bluuebunny/crossref_metadata_2025_split huggingface dataset:
Subcutaneous injections of low doses of veltuzumab (humanized anti-CD20 antibody): Objective responses in B-cell malignancies
Authors: Allen S. L. , Rai K. R. , Elstrom R. , Negrea O. G. , Farber C. M. , Abbasi R. , Teoh N. , Horne H. , Wegener W. A. , Goldenberg D. M. 
Published: August 2020

8530 Background: Low IV doses of veltuzumab, a second-generation anti-CD20 monoclonal antibody with structure-function differences from chimeric rituximab, have shown clinical activity, thus justifying subcutaneous (SC) injections. Methods: A phase I/II study was initiated in patients (pts) with previously untreated or relapsed CD20+ indolent NHL or CLL who received 4 SC injections of veltuzumab 2 weeks apart at dose levels of 80, 160, or 320 mg. Efficacy was assessed by CT-based IWG (NHL) or hematology-based NCI/IWCLL (CLL) criteria 4 and 12 weeks later, with responding pts continuing follow-up. Other evaluations included AEs, safety laboratories, B-cell blood levels (CD19), serum veltuzumab levels, and human anti-veltuzumab antibody (HAHA) titers. Results: Nineteen pts (8M/11F, median age 63), including 14 NHL pts (11 follicular, 3 other indolent NHL; 5 treatment naive) most with stage III or IV disease (11/14) and 5 CLL pts (4 treatment naïve) all with Rai stage II or III disease, have now received SC veltuzumab at 80 mg (3 NHL, 3 CLL), 160 mg (9 NHL, 2 CLL) or 320 mg (2 NHL) dose levels. Pre-treatment with antihistamines or steroids has not been required, and SC veltuzumab was well tolerated with only mild, transient injection site reactions and tenderness. To date, all HAHA results have been negative. In NHL pts, SC veltuzumab demonstrates good bio-availability, with a slow release pattern over several days and depletion of circulating B cells starting after 1st injection. Initial response information is currently available for 10 pts. For 7 NHL pts, 4 weeks after treatment with 80 or 160 mg doses, 2 pts had partial responses, 3 pts showed stable disease, and 2 pts had disease progression. For 3 CLL pts who received 80 mg doses, serum veltuzumab levels were lower, but all pts still achieved 65–75% decreases in circulating leukemic cells over the course of treatment. Conclusions: SC administration of veltuzumab is well tolerated, achieves slow but efficient delivery into the blood, and is pharmacologically active. The low doses currently evaluated in B-cell malignancies show evidence of therapeutic activity, achieving objective responses in NHL and notable reductions in circulating leukemic cells in CLL. [Table: see text]
Use of bortezomib (BOR) pharmacogenomics (PG) to identify mechanisms of drug resistance and predict survival in multiple myeloma (MM) treated with total therapy 3 (TT3)
Authors: Shaughnessy J. D. , Qu P. , Haessler J. , Crowley J. , Barlogie B. 
Published: August 2020

8538 Background: The prognosis of patients with MM is best captured by gene expression profiling (GEP) analysis of CD138-purified plasma cells (PC), distinguishing a high-risk group of 15% with dismal survival using a 70-gene baseline risk model (BLR). Translational research in TT3 was designed to investigate whether short-term BOR-induced GEP alterations could advance our understanding of BOR's novel mechanism of action. Methods: PG studies were performed as part of two TT3 trials (TT3a, n=303; TT3b, n=177), obtaining PC prior to and 48hr after a BOR test-dose (1.0mg/m2), which was accomplished in 142 patients in TT3a (training set) and 127 in TT3b (test set). Among 1051 genes significantly altered post-BOR in TT3a, 80 were identified as being significantly associated with EFS. A continuous risk score was calculated and an optimal cut-point for EFS separation determined. The independent prognostic power of the binary risk score was tested in TT3b. Multivariate analyses (MV) were employed to determine post-BOR risk (PBR) in relationship to standard prognostic variables and BLR. Results: The discriminatory power in TT3a (3-yr OS: 95% v 45%, p<0.0001; 3-yr EFS: 90% v 35%, p<0.0001) was confirmed in TT3b (18-mo OS: 100% v 65%, p=0.0004; 18-mo EFS: 95% v 45%, p<0.0001). Evaluating PBR in the context of BLR, 12/26 in TT3a and 7/21 in TT3b deemed as having low BLR had high PBR; conversely, 8/126 in TT3a and 14/106 in TT3b deemed as having high BLR had low PBR. In the context of our 8 molecular subgroup model, high PBR was over-represented in the Proliferation (PR) subgroup (7/15 in TT3a, 8/18 in TT3b) and absent in the Low Bone disease (LB) group (0/28). On MV, PBR was an independent adverse variable for both OS and EFS in TT3a (OS: HR=3.17, p=0.006, R2=55%; EFS: HR=4.40, p<0.001, R2=48%) and in TT3b (OS: HR=13.00, p=0.002, R2=48%; EFS: HR=15.57, p<0.001, R2=55%). Proteasome genes ranked first among those differentially up-regulated by BOR. Conclusions: PG identified a powerful 80-gene PBR model with unprecedented prognosis-discriminating power, dispelling BLR from MV analysis by altering BLR designation mainly from low to high risk. High PBR (18%) could be traced to up-regulation of proteasome genes, the target of BOR. [Table: see text]
PX-171–006: Phase Ib multicenter dose escalation study of carfilzomib (CFZ) plus lenalidomide (LEN) and low-dose dexamethasone (loDex) in relapsed and refractory multiple myeloma (MM): Preliminary results
Authors: Niesvizky R. , Bensinger W. , Vallone M. , Gutierrez A. , Kunkel L. 
Published: August 2020

8541 Background: CFZ is a highly specific proteasome inhibitor with single agent activity in relapsed/refractory MM (ASH 2008). The purpose of this study is to evaluate the safety and activity of CFZ in combination with LEN and loDex. Methods: This phase Ib trial evaluates 4 dose levels (≥ 3 pts each) to define the maximum tolerated dose (MTD) of CFZ/LEN/loDex in relapsed/refractory MM pts who failed 1–3 prior therapies, including prior LEN or bortezomib (BTZ). CFZ IV 15- 20 mg/m2 (d1,2,8,9,15,16), LEN 10–20 mg po (d1–21) and loDex 40 mg po (d1, 8, 15, 22) in 28-day cycles (C). An additional 10–15 pts will be evaluated at the highest dose level reached. Dose limiting toxicity (DLT) has been defined as grade (G) ≥ 3 non- hematologic; G4 neutropenia for > 7d and/or neutropenic fever; G4 thrombocytopenia > 7d or G3-G4 thrombocytopenia in association with bleeding. Overall response (CR/sCR, VGPR/PR) is assessed by IWG criteria, with secondary assessment by modified EBMT criteria which includes MR. Results: 11 pts have been enrolled. 8/11 are evaluable for response and toxicity. Median prior lines of therapy was 2 (range 2–3). Prior therapies included DEX (8/8), BTZ (6/8), LEN (7/8), alkylators (6/8), anthracyclines (5/8), stem cell transplant (5/8), and thalidomide (1/8); 6/8 pts had received both LEN and BTZ. MTD has not yet been reached after the first 2 dose cohorts. No drug related SAEs or G3/4 treatment emergent AEs were reported. Responses to date with a median of 2 C (range 1–4) are shown below. Responses were rapid and occurred within the first 28-day cycle. Conclusions: CFZ/LEN/loDex in combination was well tolerated in the first 2 cohorts. There have been no myleosuppressive or renal DLTs. The combination has achieved early encouraging responses in pts who had failed both LEN and BTZ at doses well below the single agent MTD of either LEN or CFZ. Dose escalation is ongoing. Updated data will be presented at the meeting. [Table: see text] [Table: see text]
Eight cycles of BEACOPP escalated compared with 4 cycles of BEACOPP escalated followed by 4 cycles of BEACOPP baseline with or without radiotherapy in patients in advanced stage Hodgkin lymphoma (HL): Final analysis of the HD12 trial of the German Hodgkin Study Group (GHSG)
Authors: Diehl V. , Haverkamp H. , Mueller R. , Mueller-Hermelink H. , Cerny T. , Markova J. , Ho A. D. , Kanz L. , Greil R. , Engert A. 
Published: August 2020

8544 Background: The GHSG HD9 trial had established BEACOPP escalated (BE) as new standard of care for advanced-stage HL patients. The successor study, HD12, evaluated a possible reduction in toxicity by comparing 8 cycles of BE with 4 cycles BE followed by 4 cycles BB. The second question in this trial related to the need of additional radiotherapy (RT) to initial bulk and residual disease. Methods: HL patients in stage IIB with large mediastinal mass and/or E-lesions or stage III/IV were randomised according to a 2x2-factorial design between: 8BE + RT, 8BE no RT, 4BE+4BB + RT, 4BE+4BB no RT. Primary endpoint of the trial was FFTF. Between 9/1999 and 1/2003, a total of 1,670 patients aged 16–65 were randomized. For this final analysis at a median follow up of 78 months, 99 patients were excluded for various reasons resulting in 1,571 eligible patients. Results: Patient characteristics in the 4 groups were comparable. Treatment-related toxicity of WHO grade III/IV was observed in 97% of patients. Most prominent differences between pooled chemotherapy arms were anemia (65% 8BE vs 51% 4BE+4BB) and thrombopenia (65% vs 51%). Treatment outcome: complete remission 92.4%; early progression 2.2%; progression/relapse 7.8% (6.6% and 8.5%). A total of 156 (9.9%) deaths (72 vs 84) have been observed (22 vs 32 acute or salvage treatment toxicity; 15 vs 24 HL; 22 vs 13 secondary neoplasia). Most treatment related deaths occurred in the >60 years age group, the first 4 cycles and the IPS> 3 RF groups. Secondary neoplasias were observed in 77 patients (4.9%). At 5 years, OS was 91%, FFTF 85.5% and progression free survival (PFS) 86.2% (Kaplan-Meier estimates). Estimates for the difference at 5 years are 1.8% for OS, 2.3% for FFTF and 2.7% for PFS favoring BE. However, there was no statistical difference between 8x BE and 4BE+4BB in all outcome parameters (p>0.19, log rank test). There is also no significant difference between the RT or no-RT arms in this study. Conclusions: The adoption of 4BE+4BB as a new standard in the future GHSG studies will depend on a refined analysis of the total data set and will be presented. No significant financial relationships to disclose.
Pooled analyses of two international, multicenter clinical studies of romidepsin in 167 patients with cutaneous T-cell lymphoma (CTCL)
Authors: Demierre M. , Whittaker S. , Kim Y. , Kim E. , Piekarz R. , Prince M. , Nichols J. , Balser J. , Prentice A. , Bates S. 
Published: August 2020

8546 Background: Romidepsin is a novel pan-HDAC inhibitor with demonstrated single-agent activity in 2 open-label clinical studies of 167 patients (pts) with CTCL [mycosis fungoides or Sézary Syndrome (SS)]. Data for these 2 studies were pooled for more accurate estimates of endpoints and investigation of subpopulations. Methods: GPI-04–0001 (pivotal study) enrolled 96 pts with confirmed CTCL who had recieved ≥1 prior systemic therapy. NCI 1312 (supportive study) enrolled 71 pts with CTCL. Pts recieved romidepsin, 14mg/m2 as a 4-hr infusion on days 1, 8, and 15 every 28 days until disease progression (≥25% increase). The primary efficacy endpoint for both studies was overall response rate (ORR) using a composite endpoint that included skin assessment, lymph node and visceral involvement and abnormal circulating T-cells/Sézary cells. Results: 167 pts received romidepsin (as-treated); 135 pts (81%) were in the efficacy evaluable population. Mean age was 57±12 yrs, 67% men, 87% white. 103 pts (76%) had stage ≥IIB disease. Median number of prior systemic therapies was 2 (range 1–8). ORR in the table. Responses were noted in: 42% of pts with stage ≥IIB; 11 (58%) of 19 pts with SS (erythroderma + Sézary cells, >1000/ml or >20% ); and 20 (38%) of 52 pts who received prior bexarotene and 8 (40%) of 20 pts who had received denileukin diftitox. Most common drug-related adverse events (AE), all grades, included: nausea (67%), fatigue (49%), anorexia (37%), ECG T-wave changes (29%), anemia (26%), dysgeusia (23%), neutropenia (22%), leucopenia (20%). Related serious AEs in 2% of pts: supraventicular arrhythmia, ventricular arrhythmia, infection, neutropenia, WBC decreased, hyperuricemia, hypotension; all other serious AEs in ≤1 pt. 3 deaths reported as possibly related. Conclusions: Romidepsin is a valuable new therapy for pts with CTCL based on the ORR, CR, durability of response, improvement in all disease compartments and responses at all stages and in all subpopulations analyzed. [Table: see text] [Table: see text]
Application of the mantle international prognostic index (MIPI) to patients with mantle cell lymphoma treated with fludarabine/cyclophosphamide: Results from a UK NCRI Lymphoma Group study
Authors: Rule S. , Smith P. , Qian W. , Gambell J. , Curtis N. , Johnson P. , Linch D. 
Published: August 2020

8555 Background: Mantle cell lymphoma (MCL) remains an incurable malignancy with conventional chemotherapeutic options with little randomised evidence to help direct therapy. The International Prognostic Index (IPI) for diffuse large cell lymphoma or Follicular Lymphoma International Prognostic Index (FLIPI) showed poor separation of survival curves in MCL patients. A new prognostic index (MIPI) based on age, performance status, lactate dehydrogenase (LDH), and leukocyte count was developed for patients with advanced stage MCL. Data from a randomised phase II NCRI trial designed to assess the effect of adding rituximab to an all oral chemotherapy regimen has been used to validate the MIPI. Methods: Patients with advanced stage, newly diagnosed MCL were randomised to receive either oral fludarabine 40mg/m2 and cyclophosphamide 250mg/m2 daily x 3 repeated every 28 days (FC) or FC with standard dose rituximab (375mg/m2 on day 1 of every cycle) (FCR). Patients could receive up to 8 cycles of treatment but no consolidation therapy was permitted. The primary outcome measures were response rate and the feasibility of a phase III randomised study. Results: 156 patients were randomised. Median age 64 (36–88) with a significant male predominance. With median follow up of 49 months for survivors the five year overall survival (OS) is 39%. 117 patients had complete data for calculating the simplified Mantle International Prognostic Index (MIPI) .There was equal distribution between the 3 risk groups (low risk 35%, intermediate risk 33% and high risk 31%). The median OS (months) for the 3 groups is; low not reached, intermediate 55.7 and high 20.4 (p of log rank test = 0.0048). However there is no difference between the 3 groups with regard to progression free survival (p=0.31). Conclusions: This large study of patients treated with an oral purine analogue combination confirms that the MIPI is predictive for OS. However MIPI does not discriminate for PFS suggesting that those patients with high scores have an inferior response to subsequent therapy post relapse after FC based therapy. No significant financial relationships to disclose.
Effects of FCGR3A and FCGR2A polymorphisms on outcomes of patients with diffuse large B-cell lymphoma treated with CHOP-like chemotherapy versus CHOP-rituximab
Authors: Vose J. , Loberiza F. , Armitage J. , Bierman P. , Bociek R. , Dornan D. 
Published: August 2020

8567 Background: The addition of rituximab to cyclophosphamide/ doxorubicin/ vincristine/ prednisone (R-CHOP) therapy for diffuse large B-cell lymphoma (DLBCL) has significantly improved the outcome for many patients (pts). We evaluated the impact of single nucleotide polymorphisms (SNPs) of Fc receptor (FcR) genes FCGR3A and FCGR2A on the outcomes of patients with DLBCL treated with R-CHOP compared to a historical control patientss treated with CHOP-like chemotherapy alone. Methods: 199 patients with DLBCL who had received CHOP or CHOP-like chemo (N=99) or R-CHOP (N=100) had tissue blocks assayed for FCGR3A and FCGR2A polymorphisms. The patient characteristics, progression-free survival (PFS), and overall survivals (OS) were compared and analyzed with respect to the polymorphisms. Results: In the univariate analysis, the probability of PFS of pts according to polymorphisms in the FCGR2A gene treated with CHOP-like chemotherapy; H/H (n=25), H/R (n=39), and R/R (n=35) and those treated with R-CHOP; H/H (n=24), H/R (n=41), and R/R (n=35) were both not statistically different; log-rank p=0.47 and p=0.86, respectively. The probability of PFS in the FCGR3A gene treated with CHOP-like chemotherapy; V/V (n=10), F/V (n=40), F/F (n=49) and those treated with R-CHOP; V/V (n=12), F/V (N=40), F/F (n=48) were also not statistically different; log-rank p=0.32 and p=0.22, respectively. In a multivariate analysis for risk of progression or death: FCGR2A : H/H vs. H/R or R/R by treatment type: CHOP-like [RR 0.63 (95% CI 0.37–1.08), p=0.10] and R-CHOP [RR 0.59 (0.36–0.96), p=0.04] and for FCGR3A V/V vs. F/V or F/F by treatment arm: CHOP-like [RR 0.75 (0.36–1.54), p=0.43] and R-CHOP [RR 2.28(0.70–7.44), p=0.17]. Conclusions: Generally, the addition of rituximab to CHOP chemotherapy results in better outcomes than patients who receive CHOP-like regimen regardless of polymorphisms. However, our study also suggests that a trend toward association of certain polymorphisms with clinical outcomes. Additional, larger studies are needed to confirm this data. This information may assist in targeting additional therapies in patients with less favorable outcomes. [Table: see text]
Rituximab plus gemcitabine, ifosfamide, oxaliplatin (R-GIFOX) as salvage therapy for recurrent Hodgkin lymphoma
Authors: Corazzelli G. , Frigeri F. , Marcacci G. , Capobianco G. , Arcamone M. , Becchimanzi C. , Russo F. , Pinto A. 
Published: August 2020

8579 Background: Gemcitabine (G), ifosfamide (Ifo), oxaliplatin (Ox) and rituximab (R) have been accounted of cross-synergy in preclinical and early clinical studies in Hodgkin lymphoma (HL). We assessed activity, toxicity and stem cells (SCs) mobilizing capacity of a bi-weekly salvage combination with these agents in HL recurring after conventional or high dose therapy (HDT). Methods: Patients were scheduled to receive 3 R-GIFOX courses followed by SCs mobilization and HDT if elegible for autologous transplantation (ASCT) or 3 more courses if not. R-GIFOX consisted of R 375 mg/m2 D1, G 1000 mg/m2 D2, Ox 130 mg/m2 D3 and Ifo 5 g/m2 D3, as a 24-h single infusion, G-CSF 5 mcg/kg/d DD 7–11 (10 mcg/kg/d, 3rd course until SCs mobilization). Results: Twenty-one patients (median age 33 yrs, r 22–64) with relapsed (n = 16) [post-ASCT (n=6), <12 mo.s (n=7), > 12 mo.s (n=3)] or primary progressive (n = 5) HL, were prospectively accrued. Ten patients (48%) had received ≥ 2 previous CHT lines and 15 (78%) had GHLSG recurring HL prognostic score ≥ 2. Eighty-three total courses were delivered (median 3, r 3–6). CTCAE v3.0 G4 thrombocytopenia occurred in 18% of courses, G4 infection in 11%. Ifosfamide was withdrawn at the 4th course in 2 patients, both aged 64 yrs, due to tachyarrhythmia and encephalopathy. Actual dose intensity of the first 3 courses was 82%, 86%, 92 % for G, Ifo and Ox, respectively. The overall response according to FDG-PET/IWC criteria after 3 courses was 86%, with 2 partial and 16 complete responses (CRs) (76%; CR=10, CRu=6). Four CRs were achieved among the 6 patients with post-ASCT relapses. Eight of 14 eligible patients had effective CD34+ cells harvest [median 4,35 × 106/kg (r 2,91–11.45)] and proceeded to subsequent ASCT. Five ’bad mobilizers’ had previously undergone radiation therapy (n=3) and radioimmunotherapy (n=2). At 42 mo.s. Failure Free Survival was 57%. At a median f.u. of 12 mo.s for CRs, Disease Free Survival was 79% in patients eligible for ASCT and 41% in those unfit treated with additional R-GIFOX. Conclusions: R-GIFOX retains an attractive therapeutic potential in recurring HL, enabling pre-ABMT cytoreduction and mobilization, and also a safe delivery of a full salvage program to patients unfit for HDT. No significant financial relationships to disclose.
Relationship of rapid M protein reduction to outcomes in a trial of pegylated liposomal doxorubicin (PLD) plus bortezomib (B) versus B alone in previously treated multiple myeloma (MM)
Authors: Shah J. J. , Londhe A. , Lantz K. C. , Lowery C. , Orlowski R. Z. 
Published: August 2020

8591 Background: An early response in MM results in rapid improvement in symptoms and may benefit outcomes. To investigate the relationship between rapid response and outcomes, we retrospectively evaluated early reduction in M protein (MProt) in a trial of pegylated liposomal doxorubicin + bortezomib (PLD+B) vs B alone in relapsed/refractory multiple myeloma (MM). (Orlowski, JCO 2007) Methods: Patients (pts) were randomized to bolus IV B 1.3 mg/m2 on days 1, 4, 8, & 11 of each 3-week cycle (N=322) or to the same B regimen + IV PLD 30 mg/m2 on day 4 (N=324) of each cycle. % decrease from baseline of MProt was evaluated using a landmark analysis at the end of cycles 2 and 4. Pts were categorized into 4 groups by reduction in MProt at the landmark timepoints. 199 PLD+B and 205 B pts were included in the analysis at end of cycle 2. Time to progression (TTP) post-landmark was evaluated using a Cox proportional hazard model with treatment and the three ≥25% MProt reduction groups compared to the <25% group as factors. Results: Regardless of treatment, a decrease in risk of TTP was observed for greater reduction in MProt. This was significant for the 50–75% and ≥75% MProt reduction groups. Hazard ratios (95% CI) were: [0.84 (0.55, 1.30), P=.438] for 25-<50% vs 25%; [0.41 (0.26, 0.64), P=.001] for 50-<75% vs <25%; and [0.26 (0.15, 0.45), P=.001] for ≥75% vs <25%. PLD+B had a significant benefit over B alone in extending TTP [1.68 (1.19, 2.37), P=.003]. TTP was longer as MProt decreased and improved for PLD+B vs B. Similar results were observed at the end of cycle 4 landmark. Safety profiles for the 2 regimens were consistent with known toxicities of the agents. Conclusions: PLD+B had significant benefit over B alone in extending TTP in landmark analyses similar to the overall study. A >50% reduction in MProt resulted in a significant risk reduction for progression. These data suggest that early reductions in MProt may provide better outcomes. [Table: see text] [Table: see text]
Gene expression profiling (GEP) of cd 138-purified plasma cells (pc) in previously treated multiple myeloma (PTMM): Validating prognostic models developed in newly diagnosed MM (NDMM)
Authors: Alsayed Y. , Haessler J. , Barlogie B. , Crowley J. , Shaughnessy J. 
Published: August 2020

8598 Background: We have previously reported on the strong discriminatory power in NDMM of GEP-derived 70-gene risk in CD138-purified plasma-cells developed in 351 patients enrolled in TT2 and validated in 441 patients enrolled in two TT3 trials and in PTMM treated with single agent high-dose dexamethasone or bortezomib. Here we report on the overall survival outcomes in 137 patients with PTMM. Methods: Treatment regimens included further autotransplantation and novel agent combinations. The purpose of the investigation was to determine whether PTMM OS was also governed by GEP features, such as high-risk (HR) score, proliferation score (PS), proliferation (PR) molecular subgroup, gain/amplification of chromosome 1q (amp1q) and deletion of the short arm (del1p) and TP53 deletion. Results: Compared with NDMM, PTMM was characterized by greater proportions with HR (32% v 16%, p<0.001), PS (20% v 10%, p=0.002) and PR (24% v 11%, p < 0.001); no difference was observed for TP53 deletion (21% v 30%, p=0.11); amp1q/del1p was more common in PTMM (17% v 9%, p=0.01). OS was 60% at 8yr in NDMM compared to a median of only 2.4yr in PTMM. According to HR, 4-yr OS estimates were 80% for LR v 37% for HR in NDMM (p<0.0001) and 52% for LR v 24% for HR in PTMM (p<0.01). On multivariate analysis of both standard prognostic factors and GEP HR, OS in PTMM was adversely affected by HR status (HR=2.00, p=0.047) and albumin <3.5g/dL (HR=2.66, P=0.013), accounting for a cumulative R2 value of 20%. Conclusions: GEP-derived high-risk features are more prevalent in PTMM relative to NDMM in terms of HR, PS, PR and amp1q/del1p status. As in NDMM, HR status confers poor OS in PTMM. Consistent with serial sampling where LR to HR transformation routinely occurs, these data support the concept that HR in PTMM is derived from clonal evolution. Treatment strategies that presume the existence of underlying HR cells even in LR disease, should be pursued. [Table: see text]