In a previous study the authors found that dendritic spine density was reduced on prefrontal pyramidal neurons in layer 3 of subjects with schizophrenia. From a neural circuitry perspective, ...understanding the pathophysiological significance of this finding requires knowledge of whether pyramidal neurons in other cortical layers are similarly affected. The authors' goal was to determine whether their finding in layer 3 was also present in other cortical layers in the same group of subjects with schizophrenia.
Spine density and other dendritic measures were made for pyramidal neurons in layers 5 and 6 of prefrontal area 46 in the brains of deceased subjects with schizophrenia, subjects with other psychiatric disorders, and normal comparison subjects.
None of the dendritic measures for layer 5 or 6 pyramidal neurons differed across the subject groups, but the within-subject differences in spine density between deep layer 3 and layer 5 or 6 pyramidal neurons were significantly greater in the patients with schizophrenia than in the comparison subjects.
These findings are consistent with the idea that prefrontal pyramidal neurons involved in corticocortical and/or thalamocortical connections are preferentially affected in schizophrenia.
We determined the prognostic relevance of CD25 (IL-2 receptor-α) expression in 657 patients (≤ 60 years) with de novo acute myeloid leukemia (AML) treated in the Eastern Cooperative Oncology Group ...trial, E1900. We identified CD25POS myeloblasts in 87 patients (13%), of whom 92% had intermediate-risk cytogenetics. CD25 expression correlated with expression of stem cell antigen CD123. In multivariate analysis, controlled for prognostic baseline characteristics and daunorubicin dose, CD25POS patients had inferior complete remission rates (P = .0005) and overall survival (P < .0001) compared with CD25NEG cases. In a subset of 396 patients, we integrated CD25 expression with somatic mutation status to determine whether CD25 impacted outcome independent of prognostic mutations. CD25 was positively correlated with internal tandem duplications in FLT3 (FLT3-ITD), DNMT3A, and NPM1 mutations. The adverse prognostic impact of FLT3-ITDPOS AML was restricted to CD25POS patients. CD25 expression improved AML prognostication independent of integrated, cytogenetic and mutational data, such that it reallocated 11% of patients with intermediate-risk disease to the unfavorable-risk group. Gene expression analysis revealed that CD25POS status correlated with the expression of previously reported leukemia stem cell signatures. We conclude that CD25POS status provides prognostic relevance in AML independent of known biomarkers and is correlated with stem cell gene-expression signatures associated with adverse outcome in AML.
Although randomized controlled clinical trials are optimal to evaluate the effect of an experimental therapy, single-arm trials are required whenever randomization is unethical or not feasible, such ...as de-escalation studies. We propose using prospectively identified historical controls to place results of single-arm, de-escalation trials into context.
POSITIVE is a prospective, single-arm study in young women with hormone-receptor-positive early breast cancer to determine if temporarily interrupting adjuvant endocrine therapy in order to become pregnant increases the risk of a breast cancer event. After 272 women enrolled in POSITIVE, we identified a cohort of 1499 SOFT/TEXT patients potentially eligible to enroll in POSITIVE who did not interrupt endocrine therapy. Method I used the SOFT/TEXT cohort to calculate annualized hazard rates by a piecewise exponential model. Method II used the SOFT/TEXT cohort to group-match SOFT/TEXT patients to POSITIVE patients; sample sets of SOFT/TEXT patients were randomly drawn 5000 times to obtain sets having patient, disease, and treatment characteristics more balanced with POSITIVE participants.
Compared with SOFT/TEXT, POSITIVE participants were younger, less likely to be overweight/obese, had fewer positive nodes, and fewer received aromatase inhibitor or chemotherapy. The estimated 3-year breast cancer free interval event rates were 9.5% (95% CI: 7.9%,11.1%) for Method I and 9.4% (95% CI: 7.8%,10.9%) for Method II, compared with 5.8% initially assumed when POSITIVE was designed.
External control datasets should be identified before launching single-arm, de-escalation trials and methods applied during their conduct to provide context for interim monitoring and interpretation of the final analysis.
•Prospective identification of external historical controls for single-arm studies.•Statistical methods for estimating historical control rates for single-arm studies.•Methods applied for interim monitoring and final analysis of the POSITIVE study.
Dysfunction of inhibitory neurons in the prefrontal cortex (PFC), represented by decreased expression of GABA-related genes such as the 67 kDa isoform of glutamate decarboxylase (GAD67) and ...parvalbumin (PV), appears to contribute to cognitive deficits in subjects with schizophrenia. We investigated the involvement of signaling mediated by brain-derived neurotrophic factor (BDNF) and its receptor tyrosine kinase TrkB in producing the altered GABA-related gene expression in schizophrenia. In 15 pairs of subjects with schizophrenia and matched control subjects, both BDNF and TrkB mRNA levels, as assessed by in situ hybridization, were significantly decreased in the PFC of the subjects with schizophrenia, whereas the levels of mRNA encoding the receptor tyrosine kinase for neurotrophin-3, TrkC, were unchanged. In this cohort, within-pair changes in TrkB mRNA levels were significantly correlated with those in both GAD67 and PV mRNA levels. Decreased BDNF, TrkB, and GAD67 mRNA levels were replicated in a second cohort of 12 subject pairs. In the combined cohorts, the correlation between within-pair changes in TrkB and GAD67 mRNA levels was significantly stronger than the correlation between the changes in BDNF and GAD67 mRNA levels. Neither BDNF nor TrkB mRNA levels were changed in the PFC of monkeys after a long-term exposure to haloperidol. Genetically introduced decreases in TrkB expression, but not in BDNF expression, also resulted in decreased GAD67 and PV mRNA levels in the PFC of adult mice; in addition, the cellular pattern of altered GAD67 mRNA expression paralleled that present in schizophrenia. Decreased TrkB signaling appears to underlie the dysfunction of inhibitory neurons in the PFC of subjects with schizophrenia.
IntroductionThere is a strong theoretical rationale for combining checkpoint blockade with cytotoxic chemotherapy in pleural mesothelioma and other cancers. Two recent single-arm, phase 2 trials ...DuRvalumab with chEmotherapy as first-line treAtment in advanced pleural Mesothelioma (DREAM) and Phase II multicenter study of anti-PD-L1, durvalumab, in combination with cisplatin and pemetrexed for the first-line treatment of unresectable malignant pleural mesothelioma (PrE0505) combining the programmed death ligand-1 (PD-L1) inhibitor durvalumab with standard first-line chemotherapy exceeded prespecified safety and activity criteria to proceed to a phase 3 confirmatory trial to assess this combination. We present the protocol of the DREAM3R trial.Methods and analysisThis multicentre open-label randomised trial will recruit 480 treatment-naïve adults with advanced pleural mesothelioma, randomised (2:1) to either 3-weekly durvalumab 1500 mg plus 3-weekly doublet chemotherapy (cisplatin 75 mg/m2 or carboplatin, Area Under the Curve,AUC 5 and pemetrexed 500 mg/m2) 4–6 cycles, followed by 4-weekly durvalumab 1500 mg until disease progression, unacceptable toxicity or patient withdrawal; OR doublet chemotherapy alone for 4–6 cycles, followed by observation. The target accrual time is 27 months, with follow-up for an additional 24 months. This provides over 85% power if the true HR for overall survival (OS) is 0.70, with two-sided alpha of 0.05, assuming a median OS of 15 months in the control group. Randomisation is stratified by age (18–70 years vs >70), sex, histology (epithelioid vs non-epithelioid), platinum agent (cisplatin vs carboplatin) and region (USA vs Australia/New Zealand vs Other). The primary endpoint is OS. Secondary endpoints include progression-free survival, objective tumour response (by mRECIST V.1.1 and iRECIST), adverse events, health-related quality of life and healthcare resource use. Tertiary correlative objectives are to explore and validate potential prognostic and/or predictive biomarkers (including features identified in the DuRvalumab with chEmotherapy as first-line treAtment in advanced pleural Mesothelioma (DREAM) and PrE0505 studies, PD-L1 expression, tumour mutational burden, genomic characteristics and human leukocyte antigen subtypes) in tissue and serial blood samples. An imaging databank will be assembled for validation of radiological measures of response, and studies of possible radiomic biomarkers in mesothelioma.Ethics and disseminationThe protocol was approved by human research ethics review committees for all participating sites. Results will be disseminated in peer-reviewed journals and at scientific conferences.Drug SupplyAstraZeneca.Protocol versionCTC 0231 / TOGA 18/001 / PrE0506 3.0, 29 July 2021.Trial registration numberClinicalTrials.gov Identifier: NCT04334759 ACTRN 12620001199909.
Summary
The revised International Prognostic Scoring System (IPSS‐R) was developed in a cohort of untreated myelodysplastic syndromes (MDS) patients. A French Prognostic Scoring System (FPSS) was ...recently reported to identify differential survival among azacitidine‐treated patients with high‐risk MDS. We applied the FPSS and IPSS‐R to 150 patients previously randomized to azacitidine monotherapy or a combination of azacitidine with entinostat (a histone deacetylase inhibitor). Neither score predicted response but both discriminated patients with different overall survival (OS; median OS, FPSS: 9·7, 14·7, and 25·3 months, P = 0·018; IPSS‐R: 12·5, 11·3, 20·8, and 36 months, P = 0·005). Statistical analysis suggested no improvement in OS prediction for the FPSS over the IPSS‐R in azacitidine‐treated patients.
We report the results of a prospective, randomized phase 3 trial evaluating the use of gemtuzumab ozogamicin (GO) in an intensive consolidation approach in 657 patients 17-60 years of age. Patients ...in first complete remission (CR1) after cytarabine and standard- or high-dose daunorubicin induction received 2 cycles of consolidation with high-dose cytarabine followed by peripheral blood progenitor cell collection. The 352 patients who entered consolidation were randomized to receive GO (n = 132) or not (n = 138) and then proceeded to autologous hematopoietic cell transplantation (HCT). GO was given to 67 patients. Median follow-up was 50.9 months. Results of the intention-to-treat analysis demonstrated a 4-year disease-free survival (DFS) of 33.6% versus 35.9% (P = .54) and an overall survival (OS) of 41.3% versus 41.9% (P = .52) for those randomized to receive GO versus no GO, respectively. Patients with favorable- and intermediate-risk acute myeloid leukemia (AML) treated with high-dose daunorubicin and autologous HCT had 4-year DFS rates of 60% and 40% and OS rates of 80% and 49.3%, respectively. For younger AML patients in CR1, autologous HCT should be considered in favorable- and intermediate-cytogenetic risk patients who do not have an allogeneic donor. The addition of a single dose of GO in this setting did not improve outcomes. This trial is registered at http://www.clinicaltrials.gov as NCT00049517.
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Background: Relapse remains the most common cause of treatment failure after intensive induction and consolidation (CONS) therapy in older adults with AML. We therefore performed a prospective ...randomized phase II study to determine the safety and impact on DFS (relapse or death) and OS of DAC maintenance using an abbreviated 3-day schedule administered every 4 weeks for 1 year (per Lubbert et al, Haematologica 97:393, 2012) vs. Observation (OBS) after intensive AML therapy, conducted in the large multi-center E-A E2906 Phase III trial in patients (pts) age ≥60 yrs.
Methods: The design and primary clinical results for E2906 (n=727) have been reported previously (Foran et al, ASH #217a, 2015), demonstrating superior OS following ‘Standard’ 7&3 (Daunorubicin 60mg/m2) induction and intermediate dose Ara-C consolidation (CONS) vs. single agent Clofarabine (CLO, provided by SANOFI), despite similar CR/CRi (CR with incomplete CBC recovery) and induction mortality rates. All CR/CRi pts after induction (n=311) were assigned to 2 cycles CONS with either Ara-C (1.5g/m2 x 12 doses; 6 doses if age >/=70 yrs), or single agent CLO, based on induction randomization.
Ongoing CR/CRi after recovery from CONS was confirmed with restaging BM biopsy, and eligible pts offered participation in the ‘Step 3‘ maintenance study, a 1:1 randomization (stratified by induction therapy, cytogenetic risk group, age <70 yrs) to either OBS vs. DAC (20mg/m2IV Days 1-3, q4 wks) for 1 year. DAC could be held for up to 4 weeks for delayed hematologic recovery, but dose reductions were not permitted per protocol, and DAC was not continued beyond 12 months. Patients in both arms were evaluated with CBC q4 weeks for 1 year, and surveillance BM biopsy every 3 months (or at the time of suspected clinical relapse) for 2 years.
'Step 3' was designed as a phase II pilot randomized study, with target accrual n=172, allowing 90% power to detect 36% reduction in DFS Hazard Ratio (HR) with DAC maintenance for 1 year (using protocol-specified 1-sided log-rank test significance level of 0.1), assuming 140 events & 2 years of follow-up from randomization. However, further accrual to E2906 was suspended in 2/2015 by independent DSMC due to superior OS observed with standard Arm, so that 'Step 3' completed only 70% of target accrual. P-values reported are two-sided by convention unless specified otherwise.
Results: 'Step 3' total accrual was n=120 (of 172 planned) (DAC 61, OBS 59), with median age 69 yrs (range 60-85), and groups were very well balanced for baseline clinical characteristics; most pts had Intermediate risk cytogenetics (74.2%) and ECOG performance status (PS)=0/1 (96%). The median number of DAC cycles received was 6 (range 0-13), and analysis was 'intention-to-treat'. The median follow-up is 49.8 months. There were 90 DFS events (47 OBS, 43 DAC), with 82 deaths (46 OBS, 36 DAC). Univariate DFS and OS are shown in Figure, with associated two-sided p-values; using protocol-prespecified one-sided significance level of 0.1, OS was significant (one-sided p=0.06) for DAC v. OBS, and there was a statistical trend favoring DFS (one-sided p=0.11), particularly for CLO pts (Table).
We also performed multivariate Cox model (after adjustment for ECOG PS, sex, secondary AML, and baseline hematologic parameters) which confirmed superior HR for DFS (one-sided p=0.10) & OS (one-sided p=0.07), per statistical design.
FLT3-ITD status is available for n=96 pts, and 84 were FLT3-ITD-negative (46 OBS, 38 DAC). Importantly, we observed a significant association of DAC maintenance with superior OS in the large FLT3-ITD-neg subgroup (p=0.039) (Figure).
DAC was generally well tolerated apart from grade 3 febrile neutropenia (9%) and reversible grade 4 cytopenias, with no grade 5 events.
Conclusions: In this randomized phase II study, DAC maintenance for 1 year after intensive AML therapy was associated with improved HR for OS and a trend for DFS, using protocol-specified statistical design. Furthermore there was a significant impact on OS for the FLT3-ITD-negative population. We acknowledge limitations based on incomplete accrual due to early termination of the parent E2906 study, and inherent to the phase 2 design of this E2906 endpoint, but results suggest an important impact of DAC maintenance on survival. These data strongly support a definitive phase III randomized study of DAC maintenance, particularly focused on the large intermediate risk FLT3-ITD-negative subgroup.
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Foran:Agios: Honoraria, Research Funding. Claxton:Daiichi Sankyo Co. and Ambit Biosciences Corp, Astellas Pharma, Novartis Pharmaceuticals, Incyte Corporation, Cyclacel Pharmaceuticals, Inc, Celegene Corporation, Medimmune, Inc, Merck Sharp & Dohme Corp., Gilead Sciences, Inc.: Research Funding. Lazarus:Pluristem Therapeutics, Inc: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Speakers Bureau; Genentech: Speakers Bureau; Biosight: Membership on an entity's Board of Directors or advisory committees; Actinium Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau; Adaptive Biotechnologies: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria, Speakers Bureau; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AstraZeneca: Honoraria, Speakers Bureau; Teva Pharmaceuticals: Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CSL Behring: Consultancy. Rowe:BioSight: Consultancy. Altman:Cancer Expert Now: Consultancy; Glycomimetics: Consultancy, Honoraria, Other: Data Safety and Monitoring Committee; prIME Oncology: Speakers Bureau; PeerView: Speakers Bureau; Agios: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Theradex: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; France Foundation: Speakers Bureau; Daiichi Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Biosight: Other: US Lead. Luger:Ariad: Research Funding; Agios: Honoraria; Biosight: Research Funding; Seattle Genetics: Research Funding; Pfizer: Honoraria; Onconova: Research Funding; Kura: Research Funding; Jazz: Honoraria; Genetech: Research Funding; Daichi Sankyo: Honoraria; Cyslacel: Research Funding; Celgene: Research Funding. Al-Kali:Astex Pharmaceuticals, Inc.: Research Funding. Zheng:Pfizer: Research Funding. Pratz:AbbVie: Consultancy, Research Funding; Agios: Consultancy, Research Funding; Millenium/Takeda: Research Funding; Boston Biomedical: Consultancy; Astellas Pharma: Consultancy, Research Funding. Powell:Jazz Pharmaceuticals: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy, Research Funding; Janssen: Research Funding; Novartis: Consultancy, Speakers Bureau; Rafael Pharmaceuticals: Consultancy, Research Funding. Tallman:Tetraphase: Consultancy, Membership on an entity's Board of Directors or advisory committees; Nohla: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Rigel: Consultancy, Membership on an entity's Board of Directors or advisory committees; Delta Fly Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Biosight: Research Funding; KAHR: Consultancy, Membership on an entity's Board of Directors or advisory committees; Orsenix: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BioLineRx: Consultancy, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Research Funding; UpToDate: Patents & Royalties; Cellerant: Research Funding; Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Oncolyze: Consultancy, Membership on an entity's Board of Directors or advisory committees.
Use of maintenance Decitabine in AML
To explore potential differences in efficacy, treatment completion, and adverse events (AEs) in elderly women receiving adjuvant tamoxifen or letrozole for five years in the Breast International ...Group (BIG) 1-98 trial.
This report includes the 4,922 patients allocated to 5 years of letrozole or tamoxifen in the BIG 1-98 trial. The median follow-up was 40.4 months. Subpopulation Treatment Effect Pattern Plot (STEPP) analysis was used to examine the patterns of differences in disease-free survival and incidences of AEs according to age. In addition, three categoric age groups were defined: "younger postmenopausal" patients were younger than 65 years (n = 3,127), "older" patients were 65 to 74 years old (n = 1,500), and "elderly" patients were 75 years of age or older (n = 295).
Efficacy results for subpopulations defined by age were similar to the overall trial results: Letrozole significantly improved disease-free survival (DFS), the primary end point, compared with tamoxifen. Elderly patients were less likely to complete trial treatment, but at rates that were similar in the two treatment groups. The incidence of bone fractures, observed more often in the letrozole group, did not differ by age. In elderly patients, letrozole had a significantly higher incidence of any grade 3 to 5 protocol-specified non-fracture AE compared with tamoxifen (P = .002), but differences were not significant for thromboembolic or cardiac AEs.
Adjuvant treatment with letrozole had superior efficacy (DFS) compared with tamoxifen in all age groups. On the basis of a small number of patients older than 75 years (6%), age per se should not unduly affect the choice of adjuvant endocrine therapy.
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