Absorbed Dose-Response Relationship in Patients with Gastroenteropancreatic Neuroendocrine Tumors Treated with [177Lu]Lu-DOTATATE: One Step Closer to Personalized Medicine.

[177Lu]Lu-DOTATATE has been approved for progressive and inoperable gastroenteropancreatic neuroendocrine tumors (GEP-NETs) that overexpress somatostatin receptors. The absorbed doses by limiting organs and tumors can be quantified by serial postinfusion scintigraphy measurements of the γ-emissions from 177Lu. The objective of this work was to explore how postinfusion [177Lu]Lu-DOTATATE dosimetry could influence clinical management by predicting treatment efficacy (tumor shrinkage and survival) and toxicity. Methods: Patients with GEP-NETs treated with [177Lu]Lu-DOTATATE between 2016 and 2022 and who underwent dosimetry were included. Absorbed doses were calculated for healthy organs (liver, kidneys, bone marrow, and spleen) and tumors using PLANET Dose and the local energy deposition method based on serial posttreatment SPECT/CT. Up to 5 lesions per site were selected and measured on images collected at baseline and 3 mo after treatment end (measurement masked to the somatostatin receptor imaging uptake). For toxicity assessment, laboratory parameters were regularly monitored. Clinical data, including time to death or progression, were collected from the patients' health records. Correlations between absorbed doses by organs and toxicity and between absorbed doses by lesions and tumor volume variation were studied using regression models. Results: In total, 35 dosimetric studies were performed in patients with mostly grade 2 (77%) tumors and metastases in liver (89%), lymph nodes (77%), and bone (34%), and 146 lesions were analyzed: 1-9 lesions per patient, mostly liver metastases (65%) and lymph nodes (25%). The median total absorbed dose by tumors was 94.4 Gy. The absorbed doses by tumors significantly decreased between cycles. The absorbed dose by tumors was significantly associated with tumor volume variation (P < 0.001) 3 mo after treatment end, and it was a significant prognostic factor for survival. Toxicity analysis showed a correlation between the decrease of hematologic parameters such as lymphocytes or platelet concentrations and the absorbed doses by the spleen or bone marrow. The mean absorbed dose by the kidneys was not correlated with nephrotoxicity during the studied period. Conclusion: In patients treated with [177Lu]Lu-DOTATATE for GEP-NETs, tumor and healthy organ dosimetry can predict survival and toxicities, thus influencing clinical management.

Identification of 18F-FDG PET/CT Parameters Associated with Weight Loss in Patients with Esophageal Cancer.

18F-FDG PET-CT is routinely performed as part of the initial staging of numerous cancers. Other than having descriptive, predictive and prognostic values for tumors, 18F-FDG PET-CT provides full-body data, which could inform on concurrent pathophysiological processes such as malnutrition. To test this hypothesis, we measured the 18F-FDG uptake in several organs and evaluated their association with weight loss in patients at diagnosis of esophageal cancer. Forty-eight patients were included in this retrospective monocentric study. 18F-FDG uptake quantification was performed in the brain, the liver, the spleen, bone marrow, muscle and the esophageal tumor itself and was compared between patients with different amounts of weight loss. We found that Total Lesion Glycolysis (TLG) and peak Standardized Uptake Values (SUVpeak) measured in the brain correlated with the amount of weight loss: TLG was, on average, higher in patients who had lost more than 5% of their usual weight, whereas brain SUVpeak were, on average, lower in patients who had lost more than 10% of their weight. Higher TLG and lower brain SUVpeak were associated with worse OS in the univariate analysis. This study reports a new and significant association between 18F-FDG uptake in the brain and initial weight loss in patients with esophageal cancer.

Clinical Pharmacokinetics of Radiopharmaceuticals from SPECT/CT Image Acquisition by Contouring in Patients with Gastroenteropancreatic Neuroendocrine Tumors: Lu-177 DOTATATE (Lutathera®) Case.

BACKGROUND AND OBJECTIVE: Lu-177 DOTATATE (Lutathera®) is a radiolabeled analog of somatostatin administered intravenously in patients with somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors. Biodistribution of Lu-177 DOTATATE in tumor and healthy tissues can be monitored by serial post-injection scintigraphy imaging. Patient exposure to the drug is variable with the recommended fixed dosage, and hence there is a variable response to treatment. The aim of this work was to study the pharmacokinetics of Lu-177 DOTATATE by a population modeling approach, based on single-photon emission computed tomography (SPECT)/computed tomography (CT) images used as surrogate of plasma concentrations to study the interindividual variability and finally optimize an individual dosage. METHODS: From a retrospective study, SPECT/CT images were acquired at 4 h, 24 h, 72 h, and 192 h postadministration. From these images, volumic activities were calculated in blood and bone marrow. An individual non-compartmental pharmacokinetic analysis was performed, and the mean pharmacokinetic parameters of each tissue were compared together and with reference data. Blood volumic activities were then used to perform a population pharmacokinetic analysis (NONMEM). RESULTS: The pharmacokinetic parameters (non-compartmental analysis) obtained from blood (clearance [CL] = 2.65 L/h, volume of distribution at steady state [Vss] = 309 L, elimination half-life [t1/2] = 86.3 h) and bone marrow (CL =1.68 L/h, Vss = 233 L, t1/2 = 98.8 h) were statistically different from each other and from reference values (CL = 4.50 L/h, Vss = 460 L, t1/2 = 71.0 h) published in the literature. SPECT/CT blood images were used as a surrogate of plasma concentrations to develop a population pharmacokinetic model. Weight was identified as covariate on volume of the central compartment, reducing the interindividual variability of all population pharmacokinetic parameters. CONCLUSION: This study is a proof of concept that obtaining pharmacokinetic parameters with image-based blood concentration is possible. Obtaining observed concentrations from SPECT/CT images, without the need for blood sampling, is a real advantage for the patient and the drug monitoring. Pharmacokinetic modeling could be combined with a deep learning model for automatic contouring and allow precise patient-specific dose adjustment in a non-invasive manner.

225Ac-Labeled Somatostatin Analogs in the Management of Neuroendocrine Tumors: From Radiochemistry to Clinic.

The widespread use of peptide receptor radionuclide therapy (PRRT) represents a major therapeutic breakthrough in nuclear medicine, particularly since the introduction of 177Lu-radiolabeled somatostatin analogs. These radiopharmaceuticals have especially improved progression-free survival and quality of life in patients with inoperable metastatic gastroenteropancreatic neuroendocrine tumors expressing somatostatin receptors. In the case of aggressive or resistant disease, the use of somatostatin derivatives radiolabeled with an alpha-emitter could provide a promising alternative. Among the currently available alpha-emitting radioelements, actinium-225 has emerged as the most suitable candidate, especially regarding its physical and radiochemical properties. Nevertheless, preclinical and clinical studies on these radiopharmaceuticals are still few and heterogeneous, despite the growing momentum for their future use on a larger scale. In this context, this report provides a comprehensive and extensive overview of the development of 225Ac-labeled somatostatin analogs; particular emphasis is placed on the challenges associated with the production of 225Ac, its physical and radiochemical properties, as well as the place of 225Ac-DOTATOC and 225Ac-DOTATATE in the management of patients with advanced metastatic neuroendocrine tumors.

Development and Implementation of a Professional Practices Evaluation during Radiopharmaceuticals Administration.

Securing both the patient and radiopharmaceuticals (RPs) circuit is an essential concern in nuclear medicine (NM). These circuits converge at the RP administration phase, a key step in patient management in NM. In a continuous quality improvement approach, we developed and implemented an evaluation of professional practices (EPPs) methodology focused on RPs injection to identify and correct deviations from good practices. The nuclear medicine technologists (NMTs) of a single center were evaluated. A specific audit grid was designed for this purpose, covering 4 main themes. Following the audit campaign, an improvement action plan was set up to address the non-conformities observed. Nine NMTs were audited on 4 RPs injections each. The mean total score was 93.36% with, on average, 7.01% and 3.00% of unmet and partially met criteria, respectively. In view of the non-compliance rates of hygiene and radiation protection items, theoretical reviews of these themes were included in the improvement action plan. As a part of the quality assurance system of a healthcare unit, EPPs are useful for identifying and correcting practice deviations at an early stage. They should be regularly repeated and combined with rigorous training and qualification of operators involved in RPs injection.

177Lu-Dotatate administration using an infusion pump or a peristaltic pump: comparison of two methods.

OBJECTIVES: 177Lu-oxodotreotide (Lutathera) is an intravenous peptide receptor radionuclide therapy to treat unresectable metastatic digestive neuroendocrine tumours. The recommended method for Lutathera administration is gravity infusion; however, other appropriate and safe techniques are possible. This work compares two infusion methods from a medico-economic, radiation protection, efficiency and practicality point of view. METHODS: Two infusion methods were studied, either involving a volumetric infusion pump (method 1) or a peristaltic pump (method 2). For each method, the mean residual activity per vial and the mean injection time were compared. Occupational radiation exposure was measured. The cost of initial equipment and consumables for one administration was determined. Feedback from operators and past incidents during injections were collected through a survey. RESULTS: Three operators performed 219 Lutathera injections over 70 months: 60.7% (133) with method 1 and 39.3% (86) with method 2. After infusion, the mean residual activity in vial was 124.3±16.9 MBq with method 1 and 80.9±19.3 MBq with method 2 (34.9% decrease). The average administration time was 41±7.2 min with method 1 and 39±8.5 min with method 2. Occupational exposures obtained with both methods were very low and quite similar. Method 1 required an initial investment of 1165.8 US$ plus 4.0 US$ of supplies for each administration. Initial investment for method 2 was comparable (1261.4 US$) but supplies cost per administration was higher (12.5 US$). Two major incidents were recorded with method 1 and none with method 2. From operators' experience, method 2 felt safer and more suitable. CONCLUSIONS: Method 2 appeared to be convenient and secure, despite a higher cost per injection. It could also be applied to new radioligand therapies such as 177Lu-PSMA or 225Ac-Dotatate.

Comparison of commercial dosimetric software platforms in patients treated with 177 Lu-DOTATATE for peptide receptor radionuclide therapy.

PURPOSE: The aim of this study was to quantitatively compare five commercial dosimetric software platforms based on the analysis of clinical datasets of patients who benefited from peptide receptor radionuclide therapy (PRRT) with 177 Lu-DOTATATE (LUTATHERA® ). METHODS: The dosimetric analysis was performed on two patients during two cycles of PRRT with 177 Lu. Single photon emission computed tomography/computed tomography images were acquired at 4, 24, 72, and 192 h post injection. Reconstructed images were generated using Dosimetry Toolkit® (DTK) from Xeleris™ and HybridRecon-Oncology version_1.3_Dicom (HROD) from HERMES. Reconstructed images using DTK were analyzed using the same software to calculate time-integrated activity coefficients (TIAC), and mean absorbed doses were estimated using OLINDA/EXM V1.0 with mass correction. Reconstructed images from HROD were uploaded into PLANET® OncoDose from DOSIsoft, STRATOS from Phillips, Hybrid Dosimetry Module™ from HERMES, and SurePlan™ MRT from MIM. Organ masses, TIACs, and mean absorbed doses were calculated from each application using their recommendations. RESULTS: The majority of organ mass estimates varied by <9.5% between all platforms. The highest variability for TIAC results between platforms was seen for the kidneys (28.2%) for the two patients and the two treatment cycles. Relative standard deviations in mean absorbed doses were slightly higher compared with those observed for TIAC, but remained of the same order of magnitude between all platforms. CONCLUSIONS: When applying a similar processing approach, results obtained were of the same order of magnitude regardless of the platforms used. However, the comparison of the performances of currently available platforms is still difficult as they do not all address the same parts of the dosimetric analysis workflow. In addition, the way in which data are handled in each part of the chain from data acquisition to absorbed doses may be different, which complicates the comparison exercise. Therefore, the dissemination of commercial solutions for absorbed dose calculation calls for the development of tools and standards allowing for the comparison of the performances between dosimetric software platforms.

Artificial nutrition in patients with cancer has no impact on tumour glucose metabolism: Results of the PETANC Study.

BACKGROUND & AIMS: Nutrition support is recommended in cachexic patients with cancer. However, there is no clear evidence about its impact on tumour growth. Glycolysis, which is usually higher in cancer than normal cells, can be monitored by 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) imaging that is widely used for cancer staging and therapy efficacy assessment. Here, we used 18F-FDG PET/CT imaging to investigate whether artificial nutrition has an impact on tumour glucose metabolism in patients with cancer and cachexia. METHODS: This prospective study included ten patients with histologically proven head and neck or oesophageal cancer. All patients underwent 18F-FDG PET/CT imaging at baseline and after (parenteral and/or enteral) nutrition support on average for 7 days. Tumour glucose metabolism changes were evaluated using static (SUVmax, SUVmean and SULpeak) and dynamic (glucose metabolic rate and transport constant rates, k) parameters computed from the 18F-FDG PET/CT data. RESULTS: Artificial nutrition (median energy intake of 21.83 kcal/kg/day [13.16-45.90], protein intake of 0.84 g/kg/day [0.56-1.64]) was administered. Eight patients (80%) received enteral nutrition and two patients (20%) parenteral support. Comparison of 18F-FDG PET/CT parameters did not highlight any significant difference in tumour glucose metabolism before and after the period of nutrition support. CONCLUSIONS: In cachexic patients with head and neck or oesophageal cancer, nutrition support administered according to the current guidelines shows no impact on tumour glucose metabolism, assessed by 18F-FDG PET/CT.

Implementation of patient dosimetry in the clinical practice after targeted radiotherapy using [177Lu-[DOTA0, Tyr3]-octreotate.

BACKGROUND: This study's aim was to develop our dosimetric methodology using a commercial workstation for the routine evaluation of the organs at risk during peptide receptor radionuclide therapy (PRRT) with 177Lu. METHODS: First, planar and SPECT sensitivity factors were determined on phantoms. The reconstruction parameters were optimized by SPECT/CT image acquisition using a NEMA IEC phantom containing a 500 ml bottle of 177Lu, to simulate a kidney. The recovery coefficients were determined on various phantoms. For the red marrow, this was calculated using a NEMA IEC phantom that contained a centrally placed bottle of 80 ml of 177Lu (to model the L2-L4 red marrow) flanked by two 200 ml bottles with 177Lu to simulate the kidneys. Then, SPECT/CT images were acquired at 4, 24, 72, and 192 h after injection in 12 patients with neuroendocrine tumors who underwent PRRT with 177Lu-DOTATATE. SPECT data were reconstructed using the iterative ordered subset expectation maximization (OSEM) method, with six iterations and ten subsets, attenuation, scatter, recovery resolution corrections, and a Gaussian post-filter of 0.11 cm. The liver, spleen, kidneys, and red marrow dose per administered activity (AD/A admin) values were calculated with the Medical Internal Radiation Dose (MIRD) formalism and the residence times (Dosimetry toolkit® application) using standard and CT imaging-based organ masses (OLINDA/EXM® V1.0 software). RESULTS: Sensitivity factors of 6.11 ± 0.01 and 5.67 ± 0.08 counts/s/MBq were obtained with planar and SPECT/CT acquisitions, respectively. A recovery coefficient of 0.78 was obtained for the modeled L2-L4 red marrow. The mean AD/A admin values were 0.43 ± 0.13 mGy/MBq [0.27-0.91] for kidneys, 0.54 ± 0.58 mGy/MBq [0.12-2.26] for liver, 0.61 ± 0.13 mGy/MBq [0.42-0.89] for spleen, and 0.04 ± 0.02 mGy/MBq [0.01-0.09] for red marrow. The AD/A admin values varied when calculated using the personalized and standard organ mass, particularly for kidneys (p = 1 × 10-7), spleen (p = 0.0069), and red marrow (p = 0.0027). Intra-patient differences were observed especially in organs close to or including tumor cells or metastases. CONCLUSIONS: The obtained AD/A admin values were in agreement with the literature data. This study shows the technical feasibility of patient dosimetry in clinical practice and the need to obtain patient-specific information.

Radiolabeled Antibodies Against Müllerian-Inhibiting Substance Receptor, Type II: New Tools for a Theranostic Approach in Ovarian Cancer.

We have developed the 16F12 mouse monoclonal antibody (mAb), which targets the Müllerian-inhibiting substance receptor, type II (MISRII), expressed by ovarian tumors. Here, we assessed in preclinical models the possibility of using radiolabeled 16F12 in a theranostic approach for small-volume ovarian peritoneal carcinomatosis, such as after cytoreductive surgery. Methods: DOTA-, DTPA- or deferoxamine mesylate-conjugated 16F12 mAb was radiolabeled with ß-particle (177Lu) or α-particle (213Bi) emitters for therapeutic use and with 89Zr for PET imaging. On the 13th postxenograft day, mice bearing intraperitoneal MISRII-positive AN3CA endometrial carcinoma cell xenografts were treated by conventional intraperitoneal radioimmunotherapy (IP-RIT) with 10 MBq of 177Lu-16F12 or 12.9 MBq of 213Bi-16F12 or by brief intraperitoneal radioimmunotherapy (BIP-RIT) using 50 MBq of 177Lu-16F12 or 37 MBq of 213Bi-16F12. For BIP-RIT, 30 min after injection of the radiolabeled mAbs, the peritoneal cavity was washed to remove the unbound radioactivity. The biodistribution of 177Lu- and 213Bi-16F12 mAbs was determined and then used for dose assessment. Hematologic toxicity was also monitored. Results: The 16F12 mAb was satisfactorily radiolabeled for both therapy and imaging. IP-RIT with 177Lu-16F12 was slightly more efficient in delaying tumor growth than IP-RIT with 213Bi-16F12. Conversely, 213Bi-16F12 was more efficient than 177Lu-16F12 in BIP-RIT. The biodistribution analysis showed that the tumor-to-blood uptake ratio was significantly higher with BIP-RIT than with IP-RIT for both 213Bi- and 177Lu-16F12. Hematologic toxicity was more pronounced with 177Lu-16F12 than with 213Bi-16F12. SPECT/CT images (after BIP-RIT with 177Lu-16F12) and PET/CT images (after injection of 89Zr-16F12 in the tail vein) showed focal uptake at the tumor site. Conclusion: Radiolabeled 16F12 could represent a new theranostic tool for small-volume ovarian peritoneal carcinomatosis. Specifically, 213Bi-16F12-based BIP-RIT could be proposed to selected patients as an alternative adjuvant treatment immediately after cytoreductive surgery. An anti-MISRII mAb is currently being used in a first-in-human study, thus making radiolabeled anti-MISRII mAbs a realistic theranostic option for the clinic.

Phase II Study of a Radiotherapy Total Dose Increase in Hypoxic Lesions Identified by 18F-Misonidazole PET/CT in Patients with Non-Small Cell Lung Carcinoma (RTEP5 Study).

See an invited perspective on this article on page 1043.This multicenter phase II study investigated a selective radiotherapy dose increase to tumor areas with significant 18F-misonidazole (18F-FMISO) uptake in patients with non-small cell lung carcinoma (NSCLC). Methods: Eligible patients had locally advanced NSCLC and no contraindication to concomitant chemoradiotherapy. The 18F-FMISO uptake on PET/CT was assessed by trained experts. If there was no uptake, 66 Gy were delivered. In 18F-FMISO-positive patients, the contours of the hypoxic area were transferred to the radiation oncologist. It was necessary for the radiotherapy dose to be as high as possible while fulfilling dose-limiting constraints for the spinal cord and lungs. The primary endpoint was tumor response (complete response plus partial response) at 3 mo. The secondary endpoints were toxicity, disease-free survival (DFS), and overall survival at 1 y. The target sample size was set to demonstrate a response rate of 40% or more (bilateral α = 0.05, power 1-ß = 0.95). Results: Seventy-nine patients were preincluded, 54 were included, and 34 were 18F-FMISO-positive, 24 of whom received escalated doses of up to 86 Gy. The response rate at 3 mo was 31 of 54 (57%; 95% confidence interval [CI], 43%-71%) using RECIST 1.1 (17/34 responders in the 18F-FMISO-positive group). DFS and overall survival at 1 y were 0.86 (95% CI, 0.77-0.96) and 0.63 (95% CI, 0.49-0.74), respectively. DFS was longer in the 18F-FMISO-negative patients (P = 0.004). The radiotherapy dose was not associated with DFS when adjusting for the 18F-FMISO status. One toxic death (66 Gy) and 1 case of grade 4 pneumonitis (>66 Gy) were reported. Conclusion: Our approach results in a response rate of 40% or more, with acceptable toxicity. 18F-FMISO uptake in NSCLC patients is strongly associated with poor prognosis features that could not be reversed by radiotherapy doses up to 86 Gy.

Extended liver venous deprivation before major hepatectomy induces marked and very rapid increase in future liver remnant function.

OBJECTIVE: The aim of this study was to assess the safety and efficacy of extended liver venous deprivation (eLVD), i.e. combination of right portal vein embolisation and right (accessory right) and middle hepatic vein embolisation before major hepatectomy for future remnant liver (FRL) functional increase. METHODS: eLVD was performed in non-cirrhotic patients referred for major hepatectomy in a context of small FRL (baseline FRL <25% of the total liver volume or FRL function <2.69%/min/m2). All patients underwent 99mTc-mebrofenin hepatobiliary scintigraphy (HBS) and computed tomographic evaluations. RESULTS: Ten consecutive patients underwent eLVD before surgery for liver metastases (n = 8), Klatskin tumour (n = 1) and gallbladder carcinoma (n = 1). FRL function increased by 64.3% (range = 28.1-107.5%) at day 21. In patients with serial measurements, maximum FRL function was at day 7 (+65.7 ± 16%). The FRL volume increased by +53.4% at 7 days (+25 ± 8 cc/day). Thirty-one days (range = 22-45 days) after eLVD, 9/10 patients were resected. No post-hepatectomy liver failure was reported. Two grade II and one grade III complications (Dindo-Clavien classification) occurred. No patient died with-in 90 days following surgery. CONCLUSIONS: eLVD is safe and provides a marked and very rapid increase in liver function, unprecedented for an interventional radiology procedure. KEY POINTS: • eLVD is safe • eLVD provides a marked and very rapid increase in liver function • After eLVD, the FRL-F increased by 64.3% (28.1-107.5%) at day 21 • After eLVD, the maximum FRL-F was obtained at day 7 (+65.7 ± 16%) • After eLVD, the FRL volume increased by +53.4% at 7 days (+25 ± 8 cc/day).

18F-Florbetaben: A New Tool for Amyloidosis Staging?

We report the case of a 73-year-old man with a documented (renal biopsy) light-chain amyloidosis (AL) imaged with F-AV-1 (F-florbetaben) compared with a volunteer. A cardiac amyloidosis was suspected. As it was an AL and not a transthyretin amyloidosis, F-FDG and F-florbetaben PET/CT were preferred to bone scan. F-FDG scintigraphy showed a focal cardiac hypermetabolism. In addition of the heart, F-florbetaben scintigraphy showed an intense spleen and thyroid pathologic uptake and a moderate salivary gland and kidney uptake. F-florbetaben PET/CT appears to be useful for staging systemic amyloidosis.

Impact of the Adaptive Statistical Iterative Reconstruction Technique on Radiation Dose and Image Quality in Bone SPECT/CT.

UNLABELLED: The purpose of this study was to compare a routine bone SPECT/CT protocol using CT reconstructed with filtered backprojection (FBP) with an optimized protocol using low-dose CT images reconstructed with adaptive statistical iterative reconstruction (ASiR). METHODS: In this prospective study, enrolled patients underwent bone SPECT/CT, with 1 SPECT acquisition followed by 2 randomized CT acquisitions: FBP CT (FBP; noise index, 25) and ASiR CT (70% ASiR; noise index, 40). The image quality of both attenuation-corrected SPECT and CT images was visually (5-point Likert scale, 2 interpreters) and quantitatively (contrast ratio [CR] and signal-to-noise ratio [SNR]) estimated. The CT dose index volume, dose-length product, and effective dose were compared. RESULTS: Seventy-five patients were enrolled in the study. Quantitative attenuation-corrected SPECT evaluation showed no inferiority for contrast ratio and SNR issued from FBP CT or ASiR CT (respectively, 13.41 ± 7.83 vs. 13.45 ± 7.99 and 2.33 ± 0.83 vs. 2.32 ± 0.84). Qualitative image analysis showed no difference between attenuation-corrected SPECT images issued from FBP CT or ASiR CT for both interpreters (respectively, 3.5 ± 0.6 vs. 3.5 ± 0.6 and 3.6 ± 0.5 vs. 3.6 ± 0.5). Quantitative CT evaluation showed no inferiority for SNR between FBP and ASiR CT images (respectively, 0.93 ± 0.16 and 1.07 ± 0.17). Qualitative image analysis showed no quality difference between FBP and ASiR CT images for both interpreters (respectively, 3.8 ± 0.5 vs. 3.6 ± 0.5 and 4.0 ± 0.1 vs. 4.0 ± 0.2). Mean CT dose index volume, dose-length product, and effective dose for ASiR CT (3.0 ± 2.0 mGy, 148 ± 85 mGy⋅cm, and 2.2 ± 1.3 mSv) were significantly lower than for FBP CT (8.5 ± 3.7 mGy, 365 ± 160 mGy⋅cm, and 5.5 ± 2.4 mSv). CONCLUSION: The use of 70% ASiR blending in bone SPECT/CT can reduce the CT radiation dose by 60%, with no sacrifice in attenuation-corrected SPECT and CT image quality, compared with the conventional protocol using FBP CT reconstruction technique.

Brief intraperitoneal radioimmunotherapy of small peritoneal carcinomatosis using high activities of noninternalizing 125I-labeled monoclonal antibodies.

UNLABELLED: We assessed the efficiency and toxicity of brief intraperitoneal radioimmunotherapy using high activities of (125)I-labeled monoclonal antibody (mAb) in the treatment of small-volume peritoneal carcinomatosis. METHODS: Brief intraperitoneal radioimmunotherapy consisted of a 185-MBq (740 MBq/mg) intraperitoneal injection of (125)I-35A7 (an anti-carcinoembryonic antigen mAb) into athymic nude mice 4 d after peritoneal tumor xenografting and, after 1 h, abundant washing of the peritoneal cavity with saline solution to remove unbound radioactivity. Another group of mice received this treatment plus a 37-MBq intravenous injection of (125)I-35A7 on day 7 or 11 after grafting. Control groups received a brief treatment followed by an additional intravenous injection on day 7 of either saline solution or irrelevant (125)I-PX. Tumor growth was monitored by bioluminescence imaging and SPECT/CT, and hematologic toxicity was evaluated by complete blood counts. Survival time was reported, and the mice were sacrificed when the bioluminescence signal reached 4.5 × 10(7) photons/s. The biodistribution of (125)I-35A7 mAb after intravenous or brief treatment was assessed, and the mean absorbed irradiation dose by organs and tumors was calculated using the MIRD formalism. RESULTS: Mild, transient hematologic toxicity was observed after the brief treatment plus intravenous (125)I-mAb, with no weight loss. Median survival increased from 32 d in the control groups, to 46 d in the brief treatment group, to 66 d in the group additionally receiving intravenous treatment on day 11, to 73 d in the group additionally receiving intravenous treatment on day 7. The brief treatment alone resulted in a 3-fold higher tumor-to-blood uptake ratio than did the standard intravenous treatment, and the mean absorbed irradiation doses by tumors were 11.6 Gy for the brief treatment and 16.7 Gy for the additional intravenous treatment. For healthy tissues other than blood, the mean absorbed irradiation dose did not exceed 1 Gy after brief treatment and 4.2 Gy after intravenous treatment. CONCLUSION: The efficiency, low toxicity, and high tumor-to-healthy tissue uptake ratio associated with brief intraperitoneal (125)I-35A7 radioimmunotherapy suggest that this method can be used in combination with radiation-synergistic drugs in the therapy of small-volume peritoneal carcinomatosis after cytoreductive surgery.

Noninternalizing monoclonal antibodies are suitable candidates for 125I radioimmunotherapy of small-volume peritoneal carcinomatosis.

UNLABELLED: We have previously shown that, in vitro, monoclonal antibodies (mAbs) labeled with the Auger electron emitter (125)I are more cytotoxic if they remain at the cell surface and do not internalize in the cytoplasm. Here, we assessed the in vivo biologic efficiency of internalizing and noninternalizing (125)I-labeled mAbs for the treatment of small solid tumors. METHODS: Swiss nude mice bearing intraperitoneal tumor cell xenografts were injected with 37 MBq (370 MBq/mg) of internalizing (anti-HER1) (125)I-m225 or noninternalizing (anti-CEA) (125)I-35A7 mAbs at days 4 and 7 after tumor cell grafting. Nonspecific toxicity was assessed using the irrelevant (125)I-PX mAb, and untreated controls were injected with NaCl. Tumor growth was followed by bioluminescence imaging. Mice were sacrificed when the bioluminescence signal reached 4.5 x 10(7) photons/s. Biodistribution analysis was performed to determine the activity contained in healthy organs and tumor nodules, and total cumulative decays were calculated. These values were used to calculate the irradiation dose by the MIRD formalism. RESULTS: Median survival (MS) was 19 d in the NaCl-treated group. Similar values were obtained in mice treated with unlabeled PX (MS, 24 d) and 35A7 (MS, 24 d) or with (125)I-PX mAbs (MS, 17 d). Conversely, mice treated with unlabeled or labeled internalizing m225 mAb (MS, 76 and 77 d, respectively) and mice injected with (125)I-35A7 mAb (MS, 59 d) showed a significant increase in survival. Irradiation doses were comparable in all healthy organs, independently from the mAb used, whereas in tumors the irradiation dose was 7.4-fold higher with (125)I-labeled noninternalizing than with internalizing mAbs. This discrepancy might be due to iodotyrosine moiety release occurring during the catabolism of internalizing mAbs associated with high turnover rate. CONCLUSION: This study indicates that (125)I-labeled noninternalizing mAbs could be suitable for radioimmunotherapy of small solid tumors and that the use of internalizing mAbs should not be considered as a requirement for the success of treatments with (125)I Auger electrons.

Cell membrane is a more sensitive target than cytoplasm to dense ionization produced by auger electrons.

To improve radioimmunotherapy with Auger electron emitters, we assessed whether the biological efficiency of (125)I varied according to its localization. A-431 and SK-OV-3 carcinoma cells were incubated with increasing activities (0-4 MBq/ml) of (125)I-labeled vectors targeting the cell membrane, the cytoplasm or the nucleus. We then measured cell survival by clonogenic assay and the mean radiation dose to the nucleus by assessing the cellular medical internal radiation dose (MIRD). The relationship between survival and the radiation dose delivered was investigated with a linear mixed regression model. For each cell line, we obtained dose-response curves for the three targets and the reference values (i.e., the dose leading to 75, 50 or 37% survival). When cell survival was expressed as a function of the total cumulative decays, nuclear (125)I disintegrations were more harmful than disintegrations in the cytoplasm or at the cell membrane. However, when survival was expressed as a function of the mean radiation dose to the nucleus, toxicity was significantly higher when (125)I was targeted to the cell membrane than to the cytoplasm. These findings indicate that the membrane is a more sensitive target than the cytoplasm for the dense ionization produced by Auger electrons. Moreover, cell membrane targeting is as cytotoxic as nuclear targeting in SK-OV-3 cells. We suggest that targeting the membrane rather than the cytoplasm may contribute to the development of more efficient radioimmunotherapies based on Auger electron radiation, also because most of the available vectors are directed against cell surface antigens.

[Positron emission tomography: a clinical and biological research tool]. / La tomographie par emission de positrons: un outil de recherche clinique et biologique.

Medical and biological imaging has undergone a revolution in the past decade. Positron emission tomography (PET) has been developed to visualize biochemical and physiological phenomena in living humans and animals. For instance, blood flow, blood volume, glucose metabolism, amino acid metabolism, can be quantitatively estimated by means of PET with various radioactive tracers. This functional and molecular imaging technique has progressed rapidly from being a research technique in laboratories to a routine clinical imaging modality. The most widely used radiotracer in routine is 18F-fluorodeoxyglucose (18FDG), which is an analogue of glucose. Since glucose metabolism is increased many fold in malignant tumors, PET has a major role in the field of clinical oncology and recently in cardiology and neurology. PET is also a valuable tool to study cerebral or cardiac binding sites and to image the expression of reporter genes in small animals. In this review, we summarize the most recent developments in PET imaging with particular reference to the radiotracers available and their application.

Evidence of bilateral temporal lobe involvement in primary progressive aphasia: a SPECT study.

UNLABELLED: Primary progressive aphasia (PPA) is rare. Only limited series have been reported with SPECT or PET. Moreover, in the majority of studies, the left-to-right asymmetry ratio was used, leading to difficulties in right hemisphere analyzes. METHODS: Twenty-nine patients with clinical criteria of PPA (Mesulam and Weintraub) were included and compared with 12 control subjects. Complete language examination was performed in all patients. SPECT was performed on a double-head gamma camera after intravenous injection of hexamethylpropyleneamine oxime (22 patients and 12 control subjects) or ethylcysteinate dimer (7 patients). Nineteen regions of interest (ROIs) were drawn on each hemisphere in all patients using the Talairach atlas. The perfusion index (PI = cortex-to-cerebellum ratio) was calculated for each ROI. Atrophy was quantified on MRI by consensus of 3 observers in 16 cortical ROIs. ANOVAs were used to compare the PI between (a). patients and control subjects, (b). patients with (n = 15) or without (n = 14) lexicosemantic abnormalities (LS+ vs. LS-) and patients with (n = 19) or without (n = 10) arthric disorders (A+ vs. A-), and (c). patients with or without atrophy. RESULTS: In the 29 patients, the PI was significantly lower in the left temporopolar, left lateral temporal, left Wernicke, left parietal, and right lateral temporal cortex when compared with control subjects (P < 0.001). In LS+ patients versus control subjects, the PI significantly decreased in the left temporal cortex (lateral temporal; medial temporal; temporopolar; Wernicke), left Broca, left parietal, and right lateral temporal cortex (P < 0.001). In addition, LS+ versus LS- comparison showed a significant decrease in the left lateral, left medial temporal, and left Broca cortex (P < 0.001). In comparison with control subjects, the PI was not significantly different in A+ patients, whereas in A- patients the PI was significantly decreased in the left and right lateral temporal cortex, left Wernicke, and left parietal cortex. Moreover, the PI significantly decreased in the left lateral temporal region in A+ patients compared with A- patients. Finally, in patients without atrophy, the PI significantly decreased in the right and left lateral temporal cortex and the left parietal cortex (P < 0.01). CONCLUSION: Our study demonstrates that right-handed patients with PPA present a decreased perfusion in the bilateral temporal cortex. Moreover, in these regions, morphologic abnormalities are preceded by perfusion abnormalities. Finally, our results show that large left temporal dysfunction occurs in patients with LS disorders.