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Donafenib in Progressive Locally Advanced or Metastatic Radioactive Iodine-Refractory Differentiated Thyroid Cancer: Results of a Randomized, Multicenter Phase II Trial.
Lin, YS, Yang, H, Ding, Y, Cheng, YZ, Shi, F, Tan, J, Deng, ZY, Chen, ZD, Wang, RF, Ji, QH, et al
Thyroid : official journal of the American Thyroid Association. 2021;(4):607-615
Abstract
Background: An unmet need for more effective and affordable kinase inhibitors remains in patients with progressive radioactive iodine-refractory differentiated thyroid cancer (RAIR-DTC) in China, where only sorafenib is approved for this indication. This study evaluated the 24-week objective response rate (ORR) to donafenib-a new, domestic multikinase inhibitor-in the treatment of locally advanced or metastatic RAIR-DTC in patients with measurable lesions. Two dose regimens (300 mg twice daily vs. 200 mg twice daily) were used to determine its optimal dosage and safety for further phase III studies. Methods: This study was a randomized, open-label, multicenter phase II trial. Thirty-five adult RAIR-DTC patients with at least one measurable targeted lesion according to RECIST 1.1 were enrolled from 12 centers in China and randomized to receive either 200 mg (17 patients) or 300 mg (18 patients) of donafenib orally twice daily for 24 weeks. The primary endpoint was ORR, and the secondary endpoints included progression-free survival (PFS) among others. Additionally, biochemical (serum thyroglobulin) and structural (total tumor diameter [TTD]) responses were assessed, change (ΔTTD) rates were calculated, and safety was evaluated. Results: The ORRs for the 200- and 300-mg arms were 12.5% and 13.33% (p = 1.000), respectively. The 300-mg arm had a nonsignificant, longer median PFS than the 200-mg arm (14.98 months vs. 9.44 months) (p = 0.351). There was a trend toward more tumor shrinkage in the 300-mg arm compared with the 200-mg arm (average ΔTTD rate -0.52 ± 0.71 vs. -0.04 ± 1.55 mm/month, p = 0.103). Most treatment-related adverse events (AEs) in both arms were grades 1-2. The most common grade 3 treatment-related AEs in both arms were palmar-plantar erythrodysesthesia and hypertension; the sum occurrence rates of these two AEs in the 200-mg and 300-mg arms were 11.43% and 22.86%, respectively. Conclusions: Donafenib was generally well tolerated. Both donafenib regimens demonstrated similar efficacy in terms of the ORR in locally advanced or metastatic RAIR-DTC. The results warrant further studies on donafenib as a new, feasible treatment option for RAIR-DTC patients. Clinical Trials.gov IDs: NCT02870569; CTR20160220.
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Cervical versus endometrial injection for sentinel lymph node detection in endometrial cancer: a randomized clinical trial.
Gezer, Ş, Duman Öztürk, S, Hekimsoy, T, Vural, Ç, İşgören, S, Yücesoy, İ, Çorakçı, A
International journal of gynecological cancer : official journal of the International Gynecological Cancer Society. 2020;(3):325-331
Abstract
OBJECTIVE To evaluate the relationship between pelvic/para-aortic sentinel lymph node status and two different injection sites of 99m-technetium (99mTc)-labeled phytate in patients with endometrial cancer. METHODS This was a randomized controlled trial involving 81 patients with endometrial cancer. In the cervical group (n=40), injections of 99mTc were performed at the 3 and 9 o'clock positions of the uterine cervix. In the endometrial group (n=41), 99mTc was injected into the fundal endometrium using a transcervical catheter. Sentinel lymph nodes were detected through pre-operative lymphoscintigraphy and intra-operatively using a handheld gamma probe. All patients underwent complete pelvic and para-aortic lymphadenectomy procedures. Pathologic ultra-staging was performed with immunostaining for cytokeratin in sentinel lymph nodes after routine hematoxylin and eosin histological examinations. The primary endpoint was the estimation of detection rates, sensitivity, false-negative rates, negative predictive value, and analysis of the distribution of pelvic and para-aortic sentinel lymph nodes. RESULTS The rate of detection of at least one sentinel lymph node, sensitivity, and the negative predictive value was 80%, 66.6%, 96.6% for the cervical group and 85%, 66.6%, 96.9% for the endometrial group, respectively. False-negative sentinel lymph nodes were detected in one patient from each group . There was no significant difference between the groups in terms of total sentinel lymph node count, sentinel pelvic lymph node count, and pelvic bilaterality, but the para-aortic sentinel lymph node count was significantly higher in the endometrial group (p<0.001). Ultra-staging examination of the pelvic sentinel lymph nodes revealed isolated tumor cells in one patient from each group. CONCLUSION Transcervical endometrial tracer injection in endometrial cancer revealed similar pelvic but significantly higher para-aortic sentinel lymph node detection.
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The INTERNET STUDY: A phase II study of everolimus in patients with fluorodeoxyglucose (18 F) positron-emission tomography positive intermediate grade pancreatic neuroendocrine tumors.
Lung, MS, Hicks, RJ, Pavlakis, N, Link, E, Jefford, M, Thomson, B, Wyld, DK, Liauw, W, Akhurst, T, Kuru, N, et al
Asia-Pacific journal of clinical oncology. 2020;(3):150-157
Abstract
AIMS: This multicenter phase II trial evaluates the efficacy of everolimus in poor prognosis grade 2 (G2) pancreatic neuroendocrine tumors (PNETs), defined by 2-[fluorine-18]fluoro-2-deoxy-d-glucose (FDG) positron-emission tomography (PET) avidity. FDG-PET avidity in NETs is associated with a significantly higher risk of death, outperforming Ki-67 index or liver metastases as a poor prognostic factor. We hypothesized that everolimus has efficacy in patients with FDG-PET-avid G2 PNETs and prospectively evaluated progression-free survival (PFS) and response in the first-line setting. METHODS Patients with FDG-PET-avid G2 advanced PNET received everolimus 10 mg daily until disease progression. Patients were staged every 12 weeks with CT/MRI and FDG-PET and every 24 weeks with Gallium 68 (68Ga) 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-octreotate (DOTATATE, GaTate) PET. The primary endpoint was PFS at 6 months. Overall survival rate, PET/structural imaging response and toxicity were also measured. RESULTS Nine patients were accrued from December 2012 to February 2015. Median treatment duration was 13.8 months. The estimated PFS rate at 6 months was 78%. The best response on CT/MRI was stable disease in nine patients (100%) and partial response on FDG-PET in five patients (55.5%). Treatment-related adverse effects were consistent with previous studies of everolimus. CONCLUSION Everolimus is active with prolonged disease control in poor prognosis FDG-avid G2 PNETs. Treatment individualization based on functional imaging warrants further evaluation.
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18F-fluorodeoxyglucose use after cardiac transplant: A comparative study of suppression of physiological myocardial uptake.
Felix, RCM, Gouvea, CM, Reis, CCW, Dos Santos Miranda, JS, Schtruk, LBCE, Colafranceschi, AS, Mesquita, CT
Journal of nuclear cardiology : official publication of the American Society of Nuclear Cardiology. 2020;(1):173-181
Abstract
BACKGROUND 18F-fluorodeoxyglucose (FDG) has been useful in the evaluation of myocardial inflammatory processes. However, it is challenging to identify them due to physiological 18F-FDG uptake. There are no publications demonstrating the application of FDG in post-transplant rejection in humans yet. The aim of this study is to determine the feasibility of suppression of myocardial FDG uptake in post-transplant patients, comparing three different protocols of preparation. METHODS Ten patients after heart transplantation were imaged by FDG associated with three endomyocardial biopsies (EMB), scheduled in the first year after the procedure. Before each imaging, patients were randomized to one of three preparations: (1) hyperlipidic-hypoglycemic diet; (2) fasting longer than 12 hours; and (3) fasting associated with intravenous heparin. All patients would undergo the three methods. FDG images were analyzed using visual analysis scores and relative radiotracer cardiac uptake (RRCU). RESULTS The suppression rate of radiotracer activity ranged from 55% to 62%. Visual analysis showed that preparation 3 presented less efficacy in the suppression compared to the others. However, RRCU did not show difference between the preparations. CONCLUSIONS Suppression of physiological myocardial FDG uptake after cardiac transplantation is feasible. The usefulness of heparin in the suppression is unclear.
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Transcutaneous electrical nerve stimulation attenuates cardiac sympathetic drive in heart failure: a 123MIBG myocardial scintigraphy randomized controlled trial.
Campos, MO, Nóbrega, ACL, Miranda, SM, Ribeiro, ML, Guerra, TRB, Braghirolli, AMS, Mesquita, CT, Fernandes, IA
American journal of physiology. Heart and circulatory physiology. 2019;(2):H226-H233
Abstract
Cardiac sympathetic overdrive provides inotropic support to the failing heart. However, as myocardial insult evolves, this compensatory response impairs contractile function and constitutes an independent mortality predictor and a primary target in the treatment of heart failure (HF). In this prospective, randomized, double-blind, controlled crossover trial, we proposed cervicothoracic transcutaneous electrical nerve stimulation (CTENS) as a nonpharmacological therapy on cardiac sympathetic activity in patients with HF. Seventeen patients with HF were randomly assigned to an in-home CTENS (30 min twice daily, 80-Hz frequency, and 150-μs pulse duration) or a control intervention (Sham) for 14 consecutive days. Following a 60-day washout phase, patients were crossed over to the opposite intervention. The heart-to-mediastinum ratio (HMR) and washout rate (WR) (indexes of sympathetic innervation density and activity from planar 123iodo-metaiodobenzylguanidine myocardial scintigraphy images, respectively), as well as blood pressure (BP) and heart rate (HR), were quantified before and after each intervention. HMR, BP, and HR did not change throughout the study. Nonetheless, CTENS reduced WR (CTENS -4 ± 10 vs. Sham +5 ± 15%, P = 0.03) when compared with Sham. When allocated in two independent groups, preserved (PCSI, HMR > 1.6, n = 10) and impaired cardiac sympathetic innervation (ICSI, HRM ≤1.6, n = 7), PCSI patients showed an important attenuation of WR (-11 ± 9 vs. Sham +8 ± 19%, P = 0.007) after CTENS. Nonetheless, neither Sham nor CTENS evoked changes in WR of the ICSI patients (P > 0.05). These findings indicate that CTENS attenuates the cardiac sympathetic overdrive in patients with HF and a preserved innervation constitutes an essential factor for this beneficial neuromodulatory impact. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Identifier: NCT03354689. NEW & NOTEWORTHY We found that short-term cervicothoracic transcutaneous electrical nerve stimulation (CTENS) attenuates cardiac sympathetic overdrive in patients with heart failure and a preserved autonomic innervation may constitute an essential factor to maximize this beneficial neuromodulatory effect. CTENS then emerges as an alternative noninvasive and nonpharmacological strategy to attenuate exaggerated cardiac sympathetic drive in patients with heart failure.
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TheraP: a randomized phase 2 trial of 177 Lu-PSMA-617 theranostic treatment vs cabazitaxel in progressive metastatic castration-resistant prostate cancer (Clinical Trial Protocol ANZUP 1603).
Hofman, MS, Emmett, L, Violet, J, Y Zhang, A, Lawrence, NJ, Stockler, M, Francis, RJ, Iravani, A, Williams, S, Azad, A, et al
BJU international. 2019;:5-13
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Abstract
OBJECTIVE To assess the activity and safety of cabazitaxel chemotherapy vs that of treatment with 177 Lu-PSMA-617, a novel radiolabelled small molecule that binds with high affinity to prostate-specific membrane antigen (PSMA), in men with metastatic castration-resistant prostate cancer (mCRPC) who have received prior docetaxel treatment. PATIENTS AND METHODS The TheraP trial (ANZUP 1603) is an open-label, randomized, stratified, two-arm multicentre phase 2 trial comparing the activity and safety of cabazitaxel chemotherapy vs 177 Lu-PSMA-617 therapy in the treatment of men with mCRPC. Key eligibility criteria include prior docetaxel chemotherapy, rising prostate-specific antigen (PSA) level, sufficient PSMA avidity, as defined by centrally reviewed 68 Ga-PSMA-11 and fluorodeoxyglucose (FDG)-positron emission tomography (PET)/computed tomography (CT) with no discordant FDG-avid PSMA-negative sites of disease. Patients in the control group receive standard treatment with cabazitaxel (20 mg/m2 ) i.v. every 3 weeks with prednisolone 10 mg daily orally, for a maximum of 10 cycles. Patients in the experimental group receive 177 Lu-PSMA-617 (8.5 GBq decreasing by 0.5 GBq per cycle) i.v. every 6 weeks, for up to a maximum of six cycles. In the event of an exceptional response as defined on centrally reviewed post-therapy single-photon emission CT imaging, treatment will be suspended but can recommence on progression. The trial aims to include 200 patients who will be centrally randomized to one of the two treatment groups, in a 1:1 ratio. The primary endpoint is PSA response. Secondary endpoints are overall survival, progression-free survival (PFS), radiographic PFS, PSA PFS, objective tumour response, pain response, pain PFS, health-related quality of life, and frequency and severity of adverse events. The treatment and outcomes of patients excluded on the basis of low PSMA avidity or discordant FDG-avid disease on screening 68 Ga-PSMA-11 and Fluorine-18 (18 F)-FDG-PET/CT scan will also be assessed. Enrolment in the study commenced on 29 January 2018. RESULTS AND CONCLUSIONS 177 Lu-PSMA-617 offers a potential additional life-prolonging treatment option for men with mCRPC. The results of this trial will determine, for the first time in a randomized design, the activity and safety of 177 Lu-PSMA-617, as compared with cabazitaxel chemotherapy in men with progressive mCRPC.
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Metformin Discontinuation prior to FDG PET/CT: A Randomized Controlled Study to Compare 24- and 48-hour Bowel Activity.
Hamidizadeh, R, Eftekhari, A, Wiley, EA, Wilson, D, Alden, T, Bénard, F
Radiology. 2018;(2):418-425
Abstract
Purpose To investigate the relationship of 24- and 48-hour metformin discontinuation to bowel uptake of fluorine 18 fluorodeoxyglucose (FDG) on PET/CT scans. Materials and Methods Patients with diabetes who were treated with metformin and referred for FDG PET/CT were randomized to three equal groups based on duration of metformin discontinuation: 24 hours, 48 hours, and no discontinuation (control group). Two interpreters blinded to the study groups assessed FDG uptake in multiple segments of small and large bowel qualitatively and semiquantitatively by using maximum standardized uptake values (SUVsmax). Differences in age, sex, weight, dose of metformin, duration of metformin treatment, blood glucose levels, and FDG dose injected were assessed. Data were analyzed with analysis of variance when passing normality, and by nonparametric testing when not. Results Ninety study participants (62 male, 28 female; median age, 70 years) were enrolled from July 2010 through March 2012. There were no differences between study groups in weight, blood glucose levels 3 days prior to scanning, or normal organ uptake. Large bowel SUVmax was lower after 24 hours (4.10 ± 2.00 vs 5.42 ± 2.36; P = .020) and 48 hours (2.63 ± 0.88 vs 5.42 ± 2.36; P ˂ .001) of metformin discontinuation than for no discontinuation (control), and for 48 hours versus 24 hours of discontinuation (P = .0015). Small bowel SUVmax was lower after 24 hours (2.86 ± 0.67 vs 3.73 ± 1.08 [control]; P ˂ .001) and 48 hours (2.78 ± 0.73 vs 3.73 ± 1.08 [control]; P ˂ .001) of metformin discontinuation versus no metformin discontinuation, but not for 48 hours versus 24 hours of discontinuation (P = .57). Examination-day blood glucose levels increased after 48-hour withdrawal of metformin (8.41 mmol/L ± 2.86 vs 6.83 mmol/L ± 2.13 [control]; P = .002). Conclusion Metformin discontinuation for 48 hours prior to PET/CT was associated with lower accumulation of fluorodeoxyglucose in the bowel, compared to when there was no discontinuation (control group) or 24-hour discontinuation of metformin. © RSNA, 2018.
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Bicuspid Aortic Valve Stenosis and the Effect of Vitamin K2 on Calcification Using 18F-Sodium Fluoride Positron Emission Tomography/Magnetic Resonance: The BASIK2 Rationale and Trial Design.
Peeters, FECM, van Mourik, MJW, Meex, SJR, Bucerius, J, Schalla, SM, Gerretsen, SC, Mihl, C, Dweck, MR, Schurgers, LJ, Wildberger, JE, et al
Nutrients. 2018;(4)
Abstract
BASIK2 is a prospective, double-blind, randomized placebo-controlled trial investigating the effect of vitamin K2 (menaquinone-7;MK7) on imaging measurements of calcification in the bicuspid aortic valve (BAV) and calcific aortic valve stenosis (CAVS). BAV is associated with early development of CAVS. Pathophysiologic mechanisms are incompletely defined, and the only treatment available is valve replacement upon progression to severe symptomatic stenosis. Matrix Gla protein (MGP) inactivity is suggested to be involved in progression. Being a vitamin K dependent protein, supplementation with MK7 is a pharmacological option for activating MGP and intervening in the progression of CAVS. Forty-four subjects with BAV and mild-moderate CAVS will be included in the study, and baseline 18F-sodiumfluoride (18F-NaF) positron emission tomography (PET)/ magnetic resonance (MR) and computed tomography (CT) assessments will be performed. Thereafter, subjects will be randomized (1:1) to MK7 (360 mcg/day) or placebo. During an 18-month follow-up period, subjects will visit the hospital every 6 months, undergoing a second 18F-NaF PET/MR after 6 months and CT after 6 and 18 months. The primary endpoint is the change in PET/MR 18F-NaF uptake (6 months minus baseline) compared to this delta change in the placebo arm. The main secondary endpoints are changes in calcium score (CT), progression of the left ventricularremodeling response and CAVS severity (echocardiography). We will also examine the association between early calcification activity (PET) and later changes in calcium score (CT).
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Thyroid cancer patient perceptions of radioactive iodine treatment choice: Follow-up from a decision-aid randomized trial.
Sawka, AM, Straus, S, Rodin, G, Heus, L, Brierley, JD, Tsang, RW, Rotstein, L, Ezzat, S, Segal, P, Gafni, A, et al
Cancer. 2015;(20):3717-26
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Abstract
BACKGROUND Patient decision aids (P-DAs) inform medical decision making, but longer term effects are unknown. This article describes extended follow-up from a thyroid cancer treatment P-DA trial. METHODS In this single-center, parallel-design randomized controlled trial conducted at a Canadian tertiary/quaternary care center, early-stage thyroid cancer patients from a P-DA trial were contacted 15 to 23 months after randomization/radioactive iodine (RAI) decision making to evaluate longer term outcomes. It was previously reported that the use of the computerized P-DA in thyroid cancer patients considering postsurgical RAI treatment significantly improved medical knowledge in comparison with usual care alone. The P-DA and control groups were compared for the following outcomes: feeling informed about the RAI treatment choice, decision satisfaction, decision regret, cancer-related worry, and physician trust. In a subgroup of 20 participants, in-depth interviews were conducted for a qualitative analysis. RESULTS Ninety-five percent (70 of 74) of the original population enrolled in follow-up at a mean of 17.1 months after randomization. P-DA users perceived themselves to be significantly more 1) informed about the treatment choice (P = .008), 2) aware of options (P = .009), 3) knowledgeable about treatment benefits (P = .020), and 4) knowledgeable about treatment risks/side effects (P = .001) in comparison with controls. There were no significant group differences in decision satisfaction (P = .142), decision regret (P = .199), cancer-related worry (P = .645), mood (P = .211), or physician trust (P = .764). In the qualitative analysis, the P-DA was perceived to have increased patient knowledge and confidence in decision making. CONCLUSIONS The P-DA improved cancer survivors' actual and long-term perceived medical knowledge with no adverse effects. More research on the long-term outcomes of P-DA use is needed.
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Can neutrophil gelatinase-associated lipocalin help depict early contrast material-induced nephropathy?
Lacquaniti, A, Buemi, F, Lupica, R, Giardina, C, Murè, G, Arena, A, Visalli, C, Baldari, S, Aloisi, C, Buemi, M
Radiology. 2013;(1):86-93
Abstract
PURPOSE To evaluate the utility of serum and urinary neutrophil gelatinase-associated lipocalin (NGAL) in depicting an event of contrast material-induced nephropathy (CIN) in patients who received iodinated contrast media, gadoterate meglumine, or radiopharmaceutical technetium-99m ((99m)Tc) and to evaluate the protective effect exerted by isotonic saline infusion, sodium bicarbonate administration, or N-acetylcysteine administration. MATERIALS AND METHODS Institutional ethics committee approval was given, and informed consent was obtained. One hundred twenty patients were enrolled in a prospective study and divided into three groups: iomeprol group, magnetic resonance (MR) imaging group (gadoterate meglumine), and renal scintigraphy group ((99m)Tc). They randomly received N-acetylcysteine, physiologic saline, or sodium bicarbonate. Receiver operating characteristic (ROC) analysis, Kaplan-Meier curves, and Cox proportional hazard regression analysis were used. RESULTS In the MR imaging and renal scintigraphy groups, there were significant changes in serum creatinine and NGAL levels, and there were no cases of CIN. In the iomeprol group, an early rise in NGAL was found, while serum creatinine level changes occurred 24 hours after contrast material administration. At ROC analysis, NGAL showed high sensitivity and specificity (serum NGAL area under the curve, 0.995; 95% confidence interval [CI]: 0.868, 0.992; urinary NGAL area under the curve, 0.992; 95% CI: 0.925, 1.000) in identifying CIN 8 hours after iomeprol administration. Regression analysis showed that NGAL independently predicted CIN. Administration of N-acetylcysteine, sodium bicarbonate, or physiologic saline did not influence NGAL level. CONCLUSION NGAL depicted CIN in patients who received iodinated contrast material within 8 hours of contrast material administration. SUPPLEMENTAL MATERIAL http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.12120578/-/DC1.