrease of frequency by 2.833 (-23.43%) comparing to base-line, decrease of number of urgency episodes by 1.417 (-36.22%), increase of voided volume by 33.333 ml (+19.14%), increase of quality of life index by 22.583 (+51.52%) and increase of Qmax by 0.17 ml/s (+0.58%) in the propiverin group. We observed decrease of frequency by 3.813 (-30.48%), decrease of number of urgency episodes by 1.875 (-45.52%), increase of voided volume by 51.250 ml (+26.88%), increase of quality of life index by 33.438 (+76.0%) and increase of Qmax by 2.13 ml/s (+7.87%) in the combination treatment group. No significant difference has been found between both groups except the quality of life index. CONCLUSION: Our results can not show explicitly higher efficacy of combination treatment using anticholinergics plus alpha-blockers comparing to standard therapy by anticholinergics alone. Further randomised placebo-controlled studies are needed for final evaluation of the role of alpha-blockers in the treatment of OAB.

[Efficacy and safety of solifenacin in daily clinical practice--clinical study phase IV]. / Efektivita a bezpecnost solifenacinu v bezné praxi--klinické hodnocení fáze IV.

OBJECTIVE: Symptoms of urinary urgency, frequency, nocturia with/or without urge incontinence, are reffered to as the overactive bladder (OAB). Main option for the treatment of the OAB are anticholinergic agents. The aim of the paper is to evaluate the efficacy and safety of the solifenacin in the daily clinical practice. MATERIAL AND METHODS: 344 patients with OAB symptoms (311 women, 33 men, average age 57.04 years) were enrolled into the study. Patients were treated with solifenacin 5 mg or solifenacin 10 mg in the flexible dosing regimen. Efficacy data were obtained from the validated questionnaries and micturion diaries. Safety assessment was based on adverse event reporting. RESULTS: We observed a highly significant reduction of bladder problems caused by OAB (Patient Perception of Bladder Condition--PPBC/PBC score 4.83 at baseline to 3.29 at endpoint). The decrease of micturion frequency from baseline to endpoint was 31.19%, decrease of episodes of nocturia was 54.65 % and decrease of incontinence episodes was 90.19%. Average number of urgency episodes decresed from 12.46/day at baseline to 7.28/day at endpoint (41.6%). Average urgency severity decreased from 2.43 at baseline to 1.55 at endpoint (-37.4%). Adverse events were reported in 19 patients (5.52%) between visits 1 and 2 and in 16 patients (4.68%) between visits 2 and 3. CONCLUSIONS: Results of our phase IV. study showed the excellent efficacy and safety profile of solifenacin in the treatment of OAB in accordance with results of published phase III. clinical studies.