Key Points EBF1-PDGFRB fusion accounts for ∼0.5% of B-cell precursor acute lymphoblastic leukemia and 2.7% of the B-other subtype. EBF1-PDGFRB-positive patients are MRD positive and are slow early responders who respond to imatinib.
Background:Rucaparib is an orally available potent selective small-molecule inhibitor of poly(ADP-ribose) polymerase (PARP) 1 and 2. Rucaparib induces synthetic lethality in cancer cells defective in the homologous recombination repair pathway including BRCA-1/2. We investigated the efficacy and safety of single-agent rucaparib in germline (g) BRCA mutation carriers with advanced breast and ovarian cancers.Methods:Phase II, open-label, multicentre trial of rucaparib in proven BRCA-1/2 mutation carriers with advanced breast and or ovarian cancer, WHO PS 0–1 and normal organ function. Intravenous (i.v.) and subsequently oral rucaparib were assessed, using a range of dosing schedules, to determine the safety, tolerability, dose-limiting toxic effects and pharmacodynamic (PD) and pharmacokinetic (PK) profiles.Results:Rucaparib was well tolerated in patients up to doses of 480 mg per day and is a potent inhibitor of PARP, with sustained inhibition ⩾24 h after single doses. The i.v. rucaparib (intermittent dosing schedule) resulted in an objective response rate (ORR) of only 2% but with 41% (18 out of 44) patients achieved stable disease for ⩾12 weeks and 3 patients maintaining disease stabilisation for >52 weeks. The ORR for oral rucaparib (across all six dose levels) was 15%. In the oral cohorts, 81% (22 out of 27) of the patients had ovarian cancer and 12 out of 13, who were dosed continuously, achieved RECIST complete response/partial response (CR/PR) or stable disease (SD) ⩾12 weeks, with a median duration of response of 179 days (range 84–567 days).Conclusions:Rucaparib is well tolerated and results in high levels of PARP inhibition in surrogate tissues even at the lowest dose levels. Rucaparib is active in gBRCA-mutant ovarian cancer and this activity correlates with platinum-free interval. The key lessons learned from this study is that continuous rucaparib dosing is required for optimal response, the recommended phase 2 dose (RP2D) for continuous oral scheduling has not been established and requires further exploration and, thirdly, the use of a PD biomarker to evaluate dose–response has its limitations.
Key summary pointsAim To describe the prevalence of probable sarcopenia in a sample of older adults and to investigate (1) the SARC-F tool and (2) clinical risk factors in the identification of probable sarcopenia. Findings The prevalence of probable sarcopenia at age 69 was 19%, and a SARC-F score of ≥ 1 had a reasonable balance of sensitivity (65%) and specificity (72%) for probable sarcopenia. Three clinical risk factors were independently associated with probable sarcopenia: polypharmacy, lower body osteoarthritis and physical inactivity. Message Those with any positive responses to the questions in the SARC-F tool, a history of polypharmacy, lower body osteoarthritis or physical inactivity should be prioritised for the assessment of muscle strength. AbstractPurpose The European Working Group on Sarcopenia in Older People 2 (EWGSOP2) consensus definition introduced the concept of probable sarcopenia as a basis on which to begin treatment. Our aims were to describe the prevalence of probable sarcopenia in older adults and to investigate the utility of (1) the SARC-F tool and (2) clinical risk factors for the identification of those likely to have probable sarcopenia. Methods We used data from the 1946 British birth cohort at age 69, with 1686 participants included in the analyses. We used the EWGSOP2 cut points for weak grip strength and slow chair rise time, with the presence of one or both indicating probable sarcopenia. We examined the sensitivity and specificity of the SARC-F tool for probable sarcopenia. We also examined associations between clinical risk factors and probable sarcopenia. Results The prevalence of probable sarcopenia was 19%. A SARC-F score of ≥ 4 had low sensitivity (15%) and high specificity (99%) for probable sarcopenia, whereas a score of ≥ 1 had higher sensitivity (65%) and reasonable specificity (72%). Three clinical risk factors were independently associated with probable sarcopenia: polypharmacy [OR 2.7 (95% CI 1.7,4.2)], lower body osteoarthritis [OR 1.8 (95% CI 1.3, 2.6)] and physical inactivity [OR of 2.1 (95% CI 1.5, 2.8)]. Conclusion We have shown that EWGSOP2 probable sarcopenia is common in community-dwelling adults in early old age. Those with any positive responses to the questions in the SARC-F tool, a history of polypharmacy, lower body osteoarthritis or physical inactivity should be prioritised for the assessment of muscle strength.
Poly (ADP-ribose) polymerase (PARP) inhibition can enhance the efficacy of temozolomide (TMZ) and prolong survival in orthotopic glioblastoma (GBM) xenografts. The aim of this study was to evaluate the combination of the PARP inhibitor rucaparib with TMZ and to correlate pharmacokinetic and pharmacodynamic studies with efficacy in patient-derived GBM xenograft models. The combination of rucaparib with TMZ was highly effective in vitro in short-term explant cultures derived from GBM12, and similarly, the combination of rucaparib and TMZ (dosed for 5 days every 28 days × 3 cycles) significantly prolonged the time to tumor regrowth by 40% in heterotopic xenografts. In contrast, the addition of rucaparib had no impact on the efficacy of TMZ in GBM12 or GBM39 orthotopic models. Using Madin-Darby canine kidney (MDCK) II cells stably expressing murine BCRP1 or human MDR1, cell accumulation studies demonstrated that rucaparib is transported by both transporters. Consistent with the influence of these efflux pumps on central nervous system drug distribution, Mdr1a/b−/−Bcrp1−/− knockout mice had a significantly higher brain to plasma ratio for rucaparib (1.61 ± 0.25) than wild-type mice (0.11 ± 0.08). A pharmacokinetic and pharmacodynamic evaluation after a single dose confirmed limited accumulation of rucaparib in the brain associated with substantial residual PARP enzymatic activity. Similarly, matrix-assisted laser desorption/ionization mass spectrometric imaging demonstrated significantly enhanced accumulation of drug in flank tumor compared to normal brain or orthotopic tumors. Collectively, these results suggest that limited drug delivery into brain tumors may significantly limit the efficacy of rucaparib combined with TMZ in GBM.
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