Improving susceptibility of neuroendocrine tumors to radionuclide therapies: personalized approaches towards complementary treatments.

Radionuclide therapies are an important tool for the management of patients with neuroendocrine neoplasms (NENs). Especially [131I]MIBG and [177Lu]Lu-DOTA-TATE are routinely used for the treatment of a subset of NENs, including pheochromocytomas, paragangliomas and gastroenteropancreatic tumors. Some patients suffering from other forms of NENs, such as medullary thyroid carcinoma or neuroblastoma, were shown to respond to radionuclide therapy; however, no general recommendations exist. Although [131I]MIBG and [177Lu]Lu-DOTA-TATE can delay disease progression and improve quality of life, complete remissions are achieved rarely. Hence, better individually tailored combination regimes are required. This review summarizes currently applied radionuclide therapies in the context of NENs and informs about recent advances in the development of theranostic agents that might enable targeting subgroups of NENs that previously did not respond to [131I]MIBG or [177Lu]Lu-DOTA-TATE. Moreover, molecular pathways involved in NEN tumorigenesis and progression that mediate features of radioresistance and are particularly related to the stemness of cancer cells are discussed. Pharmacological inhibition of such pathways might result in radiosensitization or general complementary antitumor effects in patients with certain genetic, transcriptomic, or metabolic characteristics. Finally, we provide an overview of approved targeted agents that might be beneficial in combination with radionuclide therapies in the context of a personalized molecular profiling approach.

EANM enabling guide: how to improve the accessibility of clinical dosimetry.

Dosimetry can be a useful tool for personalization of molecular radiotherapy (MRT) procedures, enabling the continuous development of theranostic concepts. However, the additional resource requirements are often seen as a barrier to implementation. This guide discusses the requirements for dosimetry and demonstrates how a dosimetry regimen can be tailored to the available facilities of a centre. The aim is to help centres wishing to initiate a dosimetry service but may not have the experience or resources of some of the more established therapy and dosimetry centres. The multidisciplinary approach and different personnel requirements are discussed and key equipment reviewed example protocols demonstrating these factors are given in the supplementary material for the main therapies carried out in nuclear medicine, including [131I]-NaI for benign thyroid disorders, [177Lu]-DOTATATE and 131I-mIBG for neuroendocrine tumours and [90Y]-microspheres for unresectable hepatic carcinoma.

68 Ga-DOTATATE PET and functional imaging in pediatric pheochromocytoma and paraganglioma.

Pheochromocytoma and paraganglioma (PPGL) are rare neuroendocrine tumors in childhood. Up to 40% of PPGL are currently thought to be associated with a hereditary predisposition. Nuclear medicine imaging modalities such as fluorodeoxyglucose positron emission tomography (18 F-FDG PET), 68 Ga-DOTATATE PET, and 123 I-metaiodobenzylguanidine (123 I-MIBG) scintigraphy play an essential role in the staging, response assessment, and determination of suitability for targeted radiotherapy in patients with PPGL. Each of these functional imaging modalities targets a different cellular characteristic and as such can be complementary to anatomic imaging and to each other. With the recent US Food and Drug Administration approval and increasing use of 68 Ga-DOTATATE for imaging in children, the purpose of this article is to use a case-based approach to highlight both the advantages and limitations of DOTATATE imaging as it is compared to current radiologic imaging techniques in the staging and response assessment of pediatric PPGL, as well as other neuroendocrine malignancies.

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.

The role of microscopic bone marrow examination and [123I]MIBG scintigraphy in detection of bone marrow involvement in patients with neuroblastoma.

OBJECTIVES: For the detection of bone marrow (BM) metastases in patients with neuroblastoma, microscopic BM examination and [123I]MIBG scintigraphy are advised. The aims of this study were to assess the concordance of [123I]MIBG and microscopic BM examination (aspirate and biopsy) in detecting BM involvement and to compare invasive disease in BM biopsies and aspirates, both at diagnosis and before autologous stem cell collection (ASCC). METHODS: Fifty-five patients with stage 4 or stage 4S disease were included, and 37 of them received an autologous hematopoietic stem cell transplantation (AHSCT). The concordance rate was measured and paired binary data were analysed by the McNemar test to look for a systematic difference between diagnostic tests. RESULTS: At diagnosis and before ASCC, we found acceptable concordance rates for [123I]MIBG versus microscopic BM examination (77.1% and 85.3% respectively). Discordant results were found in both directions and at both time points. The concordance rate for biopsy versus aspirate at diagnosis was 80.6%, however, before ASCC a much higher concordance rate between both microscopic examinations was found (94.1%). While none of the aspirates showed neuroblastoma cells before ASCC, two biopsies still showed tumor invasion. CONCLUSION: For patients with neuroblastoma, a [123I]MIBG scintigraphy and a microscopic examination of BM aspirate and its biopsy should be used as complementary tools in the evaluation of BM involvement, and this both at diagnosis and during treatment (before ASCC).

Clinical implication of residual MIBG-positive disease in the follow-up of high-risk neuroblastoma treated with tandem high-dose chemotherapy and autologous stem cell transplantation.

BACKGROUND: The implication of residual metaiodobenzylguanidine (MIBG)-positive disease in the era of tandem high-dose chemotherapy (HDCT) with autologous stem cell transplantation (auto-SCT) has not yet been established in neuroblastoma. Moreover, most published studies have not evaluated the long-term prognosis of patients with residual MIBG-positive disease following treatment completion. Therefore, we investigated the prognostic significance of residual MIBG-positive disease at each treatment phase and after treatment completion. METHODS: We assessed MIBG scans labeled with either iodine-123 (123 I) or 131 I from 150 patients with MIBG-avid and high-risk neuroblastoma enrolled in the NB-2004, -2009, and -2014 trials at postinduction, posttandem HDCT/auto-SCT, and completion of treatment. RESULTS: The residual MIBG-positive disease at postinduction and posttandem HDCT/auto-SCT evaluation was highly correlated with the risk of progression. However, at treatment completion, there was no significant difference in survival and risk of progression between patients with residual MIBG-positive disease and MIBG-negative patients. Patients with persistent MIBG-positive disease at the end of treatment were more likely to have indolent tumor characteristics, such as favorable histology at diagnosis, lower incidence of MYCN amplification, and slow response to chemotherapy. CONCLUSION: Residual MIBG-positive disease during treatment predicted unfavorable outcomes for patients with high-risk neuroblastoma, even under tandem HDCT/auto-SCT. However, persistent MIBG uptake at the completion of all treatments may not always indicate an active disease.

High-Specific-Activity-131I-MIBG versus 177Lu-DOTATATE Targeted Radionuclide Therapy for Metastatic Pheochromocytoma and Paraganglioma.

Targeted radionuclide therapies (TRT) using 131I-metaiodobenzylguanidine (131I-MIBG) and peptide receptor radionuclide therapy (177Lu or 90Y) represent several of the therapeutic options in the management of metastatic/inoperable pheochromocytoma/paraganglioma. Recently, high-specific-activity-131I-MIBG therapy was approved by the FDA and both 177Lu-DOTATATE and 131I-MIBG therapy were recommended by the National Comprehensive Cancer Network guidelines for the treatment of metastatic pheochromocytoma/paraganglioma. However, a clinical dilemma often arises in the selection of TRT, especially when a patient can be treated with either type of therapy based on eligibility by MIBG and somatostatin receptor imaging. To address this problem, we assembled a group of international experts, including oncologists, endocrinologists, and nuclear medicine physicians, with substantial experience in treating neuroendocrine tumors with TRTs to develop consensus and provide expert recommendations and perspectives on how to select between these two therapeutic options for metastatic/inoperable pheochromocytoma/paraganglioma. This article aims to summarize the survival outcomes of the available TRTs; discuss personalized treatment strategies based on functional imaging scans; address practical issues, including regulatory approvals; and compare toxicities and risk factors across treatments. Furthermore, it discusses the emerging TRTs.

68Ga-DOTATATE and 123I-mIBG as imaging biomarkers of disease localisation in metastatic neuroblastoma: implications for molecular radiotherapy.

PURPOSE: Iodine-131-labelled meta-iodobenzylguanidine (I-mIBG) and lutetium-177-labelled DOTATATE (Lu-DOTATATE) are used for molecular radiotherapy of metastatic neuroblastoma. These are taken up by the noradrenaline transporter (NAT) and the somatostatin receptor subtype 2 (SSTR-2), respectively. Scintigraphy of iodine-123-labelled meta-iodobenzylguanidine (I-mIBG) and gallium-68 DOTATATE (Ga-DOTATATE) PET are used to select patients for therapy. These demonstrate the extent and location of tumour, and avidity of uptake by cells expressing NAT and SSTR-2, respectively. This study compared the similarities and differences in the anatomical distribution of these two imaging biomarkers in an unselected series of patients with metastatic neuroblastoma undergoing assessment for molecular radiotherapy. METHODS: Paired whole-body planar I-mIBG views and Ga-DOTATATE maximum intensity projection PET scans of metastatic neuroblastoma patients were visually compared. The disease extent was assessed by a semiquantitative scoring method. RESULTS: Paired scans from 42 patients were reviewed. Ga-DOTATATE scans were positive in all patients, I-mIBG scans were negative in two. In two patients, there was a mismatch, with some lesions identified only on the I-mIBG scan, and others visible only on the Ga-DOTATATE scan. CONCLUSION: Ga-DOTATATE and I-mIBG scans yield complementary information. For a more comprehensive assessment, consideration could be given to the use of both I-mIBG and Ga-DOTATATE imaging scans. Because of the heterogeneity of distribution of molecular targets revealed by these techniques, a combination of both I-mIBG and Lu-DOTATATE molecular radiotherapy may possibly be more effective than either alone.

Feasibility and effectiveness of treatment strategy of tandem high-dose chemotherapy and autologous stem cell transplantation in combination with 131 I-MIBG therapy for high-risk neuroblastoma.

This study was performed to evaluate the safety and effectiveness of tandem HDCT/ASCT combined with targeted radiotherapy using 131 I-MIBG for high-risk neuroblastoma. Patients with high-risk neuroblastoma were treated with 8 to 10 cycles of induction chemotherapy before tandem HDCT/ASCT. Patients received 131 I-MIBG treatment before the second HDCT/ASCT. Local radiotherapy and maintenance therapy were performed after tandem HDCT/ASCT. Between 2012 and 2016, 19 patients were diagnosed with high-risk neuroblastoma in our institution and 18 of them received tandem HDCT/ASCT combined with 131 I-MIBG therapy. For the first HDCT/ASCT regimen, 12 patients received busulfan/melphalan and six patients received melphalan/etoposide/carboplatin. The second HDCT included ThioCy. The median dose of 131 I-MIBG was 17.2 mCi/kg for the first eight patients, while 12 patients in the latter period of the study received reduced dose of 10.7 mCi/kg. The 5-year OS and EFS rates were 79% and 61%, respectively, for all 19 patients with high-risk neuroblastoma, and 83% and 64%, respectively, for 18 patients who completed tandem HDCT/ASCT combined with 131 I-MIBG therapy. Six patients experienced disease relapse and five patients died. Treatment-related mortality was not observed. Among 15 evaluable patients, 11 patients (73%) developed hypothyroidism, six patients (40%) had CKD, and six patients (40%) had growth failure. Hypothyroidism and growth failure were less frequent in patients who received reduced doses of 131 I-MIBG therapy. Tandem HDCT/ASCT combined with HD 131 I-MIBG therapy could be feasible for patients with high-risk neuroblastoma with acceptable toxicity profiles and favorable outcomes.

Clinical usefulness of myocardial scintigraphy in patients with vasospastic angina.

BACKGROUND: Myocardial scintigraphy is defined as class IIb in the Japanese Circulation Society guideline for diagnosis of vasospastic angina (VSA). However, Caucasian guidelines had no classification of cardiac scintigraphy for diagnosis of VSA. OBJECTIVES: To clarify the clinical usefulness of myocardial scintigraphy, we analyzed the sensitivity and specificity of each cardiac scintigraphy. METHODS: We extracted the 136 papers of myocardial scintigraphy from the PubMed database from 1980 to 2018 in patients with VSA. Finally we analyzed the 88 papers including 33 papers of201-thallium (Tl), 10 papers of 123I beta-methyl 15-para-iodophenyl 3(R, S)-methylpentadecanoic acid (BMIPP), 9 papers of 123I-metaiodobenzylguanidine (MIBG), 4 papers of 99mTc-sestamibi (MIBI: methoxy-isobutyl-isonitrile), and 2 papers of tetrofosmin to investigate the sensitivity and specificity of each tracer. RESULTS: Tl, BMIPP, or MIBG cardiac scintigraphy were useful to diagnose patients with VSA, because sensitivity was 57-73%. Specificity was 55-83%. Sensitivity of left circumflex artery was significantly lower than other vessels. BMIPP imaging may be helpful for clinical course of VSA. However, myocardial scintigraphic abnormal findings may not always show the ischemic memory due to coronary artery spasm. CONCLUSIONS: Recent cardiologists do not perform hyperventilation tests or MIBG scintigraphy for diagnosis of coronary spasm. After understanding the flow of the times, cardiologists should use Tl or BMIPP myocardial scintigraphy for VSA as one of supplementary tools in the real world.

Long-Term Outcomes of 125 Patients With Metastatic Pheochromocytoma or Paraganglioma Treated With 131-I MIBG.

CONTEXT: Prognosis of metastatic pheochromocytoma/paraganglioma following 131-Iodine metaiodobenzylguanidine (MIBG) is incompletely characterized due to small samples and shorter follow-up in these rare, often indolent tumors. OBJECTIVE: To describe long-term survival, frequency, and prognostic impact of imaging, biochemical, and symptomatic response to 131-I MIBG. DESIGN: Retrospective chart and imaging review at a tertiary referral center. PATIENTS: Six hundred sixty-eight person-years of follow-up in 125 patients with metastatic pheochromocytoma/paraganglioma with progression through prior multimodal treatment. INTERVENTION: Median 18 800 MBq 131-I MIBG. MAIN OUTCOME MEASURES: Overall survival, Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST) imaging response, symptomatic response per chart review, and biochemical response (20% change over 2 consecutive assays of catecholamines, vanillylmandelic acid, metanephrines, or chromogranin A). RESULTS: Median survival standard deviation [SD] from diagnosis was 11.5 years [2.4]; following metastasis, 6.5 years [0.8]; post treatment, 4.3 years [0.7]. Among 88 participants with follow-up imaging, 1% experienced complete response, 33% partial response, 53% stability, and 13% progression. Fifty-one percent showed subsequent progression, median progression-free survival [SD] of 2.0 years [0.6]. Stability/response vs progression at first imaging follow-up (3-6 months) predicted improved survival, 6.3 vs 2.4 years (P = 0.021). Fifty-nine percent of 54 patients demonstrated biochemical response. Fifty percent of these relapsed, with median time to laboratory progression [SD] of 2.8 years [0.7]. Biochemical response did not predict extended survival. Seventy-five percent of 83 patients reported improvement in pretreatment symptoms, consisting primarily of pain (42%), fatigue (27%), and hypertension (14%). Sixty-one percent of these patients experienced subsequent symptomatic progression at median [SD] 1.8 years [0.4]. Symptomatic response did not predict extended survival. CONCLUSIONS: Imaging, symptomatic, and laboratory response to multimodal treatment including high-dose 131-I MIBG were achieved on long-term follow-up in metastatic pheochromocytoma or paraganglioma. Imaging response at 3 to 6 months was prognostic.

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.

Impact of short-acting loop diuretic doses and cardiac sympathetic nerve abnormalities on outcomes of patients with reduced left ventricular function.

Recent studies reported that high doses of short-acting loop diuretics are associated with poor outcomes in patients with heart failure (HF). Short-acting loop diuretics have been shown to activate the renin-angiotensin system (RAS) and have no favorable effects on cardiac sympathetic nervous system (SNS) activity. The goal of this study is to investigate the relationship between daily doses of furosemide and the outcomes of patients with left ventricular dysfunction (LVD) from the viewpoint of cardiac SNS abnormalities using iodine-123-labeled metaiodobenzylguanidine (l-MIBG) myocardial scintigraphy.We enrolled 137 hospitalized patients (62.5 ±â€Š14.2 years old, 103 men) with LVEF < 45% who underwent l-MIBG myocardial scintigraphy. A delayed heart-to-mediastinum ratio (delayed HMR) was assessed using l-MIBG scintigraphy. Cardiac events were defined as cardiac death or re-hospitalization due to the deterioration of HF. Cox proportional hazard analysis was used to identify predictors of cardiac events.Cardiac events occurred in 57 patients in a follow-up period of 33.1 ±â€Š30 months. In a multivariate Cox proportional hazard analysis, delayed HMR and furosemide doses were identified as independent predictors of cardiac events (P = .0042, P = .033, respectively). Inverse probability of treatment weighting Cox modeling showed that the use of furosemide (≥40 mg /day) was associated with cardiac events with a hazard ratio of 1.96 (P = .003). In the Kaplan-Mayer analysis, the cardiac event-free survival rate was significantly lower in patients treated with high doses of furosemide (≥60 mg/day vs 40-60 mg/day vs <40 mg/day, the Log-rank test P < .0001). In a receiver-operating characteristic (ROC) analysis, the cut-off value for cardiac events was 40 mg/day of furosemide. The cardiac event-free rate was significantly lower in patients with delayed HMR <1.8 (median value) and receiving furosemide ≥40 mg/day than in other patients (the Log-rank test P < .0001). Significant differences in cardiac event rates according to furosemide doses among patients with delayed HMR <1.8 were observed among patients without ß-blocker therapy (P = .001), but not among those with ß-blocker therapy (P = .127).The present results indicate that a relationship exists between higher doses of furosemide and poor outcomes. The prognosis of HF patients with severe cardiac SNS abnormalities receiving high-dose short-acting loop diuretics is poor.

Incorporation of high-dose 131I-metaiodobenzylguanidine treatment into tandem high-dose chemotherapy and autologous stem cell transplantation for high-risk neuroblastoma: results of the SMC NB-2009 study.

BACKGROUND: In our previous SMC NB-2004 study of patients with high-risk neuroblastomas, which incorporated total-body irradiation (TBI) with second high-dose chemotherapy and autologous stem cell transplantation (HDCT/auto-SCT), the survival rate was encouraging; however, short- and long-term toxicities were significant. In the present SMC NB-2009 study, only TBI was replaced with 131I-meta-iodobenzylguanidine (MIBG) treatment in order to reduce toxicities. METHODS: From January 2009 to December 2013, 54 consecutive patients were assigned to receive tandem HDCT/auto-SCT after nine cycles of induction chemotherapy. The CEC (carboplatin + etoposide + cyclophosphamide) regimen and the TM (thiotepa + melphalan) regimen with (for metastatic MIBG avid tumors) or without (for localized or MIBG non-avid tumors) 131I-MIBG treatment (18 or 12 mCi/kg) were used for tandem HDCT/auto-SCT. Local radiotherapy, differentiation therapy with 13-cis-retinoic acid, and immunotherapy with interleukin-2 were administered after tandem HDCT/auto-SCT. RESULTS: Fifty-two patients underwent the first HDCT/auto-SCT and 47 patients completed tandem HDCT/auto-SCT. There was no significant immediate toxicity during the 131I-MIBG infusion. Acute toxicities during the tandem HDCT/auto-SCT were less severe in the NB-2009 study than in the NB-2004 study. Late effects such as growth hormone deficiency, cataracts, and glomerulopathy evaluated at 3 years after the second HDCT/auto-SCT were also less significant in the NB-2009 study than in NB-2004 study. There was no difference in the 5-year event-free survival (EFS) between the two studies (67.5 ± 6.7% versus 58.3 ± 6.9%, P = 0.340). CONCLUSIONS: Incorporation of high-dose 131I-MIBG treatment into tandem HDCT/auto-SCT could reduce short- and long-term toxicities associated with TBI, without jeopardizing the survival rate. TRIAL REGISTRATION: ClinicalTrials.gov NCT03061656.

New development of diagnosis and treatment for Parkinson's disease.

New methods for the diagnosis and new treatments for Parkinson's disease (PD) were explained. As imaging tools, neuromelanin imaging using brain MRI, meta-iodobenzylguanidine (MIBG) cardiac scintigraphy, dopamine transporter scintigraphy, and transcranial sonography were introduced. Olfactory dysfunction and REM sleep behavior disorders (RBD), which are important non-motor symptoms, and the new Clinical Criteria for PD launched by Movement Disorder Society (MDS) were also described. Investigative new medications and new anti-PD medications, which recently became available in Japan, were introduced. I explained the rationale of early treatment, strategy of initial treatment, the significance of continuous dopaminergic stimulation, strategy of treatment for advanced PD, and deep brain stimulation as a surgical treatment together with promising new treatments including gene therapy and cell transplantation.

Prolonged Isotretinoin in Ultra High-Risk Neuroblastoma.

Patients with high-risk neuroblastoma remain a therapeutic challenge with significant numbers of patients failing to respond sufficiently to initial therapy. These patients with poor response to induction are considered as ultra high-risk and are in need of novel treatment strategies. Isotretinoin is part of the standard of care treatment for patients with high-risk disease who undergo high-dose chemotherapy with autologous stem cell rescue although some have questioned the optimal administration schedule. Prolonged use of isotretinoin was well tolerated and may have contributed to long-term survival in a group of patients with ultra high-risk neuroblastoma.

HIGH-DOSE 131I-MIBG THERAPIES IN CHILDREN: FEASIBILITY, PATIENT DOSIMETRY AND RADIATION EXPOSURE TO WORKERS AND FAMILY CAREGIVERS.

The objective of the present multicentric phase II study (MIITOP) was to determine the response rate, survival and toxicity of tandem infusions of 131I-meta-iodobenzylguanidine (mIBG) and topotecan in children with relapsed/refractory neuroblastoma. High-dose 131I-mIBG therapy programme requires a deal of planning, availability of hospital resources and the commitment of individuals with training and expertise in multiple disciplines. Here in the present study, procedures and the results of patient's dosimetry, as well as family and worker's exposures, were reported for the patients treated in Lille. A total of 15 children were treated with 131I-mIBG between 2009 and 2011 according to the MIITOP protocol. High activity of 131I-mIBG (444 MBq kg-1) was administered on Day 0. In vivo dosimetry was used to calculate a second activity, to be given on Day 21, to obtain a total whole body absorbed dose of 4 Gy. Family and worker's exposures were performed too. The injected activity by treatment was from 703 to 11470 MBq. Total whole body absorbed dose by patient ranged from 2.74 to 5.2 Gy. Concerning relatives, whole body exposure ranged from 0.018 to 2.8 mSv. The mean whole body exposure of the radiopharmacist was 4.4 nSv MBq-1, and the mean exposure of fingers ranged from 0.18 to 0.24 µSv MBq-1 according to each finger. The mean whole body exposure was 33.6 and 20.2 µSv d-1 per person, for night nurses and day nurses, respectively. Exposure of doctors was less than 5 µSv d-1. Under strict radiation protection precautions, this study shows the feasibility of high-activity 131I-mIBG therapy in France.

Relationship of promising methods in the detection of anthracycline-induced cardiotoxicity in breast cancer patients.

PURPOSE: It remains challenging to identify patients at risk of anthracycline-induced cardiotoxicity. To better understand the different risk-stratifying approaches, we evaluated (123)I-metaiodobenzylguanidine ((123)I-mIBG) scintigraphy and its interrelationship with conventional echocardiography, 2D strain imaging and several biomarkers. METHODS: We performed (123)I-mIBG scintigraphy, conventional and strain echocardiography and biomarker (NT-proBNP, TNF-α, galectin-3, IL-6, troponin I, ST-2 and sFlt-1) assessment in 59 breast cancer survivors 1 year after anthracycline treatment. Interobserver and intermethod variability was calculated on planar and SPECT (123)I-mIBG scintigraphy, using the heart/mediastinum (H/M) ratio and washout (WO). Pearson's r and multivariate analyses were performed to identify correlations and independent predictors of (123)I-mIBG scintigraphy results. RESULTS: Delayed planar anterior whole-heart ROI (WH) H/M ratios and WO were the most robust (123)I-mIBG parameters. Significant correlations were observed between (123)I-mIBG parameters and several conventional echo parameters, global longitudinal and radial strain (GLS and GRS) and galectin-3. The highest Pearson's r was observed between delayed H/M ratio and GRS (Pearson's r 0.36, p = 0.01). Multivariate analysis showed that GRS was the only independent predictor of the delayed WH H/M ratio (p = 0.023). CONCLUSION: The delayed planar H/M ratio is the most robust (123)I-mIBG parameter. It correlates with several conventional echocardiographic parameters, GLS, GRS and galectin-3. Of these, only GRS predicts the H/M ratio.