Mogamulizumab, a humanized defucosylated anti-C-C chemokine receptor 4 monoclonal antibody, has been approved in Japan for the treatment of C-C chemokine receptor 4-positive adult T-cell leukemia/lymphoma (ATL). This phase II study evaluated efficacy and safety of mogamulizumab in ATL patients with acute, lymphoma, and chronic subtypes with relapsed/refractory, aggressive disease in the US, Europe, and Latin America. With stratification by subtype, patients were randomized 2:1 to intravenous mogamulizumab 1.0 mg/kg once weekly for 4 weeks and biweekly thereafter (n=47) or investigator’s choice of chemotherapy (n=24). The primary end point was confirmed overall response rate (cORR) confirmed on a subsequent assessment at 8 weeks by blinded independent review. ORR was 11% (95%CI: 4-23%) and 0% (95%CI: 0-14%) in the mogamulizumab and chemotherapy arms, respectively. Best response was 28% and 8% in the respective arms. The observed hazard ratio for progression-free survival was 0.71 (95%CI: 0.41-1.21) and, after post hoc adjustment for performance status imbalance, 0.57 (95%CI: 0.337-0.983). The most frequent treatment-related adverse (grade ≥3) events with mogamulizumab were infusion-related reaction and thrombocytopenia (each 9%). Relapsed/refractory ATL is an aggressive, poor prognosis disease with a high unmet need. Investigator’s choice chemotherapy did not result in tumor response in this trial; however, mogamulizumab treatment resulted in 11% cORR, with a tolerable safety profile.
PURPOSE: Patients with advanced cancer often have a poor understanding of cancer incurability, which correlates with more aggressive treatment near the end of life (EOL). We sought to determine whether training oncologists to elicit patient values for goals-of-care (GoC) discussions will increase and improve these discussions. We explored its impact on use of aggressive care at EOL. METHODS: We enrolled and used block randomization to assign 92% of solid tumor oncologists to 2-hour communication skills training and four coaching sessions. We surveyed 265 patient with newly diagnosed advanced cancer with < 2-year life expectancy at baseline and 6 months. We assessed prevalence and quality of GoC communication, change in communication skills, and use of aggressive care in the last month of life. RESULTS: Intervention (INT) oncologists’ (n = 11) skill to elicit patient values increased (27%-55%), while usual care (UC) oncologists’ (n = 11) skill did not (9%-0%; P = .01). Forty-eight percent (n = 74) INT v 51% (n = 56) UC patients reported a GoC discussion ( P = .61). There was no difference in the prevalence or quality of GoC communication between groups (global odds ratio, 0.84; 95% CI, 0.57 to 1.23). Within 6 months, there was no difference in deaths (18 INT v 16 UC; P = .51), mean hospitalizations (0.47 INT v 0.42 UC; P = .63), intensive care unit admissions (5% INT v 9% UC; P = .65), or chemotherapy (26% INT v 16% UC; P = .39). CONCLUSION: Use of a coaching model focused on teaching oncologists to elicit patient values improved that skill but did not increase prevalence or quality of GoC discussions among patients with advanced cancer. There was no impact on high care utilization at EOL.
Experiments were performed to determine the function of a 28-nucleotide untranslated sequence lying between the envelope gene and the polypurine tract (PPT) sequence in the Moloney murine leukemia virus (Mo-MuLV) genome. A mutant virus carrying a deletion of this sequence (Mo-MuLV⌬28) replicated more slowly than wild-type (wt) virus and reverted by recombination with endogenous sequences during growth in NIH 3T3 cells. We show that this deletion did not affect the level of viral protein expression or genomic RNA packaging. Mo-MuLV⌬28 served as a helper virus as efficiently as the wt virus; in contrast, a retroviral vector harboring this mutation exhibited reduced transduction efficiency, indicating that the mutation acts not in trans but in cis. Analysis of acutely infected cells revealed that reduced levels of viral DNA were generated by reverse transcription of the Mo-MuLV⌬28 RNA as compared to the wt RNA. Analysis of DNA circle junctions revealed that plus-strand DNA of Mo-MuLV⌬28 but not wt virus often retained the PPT and additional upstream sequences. These structures suggest that aberrant 5 ends of plus-strand DNA were generated by a failure to remove the PPT RNA primer and/or by mispriming at sites upstream of the PPT. These data demonstrate that the major role of the sequences immediately upstream of the PPT is specifying efficient and accurate plus-strand DNA synthesis.Retroviruses convert their single-stranded genomic RNA into a double-stranded DNA molecule in a complex reaction mediated by the viral reverse transcriptase (RT) (for a general review, see reference 41). The synthesis of each DNA strand is initiated by a specific RNA primer: the minus strand is initiated by a primer tRNA taken from the host, while the plus strand is initiated by a polypurine oligonucleotide formed by the RNase H activity of RT acting on the RNA genome. The site of priming of both DNA strands must be accurate because these positions determine the 5Ј ends of the completed doublestranded viral DNA; these termini, in turn, are recognized by the viral integrase and serve as its substrate in the formation of the integrated provirus. Thus, mispriming would lead to incorrect sequences at the termini of the viral DNA, resulting in a block to DNA integration and further virus replication.The site of initiation of the plus-strand DNA, the polypurine tract (PPT), lies near the 3Ј end of the genomic RNA. The PPT elements of different retroviruses and retroelements exhibit considerable sequence variation but always include a stretch of 10 to 20 purines, often flanked on the 5Ј side by a T-rich block (20, 32, 33). As minus-strand DNA synthesis proceeds, the RNA genome enters into an RNA:DNA hybrid, and so the RNA becomes susceptible to the RNase H activity of RT. The PPT is relatively resistant to digestion, persisting as an oligonucleotide that remains bound to the minus-strand DNA, and is extended by RT to form plus-strand DNA. Elongation first copies the U3, R, and U5 sequences of the minus strand to form an intermediate called plus...
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.