THC2, an autosomal-dominant thrombocytopenia described so far in only two families, has been ascribed to mutations in MASTL or ACBD5. Here, we show that ANKRD26, another gene within the THC2 locus, ...and neither MASTL nor ACBD5, is mutated in eight unrelated families. ANKRD26 was also found to be mutated in the family previously reported to have an ACBD5 mutation. We identified six different ANKRD26 mutations, which were clustered in a highly conserved 19 bp sequence located in the 5′ untranslated region. Mutations were not detected in 500 controls and are absent from the 1000 Genomes database. Available data from an animal model and Dr. Watson's genome give evidence against haploinsufficiency as the pathogenetic mechanism for ANKRD26-mediated thrombocytopenia. The luciferase reporter assay suggests that these 5′ UTR mutations might enhance ANKRD26 expression. ANKRD26 is the ancestor of a family of primate-specific genes termed POTE, which have been recently identified as a family of proapoptotic proteins. Dysregulation of apoptosis might therefore be the pathogenetic mechanism, as demonstrated for another thrombocytopenia, THC4. Further investigation is needed to provide evidence supporting this hypothesis.
PALETTE is a phase 3 trial that demonstrated single-agent activity of pazopanib in advanced soft tissue sarcomas (aSTS). We performed retrospective subgroup analyses to explore potential ...relationships between patient characteristics, prior lines of therapy, dose intensity, and dose modifications on safety and efficacy of pazopanib in aSTS.
PALETTE compared pazopanib with placebo in patients with aSTS (age ≥ 18 years) whose disease had progressed during or following prior chemotherapy. In these subgroup analyses, median progression-free survival (mPFS) among patients receiving pazopanib was the efficacy outcome of interest. Adverse events (AEs) were also compared within subgroups. All analyses were descriptive and exploratory.
A total of 246 patients received pazopanib in the PALETTE study. The mPFS was longer in patients who had only 1 prior line versus 2+ prior lines of therapy (24.7 vs 18.9 weeks, respectively); AE rates were similar regardless of number of prior lines of therapy. The mPFS was similar in patients aged < 65 and ≥ 65 y (20.0 and 20.1 weeks, respectively). Although AEs leading to study discontinuation were higher in older patients (≥65 y, 30%; < 65 y, 17%), rates of dose reductions, dose interruptions, and serious AEs were similar between the 2 age groups. No reduction in mPFS was noted in patients requiring dose reductions or dose interruptions to manage toxicities.
Longer mPFS was observed in patients receiving pazopanib following only 1 line of therapy. Additionally, mPFS with pazopanib was maintained regardless of patient age or dose modifications used to manage toxicity.
NCT00753688 , first posted September 16, 2008 (registered prospectively).
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
RECORD-4 assessed everolimus in patients with metastatic renal cell carcinoma (mRCC) who progressed after 1 prior anti-vascular endothelial growth factor (VEGF) or cytokine and reinforced the ...clinical benefit of second-line everolimus. Because of the high percentage of patients from China enrolled in RECORD-4 (41%) and some reported differences in responses to certain targeted agents between Chinese and Western patients, this subanalysis evaluated outcomes in Asian versus non-Asian patients.
RECORD-4 enrolled patients with clear cell mRCC into 3 cohorts based on prior first-line therapy: sunitinib, other anti-VEGF (sorafenib, bevacizumab, pazopanib, other), or cytokines. Patients received everolimus 10 mg/d until progression of disease (RECIST, v1.0) or intolerance. Primary end point was progression-free survival per investigator review. Data cutoff was Sept 1, 2014.
Among Asian (n = 55) versus non-Asian (n = 79) patients, 98% versus 84% had good/intermediate MSKCC prognosis; 73% versus 65% were men, and 85% versus 73% were < 65 years of age. All (100%) Asian patients were of Chinese ethnicity. Median duration of exposure was 5.5 mo for Asian and 6.0 mo for non-Asian patients. Among Asian versus non-Asian patients, median progression-free survival (months) was 7.4 versus 7.8 overall, 7.4 versus 4.0 with prior sunitinib, and 5.7 versus 9.2 with prior other anti-VEGFs. Clinical benefit rate was similar between populations: 74.5% (95% CI 61.0-85.3) for Asian patients and 74.7% (95% CI 63.6-83.8) for non-Asian patients. Most patients achieved stable disease as best overall response (Asian, 63.6%; non-Asian, 69.6%). Overall rate of grade 3/4 adverse events appeared similar for Asian (58%) and non-Asian patients (54%).
This RECORD-4 subanalysis demonstrated comparable efficacy and adverse event profiles of second-line everolimus in Asian and non-Asian patients. Efficacy and safety outcomes by prior therapy should be interpreted with caution because of small patient numbers in some subpopulations.
Everolimus as Second-line Therapy in Metastatic Renal Cell. Carcinoma (RECORD-4); ClinicalTrials.gov identifier: NCT01491672 . Registration date: December 14, 2011.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Cell fusion induced by polyethylene glycol (PEG) is an efficient but poorly controlled procedure for obtaining somatic cell hybrids used in gene mapping, monoclonal antibody production, and tumour ...immunotherapy. Genetic selection techniques and fluorescent cell sorting are usually employed to isolate cell fusion products, but both procedures have several drawbacks.
Here we describe a simple improvement in PEG-mediated cell fusion that was obtained by modifying the standard single-step procedure. We found that the use of two PEG undertreatments obtains a better yield of cell fusion products than the standard method, and most of these products are bi- or trinucleated polykaryocytes. Fusion rate was quantified using fluorescent cell staining microscopy. We used this improved cell fusion and cell isolation method to compare giant cells obtained in vitro and giant cells obtained in vivo from patients with Hodgkin's disease and erythroleukemia.
In the present study we show how to improve PEG-mediated cell fusion and that cell separation by velocity sedimentation offers a simple alternative for the efficient purification of cell fusion products and to investigate giant cell formation in tumor development.
e23008
Background: Social media has revolutionized scientific communication to extend engagement beyond peer-reviewed publications and traditional media channels. Hashtags (#) promote awareness of ...key topics and enable tracking of social media engagement (Katz et al. JAMA Oncol. 2016;2(3):392-4). We evaluated the utilization of Diversity, Equity, and Inclusion (#DEI) hashtags around large oncology meetings to describe the trends of DEI-focused social media conversations. Methods: Using Symplur Signals healthcare analytics on Twitter data, 5 dashboards with # datasets (#ASCO 18-22, #AACR 18-22, #ASH 18-22, #ASHDEI) were analyzed over 2018–2022. Data were then refined by content word filters (most used DEI hashtags: #cancerdisparities, #healthdisparities, #healthequity). Utilizing proprietary natural language processing combined with artificial intelligence, the Netbase Quid platform used a Boolean algorithm to collect ASCO DEI social media data (Twitter and others) to identify discussion themes between January 2021 – January 2023. Results: Use of the ASCO hashtag resulted in high and relatively stable social media activity from 2018-2022 (Table). In contrast, a major decline in both the DEI and DEI+ASCO hashtags occurred in 2022 after the peak in 2021 (Table). The peak use of DEI hashtags coincided with sentinel events in the US, including the deaths of George Floyd and Breonna Taylor and subsequent public protests. However, DEI conversations made up only 2% of ASCO’s social media conversations and accounted for far less for American Society of Hematology (ASH) and American Association for Cancer Research (AACR) (Table). Although smaller in number, AACR hashtags (#AACR, +DEI hashtags) were stable in 2021-22 compared with ASCO and ASH, coinciding with a dedicated conference focus on DEI topics during the AACR meeting. Conclusions: In general, oncology-associated Twitter activity appeared to be less frequent, possibly due to inconsistent use of DEI hashtags. To generate consistent and searchable DEI social media activity—and to communicate the outcomes of DEI initiatives—the oncology community should develop a lexicon of DEI hashtags. Table: see text
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4574
Background: COMPARZ was a randomized, controlled, open-label, phase 3 trial that demonstrated comparable efficacy of first-line PAZ and SUN, but favorable safety and quality of ...life profiles for PAZ in patients (pts) with mRCC (NEJM 2013;369:722). We evaluated the relationship between dosing, safety, and efficacy in PAZ- and SUN-treated pts who did or did not undergo dose reduction or interruption resulting from adverse events (AEs) and other reasons. Methods: The AEs and median progression-free survival (mPFS) of PAZ and SUN were evaluated for pts with no, any, 1, and ≥2 dose reductions or dose interruptions lasting ≥7 days. Results: Similar percentages of pts in the PAZ and SUN groups had a dose interruption (44% vs 49%, respectively) or reduction (44% and 51%, respectively). The incidence of AEs in pts from the PAZ and SUN groups with dose modifications was higher compared to those with no dose modifications. Longer mPFS was observed in pts with dose modification (Table). Pts treated with PAZ or SUN with no dose reductions had mPFS of 7.3 months (mos) and 5.5 mos, respectively, whereas pts with any dose reduction had mPFS of 12.5 mos and 13.8 mos, respectively. Similarly, pts treated with PAZ or SUN with no dose interruptions lasting ≥7 days had mPFS of 8.2 mos and 5.6 mos, respectively, whereas those with any dose interruption lasting ≥7 days had mPFS of 12.6 mos and 13.8 mos, respectively. Pts with 2 or more dose interruptions or reductions had mPFS > 16 mos with both SUN and PAZ. Conclusions: Consistent with previous data for SUN, the current analyses showed longer mPFS with PAZ and SUN when dose modification is required to manage toxicity, suggesting that pts are not disadvantaged by such dose reductions or interruptions. Pts not requiring dose modification may have sub-optimal therapeutic drug exposure. Clinical trial information: NCT00720941. Table: see text
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648
Background: EVE following failure of sorafenib or sunitinib for RCC was first approved by the FDA in 2009. CATChEz (NCT01545817) was designed to test the activity of EVE following ...first-line PAZ in pts with advanced or metastatic RCC who had not received prior systemic therapy. Methods: From 2012 to 2016, pts received first-line PAZ followed by EVE until progressive disease (PD), death, unacceptable toxicity, consent withdrawal, or study termination. Pts with PD during or within 6 months of stopping PAZ were eligible for EVE. Pts off study treatment were evaluated for PD, survival, and updates on anticancer treatment every 8 weeks until death or end of study. The primary efficacy endpoint was median progression-free survival (mPFS) for the second-line EVE treatment period; secondary endpoints included other survival measures, and safety evaluations were for second-line EVE and grade 3/4 toxicities attributable to PAZ and EVE. Results: Of 74 pts who started first-line PAZ, 38 received ≥1 dose of second-line EVE. The primary endpoint of mPFS from the start of second-line EVE and the secondary endpoint of mPFS with first-line PAZ (Table) were consistent with previous reports; no unexpected adverse events (AEs) were reported. All pts had ≥1 treatment-emergent AE, 83.8% had grade ≥3 AEs, and 71.6% had serious AEs. Of 34 total deaths, 29 were due to PD and 5 were due to AEs (2 related to EVE lower respiratory tract infection; pulmonary sepsis; 3 unrelated to study treatment). Conclusions: Efficacy and safety outcomes were consistent with published phase III data. The CATChEz study supports sequential first-line use of PAZ followed by EVE for the treatment of pts with advanced or metastatic RCC. Clinical trial information: NCT01545817. Table: see text
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4572
Background: COMPARZ (NCT00720941) was a phase 3, randomized, controlled, open-label trial that demonstrated comparable efficacy of first-line PAZ and SUN, but favorable safety and ...quality of life profiles for PAZ in 1110 patients with mRCC (NEJM 2013;369:722). The objectives of this study were to identify patients from COMPARZ who exhibited a long-term response (LTR) to PAZ and SUN, determine time to response, and describe the clinical characteristics of patients who achieved LTR. Methods: Patients in the intention-to-treat population of COMPARZ were analyzed for differences in LTR (≥10 months mos) as measured by responder rate with either complete response or partial response (CR/PR) and PFS rate, and time to response. We also compared the clinical characteristics between long-term and shorter-term responders within and between each treatment arm. Results: The overall percentage of long-term responders with CR/PR (PAZ = 14%, SUN = 13%) and PFS (PAZ = 31.4%, SUN = 33.6%) in the PAZ and SUN groups were similar. This similarity was observed regardless of the cut-off for long-term duration of response. However, a shorter time to achieve CR/PR was observed in the overall population with PAZ (11.9 weeks 95% CI, 11.3–12.1 vs 17.4 weeks; 95% CI, 12.7–18.0). Analysis conducted to identify baseline clinical characteristics that may be related to LTR will be reported. Conclusions: These exploratory subanalyses in long-term responders support the overall efficacy results with PAZ and SUN, which were reported in the COMPARZ trial. However, the results here demonstrate that the time to response was shorter with PAZ versus SUN. Clinical trial information: NCT00720941.
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