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Post hoc analysis of patients with rheumatoid arthritis under clinical remission in two Japanese Phase 3 trials of peficitinib treatment (RAJ3 and RAJ4).
Tanaka, Y, Takeuchi, T, Morita, Y, Kato, D, Kaneko, Y, Terada, W
Modern rheumatology. 2024;(3):453-465
Abstract
OBJECTIVE We evaluated remission rates and their relationship with baseline characteristics in patients with rheumatoid arthritis treated with the oral Janus kinase inhibitor peficitinib. METHODS This post hoc analysis of data from two Phase 3 studies (RAJ3 and RAJ4) of peficitinib (100 and 150 mg/day) in Asian rheumatoid arthritis patients investigated clinical disease activity index (CDAI) remission and low disease activity rates from baseline to Week 52. CDAI, Health Assessment Questionnaire-Disability Index, and van der Heijde-modified total Sharp score remission/low disease activity rates at Week 52 were evaluated among patients achieving CDAI remission at Weeks 12/28. Logistic regression analyses explored the relationship between baseline characteristics and CDAI remission/low disease activity rates. RESULTS CDAI remission rates increased over time in a dose-dependent manner in both peficitinib-treated groups. Most patients achieving CDAI remission at Weeks 12/28 also achieved remission at Week 52. Following the multivariate analysis of demographic and baseline characteristics, factors associated with the achievement of CDAI remission at Week 28 included male sex, low baseline prednisone dose (RAJ3 only), and low baseline Disease Activity Score 28-C-reactive protein (RAJ4 only). CONCLUSIONS Peficitinib demonstrated persistent efficacy in clinical remission to Week 52. Baseline characteristics associated with CDAI remission were mostly consistent with previous studies using other disease-modifying antirheumatic drugs.
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Long-Term Outcomes of Radical Radiation Therapy with Hypoxia Modification with Biomarker Discovery for Stratification: 10-Year Update of the BCON (Bladder Carbogen Nicotinamide) Phase 3 Randomized Trial (ISRCTN45938399).
Song, YP, Mistry, H, Irlam, J, Valentine, H, Yang, L, Lane, B, West, C, Choudhury, A, Hoskin, PJ
International journal of radiation oncology, biology, physics. 2021;(5):1407-1415
Abstract
PURPOSE Many muscle-invasive bladder cancers are hypoxic, which limits the efficacy of radiation therapy. Hypoxia modification using carbogen and nicotinamide has been tested in a phase 3 trial, Bladder Carbogen Nicotinamide. We present mature follow-up data with biomarker predictions of outcomes. METHODS AND MATERIALS Bladder Carbogen Nicotinamide is a prospective, phase 3, multicenter, randomized, 2-arm, nonblinded clinical trial. Participants were randomized to receive radical radiation therapy (RT; control arm) alone or with the addition of carbogen (98% O2; 2% CO2) and nicotinamide (CON). Patients with muscle-invasive or high-grade non-muscle invasive bladder cancer were included. Tumor tissue was collected at entry and was analyzed for tumor necrosis, hypoxia (24-gene signature), and basal and luminal tumor molecular subtypes. Overall survival (OS) and disease-free survival and relationships with biomarker status outcomes are analyzed using multivariable Cox regression and log-rank analysis. RESULTS We analyzed 333 patients with a median follow-up of 10.3 years. The 10-year OS rates were 30% (95% confidence interval [CI], 0.23-0.39) in RT + CON patients and 24% (95% CI, 0.18-0.33) in the RT-alone patients (hazard ratio [HR], 0.80; 95% CI, 0.61-1.04; P = .08). The greatest benefit from CON was seen in patients with tumor necrosis (n = 79; 5-year OS, 53% vs. 33% in patients without tumor necrosis; HR, 0.59; 95% CI, 0.36-0.99; P = .04). Cases with a high hypoxia gene score (n = 75) had a 5-year OS rate of 51%, compared to 34% for a low score (HR, 0.64; 95% CI, 0.38-1.08; P = .09); those with the basal molecular subtype (n = 70) had a 5-year OS rate of 58%, compared to 38% for those with the luminal subtype (HR, 0.58; 95% CI, 0.32-1.06; P = .08). CONCLUSIONS Although the improvement in long-term OS in the whole population is not statistically significant, patients selected by necrosis and high hypoxia gene score benefitted from hypoxia modification.
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Head-to-Head Comparison of 18F-Prostate-Specific Membrane Antigen-1007 and 18F-Fluorocholine PET/CT in Biochemically Relapsed Prostate Cancer.
Witkowska-Patena, E, Giżewska, A, Dziuk, M, Miśko, J, Budzyńska, A, Walęcka-Mazur, A
Clinical nuclear medicine. 2019;(12):e629-e633
Abstract
PURPOSE OF THE REPORT The aim of the study was to prospectively compare performance of F-fluorocholine (FCH) and F-prostate-specific membrane antigen (PSMA)-1007 PET/CT in patients with biochemical relapse (BCR) of prostate cancer and low prostate-specific antigen levels. METHODS We prospectively enrolled 40 BCR patients after radical treatment and prostate-specific antigen levels 2.0 ng/mL or less. F-FCH and F-PSMA-1007 PET/CT imaging was performed within a mean interval of 54 ± 21 days. Scans were done 87 ± 10 and 95 ± 12 minutes after injecting 248 ± 35 and 295 ± 14 MBq of F-FCH and F-PSMA-1007, respectively. Rates of negative, equivocal, and positive scan results were compared per patient. Per lesion, findings were grouped as equivocal or highly suggestive of malignancy and then compared for their number, localization (local relapse, lymph nodes, bones), and SUVmax values. RESULTS Positive, equivocal, and negative results were reported in 60%, 27.5%, and 12.5% of F-PSMA-1007 and in 5%, 37.5%, and 57.5% of F-FCH scans, respectively. In 70% of scans, F-PSMA-1007 PET/CT upgraded F-FCH PET/CT results. F-PSMA-1007 scans also showed significantly more lesions (184 vs 63, P = 0.0006). Local relapse, lymph node, and bone lesions accounted, respectively, for 9%, 58%, and 33% of F-PSMA-1007 and 5%, 89%, and 6% F-FCH of PET/CT findings. Highly suspicious lesions accounted for 74% of F-PSMA-1007 and 11% of F-FCH PET/CT findings. In F-PSMA-1007 PET/CT SUVmax values of highly suggestive lesions were significantly higher than in equivocal lesions (median, 3.6 vs 2.5; P < 0.00001). CONCLUSIONS In early BCR patients F-PSMA-1007 showed a higher detection rate than F-FCH PET/CT. The former also showed more lesions in total, more highly suggestive lesions and less equivocal lesions.
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Phase I/II Study of Stem-Cell Transplantation Using a Single Cord Blood Unit Expanded Ex Vivo With Nicotinamide.
Horwitz, ME, Wease, S, Blackwell, B, Valcarcel, D, Frassoni, F, Boelens, JJ, Nierkens, S, Jagasia, M, Wagner, JE, Kuball, J, et al
Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2019;(5):367-374
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PURPOSE Increasing the number of hematopoietic stem and progenitor cells within an umbilical cord blood (UCB) graft shortens the time to hematopoietic recovery after UCB transplantation. In this study, we assessed the safety and efficacy of a UCB graft that was expanded ex vivo in the presence of nicotinamide and transplanted after myeloablative conditioning as a stand-alone hematopoietic stem-cell graft. METHODS Thirty-six patients with hematologic malignancies underwent transplantation at 11 sites. RESULTS The cumulative incidence of neutrophil engraftment at day 42 was 94%. Two patients experienced secondary graft failure attributable to viral infections. Hematopoietic recovery was compared with that observed in recipients of standard UCB transplantation as reported to the Center for International Blood and Marrow Transplant Research (n = 146). The median time to neutrophil recovery was 11.5 days (95% CI, 9 to 14 days) for recipients of nicotinamide-expanded UCB and 21 days (95% CI, 20 to 23 days) for the comparator ( P < .001). The median time to platelet recovery was 34 days (95% CI, 32 to 42 days) and 46 days (95% CI, 42 to 50 days) for the expanded and the comparator cohorts, respectively ( P < .001). The cumulative incidence of grade 2 to 4 acute graft-versus-host disease (GVHD) at day 100 was 44%, and grade 3 and 4 acute GVHD at day 100 was 11%. The cumulative incidence at 2 years of all chronic GVHD was 40%, and moderate/severe chronic GVHD was 10%. The 2-year cumulative incidences of nonrelapse mortality and relapse were 24% and 33%, respectively. The 2-year probabilities of overall and disease-free survival were 51% and 43%, respectively. CONCLUSION UCB expanded ex vivo with nicotinamide shortens median neutrophil recovery by 9.5 days (95% CI, 7 to 12 days) and median platelet recovery by 12 days (95% CI, 3 to 16.5 days). This trial establishes feasibility, safety, and efficacy of an ex vivo expanded UCB unit as a stand-alone graft.
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Intraindividual Comparison of 18F-PSMA-1007 and 18F-DCFPyL PET/CT in the Prospective Evaluation of Patients with Newly Diagnosed Prostate Carcinoma: A Pilot Study.
Giesel, FL, Will, L, Lawal, I, Lengana, T, Kratochwil, C, Vorster, M, Neels, O, Reyneke, F, Haberkon, U, Kopka, K, et al
Journal of nuclear medicine : official publication, Society of Nuclear Medicine. 2018;(7):1076-1080
Abstract
The introduction of 18F-labeled prostate-specific membrane antigen (PSMA)-targeted PET/CT tracers, first 18F-DCFPyL (2-(3-{1-carboxy-5-[(6-18F-fluoro-pyridine-3-carbonyl)-amino]-pentyl}-ureido)-pentanedioic acid) and more recently 18F-PSMA-1007 (((3S,10S,14S)-1-(4-(((S)-4-carboxy-2-((S)-4-carboxy-2-(6-18F-fluoronicotinamido)butanamido)butanamido)methyl)phenyl)-3-(naphthalen-2-ylmethyl)-1,4,12-trioxo-2,5,11,13-tetraazahexadecane-10,14,16-tricarboxylic acid)), have demonstrated promising results for the diagnostic workup of prostate cancer. This clinical study presents an intraindividual comparison to evaluate tracer-specific characteristics of 18F-DCFPyL versus 18F-PSMA-1007. Methods: Twelve prostate cancer patients, drug-naïve or before surgery, received similar activities of about 250 MBq of 18F-DCFPyL and 18F-PSMA-1007 48 h apart and were imaged 2 h after injection on the same PET/CT scanner using the same reconstruction algorithm. Normal-organ biodistribution and tumor uptake were quantified using SUVmaxResults: PSMA-positive lesions were detected in 12 of 12 prostate cancer patients. Both tracers, 18F-DCFPyL and 18F-PSMA-1007, detected the same lesions. No statistical significance could be observed when comparing the SUVmax of 18F-DCFPyL and 18F-PSMA-1007 for local tumor, lymph node metastases, and bone metastases. With regard to normal organs, 18F-DCFPyL had statistically significant higher uptake in kidneys, urinary bladder, and lacrimal gland. Vice versa, significantly higher uptake of 18F-PSMA-1007 in muscle, submandibular and sublingual gland, spleen, pancreas, liver, and gallbladder was observed. Conclusion: Excellent imaging quality was achieved with both 18F-DCFPyL and 18F-PSMA-1007, resulting in identical clinical findings for the evaluated routine situations. Nonurinary excretion of 18F-PSMA-1007 might present some advantage with regard to delineation of local recurrence or pelvic lymph node metastasis in selected patients; the lower hepatic background might favor 18F-DCFPyL in late stages, when rare cases of liver metastases can occur.
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Oral nicotinamide reduces transepidermal water loss: a randomized controlled trial.
Chen, AC, Martin, AJ, Dalziell, RA, Halliday, GM, Damian, DL
The British journal of dermatology. 2016;(6):1363-1365
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A phase II randomized controlled trial of nicotinamide for skin cancer chemoprevention in renal transplant recipients.
Chen, AC, Martin, AJ, Dalziell, RA, McKenzie, CA, Lowe, PM, Eris, JM, Scolyer, RA, Dhillon, HM, Vardy, JL, Bielski, VA, et al
The British journal of dermatology. 2016;(5):1073-1075
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Improved recurrence-free survival with ARCON for anemic patients with laryngeal cancer.
Janssens, GO, Rademakers, SE, Terhaard, CH, Doornaert, PA, Bijl, HP, van den Ende, P, Chin, A, Takes, RP, de Bree, R, Hoogsteen, IJ, et al
Clinical cancer research : an official journal of the American Association for Cancer Research. 2014;(5):1345-54
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PURPOSE Anemia is associated with poor tumor control. It was previously observed that accelerated radiotherapy combined with carbogen breathing and nicotinamide (ARCON) can correct this adverse outcome in patients with head and neck cancer. The purpose of this study was to validate this observation based on data from a randomized trial. EXPERIMENTAL DESIGN Of 345 patients with cT2-4 laryngeal cancer, 174 were randomly assigned to accelerated radiotherapy and 171 to ARCON. Hemoglobin levels, measured before treatment, were defined as low when <7.5 mmol/L for women and <8.5 mmol/L for men. The hypoxia marker pimonidazole was used to assess the oxygenation status in tumor biopsies. Data were analyzed 2 years after inclusion of the last patient. RESULTS Pretreatment hemoglobin levels were available and below normal in 27 of 173 (16%) accelerated radiotherapy and 27 of 167 (16%) ARCON patients. In patients with normal pretreatment, hemoglobin levels treatment with ARCON had no significant effect on 5-year loco-regional control (LRC, 79% versus 75%; P = 0.44) and disease-free survival (DFS, 75% vs. 70%; P = 0.46) compared with accelerated radiotherapy. However, in patients with low pretreatment, hemoglobin levels ARCON significantly improved 5-year LRC (79% vs. 53%; P = 0.03) and DFS (68% vs. 45%; P = 0.04). In multivariate analysis including other prognostic factors, pretreatment hemoglobin remained prognostic for LRC and DFS in the accelerated radiotherapy treatment arm. No correlation between pretreatment hemoglobin levels and pimonidazole uptake was observed. CONCLUSION Results from the randomized phase III trial support previous observations that ARCON has the potential to correct the poor outcome of cancer patients with anemia (ClinicalTrials.gov number, NCT00147732).
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Umbilical cord blood expansion with nicotinamide provides long-term multilineage engraftment.
Horwitz, ME, Chao, NJ, Rizzieri, DA, Long, GD, Sullivan, KM, Gasparetto, C, Chute, JP, Morris, A, McDonald, C, Waters-Pick, B, et al
The Journal of clinical investigation. 2014;(7):3121-8
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BACKGROUND Delayed hematopoietic recovery is a major drawback of umbilical cord blood (UCB) transplantation. Transplantation of ex vivo-expanded UCB shortens time to hematopoietic recovery, but long-term, robust engraftment by the expanded unit has yet to be demonstrated. We tested the hypothesis that a UCB-derived cell product consisting of stem cells expanded for 21 days in the presence of nicotinamide and a noncultured T cell fraction (NiCord) can accelerate hematopoietic recovery and provide long-term engraftment. METHODS In a phase I trial, 11 adults with hematologic malignancies received myeloablative bone marrow conditioning followed by transplantation with NiCord and a second unmanipulated UCB unit. Safety, hematopoietic recovery, and donor engraftment were assessed and compared with historical controls. RESULTS No adverse events were attributable to the infusion of NiCord. Complete or partial neutrophil and T cell engraftment derived from NiCord was observed in 8 patients, and NiCord engraftment remained stable in all patients, with a median follow-up of 21 months. Two patients achieved long-term engraftment with the unmanipulated unit. Patients transplanted with NiCord achieved earlier median neutrophil recovery (13 vs. 25 days, P < 0.001) compared with that seen in historical controls. The 1-year overall and progression-free survival rates were 82% and 73%, respectively. CONCLUSION UCB-derived hematopoietic stem and progenitor cells expanded in the presence of nicotinamide and transplanted with a T cell-containing fraction contain both short-term and long-term repopulating cells. The results justify further study of NiCord transplantation as a single UCB graft. If long-term safety is confirmed, NiCord has the potential to broaden accessibility and reduce the toxicity of UCB transplantation. TRIAL REGISTRATION Clinicaltrials.gov NCT01221857. FUNDING Gamida Cell Ltd.
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Pattern of CAIX expression is prognostic for outcome and predicts response to ARCON in patients with laryngeal cancer treated in a phase III randomized trial.
Rademakers, SE, Hoogsteen, IJ, Rijken, PF, Oosterwijk, E, Terhaard, CH, Doornaert, PA, Langendijk, JA, van den Ende, P, Takes, R, De Bree, R, et al
Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology. 2013;(3):517-22
Abstract
BACKGROUND AND PURPOSE In a phase III trial in patients with advanced stage laryngeal carcinoma comparing ARCON (accelerated radiotherapy with carbogen breathing and nicotinamide) to accelerated radiotherapy alone (AR) the prognostic and predictive value of CAIX, a hypoxia-associated protein, was investigated. MATERIAL AND METHODS 261 Paraffin embedded tumor biopsies and 79 fresh frozen biopsies from patients entered in the trial were immunohistochemically stained for CAIX. CAIX-fraction and CAIX expression pattern were related to tumor control and patient survival. RESULTS Low CAIX-fraction was prognostic for worse regional control and overall survival in patients treated with AR. Patients with a low CAIX-fraction treated with ARCON had better regional control and metastasis-free survival compared to AR (RC 97% vs 71%, p < 0.01 and MFS 92% vs 69%, p = 0.06). Patients with a perinecrotic CAIX staining pattern had a significantly worse local control, metastasis-free and overall survival compared to patients with a diffuse pattern (65% vs 84%, p = 0.01, 70% vs 96%, p < 0.01 and 42% vs 71%, p < 0.01 respectively), and this could not be improved with ARCON. After multivariate analysis CAIX pattern and N-stage emerged as significant predictors for metastasis-free survival and overall survival. CONCLUSIONS ARCON improves regional control and metastasis-free survival only in patients with low CAIX expression. The different patterns of CAIX expression suggest different mechanisms of upregulation and have important prognostic value.