Venetoclax (VEN), a B-cell lymphoma 2 (BCL2) inhibitor, has a promising single-agent activity in mantle cell lymphoma (MCL), acute lymphoblastic leukemia (ALL), and large BCLs, but remissions were generally short, which call for rational drug combinations. Using a panel of 21 lymphoma and leukemia cell lines and 28 primary samples, we demonstrated strong synergy between VEN and A1155463, a BCL-XL inhibitor. Immunoprecipitation experiments and studies on clones with knockout of expression or transgenic expression of BCL-XL confirmed its key role in mediating inherent and acquired VEN resistance. Of note, the VEN and A1155463 combination was synthetically lethal even in the cell lines with lack of expression of the proapoptotic BCL2L11/BIM and in the derived clones with genetic knockout of BCL2L11/BIM. This is clinically important because BCL2L11/BIM deletion, downregulation, or sequestration results in VEN resistance. Immunoprecipitation experiments further suggested that the proapoptotic effector BAX belongs to principal mediators of the VEN and A1155463 mode of action in the BIM-deficient cells. Lastly, the efficacy of the new proapoptotic combination was confirmed in vivo on a panel of 9 patient-derived lymphoma xenografts models including MCL (n = 3), B-ALL (n = 2), T-ALL (n = 1), and diffuse large BCL (n = 3). Because continuous inhibition of BCL-XL causes thrombocytopenia, we proposed and tested an interrupted 4 days on/3 days off treatment regimen, which retained the desired antitumor synergy with manageable platelet toxicity. The proposed VEN and A1155463 combination represents an innovative chemotherapy-free regimen with significant preclinical activity across diverse BCL2+ hematologic malignancies irrespective of the BCL2L11/BIM status.

• MeSH
• Apoptosis drug effects   MeSH
• Benzothiazoles MeSH
• Bridged Bicyclo Compounds, Heterocyclic * pharmacology   therapeutic use   MeSH
• Drug Resistance, Neoplasm * MeSH
• Isoquinolines MeSH
• Humans MeSH
• Mice MeSH
• Cell Line, Tumor MeSH
• bcl-X Protein * metabolism   antagonists & inhibitors   MeSH
• Bcl-2-Like Protein 11 * metabolism   genetics   MeSH
• Antineoplastic Agents pharmacology   therapeutic use   MeSH
• Proto-Oncogene Proteins c-bcl-2 metabolism   antagonists & inhibitors   MeSH
• Sulfonamides * pharmacology   therapeutic use   MeSH
• Drug Synergism MeSH
• Xenograft Model Antitumor Assays MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

OBJECTIVE: Nerve-sparing radical hysterectomy (NSRH) decreases the negative postoperative consequences of radical surgery for cervical cancer, such as bladder evacuation disorders, colorectal motility disorders, and sexual dysfunction. The aim of this study was to prospectively assess the sexuality and quality of life in a group of women who underwent NSRH with lymphadenectomy for cervical cancer. MATERIALS AND METHODS: A total of 65 patients with early-stage cervical cancer underwent NSRH between 2014 and 2016. Patient examinations and questionnaire surveys (Female Sexual Function Index questionnaire and European Organization for Research and Treatment of Cancer questionnaires QLQ-C30 and QLQ-CX24) were conducted, before and one year after the surgery. RESULTS: After the exclusion of 19 sexually inactive women and 10 women who received adjuvant anticancer treatment, 36 sexually active patients treated solely with nerve-sparing surgery were eligible for evaluation. The mean age was 47 years. The average preoperative vaginal length was 9.4 cm, whereas the postoperative length was shortened to 7.1 cm. This study showed no negative impact of NSRH on sexual desire, arousal, satisfaction, orgasm, pain, sexual activity, sexual enjoyment, and sexual worry. The worsening of sexual functioning was recorded during the one-year follow-up. The QLQ-C30 questionnaire confirmed postoperative improvement in global health status and role, emotional, and social functioning. CONCLUSION: Our study showed using standardized questionnaires that NSRH has no negative impact on sexual desire, arousal, satisfaction, orgasm, pain, sexual activity, frequency of sexual intercourse, sexual enjoyment, and sexual worry, while only the worsening of sexual functioning was recorded. Moreover, NSRH did not cause postoperative deterioration in the quality of life parameters.

• MeSH
• Pain etiology   MeSH
• Hysterectomy adverse effects   MeSH
• Quality of Life MeSH
• Middle Aged MeSH
• Humans MeSH
• Uterine Cervical Neoplasms * surgery   MeSH
• Urinary Bladder Diseases * etiology   MeSH
• Prospective Studies MeSH
• Sexuality MeSH
• Sexual Behavior MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

Mantle cell lymphoma (MCL) is a rare subtype of B-cell non-Hodgkin lymphoma (B-NHL) with chronically relapsing clinical course. Implementation of cytarabine (araC) into induction and salvage regimen became standard of care for majority of MCL patients. In this study, tailored N-(2-hydroxypropyl)methacrylamide (HPMA)-based polymer nanotherapeutics containing covalently bound araC (araC co-polymers) were designed, synthesized and evaluated for their anti-lymphoma efficacy in vivo using a panel of six patient-derived lymphoma xenografts (PDX) derived from newly diagnosed and relapsed / refractory (R/R) MCL. While free araC led to temporary inhibition of growth of MCL tumors, araC co-polymers induced long-term disappearance of the engrafted lymphomas with no observed toxicity even in the case of PDX models derived from patients, who relapsed after high-dose araC-based treatments. The results provide sound preclinical rationale for the use of HPMA-based araC co-polymers in induction, salvage or palliative therapy of MCL patients.

• MeSH
• Cytarabine pharmacology   MeSH
• Adult MeSH
• Humans MeSH
• Neoplasm Recurrence, Local MeSH
• Lymphoma, Mantle-Cell * drug therapy   MeSH
• Antineoplastic Combined Chemotherapy Protocols MeSH
• Rituximab therapeutic use   MeSH
• Treatment Outcome MeSH
• Check Tag
• Adult MeSH
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

PURPOSE: PI3K signaling is a common feature of B-cell neoplasms, including chronic lymphocytic leukemia (CLL) and diffuse large B-cell lymphoma (DLBCL), and PI3K inhibitors have been introduced into the clinic. However, there remains a clear need to develop new strategies to target PI3K signaling. PI3K activity is countered by Src homology domain 2-containing inositol-5'-phosphatase 1 (SHIP1) and, here, we have characterized the activity of a novel SHIP1 activator, AQX-435, in preclinical models of B-cell malignancies. EXPERIMENTAL DESIGN: In vitro activity of AQX-435 was evaluated using primary CLL cells and DLBCL-derived cell lines. In vivo activity of AQX-435, alone or in combination with the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib, was assessed using DLBCL cell line and patient-derived xenograft models. RESULTS: Pharmacologic activation of SHIP1 using AQX-435 was sufficient to inhibit anti-IgM-induced PI3K-mediated signaling, including induction of AKT phosphorylation and MYC expression, without effects on upstream SYK phosphorylation. AQX-435 also cooperated with the BTK inhibitor ibrutinib to enhance inhibition of anti-IgM-induced AKT phosphorylation. AQX-435 induced caspase-dependent apoptosis of CLL cells preferentially as compared with normal B cells, and overcame in vitro survival-promoting effects of microenvironmental stimuli. Finally, AQX-435 reduced AKT phosphorylation and growth of DLBCL in vivo and cooperated with ibrutinib for tumor growth inhibition. CONCLUSIONS: Our results using AQX-435 demonstrate that SHIP1 activation may be an effective novel therapeutic strategy for treatment of B-cell neoplasms, alone or in combination with ibrutinib.

• MeSH
• Enzyme Activators pharmacology   MeSH
• Apoptosis drug effects   MeSH
• Leukemia, Lymphocytic, Chronic, B-Cell drug therapy   metabolism   pathology   MeSH
• Lymphoma, Large B-Cell, Diffuse drug therapy   metabolism   pathology   MeSH
• Phosphatidylinositol 3-Kinases chemistry   metabolism   MeSH
• Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases genetics   metabolism   MeSH
• Humans MeSH
• Mice, Inbred NOD MeSH
• Mice MeSH
• Cell Line, Tumor MeSH
• Antineoplastic Agents pharmacology   MeSH
• Sesquiterpenes pharmacology   MeSH
• Signal Transduction MeSH
• Xenograft Model Antitumor Assays MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Mice MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

B-cell non-Hodgkin lymphomas (B-NHL) represent the most common type of hematologic malignancies in the Western hemisphere. The therapy of all B-NHL is based on the combination of different genotoxic cytostatics and anti-CD20 monoclonal antibody (mAb) rituximab. Unfortunately, many patients relapse after the mentioned front-line treatment approaches. The therapy of patients with relapsed/refractory (R/R) B-NHL represents an unmet medical need. We designed, developed and tested novel actively targeted hybrid mAb-polymer-drug conjugate (APDC) containing anti-CD20, anti-CD38 or anti-CD19 mAbs. Biocompatible copolymers based on N-(2-hydroxypropyl)methacrylamide (HPMA) with cytostatic agent doxorubicin attached via stimuli-sensitive hydrazone bond were employed for the mAb grafting. Anti-lymphoma efficacy of the APDC nanotherapeutics was evaluated in vivo on a panel of three patient-derived lymphoma xenografts derived from two patients with R/R B-NHL and one patient with so far untreated B-NHL. In both PDX models derived from patients with R/R B-NHL, the targeting with anti-CD38 antibody daratumumab demonstrated highly improved anti-lymphoma efficacy compared to the targeting with anti-CD20 rituximab, two experimental anti-CD19 antibodies and non-targeted controls. The results represent a proof-of-concept of a new algorithm of personalized anti-tumor therapy based on highly innovative APDC biomaterials.

• MeSH
• Pharmaceutical Preparations * MeSH
• Humans MeSH
• Antibodies, Monoclonal therapeutic use   MeSH
• Lymphoma, Non-Hodgkin * drug therapy   MeSH
• Polymers therapeutic use   MeSH
• Antineoplastic Agents * therapeutic use   MeSH
• Rituximab MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

BACKGROUND: Facing an increasing prevalence of dementia, the Czech Republic is developing a new nationwide strategy for the management and prevention of dementia. Lack of evidence about characteristics of individuals with dementia in the country is a major obstacle. OBJECTIVE: The study aimed to 1) characterize individuals with dementia, 2) compare their mortality with the general population, and 3) analyze differences in survival between different dementia disorders. METHODS: The study capitalizes on two nationwide registers in the Czech Republic, from which information about individuals who were hospitalized with dementia or died from it between 1994 and 2014 was retrieved. Standardized intensity of hospitalizations was calculated for each year, mortality was studied using standardized mortality ratio, life-tables, Kaplan-Mayer curves, and Cox proportional hazard models. RESULTS: Standardized intensity of hospitalizations for dementia increased more than 3 times from 1994 to 2014. Standardized mortality ratio was 3.03 (95% confidence interval 2.97-3.08). One-year survival rate was 45% and five-year survival rate 16%. Vascular dementia was the most common type of dementia disorders and was associated with higher hazard of death than Alzheimer's disease, even after adjusting for sociodemographic and clinical covariates (hazard ratio 1.04; 95% confidence interval 1.02-1.05). CONCLUSION: The study provides estimates on demographic characteristics and mortality of the Czech hospitalized dementia population, which have not been so far available and which are unique also in the context of the entire region of Central and Eastern Europe.

• MeSH
• Dementia epidemiology   mortality   MeSH
• Hospitalization statistics & numerical data   MeSH
• Kaplan-Meier Estimate MeSH
• Humans MeSH
• Mortality MeSH
• Proportional Hazards Models MeSH
• Registries MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Geographicals
• Czech Republic MeSH

Cell surface expression of PD-1, PD-L1 and PD-L2 immune checkpoints on B and T cells obtained from patients with mantle cell lymphoma shows ambiguous results across many studies and creates obstacles for the implementation of immune checkpoint inhibitors into the therapy of mantle cell lymphoma. Using multiparameter flow cytometry we analysed surface expression of PD-1, PD-L1 and PD-L2 molecules on B and T cells of 31 newly diagnosed mantle cell lymphomas and compared it with the results of 26 newly diagnosed chronic lymphocytic leukaemias and 20 healthy volunteers. To gain insight into the age-dependent changes of surface expression of these immune checkpoints, flow cytometric subanalysis of 30 healthy volunteers of 25-93 years of age was conducted. Overall, we demonstrated weak surface expression of PD-1, PD-L1 and PD-L2 on B and T cells of mantle cell lymphoma patients (< 10 % when compared to healthy individuals). A significant age-dependent increase in the expression of PD-1 and its ligand PD-L2 was observed in healthy volunteers. Our results suggest that neither PD-1 nor its ligands represent relevant druggable targets for the therapy of mantle cell lymphoma. The observed age-dependent changes in healthy population could impact efficiency of immune checkpoint inhibitors and could be at least partly connected with increased incidence of cancer with age.

• MeSH
• Programmed Cell Death 1 Ligand 2 Protein metabolism   MeSH
• B7-H1 Antigen metabolism   MeSH
• Programmed Cell Death 1 Receptor metabolism   MeSH
• B-Lymphocytes MeSH
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Lymphoma, Mantle-Cell metabolism   MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Case-Control Studies MeSH
• T-Lymphocytes MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Publication type
• Journal Article MeSH

Expenditures on mental health care in the Czech Republic are not being published regularly, yet they are indispensable for evaluation of the ongoing reform of Czech mental health care. The main objective of this study is to estimate the size of these expenditures in 2015 and make a comparison with the last available figures from the year 2006. The estimation is based on an OECD methodology of health accounts, which structures health care expenditures according to health care functions, provider industries, and payers. The expenditures are further decomposed according to diagnoses, and inputs used in service production. The amount spent on mental health care in 2015 reached more than 13.7 billion Czech korunas (EUR 501.6 million), which represented 4.08% of the total health care expenditures. This ratio is almost identical with the 2006 share (4.14%). There are no significant changes in the relative expenditures on mental health care and in the structure of service provision. The Czech mental health care system remains largely hospital based with most of all mental health care expenditures being spent on inpatient care. Future developments in the expenditures will indicate the success of the current effort to deinstitutionalise mental health care.

• MeSH
• Mental Disorders economics   therapy   MeSH
• Hospitalization economics   MeSH
• Humans MeSH
• Mental Health Services economics   MeSH
• Health Expenditures statistics & numerical data   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Geographicals
• Czech Republic MeSH

PURPOSE: Mantle cell lymphoma (MCL) is an aggressive subtype of B-cell non-Hodgkin lymphomas characterized by (over)expression of BCL2. A BCL2-targeting drug, venetoclax, has promising anticancer activity in MCL. We analyzed molecular mechanisms of venetoclax resistance in MCL cells and tested strategies to overcome it. EXPERIMENTAL DESIGN: We confirmed key roles of proapoptotic proteins BIM and NOXA in mediating venetoclax-induced cell death in MCL. Both BIM and NOXA are, however, differentially expressed in cell lines compared with primary cells. First, NOXA protein is significantly overexpressed in most MCL cell lines. Second, deletions of BIM gene harbored by three commonly used MCL cell lines (JEKO-1, MINO, and Z138) were not found by array comparative genomic hybridization using a validation set of 24 primary MCL samples. RESULTS: We demonstrated that MCL1 and NOXA play important roles in mediating resistance to venetoclax. Consequently, we tested an experimental treatment strategy based on cotargeting BCL2 with venetoclax and MCL1 with a highly specific small-molecule MCL1 inhibitor S63845. The combination of venetoclax and S63845 demonstrated synthetic lethality in vivo on a panel of five patient-derived xenografts established from patients with relapsed MCL with adverse cytogenetics. CONCLUSIONS: Our data strongly support investigation of venetoclax in combination with S63845 as an innovative treatment strategy for chemoresistant MCL patients with adverse cytogenetics in the clinical grounds.

• MeSH
• Bridged Bicyclo Compounds, Heterocyclic pharmacology   MeSH
• Drug Resistance, Neoplasm MeSH
• Humans MeSH
• Neoplasm Recurrence, Local drug therapy   metabolism   pathology   MeSH
• Lymphoma, Mantle-Cell drug therapy   metabolism   pathology   MeSH
• Mice, Inbred NOD MeSH
• Mice MeSH
• Cell Line, Tumor MeSH
• Myeloid Cell Leukemia Sequence 1 Protein antagonists & inhibitors   metabolism   MeSH
• Antineoplastic Agents pharmacology   MeSH
• Proto-Oncogene Proteins c-bcl-2 antagonists & inhibitors   metabolism   MeSH
• Pyrimidines pharmacology   MeSH
• Sulfonamides pharmacology   MeSH
• Drug Synergism * MeSH
• Thiophenes pharmacology   MeSH
• Xenograft Model Antitumor Assays MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Mice MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

BACKGROUND: The absence of economic evidence hinders current reforms of hospital-based mental health systems in central and eastern Europe. We aimed to assess the cost-effectiveness of discharge to community care for people with chronic psychoses compared with care in psychiatric hospitals in the Czech Republic. METHODS: We did a prospective study of people aged 18-64 years with chronic psychotic disorders in the Czech Republic who had been discharged into community services or were receiving inpatient psychiatric care for at least 3 months at baseline. We measured health-related quality of life with the EuroQol five-dimension five-level questionnaire. Adjusting for baseline differences between the two groups, we assessed differences in societal costs in 2016 and quality-adjusted life-years (QALYs) during a 12-month follow-up, which we then used to estimate the incremental cost-effectiveness ratio (ICER). We did multiple sensitivity analyses to assess the robustness of our results. FINDINGS: In our baseline case scenario, we included 115 patients who were either community service users (n=35) or inpatients (n=80) at baseline. The two groups were similar in terms of baseline characteristics. The annual QALY was 0·77 in patients receiving community care at baseline compared with 0·80 in patients in hospital at baseline (difference 0·03, 95% CI -0·04 to 0·10), but the costs of discharge to the community were €8503 compared with €16 425 for no discharge (difference €7922, 95% CI 4497-11 346), such that the ICER reached more than €250 000 per QALY. This ICER is substantially higher than levels that are conventionally considered to be cost-effective and the estimated probability that discharge to the community was cost-effective was very high (≥97%). None of the sensitivity analyses changed these results qualitatively. INTERPRETATION: This study provides economic evidence for deinstitutionalisation by showing that discharge to community care is cost-effective compared with care in psychiatric hospitals in the Czech Republic. These findings add to the human rights and clinical-based arguments for mental health-care reforms in central and eastern Europe. FUNDING: Ministry of Education, Youth and Sports of the Czech Republic; EEA and Norway Grants.

• MeSH
• Cost-Benefit Analysis * MeSH
• Adult MeSH
• Quality-Adjusted Life Years MeSH
• Middle Aged MeSH
• Humans MeSH
• Young Adult MeSH
• Prospective Studies MeSH
• Psychotic Disorders therapy   MeSH
• Community Mental Health Services economics   statistics & numerical data   MeSH
• Hospitals, Psychiatric economics   statistics & numerical data   MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Young Adult MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Geographicals
• Czech Republic MeSH