Subcutaneous Omacetaxine Mepesuccinate in Patients With Chronic-Phase Chronic Myeloid Leukemia Previously Treated With 2 or More Tyrosine Kinase Inhibitors Including Imatinib

IntroductionOmacetaxine mepesuccinate (omacetaxine) is a first-in-class cephalotaxine that has demonstrated efficacy in CML. In this analysis we evaluated omacetaxine in CML patients with resistance or intolerance to 2 or more tyrosine kinase inhibitors (TKIs).Patients and MethodsData were pooled from 2 phase II trials of subcutaneous omacetaxine, administered at 1.25 mg/m² twice daily for 14 consecutive days every 28 days until response, then for 7 days every 28 days as maintenance. Patients with resistance or intolerance to imatinib and at least 1 other approved TKI (dasatinib and/or nilotinib) were included; results for patients in chronic phase (CP) are reported here. Major cytogenetic response (MCyR) was the primary end point.ResultsEighty-one patients with CML-CP (median age, 59 years; range, 26-83 years) were included in the analysis. All patients previously received imatinib, 69 (85%) previously received dasatinib, and 48 (59%) previously received nilotinib. Median omacetaxine exposure was 7.5 months (range, 0.03-38.6 months), with 13 patients ongoing. MCyR was reported in 16 patients (20%; one-sided 95% lower confidence limit, 12.8%), including 8 complete responses; median duration was 17.7 months (95% confidence interval, 4.1 months – not reached). Fifty-six patients (69%) achieved and/or maintained hematologic response for at least 8 weeks; median duration was 12.2 months (range, 8.4-26.2 months). Median failure-free and overall survival were 9.6 months and 34 months, respectively. Toxicity was mainly hematologic: the most common grade 3/4 adverse events were thrombocytopenia (67%), neutropenia (47%), and anemia (37%).ConclusionOmacetaxine produced clinically meaningful responses with acceptable tolerability in patients with CML-CP previously treated with 2 or more TKIs.     

A prospective,multisite study analyzing the percentage of urological cases that can be completely managed by telemedicine

IntroductionThe COVID-19 pandemic has accelerated the development of telemedicine due to confinement measures. However, the percentage of outpatient urological cases that could be managed completely by telemedicine outside of the COVID-19 pandemic remains to be determined. We conducted a prospective, multisite study involving all urologists working in the region of Quebec City.MethodsDuring the first four weeks of the regional confinement, 18 pediatric and adult urologists were asked to determine, after each telemedicine appointment, if it translated into a complete (CCM), incomplete (ICM), or suboptimal case management (SCM, adequate only in the context of the pandemic).ResultsA total of 1679 appointments representing all urological areas were registered. Overall, 67.6% (95% confidence interval [CI] 65.3; 69.8), 27.1% (25.0; 29.3), and 4.3% (3.5; 5.4) were reported as CCM, SCM, and ICM, respectively. The CCM ratio varied according to the reason for consultation, with cancer suspicion (52.9% [42.9; 62.8]) and pediatric reasons (38.0% [30.0; 46.6]) showing the lowest CCM percentages. CCM percentages also varied significantly based on the setting where it was performed, ranging from 61.1% (private clinic) to 86.8% (endourology and general hospital).ConclusionsWe show that two-thirds of all urological outpatient cases could be completely managed by telemedicine outside of the pandemic. After the pandemic, it will be important to incorporate telemedicine as an alternative for a patient’s first or followup visit, especially those with geographical, pathological, and socioeconomic considerations.     

Imaging protocols for CT urography: results of a consensus conference from the French Society of Genitourinary Imaging

To develop technical guidelines for computed tomography urography. The French Society of Genitourinary Imaging organised a Delphi consensus conference with a two-round Delphi survey followed by a face-to-face meeting. Consensus was strictly defined using a priori criteria. Forty-two expert uro-radiologists completed both survey rounds with no attrition between the rounds. Ninety-six (70%) of the initial 138 statements of the questionnaire achieved final consensus. An intravenous injection of 20 mg of furosemide before iodinated contrast medium injection was judged mandatory. Improving the quality of excretory phase imaging through oral or intravenous hydration of the patient or through the use of an abdominal compression device was not deemed necessary. The patient should be imaged in the supine position and placed in the prone position only at the radiologist’s request. The choice between single-bolus and split-bolus protocols depends on the context, but split-bolus protocols should be favoured whenever possible to decrease patient irradiation. Repeated single-slice test acquisitions should not be performed to decide of the timing of excretory phase imaging; instead, excretory phase imaging should be performed 7 min after the injection of the contrast medium. The optimal combination of unenhanced, corticomedullary phase and nephrographic phase imaging depends on the context; suggestions of protocols are provided for eight different clinical situations. This expert-based consensus conference provides recommendations to standardise the imaging protocol for computed tomography urography. • To improve excretory phase imaging, an intravenous injection of furosemide should be performed before the injection of iodinated contrast medium. • Systematic oral or intravenous hydration is not necessary to improve excretory phase imaging. • The choice between single-bolus and split-bolus protocols depends on the context, but split-bolus protocols should be favoured whenever possible to decrease patient irradiation.     

ARF1 controls proliferation of breast cancer cells by regulating the retinoblastoma protein

The ADP-ribosylation factors (ARFs) 1 and 6 are small GTP-binding proteins, highly expressed and activated in several breast cancer cell lines and are associated with enhanced migration and invasiveness. In this study, we report that ARF1 has a critical role in cell proliferation. Depletion of this GTPase or expression of a dominant negative form, which both resulted in diminished ARF1 activity, led to sustained cell-growth arrest. This cellular response was associated with the induction of senescent markers in highly invasive breast cancer cells as well as in control mammary epithelial cells by a mechanism regulating retinoblastoma protein (pRB) function. When examining the role of ARF1, we found that this GTPase was highly activated in normal proliferative conditions, and that a limited amount could be found in the nucleus, associated with the chromatin of MDA-MB-231 cells. However, when cells were arrested in the G(0)/G(1) phase or transfected with a dominant negative form of ARF1, the total level of activated ARF1 was markedly reduced and the GTPase significantly enriched in the chromatin. Using biochemical approaches, we demonstrated that the GDP-bound form of ARF1 directly interacted with pRB, but not other members of this family of proteins. In addition, depletion of ARF1 or expression of ARF1T(31)N resulted in the constitutive association of pRB and E2F1, thereby stabilizing the interaction of E2F1 as well as pRB at endogenous sites of target gene promoters, preventing expression of E2F target genes, such as cyclin D1, Mcm6 and E2F1, important for cell-cycle progression. These novel findings provide direct physiological and molecular evidence for the role of ARF1 in controlling cell proliferation, dependent on its ability to regulate pRB/E2F1 activity and gene expression for enhanced proliferation and breast cancer progression.