Metaiodobenzylguanidine Therapy Research Articles

Trends in analgesia-sedation of pediatric patients receiving I-131 MIBG in the pediatric intensive care unit: A report from the Pediatric Health Information System database.

Children with neuroblastoma receiving I-131 metaiodobenzylguanidine (MIBG) therapy require sedation-analgesia for strict radiation safety precautions during MIBG infusion and clearance. We evaluated the sedation-analgesia trends of patients undergoing MIBG therapy using the Pediatric Health Information System (PHIS) database. Retrospective data from 476 patient encounters from the PHIS from 2010 to 2019. Total 240/476 (50.45%) children evaluated were under 6years of age. Compared to 2010, in 2018 there was a decrease in benzodiazepine infusion use (60% vs. 40%, p<.04), as well as a decrease in use of opiate infusion (35% vs. 25%, p<.001). Compared to 2010, in 2018 we report an increase in the use of ketamine (from 5% to 10%, p<.002), as well as an increase in dexmedetomidine use (0% vs. 30%, p<.001). Dexmedetomidine was the most used medication in the 0-3years age group compared to children older than 3years of age (14.19% vs. 5.80%, p<.001). Opiate was the most used medication in children greater than 3years compared to the 0-3-year age group (36.23 vs. 23.87, p<.05). Using PHIS data, we discovered considerable variability in the medications used for sedation in patients undergoing MIBG therapy. Although benzodiazepines and opioids were the most used agents, there was a trend toward decreasing use of benzodiazepines and opioids in these patients. Furthermore, there has been an increasing trend in the use of dexmedetomidine and ketamine.

Safety and efficacy of multiple-dose versus single-dose MIBG therapy in patients with refractory pheochromocytoma and paraganglioma: a single-center retrospective analysis.

To investigate the incidence of adverse events (AEs) following single and multiple administrations of I-131 metaiodobenzylguanidine (MIBG) therapy for inoperable pheochromocytomas and paragangliomas (PPGLs). A single-center retrospective study was conducted on patients with inoperable PPGLs who underwent I-131 MIBG therapy between January 2000 and December 2020. A total of 28 patients with available electronic medical records were included. The treatment consisted of a single intravenous administration of 150mCi (5.55GBq) of I-131 MIBG. We evaluated the first MIBG treatment and repeated MIBG treatments performed within 200days of the previous treatment. AEs for each treatment were evaluated using CTCAE version 4.0, and the statistical analysis was conducted at a significance level of p < 0.05. Objective response based on RECIST 1.1 criteria and biochemical response based on urinary catecholamines were assessed. The study included a total of 63 administrations, consisting of 28 single administrations (SAs), including the first administration for all 28 cases, and 35 multiple administrations (MAs), which included the second or later administrations. Hematological AEs were evaluable for 23 SAs and 29 MAs. Grade 3 or higher leukopenia occurred in 9.8% of all administrations, and Grade 3 or higher lymphopenia in 23.5%; both were manageable through observation. There were no significant differences in clinical AE Grades 1-2 (p = 0.32), hematological AE Grades 1-2 (p = 0.22), or hematological AE Grades 3-4 (p = 0.12) between MAs and SAs. Statistical analysis for each type of AE revealed significant increases in leukopenia (p < 0.01) and lymphopenia (p = 0.04). No significant difference in anemia, thrombocytopenia, or neutropenia was observed between MAs and SAs. There was no significant increase in the incidence rate of Grade 3 or higher hematological AEs for any of the parameters. The objective response rate was 0% for SAs and 36% for MAs. Biochemical response rates were 18% for SAs and 67% for MAs. In I-131 MIBG therapy for PPGLs, multiple administrations significantly increased only Grade 1 or 2 lymphopenia and leukopenia compared to single administration.

Advances in Radioligand Theranostics in Oncology.

Theranostics with radioligands (radiotheranostics) has played a pivotal role in oncology. Radiotheranostics explores the molecular targets expressed on tumor cells to target them for imaging and therapy. In this way, radiotheranostics entails non-invasive demonstration of the in vivo expression of a molecular target of interest through imaging followed by the administration of therapeutic radioligand targeting the tumor-expressed molecular target. Therefore, radiotheranostics ensures that only patients with a high likelihood of response are treated with a particular radiotheranostic agent, ensuring the delivery of personalized care to cancer patients. Within the last decades, a couple of radiotheranostics agents, including Lutetium-177 DOTATATE (177Lu-DOTATATE) and Lutetium-177 prostate-specific membrane antigen (177Lu-PSMA), were shown to prolong the survival of cancer patients compared to the current standard of care leading to the regulatory approval of these agents for routine use in oncology care. This recent string of successful approvals has broadened the interest in the development of different radiotheranostic agents and their investigation for clinical translation. In this work, we present an updated appraisal of the literature, reviewing the recent advances in the use of established radiotheranostic agents such as radioiodine for differentiated thyroid carcinoma and Iodine-131-labeled meta-iodobenzylguanidine therapy of tumors of the sympathoadrenal axis as well as the recently approved 177Lu-DOTATATE and 177Lu-PSMA for differentiated neuroendocrine tumors and advanced prostate cancer, respectively. We also discuss the radiotheranostic agents that have been comprehensively characterized in preclinical studies and have shown some clinical evidence supporting their safety and efficacy, especially those targeting fibroblast activation protein (FAP) and chemokine receptor 4 (CXCR4) and those still being investigated in preclinical studies such as those targeting poly (ADP-ribose) polymerase (PARP) and epidermal growth factor receptor 2.

Blood glucose level affects iodine-123 labeled MIBG uptake in the lung

The aim of this study was to evaluate the correlation of blood glucose and the metaiodobenzylguanidine (MIBG) uptake in lung and compare the difference between the lung uptake of MIBG in diabetic and non-diabetic patients. Patients who underwent iodine-123 MIBG whole-body scan (WBS) in the Department of Nuclear Medicine Seoul National University Hospital between January 2014 and July 2022 were recruited and analyzed. Semi-quantitative analysis of the mean value of lung-to-mediastinum ratio (LMR) was performed. Correlation was analyzed with Pearson correlation test and mean difference was analyzed with independent t-test. There were 36 patients in diabetic group and 57 patients in non-diabetic group with mean age of 56 &amp;plusmn; 14.1 and 52 &amp;plusmn; 14.6 years, respectively. The mean 24-h LMRs in diabetic and non-diabetic groups were 1.38 &amp;plusmn; 0.20 and 1.17 &amp;plusmn; 0.14, respectively. Fasting glucose showed a mean value of 136 &amp;plusmn; 37.7 and 96 &amp;plusmn; 8.2 mg/dL, respectively. There was a significant positive correlation in diabetic (r = 0.397; P = 0.016) and non-diabetic groups (r = 0.579; P &lt;0.001) with significant mean difference (0.21; P &lt;0.001). In conclusion, lung uptake of MIBG is positively correlated with blood sugar level, with diabetic patients displaying higher lung uptake of MIBG compared with non-diabetic patients. In addition, higher lung uptake of MIBG is evident in patients with higher fasting glucose level and even in non-diabetic patients. Thus, in the situations where MIBG therapy is required, the radiation dose to the lungs must be carefully adjusted for patients with high blood sugar level.

Predictive Factors of Early 18F-Fluorodeoxyglucose-Positron Emission Tomography Response to [131I] Metaiodobenzylguanidine Treatment for Unresectable or Metastatic Pheochromocytomas and Paragangliomas

Introduction: Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumours that produce catecholamines. [131I] metaiodobenzylguanidine (MIBG)-avid unresectable or metastatic PPGLs are treated with [131I] MIBG radionuclide therapy. A high metabolic tumour volume (MTV) and total lesion glycolysis (TLG) can be poor prognostic factors. Therefore, we evaluated the metabolic responses to [131I] MIBG therapy with respect to other clinical factors. Methods: A retrospective study was performed on a series of 20 patients who underwent FDG-PET before and after [131I] MIBG therapy. We administered a single dose comprising 5.5 GBq of [131I] MIBG (usually three times; for some cases, the number was increased or decreased considering treatment efficacy and side effects). Semi-quantitative parameters (SUVmax, MTV, and TLG) were calculated using the liver SUV (mean + 3 × standard deviation) as a threshold on Metavol software. The semi-quantitative FDG-PET parameters for determining response were complete response (CR), partial remission (PR), stable disease (SD), and progressive disease (PD). We divided our study participants into the PD and non-PD groups (i.e., SD + PR + CR) and compared the overall survival (OS) between the two groups. Subsequently, we evaluated the relationships between metabolic response and age, sex, tumour type, metastatic site, chemotherapy or external radiation history, and 24-h urine catecholamine levels by univariate logistic regression analyses. Results: Both MTV-based and TLG-based criteria for PD versus non-PD were significant prognostic factors (p = 0.014). However, treatment response as evaluated based on the SUVmax was not a significant predictor. Higher urinary dopamine levels were associated with poor metabolic response as assessed by MTV and TLG (OR 1.002, p = 0.029). The other clinical parameters were non-significant. Conclusion: Poor metabolic response (measured with MTV and TLG) to [131I] MIBG therapy in unresectable or metastatic PPGLs was related to shorter OS. The poor metabolic response can be predicted using the urinary dopamine level.

Prognostic value of [18F]FDG-PET prior to [131I]MIBG treatment for pheochromocytoma and paraganglioma (PPGL).

Pheochromocytomas and paragangliomas (PPGLs) are rare tumors arising from the neural crest cells that form the sympathetic and parasympathetic nervous systems. Radiotherapy with [131I]metaiodobenzylguanidine (MIBG) is recommended for unresectable PPGLs. We investigated the usefulness of the metabolic tumor volume (MTV) and total lesion glycolysis (TLG) derived from [18F]fluorodeoxyglucose-positron emission tomography (FDG-PET) for predicting the prognosis of patients with unresectable PPGL(s) before receiving [131I]MIBG therapy. We retrospectively analyzed the cases of 25 patients with unresectable PPGLs treated with [131I]MIBG at our hospital between 2001 and 2020. The MTV and TLG were measured in reference to liver accumulation. We divided the patients into two groups based on median values for the maximum standardized uptake value (SUVmax), MTV, and TLG, and evaluated between-group differences using log-rank tests. Cox proportional hazards models were used to determine whether there were significant differences in prognosis with respect to tumor type (pheochromocytoma vs. paraganglioma), site of metastasis, age, past treatment (chemotherapy, external radiation or [131I]MIBG treatment before the current [131I]MIBG treatment), urinary catecholamine, SUVmax, MTV, and TLG. The median follow-up time was 42months (range 2-136months). The median overall survival was 63months. The overall survival (OS) was significantly shorter in the high-MTV group (log-rank test, p = 0.049) and the high-TLG group (p = 0.049), with no significant difference between the high- and low-SUVmax groups (p = 0.19). Likewise, there was no significant difference in prognosis according to pheochromocytoma or paraganglioma, metastasis location, age, or prior chemotherapy. A history of external radiation before [131I]MIBG treatment was associated with a significantly worse prognosis (hazard ration [HR] = 7.95, p = 0.0018). Urinary adrenaline and noradrenaline were not significant prognostic factors (p = 0.70, p = 0.25, respectively), but urinary dopamine did predict a worse outcome (p = 0.022). There was no increased risk of death for higher SUVmax or TLG (p = 0.63 and 0.057, respectively), but higher MTV did predict a worse outcome (HR = 7.27, p = 0.029). High MTV and high TLG were significantly associated with a poor prognosis after [131I]MIBG therapy for PPGLs. Other treatment strategies for such patients may need to be explored.

Failure modes and effects analysis of pediatric I-131 MIBG therapy: Program design and potential pitfalls.

There is growing interest among pediatric institutions for implementing iodine-131 (I-131) meta-iodobenzylguanidine (MIBG) therapy for treating children with high-risk neuroblastoma. Due to regulations on the medical use of radioactive material (RAM), and the complexity and safety risks associated with the procedure, a multidisciplinary team involving radiation therapy/safety experts is required. Here, we describe methods for implementing pediatric I-131 MIBG therapy and evaluate our program's robustness via failure modes and effects analysis (FMEA). We formed a multidisciplinary team, involving pediatric oncology, radiation oncology, and radiation safety staff. To evaluate the robustness of the therapy workflow and quantitatively assess potential safety risks, an FMEA was performed. Failure modes were scored (1-10) for their risk of occurrence (O), severity (S), and being undetected (D). Risk priority number (RPN) was calculated from a product of these scores and used to identify high-risk failure modes. A total of 176 failure modes were identified and scored. The majority (94%) of failure modes scored low (RPN <100). The highest risk failure modes were related to training and to drug-infusion procedures, with the highest S scores being (a) caregivers did not understand radiation safety training (O=5.5, S=7, D=5.5, RPN=212); (b) infusion training of staff was inadequate (O=5, S=8, D=5, RPN=200); and (c) air in intravenous lines/not monitoring for air in lines (O=4.5, S=8, D=5, RPN=180). Through use of FMEA methodology, we successfully identified multiple potential points of failure that have allowed us to proactively mitigate risks when implementing a pediatric MIBG program.

I-131 metaiodobenzylguanidine therapy is a significant treatment option for pheochromocytoma and paraganglioma.

Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumours of chromaffin cells. Several modalities are currently available to treat patients with PPGL. These treatment modalities include surgery, chemotherapy, molecular targeted therapy and radiopharmaceuticals. I-131 metaiodobenzylguanidine (mIBG), a classic radiopharmaceutical, can be taken up through specific receptors and sited into many, but not all, PPGL cells. Many studies have investigated the efficacy and toxicity of I-131 mIBG therapy. These studies reported significant results in terms of objective, hormonal and symptomatic responses as well as tolerable toxicities in patients. This article reviews the reported experiences of patients who underwent I-131 mIBG therapy for PPGL with a focus on functions and deficiencies of the therapy.

Metastatic Extra-Adrenal Pheochromocytoma with Single Kidney and Renal Compromise: A Case Report of Excellent Response, Tolerability, and Outcome to a Modified Regimen of 131I-mIBG, and Decision-Making between 131I-mIBG Therapy and PRRT

AbstractDetermining the choice and the goal is key element for decision-making of a systemic radionuclide therapy. They should be clearly defined in deciding and individualizing the dose and regimen. For iodine-131 metaiodobenzylguanidine (131I-mIBG) therapy, the important considerations during dose fractionation include disease burden, tumor biology, functional symptoms, and associated comorbidities, all of which are important determinants for the intent and course of treatment. Herein, we present the case of a 67-year-old elderly female with highly functional metastatic recurrent extra-adrenal pheochromocytoma (presenting 42 years after the primary surgery and 32 years following excision of pararenal recurrence) with multiple comorbidities including single kidney and borderline renal compromise, treated successfully with a relatively lower dose of 131I-mIBG (cumulative dose of 22.2 GBq in four cycles with a mean dose of 5.7 GBq per therapy cycle). The excellent tumor burden reduction, hormonal tumor marker response, and most importantly asymptomatic status could be achieved with the administered dose. On follow-up, none of the pretherapeutic parameters (including renal function) showed any further derangement compared with the baseline during next 24 months following the treatment. All cycles were well tolerated with only reversible hematological toxicity that normalized without any active intervention. The report is intended to provide some guidance for future therapeutic regimens.

An open-label, single-arm, multi-center, phase II clinical trial of single-dose [131I]meta-iodobenzylguanidine therapy for patients with refractory pheochromocytoma and paraganglioma

ObjectiveIn this phase II study, we aimed to investigate the efficacy and safety of single-dose [131I]meta-iodobenzylguanidine (131I-mIBG) therapy in patients with refractory pheochromocytoma and paraganglioma (PPGL).Patients and methodsThis study was designed as an open-label, single-arm, multi-center, phase II clinical trial. The enrolled patients were administered 7.4 GBq of 131I-mIBG. Its efficacy was evaluated 12 and 24 weeks later, and its safety was monitored continuously until the end of the study. We evaluated the biochemical response rate as the primary endpoint using the one-sided exact binomial test based on the null hypothesis (≤ 5%).ResultsSeventeen patients were enrolled in this study, of which 16 were treated. The biochemical response rate (≥ 50% decrease in urinary catecholamines) was 23.5% (90% confidence interval: 8.5–46.1%, p = 0.009). The radiographic response rates, determined with CT/MRI according to the response evaluation criteria in solid tumors (RECIST) version 1.1 and 123I-mIBG scintigraphy were 5.9% (0.3%–25.0%) and 29.4% (12.4%–52.2%), respectively. The most frequent non-hematologic treatment-emergent adverse events (TEAEs) were gastrointestinal symptoms including nausea, appetite loss, and constipation, which were, together, observed in 15 of 16 patients. Hematologic TEAEs up to grade 3 were observed in 14 of 16 patients. No grade 4 or higher TEAEs were observed. All patients had experienced at least one TEAE, but no fatal or irreversible TEAEs were observed.ConclusionA single dose 131I-mIBG therapy was well tolerated by patients with PPGL, and statistically significantly reduced catecholamine levels compared to the threshold response rate, which may lead to an improved prognosis for these patients.

Anatomic patterns of relapse and progression following treatment with 131 I-MIBG in relapsed or refractory neuroblastoma.

Patients with metaiodobenzylguanidine (MIBG)-avid relapsed or refractory neuroblastoma after initial therapy may exhibit transient responses to salvage treatment with iodine-131 metaiodobenzylguanidine (131 I-MIBG). It is unclear whether disease progression following 131 I-MIBG treatment occurs in previously involved versus new anatomic sites of disease. Understanding this pattern of relapse will inform the use of consolidation therapy following 131 I-MIBG administration. Patients with relapsed or refractory metastatic MIBG-avid neuroblastoma or ganglioneuroblastoma, who received single-agent 131 I-MIBG, had stable or responding disease 6-8weeks following 131 I-MIBG, but subsequently experienced disease progression were included. MIBG scans were reviewed to establish anatomic and temporal evolution of MIBG-avid disease. A total of 84 MIBG-avid metastatic sites were identified immediately prior to MIBG therapy in a cohort of 12 patients. At first progression, a total of 101 MIBG-avid sites were identified, of which 69 (68%) overlapped with pre-treatment disease sites, while 32 (32%) represented anatomically new disease areas. Eight of 12 patients had one or more new MIBG-avid sites at first progression. Of the 69 involved sites at progression that overlapped with pre-treatment disease, 11 represented relapsed sites that had cleared following MIBG therapy, two were persistent but increasingly MIBG-avid, and 56 were stably persistent. Previously involved anatomic disease sites predominate at disease progression following 131 I-MIBG treatment. Nevertheless, the majority of patients progressed in at least one new anatomic disease site. This suggests that consolidation focal therapies targeting residual disease sites may be of limited benefit in preventing systemic disease progression following 131 I-MIBG treatment of relapsed or refractory neuroblastoma.

Transplantation for ultra high-risk neuroblastoma patients: effect of tandem autologous stem cell transplantation

Aim: Neuroblastoma is a tumor with a high mortality rate originating from primitive sympathetic ganglion cells. In recent years, the definition of "ultra high-risk" has been used, in which the response to treatment is added in addition to the disease characteristics. In this study, the results of tandem high-dose Iodine 131 (131I) metaiodobenzylguanidine (MIBG) and tandem autologous hematopoietic stem cell transplantation (HSCT) in patients who were diagnosed as refractory after first-line treatments and considered with ultra-high risk nöroblastom (NBL) in Erciyes University Medical Faculty Pediatric Bone Marrow Transplant Center were shared.&#x0D; Material and Method: Eleven patients who underwent tandem MIBG and autologous HSCT with the diagnosis of refractory/ultra high-risk NBL between 2011 and 2021 were included in the study. Patient's data were obtained retrospectively using an electronic or manuscript medical record.&#x0D; Results: Tandem autologous HSCT and MIBG treatment were applied to 11 patients with a median age of 40.5 months who were diagnosed with refractory/ultra high-risk neuroblastoma. In our study, the overall survival rate was 54.5% and event-free survival (EFS) was 39% at a median follow-up of 20.7 (7.8-105.6) months. Of the 6 surviving patients, 4 are followed in complete remission and 2 in partial remission.&#x0D; Conclusion: Our study is the only study that includes a group of patients who received tandem high-dose MIBG and tandem autologous HSCT transplantation in refractory NBL patients without cytokine and immunotherapy. Tandem transplantation and MIBG therapy in ultra-high-risk NBL cases remain promising with acceptable toxicity. Adding immunotherapy to this treatment protocol and combining it with new treatment modalities such as anaplastic lymphoma kinase (ALK), which also takes into account genetic characteristics, may increase survival and event-free survival rates.

Thrombocytopenia after meta-iodobenzylguanidine (MIBG) therapy in neuroblastoma patients may be caused by selective MIBG uptake via the serotonin transporter located on megakaryocytes

BackgroundThe therapeutic use of [131I]meta-iodobenzylguanidine ([131I]MIBG) is often accompanied by hematological toxicity, primarily consisting of severe and persistent thrombocytopenia. We hypothesize that this is caused by selective uptake of MIBG via the serotonin transporter (SERT) located on platelets and megakaryocytes. In this study, we have investigated whether in vitro cultured human megakaryocytes are capable of selective plasma membrane transport of MIBG and whether pharmacological intervention with selective serotonin reuptake inhibitors (SSRIs) may prevent this radiotoxic MIBG uptake.MethodsPeripheral blood CD34+ cells were differentiated to human megakaryocytic cells using a standardized culture protocol. Prior to [3H]serotonin and [125I]MIBG uptake experiments, the differentiation status of megakaryocyte cultures was assessed by flow cytometry. Real-time quantitative polymerase chain reaction (RT-qPCR) was used to assess SERT and NET (norepinephrine transporter) mRNA expression. On day 10 of differentiation, [3H]serotonin and [125I]MIBG uptake assays were conducted. Part of the samples were co-incubated with the SSRI citalopram to assess SERT-specific uptake. HEK293 cells transfected with SERT, NET, and empty vector served as controls.ResultsIn vitro cultured human megakaryocytes are capable of selective plasma membrane transport of MIBG. After 10 days of differentiation, megakaryocytic cell culture batches from three different hematopoietic stem and progenitor cell donors showed on average 9.2 ± 2.4 nmol of MIBG uptake per milligram protein per hour after incubation with 10–7 M MIBG (range: 6.6 ± 1.0 to 11.2 ± 1.0 nmol/mg/h). Co-incubation with the SSRI citalopram led to a significant reduction (30.1%—41.5%) in MIBG uptake, implying SERT-specific uptake of MIBG. A strong correlation between the number of mature megakaryocytes and SERT-specific MIBG uptake was observed.ConclusionOur study demonstrates that human megakaryocytes cultured in vitro are capable of MIBG uptake. Moreover, the SSRI citalopram selectively inhibits MIBG uptake via the serotonin transporter. The concomitant administration of citalopram to neuroblastoma patients during [131I]MIBG therapy might be a promising strategy to prevent the onset of thrombocytopenia.

Neuroblastoma.

The survival of patients with high-risk neuroblastoma has improved significantly with the use of intensive multimodality treatment regimens, including chemotherapy, surgery, radiation therapy, myeloablative chemotherapy followed by stem cell rescue, and immunotherapy. This report summarizes the current treatment strategies used in the COG and SIOP for children with neuroblastoma. The improved global collaboration and the adoption of a uniform International Neuroblastoma Risk Group Staging System will help facilitate comparison of homogeneous pretreatment cohorts across clinical trials. Future research strategies regarding the indications for and dosages of radiation therapy to the primary and metastatic sites, and the integration of meta-iodobenzyl guanidine therapy into the multimodal treatment program, are discussed.

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 (5mSv, 500mrem) per patient managed.

Selective serotonin reuptake inhibitors (SSRIs) prevent meta-iodobenzylguanidine (MIBG) uptake in platelets without affecting neuroblastoma tumor uptake

BackgroundThe therapeutic use of [131I]meta-iodobenzylguanidine ([131I]MIBG) is often accompanied by hematological toxicity, mainly consisting of persistent and severe thrombocytopenia. While MIBG accumulates in neuroblastoma cells via selective uptake by the norepinephrine transporter (NET), the serotonin transporter (SERT) is responsible for cellular uptake of MIBG in platelets. In this study, we have investigated whether pharmacological intervention with selective serotonin reuptake inhibitors (SSRIs) may prevent radiotoxic MIBG uptake in platelets without affecting neuroblastoma tumor uptake.MethodsTo determine the transport kinetics of SERT for [125I]MIBG, HEK293 cells were transfected with SERT and uptake assays were conducted. Next, a panel of seven SSRIs was tested in vitro for their inhibitory potency on the uptake of [125I]MIBG in isolated human platelets and in cultured neuroblastoma cells. We investigated in vivo the efficacy of the four best performing SSRIs on the accumulation of [125I]MIBG in nude mice bearing subcutaneous neuroblastoma xenografts. In ex vivo experiments, the diluted plasma of mice treated with SSRIs was added to isolated human platelets to assess the effect on [125I]MIBG uptake.ResultsSERT performed as a low-affinity transporter of [125I]MIBG in comparison with NET (Km = 9.7 μM and 0.49 μM, respectively). Paroxetine was the most potent uptake inhibitor of both serotonin (IC50 = 0.6 nM) and MIBG (IC50 = 0.2 nM) in platelets. Citalopram was the most selective SERT inhibitor of [125I]MIBG uptake, with high SERT affinity in platelets (IC50 = 7.8 nM) and low NET affinity in neuroblastoma cells (IC50 = 11.940 nM). The in vivo tested SSRIs (citalopram, fluvoxamine, sertraline, and paroxetine) had no effect on [125I]MIBG uptake levels in neuroblastoma xenografts. In contrast, treatment with desipramine, a NET selective inhibitor, resulted in profoundly decreased xenograft [125I]MIBG levels (p < 0.0001). In ex vivo [125I]MIBG uptake experiments, 100- and 34-fold diluted murine plasma of mice treated with citalopram added to isolated human platelets led to a decrease in MIBG uptake of 54–76%, respectively.ConclusionOur study demonstrates for the first time that SSRIs selectively inhibit MIBG uptake in platelets without affecting MIBG accumulation in an in vivo neuroblastoma model. The concomitant application of citalopram during [131I]MIBG therapy seems a promising strategy to prevent thrombocytopenia in neuroblastoma patients.

A phase I clinical trial for [131I]meta-iodobenzylguanidine therapy in patients with refractory pheochromocytoma and paraganglioma

Refractory pheochromocytoma and paraganglioma (PPGL) have a poor prognosis and the treatment strategy remains to be established. This multi-institutional phase I study was performed to determine the safety, dose-limiting toxicity (DLT), and efficacy of [131I]-meta-iodobenzylguanidine (131I-mIBG) therapy for refractory PPGLs. Twenty patients with refractory PPGL were enrolled in this study. We administered fixed doses of 131I-mIBG to all patients, delivering a second and third course of 131I-mIBG to eight and three patients, respectively. During the 20 weeks after 131I-mIBG injection, the authors surveyed the adverse events in accordance with the Common Terminology Criteria for Adverse Events. All patients experienced adverse events and adverse reactions, but none experienced a grade 4 adverse event. Twelve weeks after 131I-mIBG injection, examinations for the evaluation of therapeutic effects was performed in accordance with the Response Evaluation Criteria in Solid Tumours (RECIST). The best overall response rates (based on RECIST categories) were 10% (complete response), 65% (stable disease), 15% (progressive disease), and 10% (not all evaluated). The efficacy and safety of 131I-mIBG therapy was shown in patients with refractory PPGL, and DLT was observed in neither single nor repeated 131I-mIBG therapy, indicating a tolerability for 131I-mIBG therapy.

Assessment of the dicentric chromosome assay as a biodosimetry tool for more personalized medicine in a case of a high risk neuroblastoma 131I-mIBG treatment

Purpose: The aims of this study were to estimate the whole - body absorbed - dose with the Dicentric Chromosome Assay (DCA) (biodosimetry) for 131I - metaiodobenzylguanidine (131I - mIBG) therapy for high - risk neuroblastoma, and to obtain an initial correlation with the physical dosimetry calculated as described by the Medical Internal Radiation Dosimetry formalism (MIRD). Together both objectives will aid the optimization of personalized targeted radionuclide therapies.Material and methods: A 12 year-old child with relapsed high-risk neuroblastoma was treated with 131I-mIBG: a first administration with activity <444 MBq/kg was used as a tracer in order to calculate the activity needed in a second administration to achieve a whole body prescribed dose of ∼4 Gy. Blood samples were obtained before and seven days after each administration to analyze the frequency of dicentrics. Moreover, consequent estimations of retained activity were done every few hours from equivalent dose rate measurements at a fixed position, two meters away from the patient, in order to apply the MIRD procedure. Blood samples were also drawn every 2- to -3 days to assess bone marrow toxicity.Results: For a total activity of 22,867 MBq administered over two phases, both biological and physical dosimetries were performed. The former estimated a whole-body cumulated dose of 3.53 (2.58–4.41) Gy and the latter a total whole-body absorbed dose of 2.32 ± 0.48 Gy. The patient developed thrombocytopenia grade 3 after both infusions and neutropenia grade 3 and grade 4 (based on CTCAE 4.0) during respective phases.Conclusion: The results indicate a possible correlation between biodosimetry and standard physical dosimetry in 131I-mIBG treatment for high-risk neuroblastoma. A larger cohort and refinement of the DCA for internal irradiation are needed to define the role of biodosimetry in clinical situations.

Surgical Treatment of Malignant Pheochromocytomas in Spine

Surgical Treatment of Malignant Pheochromocytomas in Spine

Current Consensus on I-131 MIBG Therapy.

Metaiodobenzylguanidine (MIBG) is structurally similar to the neurotransmitter norepinephrine and specifically targets neuroendocrine cells including some neuroendocrine tumors. Iodine-131 (I-131)-labeled MIBG (I-131 MIBG) therapy for neuroendocrine tumors has been performed for more than a quarter-century. The indications of I-131 MIBG therapy include treatment-resistant neuroblastoma (NB), unresectable or metastatic pheochromocytoma (PC) and paraganglioma (PG), unresectable or metastatic carcinoid tumors, and unresectable or metastatic medullary thyroid cancer (MTC). I-131 MIBG therapy is one of the considerable effective treatments in patients with advanced NB, PC, and PG. On the other hand, I-131 MIBG therapy is an alternative method after more effective novel therapies are used such as radiolabeled somatostatin analogs and tyrosine kinase inhibitors in patients with advanced carcinoid tumors and MTC. No-carrier-aided (NCA) I-131 MIBG has more favorable potential compared to the conventional I-131 MIBG. Astatine-211-labeled meta-astatobenzylguanidine (At-211 MABG) has massive potential in patients with neuroendocrine tumors. Further studies about the therapeutic protocols of I-131 MIBG including NCA I-131 MIBG in the clinical setting and At-211 MABG in both the preclinical and clinical settings are needed.