Questions and Controversies in the Clinical Application of Tyrosine Kinase Inhibitors to Treat Patients with Radioiodine-Refractory Differentiated Thyroid Carcinoma: Expert Perspectives.

Notwithstanding regulatory approval of lenvatinib and sorafenib to treat radioiodine-refractory differentiated thyroid carcinoma (RAI-R DTC), important questions and controversies persist regarding this use of these tyrosine kinase inhibitors (TKIs). RAI-R DTC experts from German tertiary referral centers convened to identify and explore such issues; this paper summarizes their discussions. One challenge is determining when to start TKI therapy. Decision-making should be shared between patients and multidisciplinary caregivers, and should consider tumor size/burden, growth rate, and site(s), the key drivers of RAI-R DTC morbidity and mortality, along with current and projected tumor-related symptomatology, co-morbidities, and performance status. Another question involves choice of first-line TKIs. Currently, lenvatinib is generally preferred, due to greater increase in progression-free survival versus placebo treatment and higher response rate in its pivotal trial versus that of sorafenib; additionally, in those studies, lenvatinib but not sorafenib showed overall survival benefit in subgroup analysis. Whether recommended maximum or lower TKI starting doses better balance anti-tumor effects versus tolerability is also unresolved. Exploratory analyses of lenvatinib pivotal study data suggest dose-response effects, possibly favoring higher dosing; however, results are awaited of a prospective comparison of lenvatinib starting regimens. Some controversy surrounds determination of net therapeutic benefit, the key criterion for continuing TKI therapy: if tolerability is acceptable, overall disease control may justify further treatment despite limited but manageable progression. Future research should assess potential guideposts for starting TKIs; fine-tune dosing strategies and further characterize antitumor efficacy; and evaluate interventions to prevent and/or treat TKI toxicity, particularly palmar-plantar erythrodysesthesia and fatigue.

Interim PET Evaluation in Diffuse Large B-Cell Lymphoma Using Published Recommendations: Comparison of the Deauville 5-Point Scale and the ΔSUVmax Method.

The value of interim 18F-FDG PET/CT (iPET)-guided treatment decisions in patients with diffuse large B-cell lymphoma (DLBCL) has been the subject of much debate. This investigation focuses on a comparison of the Deauville score and the change-in-SUVmax (ΔSUVmax) approach-2 methods to assess early metabolic response to standard chemotherapy in DLBCL. Methods: Of 609 DLBCL patients participating in the PET-Guided Therapy of Aggressive Non-Hodgkin Lymphomas trial, iPET scans of 596 patients originally evaluated using the ΔSUVmax method were available for post hoc assessment of the Deauville score. A commonly used definition of an unfavorable iPET result according to the Deauville score is an uptake greater than that of the liver, whereas an unfavorable iPET scan with regard to the ΔSUVmax approach is characterized as a relative reduction of the SUVmax between baseline and iPET staging of less than or equal to 66%. We investigated the 2 methods' correlation and concordance by Spearman rank correlation coefficient and the agreement in classification, respectively. We further used Kaplan-Meier curves and Cox regression to assess differences in survival between patient subgroups defined by the prespecified cutoffs. Time-dependent receiver-operating-characteristic curve analysis provided information on the methods' respective discrimination performance. Results: Deauville score and ΔSUVmax approach differed in their iPET-based prognosis. The ΔSUVmax approach outperformed the Deauville score in terms of discrimination performance-most likely because of a high number of false-positive decisions by the Deauville score. Cutoff-independent discrimination performance remained low for both methods, but cutoff-related analyses showed promising results. Both favored the ΔSUVmax approach, for example, for the segregation by iPET response, where the event-free survival hazard ratio was 3.14 (95% confidence interval, 2.22-4.46) for ΔSUVmax and 1.70 (95% confidence interval, 1.29-2.24) for the Deauville score. Conclusion: When considering treatment intensification, the currently used Deauville score cutoff of an uptake above that of the liver seems to be inappropriate and associated with potential harm for DLBCL patients. The ΔSUVmax criterion of a relative reduction in SUVmax of less than or equal to 66% should be considered as an alternative.

Six versus eight doses of rituximab in patients with aggressive B cell lymphoma receiving six cycles of CHOP: results from the "Positron Emission Tomography-Guided Therapy of Aggressive Non-Hodgkin Lymphomas" (PETAL) trial.

Standard first-line treatment of aggressive B cell lymphoma comprises six or eight cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) plus eight doses of rituximab (R). Whether adding two doses of rituximab to six cycles of R-CHOP is of therapeutic benefit has not been systematically investigated. The Positron Emission Tomography-Guided Therapy of Aggressive Non-Hodgkin Lymphomas (PETAL) trial investigated the ability of [18F]-fluorodesoxyglucose PET scanning to guide treatment in aggressive non-Hodgkin lymphomas. Patients with B cell lymphomas and a negative interim scan received six cycles of R-CHOP with or without two extra doses of rituximab. For reasons related to trial design, only about a third underwent randomization between the two options. Combining randomized and non-randomized patients enabled subgroup analyses for diffuse large B cell lymphoma (DLBCL; n = 544), primary mediastinal B cell lymphoma (PMBCL; n = 37), and follicular lymphoma (FL) grade 3 (n = 35). With a median follow-up of 52 months, increasing the number of rituximab administrations failed to improve outcome. A non-significant trend for improved event-free survival was seen in DLBCL high-risk patients, as defined by the International Prognostic Index, while inferior survival was observed in female patients below the age of 60 years. Long-term outcome in PMBCL was excellent. Differences between FL grade 3a and FL grade 3b were not apparent. The results were confirmed in a Cox proportional hazard regression model and a propensity score matching analysis. In conclusion, adding two doses of rituximab to six cycles of R-CHOP did not improve outcome in patients with aggressive B cell lymphomas and a fast metabolic treatment response.

Positron Emission Tomography-Guided Therapy of Aggressive Non-Hodgkin Lymphomas (PETAL): A Multicenter, Randomized Phase III Trial.

Purpose Interim positron emission tomography (PET) using the tracer, [18F]fluorodeoxyglucose, may predict outcomes in patients with aggressive non-Hodgkin lymphomas. We assessed whether PET can guide therapy in patients who are treated with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP). Patients and Methods Newly diagnosed patients received two cycles of CHOP-plus rituximab (R-CHOP) in CD20-positive lymphomas-followed by a PET scan that was evaluated using the ΔSUVmax method. PET-positive patients were randomly assigned to receive six additional cycles of R-CHOP or six blocks of an intensive Burkitt's lymphoma protocol. PET-negative patients with CD20-positive lymphomas were randomly assigned or allocated to receive four additional cycles of R-CHOP or the same treatment with two additional doses rituximab. The primary end point was event-free survival time as assessed by log-rank test. Results Interim PET was positive in 108 (12.5%) and negative in 754 (87.5%) of 862 patients treated, with statistically significant differences in event-free survival and overall survival. Among PET-positive patients, 52 were randomly assigned to R-CHOP and 56 to the Burkitt protocol, with 2-year event-free survival rates of 42.0% (95% CI, 28.2% to 55.2%) and 31.6% (95% CI, 19.3% to 44.6%), respectively (hazard ratio, 1.501 [95% CI, 0.896 to 2.514]; P = .1229). The Burkitt protocol produced significantly more toxicity. Of 754 PET-negative patients, 255 underwent random assignment (129 to R-CHOP and 126 to R-CHOP with additional rituximab). Event-free survival rates were 76.4% (95% CI, 68.0% to 82.8%) and 73.5% (95% CI, 64.8% to 80.4%), respectively (hazard ratio, 1.048 [95% CI, 0.684 to 1.606]; P = .8305). Outcome prediction by PET was independent of the International Prognostic Index. Results in diffuse large B-cell lymphoma were similar to those in the total group. Conclusion Interim PET predicted survival in patients with aggressive lymphomas treated with R-CHOP. PET-based treatment intensification did not improve outcome.

Residual thymic tissue and lymph node involvement by acute myeloid leukaemia presenting as mediastinal, strongly 18 FDG-PET-positive masses.

We report on a multidisciplinary management of a 68-year-old AML patient presenting with a PET-positive mediastinal tumour typical for lymph node metastasis. It was removed via minimally invasive thoracoscopic intervention and was identified as a thymus residual infiltrated by AML. Follow-up PET-CT scan after resection and remission induction chemotherapy was completely normal. To our knowledge, this is the first documented case report of AML presenting with PET-positive infiltrates of thymic and lymph node tissue along the aortic bow mimicking a second intrathoracic malignancy. Our observation indicates the usefulness of this imaging technique and supports clarification of these unusual findings in AML patients, in case of need also by invasive diagnostic procedures, to enable an adequate therapeutic decision.

Is there an optimal scan time for 6-[F-18]fluoro-L-DOPA PET in pheochromocytomas and paragangliomas?

PURPOSE: To define the appropriate scan time for fluorine-18-labeled dihydroxyphenylalanine (F-18 DOPA) PET in oncological imaging of pheochromocytomas and paragangliomas. MATERIALS AND METHODS: F-18 DOPA PET examinations were performed in 9 patients with 7 pheochromocytomas and 4 head and neck paragangliomas using a dedicated PET scanner. The acquisition started with a dynamic single-bed scan in the tumor region over the first 60 minutes after tracer injection followed by a late time whole-body scan at approximately 130 minutes. Standard uptake values (SUVs) were calculated in tumors, surrounding background, and adjacent normal tissues of relevance. Furthermore, kinetic analysis was performed using a 2-compartment model with rate constants for uptake (K1'), release (k2'), metabolism (k3'), and reverse reaction (k4') for region of interest and pixel-wise analysis. RESULTS: All tumors show a marked increased F-18 DOPA uptake, which was visually detectable and distinguishable from the surrounding tissue. The SUV is significantly lower in neck paraganglioma compared with abdominal pheochromocytomas. Mean time-activity curves of F-18 DOPA in tumors show a rapid uptake of the tracer. Already 2 minutes after the injection, the activity in the tumor is beyond that of the blood pool. The average maximum value (SUVmean = 8.2) has already been reached after 20 minutes. Afterward, a very slight decrease of the tumor SUV starts, which still amounts to 80% of the maximum value after 132 minutes. Due to the continuous decrease of activity in the background tissue, the tumor-to-background ratio of SUVs shows a constant increase within the entire period of examination. The mean values of apparent kinetic constants obtained by region of interest analysis averaged over all tumors are as follows: K1' = 2.89 ± 2.56 min(-1), k2' = 2.59 ± 2.81 min(-1), k3' = 0.301 ± 0.395 min(-1), and k4' = 0.044 ± 0.043 min(-1). CONCLUSIONS: Pheochromocytoma and paraganglioma take up F-18 DOPA very quickly. At best, the acquisition for static clinical PET imaging of paraganglioma with F-18 DOPA can start at 20 minutes postinjection for maximum uptake in tumors. Separation of tumor, background, and adjacent normal tissues is feasible due to their differences in SUV values and kinetics. The kinetic analysis demonstrates an F-18 DOPA accumulation within the tumor due to considerable differences between the rate constants of uptake and metabolism. Second, in contradiction to healthy brain, paraganglionic tumors show a reversible F-18 DOPA metabolism.

First clinical evidence that imaging with somatostatin receptor antagonists is feasible.

UNLABELLED: Preclinical studies have indicated that somatostatin receptor (sst)-expressing tumors demonstrate higher uptake of radiolabeled sst antagonists than of sst agonists. In this study, we evaluated whether imaging with sst antagonists was feasible in patients. METHODS: Biodistribution and tumor uptake of the sst antagonist (111)In-DOTA-pNO(2)-Phe-c(DCys-Tyr-DTrp-Lys-Thr-Cys)DTyrNH(2) ((111)In-DOTA-BASS) were studied in 5 patients with metastatic thyroid carcinoma or neuroendocrine tumors. Findings were compared with (111)In-pentetreotid ((111)In-DTPA-octreotide) scan. RESULTS: No adverse effects of (111)In-DOTA-BASS (20 µg) were observed. (111)In-DOTA-BASS detected 25 of 28 lesions, whereas (111)In-DTPA-octreotide detected only 17 of 28 lesions. In the same patient, (111)In-DOTA-BASS showed higher tumor and lower renal uptake than (111)In-DTPA-octreotide (3.5 ± 2.8 percentage injected activity [%IA] vs. 1.0 ± 0.99%IA and 1.5 ± 0.3 %IA vs. 2.3 ± 0.7 %IA) at 4 h after injection. CONCLUSION: Imaging of neuroendocrine tumors with sst antagonists is clinically feasible. The favorable human biodistribution data suggest that sst antagonists could significantly affect peptide receptor-mediated imaging and therapy.

Comparison of C-11 methionine and C-11 choline for PET imaging of brain metastases: a prospective pilot study.

PURPOSE: The aim of the study was the comparison of C-11 methionine (MET) and C-11 choline (CHO) in the positron emission tomography (PET) imaging of brain metastases in correlation to the histopathology findings in stereotactic biopsy. METHODS: In all, 8 patients underwent MET and CHO PET and magnetic resonance imaging, in 7 of these, the metastases were previously treated by radiation therapy. Histopathologic diagnosis was made for each patient by frame-based stereotactic serial biopsy. Standardized uptake values of tumor uptake and lesion-to-normal brain tissue ratios (LNRs) of the lesions were determined. LNRs for each tracer were compared with the histopathology findings and follow-up. RESULTS: In 6 patients, biopsy revealed viable metastases, 1 patient suffered from tumor recurrence in follow-up and 1 patient was tumor free in biopsy and follow-up. In the last mentioned patient, LNR was the lowest determined in all patients for CHO, but not for MET. Mean standardized uptake values of the lesions were in median 1.8 for MET and 1.1 for CHO, median LNRs were 1.5 for MET and 6.6 for CHO. LNRs for CHO were significant higher than those for MET (P = 0.007). CONCLUSIONS: In the direct comparison to the well-established amino acid tracer MET, CHO seems to be promising for the imaging of brain metastases because of significantly higher LNRs in tumor tissue compared with MET without evidence for a lower specificity of CHO uptake.

Long-term benefit of intracardiac delivery of autologous granulocyte-colony-stimulating factor-mobilized blood CD34+ cells containing cardiac progenitors on regional heart structure and function after myocardial infarct.

BACKGROUND AIMS: Starting from experimental data proposing hematopoietic stem cells as candidates for cardiac repair, we postulated that human peripheral blood (PB) CD34+ cells mobilized by hematopoietic growth-factor (G-CSF) would contain cell subpopulations capable of regenerating post-ischemic myocardial damages. METHODS: In a phase I clinical assay enrolling seven patients with acute myocardial infarct, we directly delivered to the injured myocardium autologous PB CD34+ cells previously mobilized by G-CSF, collected by leukapheresis and purified by immunoselection. In parallel, we looked for the eventual presence of cardiomyocytic and endothelial progenitor cells in leukapheresis products of these patients and controls, using flow cytometry, reverse transcription-quantitative (RTQ)-polymerase chain reaction (PCR), cell cultures and immunofluorescence analyzes. RESULTS: The whole clinical process was feasible and safe. All patients were alive at an average follow-up of 49 months (range 24-76 months). Improvement of heart function parameters became obvious from the third month following cell reinjection. Left ventricular ejection fraction values progressively and dramatically increased with time, associated with PetScan demonstration of myocardial structure regeneration and revascularization and New York Heart Association (NYHA) grade improvement. Furthermore, we identified PB CD34+ cell subpopulations expressing characteristics of both immature and mature endothelial and cardiomyocyte progenitor cells. In vitro CD34+ cell cultures on a specific medium induced development of adherent cells featuring morphologies, gene expression and immunocytochemistry characteristics of endothelial and cardiac muscle cells. CONCLUSIONS: Mobilized CD34+ cells contain stem cells committed along endothelial and cardiac differentiation pathways, which could play a key role in a proposed two-phase mechanism of myocardial regeneration after direct intracardiac delivery, probably being responsible for the long-term clinical benefit observed.

Positron emission tomography/computed tomography and whole-body magnetic resonance imaging in staging of advanced nonsmall cell lung cancer--initial results.

OBJECTIVE: To evaluate and compare positron emission tomography/computed tomography (PET/CT) with whole-body magnetic resonance imaging (wbMRI) in the correct staging of patients with advanced nonsmall cell lung cancer (NSCLC). MATERIALS AND METHODS: Fifty-two patients with an NSCLC stage IIIa or IIIb (36 males and 16 females) were included in this study. Patients were referred to our department for restaging. Within 1 week PET/CT and wbMRI were performed in all patients. Images were examined independently by 2 experienced physicians from the Department of Nuclear Medicine and Radiology. Afterward, consensus reading was performed. In 22 patients, surgery served as gold standard, whereas in 30 patients, follow-up controls (after 2 months) were performed. RESULTS: The use of wbMRI correctly T-staged all patients. Especially volume interpolated breathhold examination sequence correctly T-staged all tumors. PET/CT did not correctly stage chest wall infiltration in 4 cases [sensitivity 92.3% (P < 0.05 to wbMRI)/specificity 100%], verified by surgery. PET/CT correctly N-staged 51 patients (sensitivity 96.1%/specificity 100%). WbMRI showed a significant tendency to understage N-status [sensitivity 88.5% (P < 0.05)/specificity 96.1%]. Different N-status by PET/CT changed operability in 4 patients. In 2 patients, distant metastases were detected by both techniques. CONCLUSION: In the correct staging of advanced NSCLC, PET/CT has advantages in N-staging. This is of high relevance for therapy planning. WbMRI especially using volume interpolated breathhold examination sequences, has certain advantages in T-staging.

Analysis of blood flow and glucose metabolism in mammary carcinomas and normal breast: a H2(15)O PET and 18F-FDG PET study.

OBJECTIVE: To determine parameters of perfusion, distribution coefficient, and glucose metabolism as part of the tumour-specific micromilieu of breast cancer and compare them with corresponding values in normal breast tissue. METHODS: H2(15)O PET and 18F-FDG PET were performed on 10 patients with advanced invasive ductal carcinomas of the breast. Perfusion, distribution coefficient, and glucose metabolism and standardized uptake were quantified and analysed. RESULTS: Mean values based on the regions of interest were 59.2+/-43.9 ml x min(-1) x 100 g(-1) (perfusion), 0.58+/-0.26 ml x g(-1) (distribution coefficient), 7.76+/-6.10 (standardized uptake), and 5.4+/-2.5 mg x min(-1) x 100 g(-1) (glucose metabolism). The corresponding values for normal breast tissue were 22.1+/-13.2 ml x min x 100 g(-1) (perfusion), 0.16+/-0.05 ml x g(-1) (distribution coefficient), 0.33+/-0.07 (standardized uptake), and 0.18+/-0.08 mg x min x 100 g(-1) (glucose metabolism). For each tumour-normal tissue parameter pair, the mean values were significantly higher in tumours than normal breast tissue. Region-of-interest and pixel-wise correlation analysis revealed a positive association between glucose metabolism and distribution coefficient and glucose metabolism and perfusion for 7/10 tumours investigated. CONCLUSIONS: H2(15)O PET and 18F-FDG PET were able to differentiate breast cancer and normal breast tissue. The pixel-wise analysis revealed information about the heterogeneity of tumour fine structure in perfusion, distribution coefficient, and glucose metabolism, which may provide important guidelines for improving individual treatment.

MRI and (18)FDG-PET in the assessment of bone marrow infiltration of the spine in cancer patients.

The aim of this study was to evaluate the diagnostic value of MRI and (18)FDG-PET in bone marrow infiltration of the spine due to metastases of solid tumours and lymphoma in cancer patients. In 35 cancer patients (solid tumours n = 26, lymphoma n = 9) MRI of the spine and (18)FDG-PET were reviewed and the detectability of metastases, infiltration of the spine, extent of disease, and therapeutic implications were compared. In 8/35 cases (23%) imaging technique showed concordantly no bone marrow infiltration. In 19/35 patients (54%), both MRI and (18)FDG-PET revealed bone marrow infiltration of the axial skeleton. In 12/19 patients (63%), MRI showed more extensive disease which lead to subsequent therapy. The imaging findings of MRI and (18)FDG-PET were discordant in 8/35 cases (23%). (18)FDG-PET was false positive in two patients. In six patients, (18)FDG-PET failed to detect bone metastases and bone marrow infiltration of the spine, which was detected by MRI and proven by clinical follow-up with subsequent therapy in two cases. MRI is more sensitive and specific than (18)FDG-PET detecting bone marrow metastases and infiltration of the spine and has a great impact in staging cancer patients.

Genetic and clinical investigation of pheochromocytoma: a 22-year experience, from Freiburg, Germany to international effort.

Although deceptively simple, the etio-pathogenesis of pheochromocytoma represents a clinical and molecular genetic investigative challenge. Here, we summarize, from a historical point of view, the 22-year-long studies initiated at the University of Freiburg, which developed from a local experience to a national and finally an international effort. All research activities are translational and clinical and hence, registry based and intended to improve the outcome of the patients, whether by improved detection, prevention, or treatment. Major clinical steps are the prospective study on hormone tests and imaging techniques for adrenal and extra-adrenal abdominal tumors as well as the concept of organ sparing and endoscopic tumor resection. Further, we introduced 18-fluoro-dopa positron emission tomography. Population-based registries were used in order to identify germline mutations in the susceptibility genes VHL, RET, SDHB, and SDHD in non-syndromic pheochromocytoma. We differentiated distinct clinical features of paraganglioma syndromes associated with SDHB and SDHD gene mutations. Finally, we identified predictors and prevalence of paraganglioma syndromes associated with mutations of the SDHC gene.

Fluorine-18 DOPA PET imaging of paraganglioma syndrome.

A 12-year-old boy was admitted after recently having had a resection performed of an extraadrenal retroperitoneal paraganglioma and left adrenalectomy for pheochromocytoma. Despite these procedures, the blood pressure and urinary noradrenalin were elevated. Screening with fluorine-18 DOPA PET demonstrated increased tracer uptake in the right adrenal gland, in a second abdominal lesion, which was prevertebral, and 2 cervical hot spots near the carotid bifurcation, one on each side of the neck. The patient carries a mutation of the gene Succinate dehydrogenasis subunits D (SDHD) and is thus classified with the paraganglioma syndrome type 1.

Impact of FDG PET for staging of Ewing sarcomas and primitive neuroectodermal tumours.

AIM: High-grade Ewing sarcomas and Primitive neuroectodermal tumours (PNET) make up the tumours of the Ewing family. Our purpose was to evaluate the value of [18F]fluorodeoxyglucose positron emission tomography (FDG PET) in patients with Ewing tumours. PATIENTS AND METHODS: Twenty-four patients who had PET because of a suspected Ewing tumour during a 5-year period were included in this retrospective study. The images of 33 whole-body FDG PET investigations performed in primary or secondary diagnostics were analysed visually and semi-quantitatively by using standardized uptake values (SUVs). In 14 cases, PET was compared to bone scintigraphy regarding bone lesions. The final diagnosis was based on histology, imaging and follow-up. RESULTS: Histologically, the primary lesions were 10 Ewing sarcoma, 13 PNET and one osteomyelitis. The sensitivity and specificity of an examination-based analysis (presence of Ewing tumour and/or its metastases) were 96 and 78%, respectively. Altogether, 163 focal lesions were evaluated. Sensitivity and specificity regarding individual lesions were 73 and 78%. This lower sensitivity is mainly due to small lesions. In true-positive cases, the mean SUV was 4.54+/-2.79, and the SUVs in two false-positive cases were 4.66 and 1.60. True-positive and false-positive cases could not be differentiated definitively based on SUVs because of overlap and low values in true-positive lesions. In four cases, PET depicted 70 while bone scintigraphy depicted only eight bone metastases. CONCLUSION: An FDG PET investigation is a valuable method in the case of Ewing tumours. PET is superior to bone scintigraphy in the detection of bone metastases of Ewing tumours. For the depiction of small lesions, mainly represented by pulmonary metastases, PET is less sensitive than helical computed tomography. Determination of the role of whole-body FDG PET in diagnostic algorithm needs further investigation.

Predictors and prevalence of paraganglioma syndrome associated with mutations of the SDHC gene.

CONTEXT: Paraganglioma syndrome includes inherited head and neck paragangliomas (HNPs) and adrenal or extra-adrenal pheochromocytomas and are classified according to the susceptibility genes SDHB, SDHC, and SDHD. In contrast with those with germline mutations of the SDHB and SDHD genes, clinical and genetic data on patients with mutations of SDHC are scarce. OBJECTIVE: To determine the prevalence and clinical characteristics of SDHC mutation carriers compared with patients with SDHB and SDHD mutations and with sporadic cases. DESIGN, SETTING, AND PATIENTS: Genetic screening for SDHC mutations in an international HNP registry of 121 unrelated index cases and in 371 sporadic cases from a pheochromocytoma registry, conducted January 1, 2001, until December 31, 2004. Identified index cases and affected relatives were clinically evaluated. MAIN OUTCOME MEASURES: Prevalence of and clinical findings for SDHC mutation-associated HNPs vs those with SDHB and SDHD mutations. RESULTS: The prevalence of SDHC carriers was 4% in HNP but 0% in pheochromocytoma index cases. None of the SDHC mutation carriers had signs of pheochromocytoma. We compared HNPs in 22 SDHC mutation carriers with the HNPs of SDHB (n = 15) and SDHD (n = 42) mutation carriers and with 90 patients with sporadic HNPs. Location, number of tumors, malignancy, and age were different: more carotid body tumors were found in SDHC (13/22 [59%]) than in sporadic HNPs (29/90 [32%], P = .03), as well as fewer instances of multiple tumors in SDHC (2/22) than in SDHD (24/42; P<.001), 0 malignant tumors in SDHC vs 6/15 in SDHB (P = .002), and younger age at diagnosis in SDHC than in sporadic HNPs (45 vs 52 years; P = .03). CONCLUSIONS: Patients with HNP, but not those with pheochromocytoma, harbor SDHC mutations in addition to those in SDHB and SDHD. In total, more than one quarter of HNP patients carry a mutation in 1 of these 3 genes. Head and neck paragangliomas associated with SDHC mutations are virtually exclusively benign and seldom multifocal. Analysis for germline mutations of SDHC is recommended in apparently sporadic HNP to identify risk of inheritance.

Factors influencing [F-18] 2-fluoro-2-deoxy-D-glucose (F-18 FDG) uptake in melanoma cells: the role of proliferation rate, viability, glucose transporter expression and hexokinase activity.

Using human (SK-MEL 23, SK-MEL 24 and G361) and murine (B16) melanoma cell lines, the coregulatory potential of the uptake of the positron emission tomography (PET) tracer, [Fluorine-18] 2-fluoro-2-deoxy-D-glucose (F-18 FDG) has been investigated in relationship to tumor characteristics. Comparative studies among the four melanoma cell lines demonstrated that the lowest FDG uptake in SK-MEL 24 corresponded strongly to the data for DT (population doubling time) and MTT (tetrazolium salt) cell viability as well as hexokinase (HK) activity, but was not related to the glucose transporter 1 (GLUT 1) expression level. Furthermore, the FDG uptake in each melanoma cell line measured by cell cycle kinetics was significantly positively correlated to both the proliferation index (PI=S/G2M phase fractions) and the cell viability, though with one exception relating to the PI of the lowest FDG uptake cell line, SK-MEL 24. No positive correlation was found between the expression of GLUT 1 and FDG uptake in any individual cell line. However, the HK activities in SK-MEL 23 and 24 showed considerable positive relationships with FDG uptake. Our present study suggests that both the proliferation rate and the cell viability of melanoma cells may be key factors for FDG uptake and that HK activity, rather than GLUT 1 expression, seems to be a major factor.

Factors influencing [F-18] 2-fluoro-2-deoxy-D-glucose (F-18 FDG) accumulation in melanoma cells: is FDG a substrate of multidrug resistance (MDR)?

In order to specify the influence of multidrug-resistance (MDR) on the accumulation of the PET tracer, F-18 FDG ([Fluorine-18] 2-fluoro-2-deoxy-D-glucose, in melanoma cells, both the MDR function and expression of two human melanoma cell lines SK-MEL 23 and 24, were evaluated. The effects of MDR modulators on FDG accumulation and efflux were also investigated. A functional analysis using representative MDR fluorescent substrates and inhibitors clarified the following characteristics: 1) SK-MEL 23 possesses a highly active function of MRP, but not P-gp. 2) SK-MEL 24 possesses weak functions of both MRP and P-gp. Western blot analysis using monoclonal antibodies for MDR expression demonstrated an exceedingly high MRP expression of SK-MEL 23 and only slight P-gp and MRP expression of SK-MEL 24, corresponding to the functional data. The efflux inhibition assay using F-18 FDG revealed a considerable retention of FDG in SK-MEL 23 in the presence of the MRP inhibitor probenecid. It was also found that the P-gp inhibitor verapamil depressed the FDG efflux of SK-MEL 24. Our present in vitro study suggests that FDG may be a substrate of MDR in some melanoma cells and further MDR may be one of the important factors affecting FDG-PET melanoma imaging.