Clinical added-value of 18FDG PET in neuroendocrine-merkel cell carcinoma.

Merkel cell carcinoma (MCC) is a rare and highly malignant skin cancer with neuroendocrine differentiation. We studied the potential value of 18FDG PET in the management of MCC. Eleven patients with MCC were examined by 18FDG PET and PET-CT for staging purpose (n=4) or for detection of recurrence (n=7). Qualitative and quantitative interpretation of PET studies was performed routinely. 18FDG PET observations were compared to clinical and radiological findings. In 6 patients, PET findings were also compared to histology. In 7 patients, the 18FDG tumor uptake was compared to the MCC proliferative activity expressed by the Ki-67 index. 18FDG PET was contributive in 10/11 MCC patients. In 7 patients, 18FDG PET detected focal lesions or a disseminated stage of the disease including dermal, nodal and visceral metastases. In 3 patients, a normal 18FDG PET confirmed complete remission of disease. Most MCC patients exhibited highly 18FDG-avid sites suggestive of increased glucose metabolism. This imaging pattern was related to a high proliferative activity (Ki-67 index >50%). In 1 patient with a weakly proliferative nodal MCC (Ki-67<10%), a false negative result was yielded by metabolic imaging. In 4/11 patients, 18FDG PET revealed an unsuspected second neoplasm in addition to MCC. It is concluded that whole-body 18FDG PET may be useful in the management of MCC patients. However, a normal 18FDG PET aspect cannot rule out MCC with low proliferative activity.

Increased uptake of the apoptosis-imaging agent (99m)Tc recombinant human Annexin V in human tumors after one course of chemotherapy as a predictor of tumor response and patient prognosis.

PURPOSE: Many anticancer therapies exert their therapeutic effect by inducing apoptosis in target tumors. We evaluated in a Phase I study the safety and the feasibility of (99m)Tc-Annexin V for imaging chemotherapy-induced apoptosis in human cancers immediately after the first course of chemotherapy. EXPERIMENTAL DESIGN: Fifteen patients presenting with lung cancer (n = 10), lymphoma (n = 3), or breast cancer (n = 2) underwent (99m)Tc-Annexin V scintigraphy before and within 3 days after their first course of chemotherapy. Tumor response was evaluated by computed tomography and (18)F-fluoro-2-deoxy-D-glucose positron emission tomography scans, 3 months in average after completing the treatment. Median follow-up was 117 days. RESULTS: In all cases, no tracer uptake was observed before treatment. However, 24-48 h after the first course of chemotherapy, 7 patients who showed (99m)Tc-Annexin V uptake at tumor sites, suggesting apoptosis, had a complete (n = 4) or a partial response (n = 3). Conversely, 6 of the 8 patients who showed no significant posttreatment tumor uptake had a progressive disease. Despite the lack of tracer uptake after treatment, the 2 patients with breast cancer had a partial response. Overall survival and progression-free survival were significantly related to tracer uptake in treated lung cancers and lymphomas (P < 0.05). No serious adverse events were observed. CONCLUSIONS: Our preliminary results demonstrated the feasibility and the safety of (99m)Tc-Annexin V for imaging apoptosis in human tumors after the first course of chemotherapy. Initial data suggest that early (99m)Tc-Annexin V tumor uptake may be a predictor of response to treatment in-patients with late stage lung cancer and lymphoma.

High-Throughput Screening Using iPSC-Derived Neuronal Progenitors to Identify Compounds Counteracting Epigenetic Gene Silencing in Fragile X Syndrome.

Fragile X syndrome (FXS) is the most common form of inherited mental retardation, and it is caused in most of cases by epigenetic silencing of the Fmr1 gene. Today, no specific therapy exists for FXS, and current treatments are only directed to improve behavioral symptoms. Neuronal progenitors derived from FXS patient induced pluripotent stem cells (iPSCs) represent a unique model to study the disease and develop assays for large-scale drug discovery screens since they conserve the Fmr1 gene silenced within the disease context. We have established a high-content imaging assay to run a large-scale phenotypic screen aimed to identify compounds that reactivate the silenced Fmr1 gene. A set of 50,000 compounds was tested, including modulators of several epigenetic targets. We describe an integrated drug discovery model comprising iPSC generation, culture scale-up, and quality control and screening with a very sensitive high-content imaging assay assisted by single-cell image analysis and multiparametric data analysis based on machine learning algorithms. The screening identified several compounds that induced a weak expression of fragile X mental retardation protein (FMRP) and thus sets the basis for further large-scale screens to find candidate drugs or targets tackling the underlying mechanism of FXS with potential for therapeutic intervention.

Staging of primary cervical cancers: the role of nuclear medicine.

In nuclear medicine, [18F]-fluorodeoxyglucose positron emission tomography (18FDG PET) and lymphatic mapping and sentinel lymphadenectomy (LM/SL) may significantly improve the staging of primary cervical cancers. Indeed, the disease progresses in a 'level by level' fashion to regional nodes through the lymphatic channels, and also to extra-nodal sites via the hematogenous stream. Additionally, the sub-optimal efficacy of routine radiological protocols, while new combined therapies are proving to be more efficient, stresses the need for alternative staging procedures. Current data suggest that LM/SL accurately reflects the regional lymph node status in early stage cervical cancers, and thus could avoid unnecessary complete lymphadenectomies. Also, whole body 18FDG PET may provide valuable insights on extra-pelvic and distant tumor spreading, with a significant impact on treatment choices. If these promising results are confirmed on large controlled trials, LM/SL and 18FDG PET imaging could be incorporated in the routine staging work-up of primary cervical cancers.

In vivo imaging of chemotherapy-induced apoptosis in human cancers.

RATIONALE: Induction of apoptosis in sensitive tumor cells is the main mechanism of action of chemotherapy agents in human cancers. Also, the assessment of drug-induced apoptosis soon after chemotherapy may be an early predictor of treatment efficacy. PATIENTS AND METHODS: A phase I/II study was prospectively conducted in 15 patients presenting with proven lung cancers (n = 10), breast cancers (n = 2), and lymphomas (n = 3) to assess the value of the (99m)Tc-radiolabeled recombinant human (rh) Annexin V for imaging apoptosis immediately after completion of the first course of chemotherapy. Early Annexin V findings post-chemotherapy (day+1, day+2) were also compared to the tumor status at 6 to 12 weeks post-treatment. RESULTS: All lung and lymphoma patients with an increased tracer uptake post-treatment (n = 8) had either partial or complete tumor response. Five patients with no tracer uptake had progressive disease. However, two breast cancers had a response to treatment, although no significant tracer uptake was observed. Tumor response and survival time were significantly correlated with the (99m)Tc-labeled Annexin V uptake. No serious events related to tracer administration were noted. CONCLUSION: : Preliminary results of this pilot study demonstrate the feasibility of the 99mTc-labeled Annexin V uptake for the in vivo imaging of apoptosis after one course of chemotherapy. If confirmed on larger series, these promising results may open new perspectives in the management of oncology patients.

18F-FDG PET in children with lymphomas.

PURPOSE: The aim of this study was to retrospectively evaluate the performance of positron emission tomography (PET) with 18F-fluorodeoxyglucose (18F-FDG) in children with lymphomas, at various stages of their disease. METHODS: Twenty-eight children (mean age 12.5 years, 14 girls, 14 boys) with Hodgkin's disease (HD, n=17) or non-Hodgkin's lymphoma (NHL, n=11) were evaluated. Patients were investigated at initial staging (n=19), early in the course of treatment (n=19), at the end of treatment (n=16) and during long-term follow-up (n=19). A total of 113 whole-body PET studies were performed on dedicated scanners. PET results were compared with the results of conventional methods (CMs) such as physical examination, laboratory studies, chest X-rays, computed tomography, magnetic resonance imaging, ultrasonography and bone scan when available. RESULTS: At initial evaluation (group 1), PET changed the disease stage and treatment in 10.5% of the cases. In early evaluation of the response to treatment (group 2), PET failed to predict two relapses and one incomplete response to treatment. In this group, however, PET did not show any false positive results. There were only 4/75 false positive results for PET among patients studied at the end of treatment (group 3, specificity 94%) or during the systematic follow-up (group 4, specificity 95%), as compared with 27/75 for CMs (specificity 54% and 66%, respectively). CONCLUSION: 18F-FDG-PET is a useful tool for evaluating children with lymphomas. Large prospective studies are needed to appreciate its real impact on patient management.

Staging of regional nodes in AJCC stage I and II melanoma: 18FDG PET imaging versus sentinel node detection.

PRIMARY PURPOSE: The staging of regional nodes by means of sentinel node detection has been shown to accurately detect subclinical nodal metastases from cutaneous melanoma. On the other hand, the oncological applications of 18F-fluoro-2-deoxy-D-glucose positron emission tomography (18FDG PET) are, nowadays, firmly established. However, the sensitivity of such metabolic imaging for staging the regional nodes in primary melanoma remains debatable. We prospectively assessed the actual value of PET for detecting sentinel node metastases in 21 consecutive patients presenting with early-stage melanoma. MATERIALS AND METHODS: Twenty-one melanoma patients scheduled for lymphatic mapping and sentinel lymphadenectomy underwent fully corrected whole-body PET using 18FDG. In all cases, the disease was initially classified as either stage I or II, from the latest version of the American Joint Committee on Cancer staging system. The sentinel node detection was systematically performed within the week following the PET scan. Serial sections of the sentinel nodes were analyzed by both conventional pathology and immunohistochemical staining. Metastatic sentinel nodes were also assessed for the size of tumor deposits and the degree of nodal involvement (focal, partial, or massive). The median follow-up time was 12 months. RESULTS: Six of the 21 patients (28.5%) had an involved sentinel node. PET was positive in only one case with a sentinel node >1 cm. In the five other cases, the sentinel nodes missed by PET were <1 cm with focal and/or partial involvements. One patient, free of regional nodal metastases in both sentinel node detection and PET imaging, had, however, a same-basin recurrence 3 months later. In another case, PET had one false positive result. Overall, the sentinel detection of subclinical nodal metastases had a sensitivity of 86%. PET detected only 14% of sentinel node metastases. CONCLUSIONS: Sentinel node detection remains the procedure of choice for detecting subclinical lymph node involvement from primary cutaneous melanoma. Owing to its limited spatial resolution, PET appears insufficiently sensitive to identify microscopic nodal metastases. As a practical consequence, metabolic imaging is not recommended as a first-line imaging strategy for staging regional lymph nodes in patients with stage I or II melanoma.

Fluorinated tracers for imaging cancer with positron emission tomography.

2-[18F]fluoro-2-deoxy-D-glucose (FDG) is currently the only fluorinated tracer used in routine clinical positron emission tomography (PET). Fluorine-18 is considered the ideal radioisotope for PET imaging owing to the low positron energy (0.64 MeV), which not only limits the dose rate to the patient but also results in a relatively short range of emission in tissue, thereby providing high-resolution images. Further, the 110-min physical half-life allows for high-yield radiosynthesis, transport from the production site to the imaging site and imaging protocols that may span hours, which permits dynamic studies and assessment of potentially fairly slow metabolic processes. The synthesis of fluorinated tracers as an alternative to FDG was initially tested using nucleophilic fluorination of the molecule, as performed when radiolabelling with iodine-124 or bromide-76. However, in addition to being long, with multiple steps, this procedure is not recommended for bioactive molecules containing reactive groups such as amine or thiol groups. Radiochemical yields are also often low. More recently, radiosynthesis from prosthetic group precursors, which allows easier radiolabelling of biomolecules, has led to the development of numerous fluorinated tracers. Given the wide availability of 18F, such tracers may well develop into important routine tracers. This article is a review of the literature concerning fluorinated radiotracers recently developed and under investigation for possible PET imaging in cancer patients. Two groups can be distinguished. The first includes "generalist" tracers, i.e. tracers amenable to use in a wide variety of tumours and indications, very similar in this respect to FDG. These are tracers for non-specific cell metabolism, such as protein synthesis, amino acid transport, nucleic acid synthesis or membrane component synthesis. The second group consists of "specific" tracers for receptor expression (i.e. oestrogens or somatostatin), cell hypoxia or bone metabolism.

Contribution of whole-body 18FDG PET imaging in the management of cervical cancer.

OBJECTIVE: The objective of this study was to assess the contribution of [(18)F]fluoro-2-deoxy-D-glucose positron emission tomography ((18)FDG PET) imaging in the management of cervical cancer. METHODS: Fully corrected whole-body PET was performed in 60 patients (pts) with proven cervical cancer. In pretreatment staging, 22 pts underwent PET in addition to routine protocol including International Federation of Obstetrics and Gynecology (FIGO) staging and pelvic magnetic resonance imaging (MRI). Eighteen of them had pelvic lymphadenectomy. After treatment, PET was performed in 38 pts routinely followed up by clinical and radiological examinations. Results of PET and routine protocols were compared to final diagnoses, including histological findings in 31 pts and clinical outcomes in the other cases. Median follow-up time was 12 +/- 7.3 months. RESULTS: In all but 2 patients (FIGO stage IA), both PET and MRI detected the primary tumor. In 6 pts, MRI alone noted loco-regional tumor spread but PET localized 9 unsuspected extrapelvic nodal sites (6 para-aortic, 2 mediastinal, and 1 supra-clavicular). However, PET missed 8 microscopic pelvic nodal metastases. In 18% of the patients, PET staging significantly influenced the treatment choices. In follow-up, PET accurately diagnosed a recurrent disease in 13 pts with falsely negative or equivocal conventional imaging (CI). Ten patients with a negative PET were still in complete remission after a minimal follow-up time of 12 months. Overall, the agreement of PET with final diagnosis was significantly better than that of routine protocol (P < 0.05). CONCLUSIONS: Whole-body (18)FDG PET appears useful in the management of cervical cancer, in particular for staging extrapelvic metastases or optimally detecting a recurrence. MRI is better indicated for evaluating the loco-regional status of the disease.