Search

Background: The bromodomain and extraterminal protein (BET) inhibitor trotabresib has demonstrated antitumor activity in patients with advanced solid tumors, including high-grade gliomas. CC-90010-GBM-001 (NCT04047303) is a phase I study investigating the pharmacokinetics, pharmacodynamics, and CNS penetration of trotabresib in patients with recurrent high-grade gliomas scheduled for salvage resection., Methods: Patients received trotabresib 30 mg/day on days 1-4 before surgery, followed by maintenance trotabresib 45 mg/day 4 days on/24 days off after surgery. Primary endpoints were plasma pharmacokinetics and trotabresib concentrations in resected tissue. Secondary and exploratory endpoints included safety, pharmacodynamics, and antitumor activity., Results: Twenty patients received preoperative trotabresib and underwent resection with no delays or cancelations of surgery; 16 patients received maintenance trotabresib after recovery from surgery. Trotabresib plasma pharmacokinetics were consistent with previous data. Mean trotabresib brain tumor tissue:plasma ratio was 0.84 (estimated unbound partition coefficient [KPUU] 0.37), and modulation of pharmacodynamic markers was observed in blood and brain tumor tissue. Trotabresib was well tolerated; the most frequent grade 3/4 treatment-related adverse event during maintenance treatment was thrombocytopenia (5/16 patients). Six-month progression-free survival was 12%. Two patients remain on treatment with stable disease at cycles 25 and 30., Conclusions: Trotabresib penetrates the blood-brain-tumor barrier in patients with recurrent high-grade glioma and demonstrates target engagement in resected tumor tissue. Plasma pharmacokinetics, blood pharmacodynamics, and safety were comparable with previous results for trotabresib in patients with advanced solid tumors. Investigation of adjuvant trotabresib + temozolomide and concomitant trotabresib + temozolomide + radiotherapy in patients with newly diagnosed glioblastoma is ongoing (NCT04324840)., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.)

Bromodomain and extraterminal proteins (BET) play key roles in regulation of gene expression, and may play a role in cancer-cell proliferation, survival, and oncogenic progression. CC-90010-ST-001 (NCT03220347) is an open-label phase I study of trotabresib, an oral BET inhibitor, in heavily pretreated patients with advanced solid tumors and relapsed/refractory diffuse large B-cell lymphoma (DLBCL). Primary endpoints were the safety, tolerability, maximum tolerated dose, and RP2D of trotabresib. Secondary endpoints were clinical benefit rate (complete response [CR] + partial response [PR] + stable disease [SD] of ≥4 months' duration), objective response rate (CR + PR), duration of response or SD, progression-free survival, overall survival, and the pharmacokinetics (PK) of trotabresib. In addition, part C assessed the effects of food on the PK of trotabresib as a secondary endpoint. The dose escalation (part A) showed that trotabresib was well tolerated, had single-agent activity, and determined the recommended phase 2 dose (RP2D) and schedule for the expansion study. Here, we report long-term follow-up results from part A (N = 69) and data from patients treated with the RP2D of 45 mg/day 4 days on/24 days off or an alternate RP2D of 30 mg/day 3 days on/11 days off in the dose-expansion cohorts (parts B [N = 25] and C [N = 41]). Treatment-related adverse events (TRAEs) are reported in almost all patients. The most common severe TRAEs are hematological. Toxicities are generally manageable, allowing some patients to remain on treatment for ≥2 years, with two patients receiving ≥3 years of treatment. Trotabresib monotherapy shows antitumor activity, with an ORR of 13.0% (95% CI, 2.8-33.6) in patients with R/R DLBCL (part B) and an ORR of 0.0% (95% CI, 0.0-8.6) and a CBR of 31.7% (95% CI, 18.1-48.1) in patients with advanced solid tumors (part C). These results support further investigation of trotabresib in combination with other anticancer agents., (© 2023. The Author(s).)

Background: Standard-of-care treatment for newly diagnosed glioblastoma (ndGBM), consisting of surgery followed by radiotherapy (RT) and temozolomide (TMZ), has improved outcomes compared with RT alone; however, prognosis remains poor. Trotabresib, a novel bromodomain and extraterminal inhibitor, has demonstrated antitumor activity in patients with high-grade gliomas., Methods: In this phase Ib, dose-escalation study (NCT04324840), we investigated trotabresib 15, 30, and 45 mg combined with TMZ in the adjuvant setting and trotabresib 15 and 30 mg combined with TMZ+RT in the concomitant setting in patients with ndGBM. Primary endpoints were to determine safety, tolerability, maximum tolerated dose, and/or recommended phase II dose (RP2D) of trotabresib. Secondary endpoints were assessment of preliminary efficacy and pharmacokinetics. Pharmacodynamics were investigated as an exploratory endpoint., Results: The adjuvant and concomitant cohorts enrolled 18 and 14 patients, respectively. Trotabresib in combination with TMZ or TMZ+RT was well tolerated; most treatment-related adverse events were mild or moderate. Trotabresib pharmacokinetics and pharmacodynamics in both settings were consistent with previous data for trotabresib monotherapy. The RP2D of trotabresib was selected as 30 mg 4 days on/24 days off in both settings. At last follow-up, 5 (28%) and 6 (43%) patients remain on treatment in the adjuvant and concomitant settings, respectively, with 1 patient in the adjuvant cohort achieving complete response., Conclusions: Trotabresib combined with TMZ in the adjuvant setting and with TMZ+RT in the concomitant setting was safe and well tolerated in patients with ndGBM, with encouraging treatment durations. Trotabresib 30 mg was established as the RP2D in both settings., (© The Author(s) 2022. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

Human coronaviruses have neuroinvasive and neurotropic abilities that might explain psychiatric outcomes in affected patients. We hypothesized that delirium might be the sole clinical manifestation or even the prodrome of a psychiatric episode consistent with the mental history of a few infected patients with a preexisting diagnosed cognitive impairment. We examined three patients with preexisting mild cognitive impairment and delirium at admission for suspected SARS-CoV-2 infection. We diagnosed delirium using DSM-5 and Confusion Assessment Method (CAM) and measured consciousness level by the Glasgow Coma Scale. All the patients had no history of fever, respiratory complications, anosmia or ageusia, meningitis, and negative cerebrospinal fluid analysis for SARS-CoV-2. Our first patient had no psychiatric history, the second reported only a depressive episode, and the third had a history of bipolar disorder dated back to 40 years before. In the first patient, delirium resolved 2 days following the admission. The other two patients recovered in 4 and 14 days, and delirium appeared as the prodrome of a new psychiatric episode resembling past events. Clinicians should monitor the possibility that SARS-CoV-2 presence in the brain might clinically manifest in the form of delirium and acute psychiatric sequelae, even without other systemic symptoms. Psychiatric history and preexisting mild cognitive impairment are to be considered as predisposing factors for COVID-19 sequelae in delirium patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Fabrazzo, Russo, Luciano, Camerlengo, Catapano, Amoroso, Catapano and Coppola.)

Identification of patients at risk of early disease progression is the mainstay of tailored management in chronic lymphocytic leukemia (CLL). Although application of established biomarkers is limited by intrinsic detection/readout complexities, abnormality of κ and λ serum-free light chain ratio [sFLC (κ/λ)] was proposed as a straightforward prognosticator in CLL. By analyzing 449 therapy-naive patients, we show that an abnormal sFLC(κ/λ), along with CD38, ZAP-70, IGHV mutations, cytogenetics and stage, independently predicts treatment-free survival (TFS) but becomes prognostically irrelevant if the cumulative amount of clonal and nonclonal FLCs [sFLC(κ + λ)], a variable associated with cytogenetic risk, exceeds the threshold of 60.6 mg/mL. Patients with sFLC(κ + λ) above cut-off displayed a poorer TFS outcome, irrespective of sFLC(κ/λ). Only ZAP-70, cytogenetics, stage, and TFS remained associated with sFLC(κ + λ) in a multivariate model. By assigning 1 point each for these variables, the 3-year probability of TFS was 94.8%, 84.5%, 61.6%, and 21.1% for patients scoring 0, 1, 2, and 3 + 4, respectively (P < .0001). These data, and the demonstration that monoclonal and polyclonal B cells concur to FLC synthesis in tumor tissues, suggest that sFLC(κ/λ) and sFLC(κ + λ) mirror distinct biologic processes in CLL. sFLC(κ + λ) assessment represents a sensitive and cost-effective tool for identifying CLL patients requiring early treatment.

Objective: Our goals were to demonstrate that functional gastrointestinal disorders (FGIDs) can be diagnosed in a positive fashion and managed by family pediatricians (FPs); to assess the compliance of FPs with a predefined diagnostic/therapeutic protocol for managing FGIDs to evaluate efficacy of continuing medical education; and to evaluate the success of reassurance by using a biopsychosocial model in comparison to drug treatment in an open-label, nonrandomized study., Patients and Methods: A total of 9291 patients, aged birth to 14 years, were prospectively enrolled during a 3-month period by 21 FPs. Follow-up was performed at 1-, 3-, and 12-month intervals. To assess compliance, after diagnosis, FPs that participated in the study were asked to comply with the diagnostic/therapeutic protocol and record investigations and treatment prescribed., Results: Two hundred sixty-one patients (2.8%) met Rome II criteria and were included in the study. In all cases but 4, diagnosis of FGIDs was confirmed at the end of follow-up (98.4%). Average compliance of FPs was >80%. Among 56 patients treated only with the explanation of symptom and reassurance, 52 (92.8%) have reported success, in comparison with 26 of 35 patients (74.3%) treated with drugs (odds ratio: 4.5 [95% confidence interval: 1.3-16])., Conclusions: FGIDs can be diagnosed and managed in primary care. Prospective studies in primary care allow assessment of compliance of pediatricians and implementation of what is learned in courses developed in continuing medical education. Informed reassurance and availability of FPs are more useful than over-the-counter drugs, which are often used for FGIDs.

Background: The prognostic value of changes in paraprotein markers after stem cell transplantation is unknown. We evaluated disease response using serum immunofixation (s-IFIX), total kappa and lambda ratio (KLR), and free light chain (FLC) ratio in myeloma patients who underwent autologous or autologous plus allogeneic stem cell transplantation., Methods: We studied s-IFIX, KLR, and FLC ratio in sera from 203 patients, 3 months after transplantation. We evaluated overall and event-free survival (OS and EFS, interval between date of study enrollment and date of death from any cause or date of progression, relapse, or death from any cause, respectively) by the Kaplan-Meier method., Results: Of the 203 patients, 51 were negative by s-IFIX, 99 reached a normal KLR, and 92 had a normal FLC ratio. Of the 51 patients with negative s-IFIX, 40 (78%) also had a normal FLC ratio. The median duration of OS was 54.3 months, and the median EFS was 19.5 months. None of the measured paraprotein parameters showed an association with OS. Only a normal KLR was associated with prolonged EFS (P = 0.016). Even a negative s-IFIX associated with a normal FLC ratio did not show a significant difference in terms of EFS and OS., Conclusions: Our analysis with a small cohort of patients did not show a significant impact of achieving complete response (CR) or stringent CR on patient survival.

Estrogen receptors (ER) are routinely measured in tissue extracts from breast cancer using a radioligand binding assay (RBA) and an enzyme immunoassay (EIA). Although good correlation was found between the two methods, they are expected to measure, at least in part, different ER amounts in individual samples, because the RBA should detect unfilled ER only, whereas EIA should recognize both unfilled receptors and those filled by endogenous estrogens. The purpose of the present investigation was to evaluate if ER-EIA mainly detects ER filled by endogenous estrogens when using an estrogen-free buffer to dilute cytosol samples. Indeed, the commercially available EIA assay kit (ER-EIA; Abbott) is equipped with a sample dilution buffer containing a high concentration of 17beta-estradiol which should allow for the saturation of all the ERs. ER was measured in 57 cytosol samples from primary breast cancer with RBA and ER-EIA. In the latter case, samples were diluted using both the estradiol-rich dilution buffer of the kit and an estrogen-free low salt phosphate buffer. RBA and ER-EIA showed tightly correlated results. However, ER-EIA detected higher ER levels than RBA in the majority of cases. Results obtained by low salt ER-EIA were also correlated to both RBA and ER-EIA, showing, however, lower ER concentrations. ER levels measured by ER-EIA were not significantly different from the sum of ER concentrations found by RBA and low salt ER-EIA. These findings suggest that ER-EIA detects ER only in the conformational status that is achieved after saturation by estrogens. These findings were confirmed by sedimentation shift experiments, which showed that the monoclonal antibody D547 used in the kit binds ER in the occupied form only. This leads to the conclusion that ER-EIA detects functioning (in terms of binding with estradiol) ERs. From the present investigation, we suggest that it is possible and probably worthwhile to optimize the EIA method by using different buffers to measure: (a) the total number of ERs capable of binding estradiol; (b) the ER filled by endogenous estrogens; and (c) by difference, the unfilled ER concentrations.