Phase I/II clinical trial of high-dose [131I] meta-iodobenzylguanidine therapy for high-risk neuroblastoma preceding single myeloablative chemotherapy and haematopoietic stem cell transplantation.

PURPOSE: Paediatric high-risk neuroblastoma has poor prognosis despite modern multimodality therapy. This phase I/II study aimed to determine the safety, dose-limiting toxicity (DLT), and efficacy of high-dose 131I-meta-iodobenzylguanidine (131I-mIBG) therapy combined with single high-dose chemotherapy (HDC) and haematopoietic stem cell transplantation (HSCT) in high-risk neuroblastoma in Japan. METHODS: Patients received 666 MBq/kg of 131I-mIBG and single HDC and HSCT from autologous or allogeneic stem cell sources. The primary endpoint was DLT defined as adverse events associated with 131I-mIBG treatment posing a significant obstacle to subsequent HDC. The secondary endpoints were adverse events/reactions, haematopoietic stem cell engraftment and responses according to the Response Evaluation Criteria in Solid Tumours version 1.1 (RECIST 1.1) and 123I-mIBG scintigraphy. Response was evaluated after engraftment. RESULTS: We enrolled eight patients with high-risk neuroblastoma (six females; six newly diagnosed and two relapsed high-risk neuroblastoma; median age, 4 years; range, 1-10 years). Although all patients had adverse events/reactions after high-dose 131I-mIBG therapy, we found no DLT. Adverse events and reactions were observed in 100% and 25% patients during single HDC and 100% and 12.5% patients during HSCT, respectively. No Grade 4 complications except myelosuppression occurred during single HDC and HSCT. The response rate according to RECIST 1.1 was observed in 87.5% (7/8) in stable disease and 12.5% (1/8) were not evaluated. Scintigraphic response occurred in 62.5% (5/8) and 37.5% (3/8) patients in complete response and stable disease, respectively. CONCLUSION: 131I-mIBG therapy with 666 MBq/kg followed by single HDC and autologous or allogeneic SCT is safe and efficacious in patients with high-risk neuroblastoma and has no DLT. TRIAL REGISTRATION NUMBER: jRCTs041180030. NAME OF REGISTRY: Feasibility of high-dose iodine-131-meta-iodobenzylguanidine therapy for high-risk neuroblastoma preceding myeloablative chemotherapy and haematopoietic stem cell transplantation (High-dose iodine-131-meta-iodobenzylguanidine therapy for high-risk neuroblastoma). URL OF REGISTRY: https://jrct.niph.go.jp/en-latest-detail/jRCTs041180030 . DATE OF ENROLMENT OF THE FIRST PARTICIPANT TO THE TRIAL: 12/01/2018.

Randomized Phase II Trial of MIBG Versus MIBG, Vincristine, and Irinotecan Versus MIBG and Vorinostat for Patients With Relapsed or Refractory Neuroblastoma: A Report From NANT Consortium.

PURPOSE: 131I-metaiodobenzylguanidine (MIBG) is an active radiotherapeutic for neuroblastoma. The primary aim of this trial was to identify which of three MIBG regimens was likely associated with the highest true response rate. PATIENTS AND METHODS: Patients 1-30 years were eligible if they had relapsed or refractory neuroblastoma, at least one MIBG-avid site, and adequate autologous stem cells. Patients received MIBG 18 mCi/kg on day 1 and autologous stem cell on day 15. Patients randomly assigned to arm A received only MIBG; patients randomly assigned to arm B received intravenous vincristine on day 0 and irinotecan daily on days 0-4; patients randomly assigned to arm C received vorinostat (180 mg/m2/dose) orally once daily on days 1 to 12. The primary end point was response after one course by New Approaches to Neuroblastoma Therapy criteria. The trial was designed with 105 patients to ensure an 80% chance that the arm with highest response rate was selected. RESULTS: One hundred fourteen patients were enrolled, with three ineligible and six unevaluable, leaving 105 eligible and evaluable patients (36 in arm A, 35 in arm B, and 34 in arm C; 55 boys; and median age 6.5 years). After one course, the response rates (partial response or better) on arms A, B, and C were 14% (95% CI, 5 to 30), 14% (5 to 31), and 32% (18 to 51). An additional five, five, and four patients met New Approaches to Neuroblastoma Therapy Minor Response criteria on arms A, B, and C, respectively. On arms A, B, and C, rates of any grade 3+ nonhematologic toxicity after first course were 19%, 49%, and 35%. CONCLUSION: Vorinostat and MIBG is likely the arm with the highest true response rate, with manageable toxicity. Vincristine and irinotecan do not appear to improve the response rate to MIBG and are associated with increased toxicity.

Myocardial salvage is increased after sympathetic renal denervation in a pig model of acute infarction.

RATIONALE: Despite advances in treatment of acute myocardial infarction (AMI), many patients suffer significant myocardial damage with cardiac dysfunction. Sympathetic renal denervation (RD) may reduce adrenergic activation following AMI. OBJECTIVE: To investigate the potential role of RD limiting myocardial damage and remodeling when performed immediately after AMI. METHODS AND RESULTS: Sixteen farm pigs underwent 90 min left anterior descending artery balloon occlusion. Eight pigs underwent RD immediately after reperfusion. LV function, extent of myocardium at risk, and myocardial necrosis were quantified by cardiac magnetic resonance 5 and 30 days after AMI. 123I-MIBG scintigraphy was performed 31 days after AMI to image myocardial sympathetic innervation. Heart norepinephrine was quantified (from necrotic, border and remote zone). RD and control did not differ in myocardium at risk extent (59 ± 9 vs 55 ± 11% of LV mass) at 5 days. At 30 days CMR, RD pigs had smaller necrotic areas than control as assessed by gadolinium delay enhancement (18 ± 7 vs 30 ± 12% of LV mass, p = 0.021) resulting in improved myocardial salvage index (60 ± 11 vs 44 ± 27%, p < 0.001). RD pigs had higher cardiac output (3.7 ± 0.8 vs 2.66 ± 0.7 L/min, p < 0.001) and lower LV end diastolic volume (98 ± 16 vs 113 ± 31 ml, p = 0.041). 123I-MIBG defect extension was smaller in RD than control (60 ± 28 vs 78 ± 17%, p < 0.05) with significant reduction in the difference between innervation and perfusion defects (25 ± 12 vs 36 ± 30%, p = 0.013). NE content from necrotic area (238; IQR 464 vs 2546; IQR 1727 ng/g in RD and control, respectively, p < 0.001) and from border zone (295; IQR 264 vs 837; IQR 207 in RD and control, respectively, p = 0.031) was significantly lower in RD than control. CONCLUSIONS: RD results in increased myocardial salvage and better cardiac function, when performed immediately after AMI. Reduction of sympathetic activation with preservation of cardiac sympathetic functionality warranted by RD may sustain these effects.

Calibrated scintigraphic imaging procedures improve quantitative assessment of the cardiac sympathetic nerve activity.

The 123I-labeled meta-iodobenzylguanidine (MIBG) is an analogue of noradrenaline that can evaluate cardiac sympathetic activity in scintigraphy. Quantitative analysis of 123I-MIBG images has been verified in patients with heart failure and neurodegenerative diseases. However, quantitative results differ due to variations in scintigraphic imaging procedures. Here, we created and assessed the clinical feasibility of a calibration method for 123I-MIBG imaging. The characteristics of scintigraphic imaging systems were determined using an acrylic calibration phantom to generate a multicenter phantom imaging database. Calibration factors corresponding to the scintigraphic imaging procedures were calculated from the database and applied to a clinical study. The results of this study showed that the calibrated analysis eliminated inter-institutional differences among normal individuals. In summary, our standardization methodology for 123I-MIBG scintigraphy could provide the basis for improved diagnostic precision and better outcomes for patients.

A model for in situ plan of care for a critically unstable pediatric patient following I-131 MIBG infusion.

Recent clinical trials have moved iodine-131 (I-131) metaiodobenzylguanidine (MIBG) therapy into frontline management of high-risk neuroblastoma. With this expansion, it is reasonable to anticipate the need for intensive care level resuscitations. Radiation exposure remains the greatest risk to health care professionals managing these patients. We combined shock simulation scenario data with actual radiation dosimetry data to create a care model allowing for aggressive, prolonged in situ resuscitation of a critically ill pediatric patient after I-131 MIBG administration. This model will maintain a critical care provider's radiation level below 10% of the annual occupational dose limit (5 mSv, 500 mrem) per patient managed.

Relationship between the washout rate of I-123 MIBG scans and autonomic function in Parkinson's disease.

PURPOSE: We have evaluated the clinical significance of the washout rate (WR) on I-123 MIBG scans through the analysis of the relationship between the I-123 MIBG scans and autonomic status in patients with Parkinson's disease (PD). MATERIALS AND METHODS: Sixty patients with clinical PD who had decreased HMR were enrolled. An autonomic symptom was evaluated using a head-up tilt test and the Composite Autonomic Severity Score (CASS). An I-123 MIBG scan and F-18 FP-CIT positron emission tomography (PET) were performed. All of the patients were classified into three groups according to the WR. The differences in patient characteristics and the imaging parameters among the three groups were evaluated, and a correlation analysis was also performed. RESULTS: The frequency of orthostatic hypotension was significantly different among the three groups. The difference in systolic pressure (dSysPr) and the difference in diastolic pressure (dDiaPr) of group 3 was significantly larger than those of groups 1 and 2. From the correlation analysis, it can be seen that age, Hoehn and Yahr (H&Y) stage, dSysPr, and dDiaPr had a weak positive correlation with the WR. The total CASS score was significantly higher in group 3 compared with groups 1 and 2. The WR had a moderate positive correlation with the cardiosympathetic score and the total CASS score. CONCLUSION: The WR is related to autonomic dysfunction. An I-123 MIBG cardiac scan is considered to be a good method to evaluate not only the differential diagnosis of Parkinson's disease but also the degree of autonomic dysfunction.

Nuclear Imaging of the Cardiac Sympathetic Nervous System: A Disease-Specific Interpretation in Heart Failure.

Abnormalities in the cardiac sympathetic nervous system have been documented in various heart diseases and have been directly implicated in their pathogenesis and disease progression. Noninvasive techniques using single-photon-emitting radiotracers for planar scintigraphy and single-photon emission computed tomography, and positron-emitting tracers for positron emissions tomography, have been used to characterize the cardiac sympathetic nervous system with norepinephrine analogs [123I]meta-iodobenzylguanidine for planar and single-photon emission computed tomography imaging and [11C]meta-hydroxyephedrine for positron emissions tomography. Their usefulness in prognostication and risk stratification for cardiac events has been demonstrated. This review bridges basic and clinical research and focuses on applying an understanding of tracer kinetics and neuronal biology, to aid in the interpretation of nuclear imaging of cardiac sympathetic innervation.

Successful treatment of refractory metastatic neuroblastoma with panobinostat in combination with chemotherapy agents and iodine-131-meta-iodobenzylguanidine therapy.

INTRODUCTION: Neuroblastoma commonly required multimodal therapy containing surgery, chemotherapy, radiotherapy, and immunotherapy. CASE REPORT: In our case, who had refractory metastatic neuroblastoma, we use histone deacetylase inhibitor (panobinostat) in combination with chemotherapy agents and iodine-131-meta-iodobenzylguanidine (MIBG) therapy. MANAGEMENT AND OUTCOME: This approach leads to successfully treat the patient. MIBG scan and bone marrow examination after therapy revealed no evidence of tumor. Now, she underwent autologous transplantation six months ago and free of tumor. CONCLUSION: Panobinostat can cause apoptosis induction in refractory metastatic neuroblastoma in combination with MIBG therapy and chemotherapy.

Neuroendocrine tumour of urinary bladder: a rare case of aggressively behaving primary well-differentiated neuroendocrine tumour with review of literature.

Neuroendocrine tumour (NET) of the urinary bladder (UB) is a rare entity and comprises of well-differentiated, small cell and large cell types. Small and large cell NET like that in lung and gastrointestinal tract have an aggressive nature and are considered high-grade disease. Well-differentiated NET has been thought to be localised and having a good prognosis. We report the first case of metastatic well-differentiated NET of the UB. Our case is a 44-year-old man with well-differentiated NET of UB presented with hepatic and peritoneal metastases on initial diagnosis. He was treated with metaiodobenzylguanidine (MIBG) therapy and had a modest survival of 16 months. The primary well-differentiated NETs can present as a metastatic disease with an aggressive nature. MIBG therapy can be considered as a useful option but overall prognosis is poor. Further research is needed for better understanding and better treatment protocol.

Diagnostic value of whole-body MRI in Opsoclonus-myoclonus syndrome: a clinical case series (3 case reports).

BACKGROUND: Opsoclonus-myoclonus syndrome (OMS) is a rare clinical disorder and typically occurs in association with occult neuroblastic tumor in pediatric patients. I-123 metaiodobenzylguanidine (mIBG) scintigraphy is widely adopted as screening procedure in patients with suspected neuroblastic tumor. Also, contrast-enhanced magnetic resonance imaging (MRI) or computed tomography (CT) are involved in the imaging workup, primarily for the assessment of the primary tumor region. However, the diagnostic value of whole-body MRI (WB-MRI) for the detection of occult neuroblastic tumor in pediatric patients presenting with OMS remains unknown. CASE PRESENTATION: We present three cases of patients with OMS, in whom WB-MRI revealed occult neuroblastic tumor masses, whereas scintigraphy was inconclusive: In a 17 months old girl with OMS, WB-MRI revealed a paravertebral mass. After thoracoscopic resection, histopathology revealed a ganglioneuroblastoma. A 13 months old boy presenting with OMS WB-MRI detected a tumor of the left adrenal gland; histopathology demonstrated a ganglioneuroblastoma after adrenalectomy. In a 2 year old boy with OMS, immunoscintigraphy at the time of diagnosis was inconclusive. At the age of 13 years, a WB-MRI was performed due to persistent neurological symptoms, revealing a paravertebral retroperitoneal mass, which was classified as ganglioneuroblastoma. CONCLUSION: In OMS, particularly in the setting of inconclusive scintigraphy, WB-MRI may be considered as a valuable alternative in the early phase of diagnostic work-up.

Transcutaneous electrical nerve stimulation attenuates cardiac sympathetic drive in heart failure: a 123MIBG myocardial scintigraphy randomized controlled trial.

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.

Late gadolinium enhancement on cardiac magnetic resonance combined with 123I- metaiodobenzylguanidine scintigraphy strongly predicts long-term clinical outcome in patients with dilated cardiomyopathy.

Late gadolinium enhancement (LGE) on cardiac magnetic resonance (CMR) is limited in its ability to detect diffuse interstitial fibrosis, which is commonly found in idiopathic dilated cardiomyopathy (DCM). On the other hand, Washout rate (WR) by cardiac 123I- metaiodobenzylguanidine (123I-MIBG) scintigraphy which evaluates cardiac sympathetic nervous function, is a useful tool for predicting the prognosis in DCM. We investigated the predictive value of the combination of two different types of examinations, LGE on CMR and WR by 123I-MIBG scintigraphy for outcomes in DCM compared with LGE alone. One-hundred forty-eight DCM patients underwent CMR and 123I-MIBG scintigraphy. Patients were divided into 4 groups according to the presence or absence of LGE and WR cut-off value of 45% for predicting prognosis based on receiver operating characteristic curve analysis. Cardiac deaths, re-hospitalization for heart failure, implantation of a left ventricular assist device, and life-threatening ventricular arrhythmias were defined as clinical events. Forty-two DCM patients reached the clinical events during the median follow-up for 9.1 years (interquartile range, 8.0-9.2 years).Multivariable Cox regression analysis identified WR≥45%+LGE positive group as an independent predictor of cardiac events (HR 3.18, 95%CI 1.36-7.45, p = 0.008). Notably, there was no significance in the cardiac event-free survival rate between the WR<45%+LGE positive and WR≥45%+LGE negative groups (p = 0.89). The combination of WR by 123I-MIBG scintigraphy and LGE on CMR, which evaluate different type of cardiac deterioration, serves as a stronger predictor of long-term outcomes in DCM patients than LGE alone.

Cardiac sympathetic innervation scintigraphy with 123I-meta-iodobenzylguanidine. Basis, protocols and clinical applications in Cardiology. / Gammagrafía de inervación simpática cardiaca con 123I-metayodobencilguanidina. Fundamento, protocolos y aplicaciones clínicas en Cardiología.

Imaging of cardiac sympathetic innervation is only possible by nuclear cardiology techniques and its assessment is key in the evaluation of and decision-making for patients with cardiac sympathetic impairment. This review includes the basis of cardiac sympathetic scintigraphy with 123I-meta-iodobenzylguanidine (123I-MIBG), recommended protocols, patient preparation, image acquisition and quantification, reproducibility, dosimetry, etc., and also the clinical indications for cardiac patients, mainly with regard to heart failure, arrhythmia, coronary artery disease, cardiotoxicity, including its contribution to establishing the indication for and monitoring the response to implantable cardiac devices, pharmacological treatment, heart transplantation and other.

Dosimetry-based high-activity therapy with 131I-metaiodobenzylguanidine (131I-mIBG) and topotecan for the treatment of high-risk refractory neuroblastoma.

PURPOSE: Patients with high-risk neuroblastoma have an increased risk of recurrence and relapse of disease and a very poor prognosis. 131I-metaiodobenzylguanidine (131I-mIBG) in combination with topotecan as a radiosensitizer can be an effective and relatively well-tolerated agent for the treatment of refractory neuroblastoma. The aim of this retrospective study was to evaluate response and outcome of combined therapy with 131I-mIBG and topotecan. METHODS: Ten patients, between 3 and 20 years of age, were included. Nine patients had been refractory to several lines of chemotherapy and radiotherapy. One patient with a very high-risk neuroblastoma had received only induction therapy. Response was graded according to the International Neuroblastoma Staging System. RESULTS: Regarding treatment response, two patients achieved complete remission, one with relapse at 16 months, five achieved a partial remission, four showed progression at between 1 and 18 months; two showed stable disease with progression at between 1 and 5 months, and one showed progressive disease. Eight of the ten patients died with overall survival between 4 and 63 months, and two patients were still alive without disease at the time of this report: 52 and 32 months (patient had received only induction therapy). Acute and subacute adverse effects were mainly haematological, and one patient developed a differentiated thyroid cancer. CONCLUSION: In patients with high-risk refractory neuroblastoma, administration of high activities of 131I-mIBG in combination with topotecan was found to be an effective therapy, increasing overall survival and progression-free survival. Further studies including a larger number of patients and using 131I-mIBG for first-line up-front therapy are warranted.