Using PET for therapy monitoring in oncological clinical trials: challenges ahead.

Molecular imaging with PET has emerged as a powerful imaging tool in the clinical care of oncological patients. Assessing therapy response is a prime application of PET and so the integration of PET into multicentre trials can offer valuable scientific insights and shape future clinical practice. However, there are a number of logistic and methodological challenges that have to be dealt with. These range from availability and regulatory compliance of the PET radiopharmaceutical to availability of scan time for research purposes. Standardization of imaging and reconstruction protocols, quality control, image processing and analysis are of paramount importance. Strategies for harmonization of the final image and the quantification result are available and can be implemented within the scope of multicentre accreditation programmes. Data analysis can be performed either locally or by centralized review. Response assessment can be done visually or using more quantitative approaches, depending on the research question. Large-scale real-time centralized review can be achieved using web-based solutions. Specific challenges for the future are inclusion of PET/MRI scanners in multicentre trials and the incorporation of radiomic analyses. Inclusion of PET in multicentre trials is a necessity to guarantee the further development of PET for routine clinical care and may yield very valuable scientific insights.

[Use of PET for evaluation of treatment response in oncology]. / Place actuelle de la TEP dans l'évaluation des traitements en oncologie.

18FDG -PET is now usually included in the treatment strategy, for the staging or the diagnosis of recurrence. In lymphoma, PET is well documented for evaluation of tumour response. For solid tumours, despite good published results, the accuracy of PET has to be confirmed by large series of patients. A good interpretation of PET needs a SUV analysis. New radiotraceurs of the nuclear synthesis could certainly improve the accuracy of response evaluation by PET.

[2005 monitoring report: use of positron emission tomography with fluorodeoxyglucose in the management of patients with breast cancer, ovarian cancer, and uterine cancer]. / Bulletin de synthèse de veille 2005: recommandations pour la pratique clinique: utilisation de la TEP-FDG dans les cancers du sein, de l'ovaire et de l'utérus.

CONTEXT: The validity of the recommendations is based on their actualisation as well as on the quality of the initial elaboration process. Therefore the "Standards, Options and Recommendations" (SOR) from the National French federation of comprehensive cancer centres (FNCLCC) has set up a literature monitoring process. OBJECTIVES: To identify new data, which are likely to modify existing recommendations, evaluate their impact and inform potential users on their validity. METHODS: The monitoring process is based on 3 main steps lead in collaboration with experts: collect data, select and classify information and analyse information. Analysis of information consists of comparing the conclusions of new data with the conclusions of the initial report and then to identify the recommendations that need to be updated. RESULTS: This article presents the 2005 monitoring report concerning "the use of positron emission tomography with FDG in the management of breast cancer, ovarian cancer and uterin cancer". Following the monitoring process,all the existing recommendations (initial report from 2003) are still valid. However three modifications have been proposed by the working group: 1) increased level of evidence concerning the use of PET-scan for suspicion of local or metastatic recurrence (option, level of evidence: A); 2) a new option for the use of PET-scan for revealed cervix cancer recurrence, especially for the therapeutic decision strategy (level of evidence: B2); and 3) new formulation (less strict) of the recommendation concerning the use of PET-scan in the management of endometrial cancer.

Main applications of hybrid PET-MRI contrast agents: a review.

In medical imaging, the continuous quest to improve diagnostic performance and optimize treatment strategies has led to the use of combined imaging modalities. Positron emission tomography (PET) and computed tomography (CT) is a hybrid imaging existing already for many years. The high spatial and contrast resolution of magnetic resonance imaging (MRI) and the high sensitivity and molecular information from PET imaging are leading to the development of this new hybrid imaging along with hybrid contrast agents. To create a hybrid contrast agent for PET-MRI device, a PET radiotracer needs to be combined with an MRI contrast agent. The most common approach is to add a radioactive isotope to the surface of a small superparamagnetic iron oxide (SPIO) particle. The resulting agents offer a wide range of applications, such as pH variation monitoring, non-invasive angiography and early imaging diagnosis of atherosclerosis. Oncology is the most promising field with the detection of sentinel lymph nodes and the targeting of tumor neoangiogenesis. Oncology and cardiovascular imaging are thus major areas of development for hybrid PET-MRI imaging systems and hybrid contrast agents. The aim is to combine high spatial resolution, high sensitivity, morphological and functional information. Future prospects include the use of specific antibodies and hybrid multimodal PET-MRI-ultrasound-fluorescence imaging with the potential to provide overall pre-, intra- and postoperative patient care.

Description and technical pitfalls of a hepatoma model and of intra-arterial injection of radiolabelled lipiodol in the rat.

Intra-arterial metabolic radiotherapy (using lipiodol labelled with iodine-131 or rhenium-188) is a therapeutic approach that can be used for the treatment of hepatocellular carcinomas (HCC). We propose a detailed description of the tumoral model using the N1-S1 cell line as well as a technique for intra-arterial injection of radiolabelled lipiodol in order to undertake preclinical studies necessary for the evaluation of a new molecule. We also report the principal technical pitfalls that were faced. The speed of injection of the tumoral cells is a key factor in the tumoral induction since slow injections lead to a tumoral induction rate of 36.3% compared with 76.6% (P<0.01) when using very slow injections. This parameter should thus be controlled carefully during the subcapsular injection of the tumoral cells. In addition, when injecting radiolabelled lipiodol, anaesthesia should not be performed with isoflurane since this leads to a reduction in tumoral uptake. Indeed, we found a 'tumour/healthy liver' uptake ratio of only 2.1+/-0.7 with isoflurane as against 4.4+/-2.6 (P<0.05) when anaesthesia was carried out by intraperitoneal injection of ketamine. Lastly, we show that the tumour size has an influence on the tumoral uptake of radiolabelled lipiodol; therefore, this parameter must also be carefully controlled.

Two messenger RNAs and five isoforms for Po66-CBP, a galectin-8 homolog in a human lung carcinoma cell line.

Galectins are animal proteins which specifically bind beta-D-galactoside residues and their specific cellular function is not yet clearly established. However, these proteins seem to play a role in neoplastic transformations. Po66 is a murine monoclonal antibody directed against a protein from human lung carcinoma, Po66 Carbohydrate-Binding-Protein (Po66-CBP), which belongs to the galectin-8 family. Our results show that the Po66-CBP gene generates five transcripts by alternative splicing, which could give rise to five proteins: two proteins belong to the tandemly repeated galectin family and three belong to the single carbohydrate recognition domain galectins. All these proteins are encoded by a unique gene located in 1q42. Experiments carried out by reverse transcriptase-polymerase chain reaction show that the levels of expression of these five galectin-8 isoforms are variable during the culture time in SK-MES-1, a human lung squamous carcinoma cell line. Cancer Genome Anatomy Project database analysis confirms the presence of Po66-CBP in lung cancer and its absence in healthy lung.

Direct quantitation of thoracic gallium-67 uptake in sarcoidosis.

A method of direct quantitation of 67Ga uptake in the lung is described. The attenuation coefficient requires calculation and is obtained simply for each patient by transmission using a planar radionuclide source. The validity of the method was tested with a phantom (error less than 10%). Forty-three patients with pulmonary and/or mediastinal sarcoidosis were classified. The different groups of patients as defined clinically and radiographically (controls, nonactive, and active sarcoidosis) were well-differentiated (p less than 0.001).

Gallium-67 imaging in muscular sarcoidosis.

A case is presented of sarcoid myopathy in which radiogallium was seen to accumulate in the sites of muscle involvement. Uptake of the radiotracer disappeared following institution of corticosteroid therapy. The exceptional nature of this case contrasts with the high frequency of biopsy evidence of sarcoid muscle disease but is consistent with the rarity of clinical evidence of sarcoid granulomas in muscle. Gallium-67 imaging can be used to determine the extent of muscle involvement and, through evaluation of uptake intensity, the degree of disease activity before and after treatment.

In vitro demonstration of synergy between radionuclide and chemotherapy.

UNLABELLED: Radionuclide therapy is currently used in the treatment of some malignancies, including hepatocellular carcinoma. The effects of external beam radiotherapy are improved by combining it with chemotherapy. The aim of this study was to determine whether such a synergistic effect could be demonstrated in vitro with internal radiation therapy. METHODS: HepG2 cells were cultured from Day 0 to Day 8 under the following conditions: exposure for 4 hr on Day 2 to increasing concentrations of 5-fluorouracil (5FU), doxorubicin or cisplatin (CDDP); exposure from Day 2 to Day 8 to increasing concentrations of 131-iodide; exposure on Day 2 to low-toxicity doses of drugs for 4 hr, followed by exposure to 131I at increasing concentrations; and exposure to increasing concentrations of 131I from Day 2 to Day 8, with exposure for 4 hr on Day 6 to the drugs. Cell toxicity was assessed by enzyme release (lactate dehydrogenase and aspartate aminotransferase) in the culture medium and on cell survival (protein and tetrazolium dye test). All cultures were run in triplicate. RESULTS: A dose- and time-dependent toxicity was demonstrated with doxorubicin and CDDP but not with 5FU. When HepG2 cells were exposed to 131I, the toxicity was rather low, but significant, and was time- and dose-dependent. Treating these cells with combination radiotherapy and chemotherapy resulted in a toxicity that was significantly greater than that with 131I or chemotherapy drugs alone. CONCLUSION: The radiosensitivity of HepG2 cells is low; combining a chemotherapeutic drug with a radiotherapeutic agent improves the radiosensitivity in a synergistic fashion. This combination is thus able to strengthen the therapeutic effect of internal radiation therapy in different malignancies, particularly in hepatocellular carcinoma.

Iterative reconstruction methods for nonuniform attenuation distribution in SPECT.

Two iterative methods, a generalization of the Chang method and a projection precorrection, were investigated to determine whether the use of an attenuation map could improve nonuniform attenuation compensation. After a detailed description of the methods, results obtained with simulated and phantom data were compared. This study demonstrates that projection precorrection provides accurate quantification and good image quality as early as the precorrection step, whereas the generalized Chang method requires computation of one more iteration.

Randomized controlled trial for hepatocellular carcinoma with portal vein thrombosis: intra-arterial iodine-131-iodized oil versus medical support.

UNLABELLED: Portal vein thrombosis is a poor prognostic factor in patients with hepatocellular carcinoma (HCC) and a contraindication for chemoembolization. Intra-arterial injection of 131I-iodized oil which does not modify arterial flow, is feasible in this condition. The aim of this prospective randomized controlled trial was to compare the efficacy of treatment with radiolabeled oil (treated group) versus medical support (control group) in patients with stage I or II HCC (classification of Okuda) with portal vein thrombosis. METHODS: Twenty-seven HCC patients (26 males, 1 female), aged 53-79 yr, with portal vein thrombosis were randomly assigned to Lipiocis group (n = 14) or Control group (n = 13). Additional injections of radiolabeled oil were given 2, 5, 8 and 12 mo after initial therapy. Medical support treatment consisted of: tamoxifen (n = 5), 5 FU intravenously (n = 1), NSAIDs or corticosteroids (n = 5). Efficacy was evaluated according to survival rate (Kaplan-Meier method; log rank test), AFP serum values (measured at 2, 5, 8 and 12 mo) and angiography. RESULTS: The two groups were comparable (Child's classification, Okuda's classification, liver function tests, location of the thrombus). Tolerance was excellent in the Treated group. The actuarial survival curves were significantly different (p < 0.01) between the two groups, the survival rates (Cl 95%) at 3, 6 and 9 mo being 71% (48%-95%), 48% (12%-55%), 7% (1%-31%) for the Treated group; and 10% (1%-33%), 0% and 0% for the Control group. CONCLUSION: Intra-arterial hepatic injection of 131I-labeled iodized oil is a safe and effective palliative treatment of HCC with portal vein thrombosis.

The uptake of a monoclonal antibody (Po66) in lung tumour cell aggregates involves a phagocytose-like phenomenon.

The efficacy of radioimmunotherapy with radiolabelled monoclonal antibody (Mab) depends on the amount of antibody taken up by the tumour and on its intratumoral distribution. Multicellular spheroids (MTS) of lung cell carcinoma was investigated to study cellular and subcellular distribution of a Mab Po66 labelled with I-125. We have shown that the incorporation of Po66 in MTS regularly increases during 3 days while Py, a non specific Mab, remains low. The distribution of radiolabelled studied by light and electron microscopy autoradiography have demonstrated that Po66 first localized on extra cellular debris, is then phagocyted and observed in the cytoplasm of viable cells. This mechanism of penetration and distribution of Mab Po66 is a new and interesting phenomenon, and emphasizes contribution of transmission electron microscopy in nuclear medicine.

Limitations of hyperselective intraarterial injections for the treatment of hepatocellular carcinoma.

The authors report the case of a cirrhotic patient with a multinodular hepatocellular carcinoma. Two nodules were located in the right liver lobe and a minute nodule was in the left lobe. Because of poor liver function, two injections of iodine-131-labeled Lipiodol were delivered in the right hepatic artery to protect the left lobe. The efficacy was obvious in the treated areas, but the minute lesion enlarged dramatically and was responsible for the patient's death.

Role of vagal innervation on intragastric distribution and emptying of liquid and semisolid meals in conscious pigs.

The role of vagal innervation on emptying patterns and intragastric distributions of liquid and semisolid meals is still controversial. We aimed to record these features after dorsal, ventral and truncal vagotomies, using external gamma scintigraphy in conscious pigs in which the dorsal vagus specifically innervates the proximal stomach. Imaging of the stomach was performed for all experimental situations and before surgery using 99mTc-labelled glucose and porridge meals. Emptying of liquids was faster after dorsal vagotomy, whereas it was unchanged after ventral and truncal vagotomies (T1/2 = 57 +/- 8.5, 31 +/- 14.4, 54 +/- 9.1 and 42 +/- 14.9 min for intact, dorsal, ventral and truncal vagotomies, respectively). On the other hand, truncal vagotomy significantly reduced the emptying rate of semisolids whereas dorsal and ventral vagotomies had no significant effect (T1/2 = 96 +/- 7.2, 113 +/- 8.1, 75 +/- 9.9 and 260 +/- 56.6 min for intact, dorsal, ventral and truncal vagotomies). Morphological analysis of the gastric shape confirmed an overdistended proximal stomach after truncal vagotomy only. For semisolids, proximal stomach emptying followed the same emptying pattern as the entire stomach, irrespective of the surgical procedure. We concluded that the proximal stomach is the main control for the emptying of liquids and semisolids. The vagal control of overall gastric emptying for semisolids is probably identical to that modulating the intragastric distribution of the meal.

Labeled granulocyte scanning for the diagnosis of infected necrosis in acute pancreatitis: what kind of labeling should be used?

Clinical and laboratory data or imaging results cannot provide a positive diagnosis of septic complications of pancreatic and peripancreatic necrosis in patients with acute pancreatitis. Confirmation can be obtained only after percutaneous computed tomography (CT)-guided aspiration of the necrotic tissues or fluid collection; although the important role of 99Tc(m)-HMPAO-labeled granulocyte scintigraphy has been recently emphasized. The aim of this study was to determine the sensitivity and specificity of 99m-technetium-hexamethylpropyleneamine oxime (99Tc(m)-HMPAO)- or 111In-oxine-labeled granulocyte scintigraphy for the diagnosis of infection in pancreatic or peripancreatic necrosis to define the ideal label for diagnosis. Thirty-six scintigraphic examinations were performed in 34 consecutive patients (mean age, 58 +/- 2 years) 20 +/- 2 days after the onset of acute pancreatitis (Balthazar classes A-C, n = 7; classes D and E, n = 29). The scintigraphic study included scintigraphic tomography and static acquisition 1 and 3 h, respectively, after reinjection of the autologous 99Tc(m)-labeled granulocytes and static images 3-4 and 24 h after the simultaneous reinjection of 111In-oxine-labeled autologous granulocytes. The diagnosis of infected pancreatic or peripancreatic necrosis was confirmed with percutaneous CT-guided aspiration (14 positive aspirates among 20 performed) and sterile necrosis after negative aspiration (6 negative aspirates) or after a 6 +/- 1-month follow-up free of clinical or biological signs of ongoing sepsis. The sensitivity and specificity were 86 and 73%, respectively, for scintigraphic tomography, 100 and 55% for 3-h 111In images, 93 and 68% for 3-4-h 111In images, and 100 and 64% for 24-h 111In images. The fall in splenic activity between the 3-4 and the 24-h 111In images was 26 +/- 3% in patients with septic pancreatic and peripancreatic necrosis (n = 14) and 16 +/- 3% in those with sterile necrosis (n = 22) (p < 0.01). Labeled granulocyte scintigraphy was thus shown to be an effective tool for the diagnosis of infection in pancreatic and/or peripancreatic necrosis due to acute pancreatitis, especially when the scintiscans are performed early after injection of 99Tc(m) or when the fall in splenic activity over the 24 h following reinjection of 111In is measured in particularly difficult cases. These promising preliminary results should be confirmed by a prospective study.

Diagnosis of osteomyelitis in the diabetic foot with a 99mTc-HMPAO leucocyte scintigraphy combined with a 99mTc-MDP bone scintigraphy.

BACKGROUND: The aim of this prospective study was to assess the role of 99mTc-HMPAO leucocyte scintigraphy combined with a 99mTc-MDP bone scintigraphy in the diagnosis of the diabetic foot infection (HMPAO-Leu/MDP). METHODS: 75 diabetic patients with suspected osteomyelitis were included. The HMPAO-Leu/MDP scan was considered to be consistent with osteomyelitis when the HMPAO-Leu uptake was concordant in all the incidences with an MDP bone uptake. A HMPAO-Leu uptake without concordant bone MDP activity was considered as a soft-tissue infection. The results of the HMPAO-Leu/MDP scan were compared to the following diagnostic criteria: bone infection was confirmed by radiological follow-up or bone biopsy; the absence of bone infection was confirmed by clinical (healing of the ulcer without antibiotherapy) and radiological follow up. RESULTS: According to these criteria, among the 83 ulcers, bone infection was observed in 41 (49.4%): the HMPAO-Leu/MDP scan was positive in 38 cases, including 14 ulcers with normal or doubtful radiographs at inclusion. In the group of 42 ulcers without proven bone infection, the HMPAO-Leu/MDP scan was negative in 41 cases, including 17 lesions with a soft-tissue infection. CONCLUSION: With a sensitivity of 92.6%, a specificity of 97.6%, the HMPAO-Leu/MDP scan is a reliable tool for the diagnosis of osteomyelitis in the diabetic foot. Neuroarthropathy did not affect the performances of the HMPAO-Leu/MDP scan. Owing to a high spatial resolution this test is very helpful to differentiate bone infection from soft-tissue infection especially in case of neuroarthropathy.

111Indium-F(ab)'2-NCA 102 monoclonal antibody: in vitro study of a specific agent for the detection of inflammatory foci.

A new antigranulocyte antibody was evaluated in vitro for the detection of inflammatory foci in man. The specificity for polymorphonuclear cells (PMN) of NCA 102, an anti-NCA 95 monoclonal IgG1, was determined with immunohistochemical and cytofluorometrical tests. Its affinity, assessed by Scatchard analysis, was 1.1 x 10(9) L/mol and the number of epitopes per granulocyte reached about 10(5). The biological properties of PMNs incubated with NCA 102 were not inhibited even when coupled with DTPA. A F(ab)'2 fragment was radiolabelled with 111Indium and incubated in the presence of whole blood. More than 65% radioactivity was selectively taken up by the PMN population. These findings indicated that NCA 102 antibody is suitable for sepsis detection.

Galectin-8: a complex sub-family of galectins (Review).

Galectins are animal lectins, that can specifically bind beta-galactosides. Twelve galectins have been described in vertebrates, belonging to three different groups: prototype, tandem-repeat and chimeric. These proteins seem to be involved in cellular interactions and neoplastic transformations. We present an overview of a particular galectin member: galectin-8. This galectin, which has been intensively studied over the last six years, presents a particular type of gene regulation. It is widely expressed in tumoral tissues and seems to be involved in integrin-like cell interactions. Studies show that the LGALS8 gene encodes for almost seven mRNAs by alternative splicing pathways and various polyadenylation sites. These mRNAs could encode for six isoforms of galectin-8, of which three belong to the tandem-repeat galectin group (with two carbohydrate binding domains) and the three others to the prototype group (one carbohydrate binding domain). All these isoforms seem to be differentially expressed in various tumoral cells. This untypical galectin-8 subfamily seems to have a complex expression regulation, that could be involved in cancer phenomena.

Sodium butyrate induces growth inhibition and modulates galectin-8 expression in human lung carcinoma cells.

Galectins are animal lectins, which may play a role in neoplastic transformation. Po66-Carbohydrate Binding Protein (Po66-CBP) belongs to the galectin-8 family and is expressed in lung tumor cells but not in normal ones. Recent studies showed that galectin-8 could be used for human lung squamous cell carcinoma radioimmunotherapy. To optimize this method of treatment, we attempted to increase galectin-8 expression in human lung tumor cells. A human lung squamous (SK-MES-1) or adeno (A 549) carcinoma cell line was grown with or without sodium butyrate. Cell growth, morphology, transcriptional, expression translational expression and cellular localization of galectin-8 were studied. 3 mM of sodium butyrate inhibited the two cell lines' growth after 48 hours of treatment, but only in SK-MES-1 cells galectin-8 expression is modulated without any secretion and cellular localization modifications, apoptosis or necrosis. Sodium butyrate could be an interesting tool in optimizing the radioimmunotherapy of human lung squamous carcinoma, but not of adenocarcinoma.

Importance of the choice of the collimator for the detection of small lesions in scintimammography: a phantom study.

99mTc methoxyisobutylisonitrile planar scintimammography (SMM) is mostly performed using low-energy high-resolution (LEHR) parallel collimators. We studied whether using a different collimator could improve the detection of small (< 1.5 cm) lesions for which SMM sensitivity is poor. Thirty four breast phantom configurations were considered, either with hot spheres simulating lesions or without any spheres. For each configuration, four planar acquisitions were performed using LEHR, low-energy ultra high-resolution (LEUHR), high-resolution fan-beam (HRFB) and ultra high-resolution fan-beam (UHRFB) collimators. Images corresponding to the 20% and 10% energy windows and to the Jaszczak subtraction were calculated. A database including 156 borderline images was derived. After training, 10 observers scored the images for the presence of a sphere. The performances in sphere detection were studied using receiver operating characteristic (ROC) analysis. For all types of image, the area under the ROC curve was highest with the UHRFB collimator and lowest with either the LEUHR or the HRFB collimator. For the 10% energy window images conventionally used in SMM, the detection sensitivities averaged 91%, 73%, 60% and 55% for the UHRFB, LEHR, HRFB and LEUHR collimators respectively, for the same specificity of 64%. We conclude that detection of small tumours in planar SMM might be significantly improved by using a UHRFB collimator instead of an LEHR collimator.