Hyper-activation of Aurora kinase a-polo-like kinase 1-FOXM1 axis promotes chronic myeloid leukemia resistance to tyrosine kinase inhibitors.

BACKGROUND: Chronic myeloid leukemia (CML) is a myeloproliferative disease caused by the constitutive tyrosine kinase (TK) activity of the BCR-ABL1 fusion protein. Accordingly, TK inhibitors have drastically changed the disease prognosis. However, persistence of the transformed hematopoiesis even in patients who achieved a complete response to TK inhibitors and the disease relapse upon therapy discontinuation represent a major obstacle to CML cure. METHODS: Thiostrepton, Danusertib and Volasertib were used to investigate the effects of FOXM1, AKA and Plk1 inhibition in K562-S and K562-R cells. Apoptotic cell death was quantified by annexin V/propidium iodide staining and flow cytometry. Quantitative reverse transcription (RT)-PCR was used to assess BCR-ABL1, FOXM1, PLK1 and AURKA expression. Protein expression and activation was assessed by Western Blotting (WB). Clonogenic assay were performed to confirm K562-R resistance to Imatinib and to evaluate cells sensitivity to the different drugs. RESULTS: Here we proved that BCR-ABL1 TK-dependent hyper-activation of Aurora kinase A (AURKA)-Polo-like kinase 1 (PLK1)-FOXM1 axis is associated with the outcome of Imatinib (IM) resistance in an experimental model (K562 cell line) and bone marrow hematopoietic cells. Notably, such a biomolecular trait was detected in the putative leukemic stem cell (LSC) compartment characterized by a CD34+ phenotype. Constitutive phosphorylation of FOXM1 associated with BCR-ABL1 TK lets FOXM1 binding with ß-catenin enables ß-catenin nuclear import and recruitment to T cell factor/lymphoid enhancer-binding factor (TCF/LEF) transcription complex, hence supporting leukemic cell proliferation and survival. Lastly, the inhibition of single components of AURKA-PLK1-FOXM1 axis in response to specific drugs raises the expression of growth factor/DNA damage-inducible gene a (GADD45a), a strong inhibitor of AURKA and, as so, a critical component whose induction may mediate the eradication of leukemic clone. CONCLUSIONS: Our conclusion is that AURKA, PLK1 and FOXM1 inhibition may be considered as a promising therapeutic approach to cure CML.

Robotic versus laparoscopic sacrocolpopexy for apical prolapse: a case-control study.

The apical prolapse has always been considered the most complex of the defects of the pelvic floor, for both the difficulty of the surgical corrective technique and for the high post-surgical recurrence rate. Today, the laparoscopic sacrocolpopexy can be considered the standard treatment for apical prolapse. In the last years, several author performed robotic sacrocolpopexy, obtaining positive results. So, we developed a casecontrol study in order to compare the surgical outcome of robotic group with a control group of laparoscopic approach in patients with symptomatic apical pro-lapsed between January 2015 and December 2015 at University Hospital Policlinico "P. Giaccone" and Ospedali Riuniti "Villa Sofia-Cervello", Palermo. Our experience shows that robotic sacrocolpopexy can be considered in positive way for clinical results obtained: all procedures were executed with no complications, we noted a lower intraoperative blood loss and a shorter hospital stay than in laparoscopic group. Although the mean operative time and the economic costs are higher in robotic surgery, this study demonstrates that the use of robotic platform for repairing of symptomatic apical vaginal prolapse is feasible, safe and associated with short-term satisfactory results, representing therefore a valid alternative to laparoscopic approach.

Is vaginal fractional CO2 laser treatment effective in improving overactive bladder symptoms in post-menopausal patients? Preliminary results.

OBJECTIVE: To evaluate the role of vaginal fractional CO2 laser treatment in the relief of Overactive Bladder (OAB) symptoms in post-menopausal women. PATIENTS AND METHODS: Post-menopausal women who complained of one or more symptoms related to vulvo-vaginal atrophy (VVA), who experienced symptoms of OAB and who underwent vaginal treatment with fractional CO2 laser were enrolled in the study. At baseline (T0) and 30 days post-treatment T1), vaginal status (using Vaginal Health Index - VHI), subjective intensity of VVA symptoms (using a visual analog scale - VAS) and micturition diary were evaluated. OAB symptoms were also assessed using a validated questionnaire. RESULTS: Thirty patients were enrolled. A statistically significant improvement in VVA symptoms was observed and in VHI at T1 (p < 0.0001). A significant improvement was also identified in the micturition diary, in number of urge episodes and OAB-q (p < 0.0001). Nine of the 30 patients suffered from incontinence episodes and had improved at T1. CONCLUSIONS: We showed that fractionated CO2 laser vaginal treatment has proved to be effective in improving OAB symptoms in post-menopausal women. Moreover, it is a safe and efficacious measure for the relief of VVA related conditions. Further long-term studies are needed to confirm these preliminary results.

Long-term outcome of chronic myeloid leukemia patients treated frontline with imatinib.

For almost 10 years imatinib has been the therapeutic standard of chronic myeloid leukemia. The introduction of other tyrosine kinase inhibitors (TKIs) raised a debate on treatment optimization. The debate is still heated: some studies have protocol restrictions or limited follow-up; in other studies, some relevant data are missing. The aim of this report is to provide a comprehensive, long-term, intention-to-treat, analysis of 559 newly diagnosed, chronic-phase, patients treated frontline with imatinib. With a minimum follow-up of 66 months, 65% of patients were still on imatinib, 19% were on alternative treatment, 12% died and 4% were lost to follow-up. The prognostic value of BCR-ABL1 ratio at 3 months (⩽10% in 81% of patients) was confirmed. The prognostic value of complete cytogenetic response and major molecular response at 1 year was confirmed. The 6-year overall survival was 89%, but as 50% of deaths occurred in remission, the 6-year cumulative incidence of leukemia-related death was 5%. The long-term outcome of first-line imatinib was excellent, also because of second-line treatment with other TKIs, but all responses and outcomes were inferior in high-risk patients, suggesting that to optimize treatment results, a specific risk-adapted treatment is needed for such patients.

Differences among young adults, adults and elderly chronic myeloid leukemia patients.

BACKGROUND: The incidence of chronic myeloid leukemia (CML) increases with age, but it is unclear how the characteristics of the disease vary with age. In children, where CML is very rare, it presents with more aggressive features, including huge splenomegaly, higher cell count and higher blast cell percentage. PATIENTS AND METHODS: To investigate if after childhood the disease maintains or loses these characteristics of aggressiveness, we analyzed 2784 adult patients, at least 18 years old, registered by GIMEMA CML WP over a 40-year period. RESULTS: Young adults (YAs: 18-29 years old) significantly differed from adults (30-59 years old) and elderly patients (at least 60 years old) particularly for the frequency of splenomegaly (71%, 63% and 55%, P < 0.001), and the greater spleen size (median value: 4.5, 3.0 and 1.0 cm, P < 0.001). According to the EUTOS score, that is age-independent, high-risk patients were more frequent among YAs, than among adult and elderly patients (18%, 9% and 6%, P < 0.001). In tyrosine kinase inhibitors-treated patients, the rates of complete cytogenetic and major molecular response were lower in YAs, and the probability of transformation was higher (16%, 5% and 7%, P = 0.011). CONCLUSIONS: The characteristics of CML or the host response to leukemia differ with age. The knowledge of these differences and of their causes may help to refine the treatment and to improve the outcome. CLINICAL TRIAL NUMBERS: NCT00510926, NCT00514488, NCT00769327, NCT00481052.