18F-fluorocholine PET/MRI versus ultrasound and sestamibi for the localization of parathyroid adenomas.

PURPOSE: Accurate preoperative localization is imperative to facilitate a minimally invasive parathyroidectomy (MIP) in primary hyperparathyroidism (pHPT). This study aims to compare the diagnostic value of standard-of-care localization techniques (ultrasound [US] and 99mTechnetium (99mTc) -sestamibi scintigraphy) to [F-18]-fluorocholine positron emission tomography/magnetic resonance imaging (FCH-PET/MRI) to determine the additional clinical usefulness of PET/MRI in a Canadian cohort. METHODS: We conducted a prospective, appropriately powered, study to compare the diagnostic value of -FCH PET/MRI to that of the US and 99mTc-sestamibi scintigraphy for localization of parathyroid adenomas in a patient with pHPT. The primary outcome was the per-lesion sensitivity and positive predictive value (PPV) of FCH-PET/MRI, US, and 99mTc-sestamibi scintigraphy. Intraoperative surgeon localization, parathormone levels, and histopathological findings were used as reference standards. RESULTS: Forty-one patients underwent FCH-PET/MRI of which 36 patients had parathyroidectomy. In these 36 patients, 41 parathyroid lesions were histologically confirmed as adenomas or hyperplastic glands. Per-lesion sensitivity of FCH-PET/MRI was 82.9% and of US and 99mTc-sestamibi scintigraphy combined at 50.0%, respectively. The sensitivity of FCH-PET/MRI was superior to that of US and 99mTc-sestamibi scintigraphy (p = 0.002). In the 19 patients in whom both US and 99mTc-sestamibi scintigraphy were negative, PET/MRI correctly identified the parathyroid adenoma in 13 patients (68%). CONCLUSIONS: FCH-PET/MRI is a highly accurate imaging modality for localization of parathyroid adenomas in a tertiary center in North America. It is a superior functional imaging modality to 99mTc-sestamibi scintigraphy alone and more sensitive for localization of parathyroid lesions than US and 99mTc-sestamibi scintigraphy combined. This imaging modality could become the most valuable preoperative localization study given its superior performance in localizing parathyroid adenomas.

89Zr-pembrolizumab imaging as a non-invasive approach to assess clinical response to PD-1 blockade in cancer.

BACKGROUND: Programmed cell death protein 1 (PD-1) antibody treatment is standard of care for melanoma and non-small-cell lung cancer (NSCLC). Accurately predicting which patients will benefit is currently not possible. Tumor uptake and biodistribution of the PD-1 antibody might play a role. Therefore, we carried out a positron emission tomography (PET) imaging study with zirconium-89 (89Zr)-labeled pembrolizumab before PD-1 antibody treatment. PATIENTS AND METHODS: Patients with advanced or metastatic melanoma or NSCLC received 37 MBq (1 mCi) 89Zr-pembrolizumab (∼2.5 mg antibody) intravenously plus 2.5 or 7.5 mg unlabeled pembrolizumab. After that, up to three PET scans were carried out on days 2, 4, and 7. Next, PD-1 antibody treatment was initiated. 89Zr-pembrolizumab tumor uptake was calculated as maximum standardized uptake value (SUVmax) and expressed as geometric mean. Normal organ uptake was calculated as SUVmean and expressed as a mean. Tumor response was assessed according to (i)RECIST v1.1. RESULTS: Eighteen patients, 11 with melanoma and 7 with NSCLC, were included. The optimal dose was 5 mg pembrolizumab, and the optimal time point for PET scanning was day 7. The tumor SUVmax did not differ between melanoma and NSCLC (4.9 and 6.5, P = 0.49). Tumor 89Zr-pembrolizumab uptake correlated with tumor response (P trend = 0.014) and progression-free (P = 0.0025) and overall survival (P = 0.026). 89Zr-pembrolizumab uptake at 5 mg was highest in the spleen with a mean SUVmean of 5.8 (standard deviation ±1.8). There was also 89Zr-pembrolizumab uptake in Waldeyer's ring, in normal lymph nodes, and at sites of inflammation. CONCLUSION: 89Zr-pembrolizumab uptake in tumor lesions correlated with treatment response and patient survival. 89Zr-pembrolizumab also showed uptake in lymphoid tissues and at sites of inflammation.

Focal Thyroid Incidentalomas on 18F-FDG PET/CT: A Systematic Review and Meta-Analysis on Prevalence, Risk of Malignancy and Inconclusive Fine Needle Aspiration.

Background: The rising demand for 18F-fluorodeoxyglucose positron emission tomography with computed tomography (18F-FDG PET/CT) has led to an increase of thyroid incidentalomas. Current guidelines are restricted in giving options to tailor diagnostics and to suit the individual patient. Objectives: We aimed at exploring the extent of potential overdiagnostics by performing a systematic review and meta-analysis of the literature on the prevalence, the risk of malignancy (ROM) and the risk of inconclusive FNAC (ROIF) of focal thyroid incidentalomas (FTI) on 18F-FDG PET/CT. Data Sources: A literature search in MEDLINE, Embase and Web of Science was performed to identify relevant studies. Study Selection: Studies providing information on the prevalence and/or ROM of FTI on 18F-FDG PET/CT in patients with no prior history of thyroid disease were selected by two authors independently. Sixty-one studies met the inclusion criteria. Data Analysis: A random effects meta-analysis on prevalence, ROM and ROIF with 95% confidence intervals (CIs) was performed. Heterogeneity and publication bias were tested. Risk of bias was assessed using the quality assessment of diagnostic accuracy studies (QUADAS-2) tool. Data Synthesis: Fifty studies were suitable for prevalence analysis. In total, 12,943 FTI were identified in 640,616 patients. The pooled prevalence was 2.22% (95% CI = 1.90% - 2.54%, I2 = 99%). 5151 FTI had cyto- or histopathology results available. The pooled ROM was 30.8% (95% CI = 28.1% - 33.4%, I2 = 57%). 1308 (83%) of malignant nodules were papillary thyroid carcinoma (PTC). The pooled ROIF was 20.8% (95% CI = 13.7% - 27.9%, I2 = 92%). Limitations: The main limitations were the low to moderate methodological quality of the studies and the moderate to high heterogeneity of the results. Conclusion: FTI are a common finding on 18F-FDG PET/CTs. Nodules are malignant in approximately one third of the cases, with the majority being PTC. Cytology results are non-diagnostic or indeterminate in one fifth of FNACs. These findings reveal the potential risk of overdiagnostics of FTI and emphasize that the workup of FTI should be performed within the context of the patient's disease and that guidelines should adopt this patient tailored approach.

Targeted optical fluorescence imaging: a meta-narrative review and future perspectives.

PURPOSE: The aim of this review is to give an overview of the current status of targeted optical fluorescence imaging in the field of oncology, cardiovascular, infectious and inflammatory diseases to further promote clinical translation. METHODS: A meta-narrative approach was taken to systematically describe the relevant literature. Consecutively, each field was assigned a developmental stage regarding the clinical implementation of optical fluorescence imaging. RESULTS: Optical fluorescence imaging is leaning towards clinical implementation in gastrointestinal and head and neck cancers, closely followed by pulmonary, neuro, breast and gynaecological oncology. In cardiovascular and infectious disease, optical imaging is in a less advanced/proof of concept stage. CONCLUSION: Targeted optical fluorescence imaging is rapidly evolving and expanding into the clinic, especially in the field of oncology. However, the imaging modality still has to overcome some major challenges before it can be part of the standard of care in the clinic, such as the provision of pivotal trial data. Intensive multidisciplinary (pre-)clinical joined forces are essential to overcome the delivery of such compelling phase III registration trial data and subsequent regulatory approval and reimbursement hurdles to advance clinical implementation of targeted optical fluorescence imaging as part of standard practice.

A retrospective analysis of the diagnostic performance of 11C-choline PET/CT for detection of hyperfunctioning parathyroid glands after prior negative or discordant imaging in primary hyperparathyroidism.

BACKGROUND: Identifying the correct location of a parathyroid adenoma in patients with primary hyperparathyroidism (pHPT) is crucial as it can guide surgical treatment. This study aimed to determine the diagnostic performance of 11C-choline PET/CT in patients with pHPT as a next in-line scan after primary negative or discordant first-line imaging. METHODS: This was a retrospective single-center cohort study. All patients with pHPT that were scanned utilizing 11C-choline PET/CT, after prior negative or discordant imaging, between 2015 and 2019 and who subsequently underwent parathyroid surgery were included. The results of the 11C-choline PET/CT were evaluated lesion-based, with surgical exploration and histopathological examination as the gold standard. RESULTS: In total, 36 patients were included of which three patients were known to have Multiple Endocrine Neoplasia (MEN) syndrome. In these 36 patients, 40 lesions were identified on 11C-choline PET/CT and 37 parathyroid lesions were surgically removed. In 34/36 (94%) patients a focused parathyroidectomy was performed, in one patient a cervical exploration due to an ectopically identified adenoma, and in one patient a bilateral exploration was performed because of a double adenoma. Overall, per-lesion sensitivity of 11C-choline PET/CT was 97%, the positive predictive value was 95% and the accuracy was 94% for all parathyroid lesions. CONCLUSIONS: In patients with pHPT and prior negative or discordant first-line imaging results, pathological parathyroid glands can be localized by 11C-choline PET/CT with high sensitivity and accuracy.

The association between active tumor volume, total lesion glycolysis and levels of S-100B and LDH in stage IV melanoma patients.

INTRODUCTION: The Standardized Uptake Value (SUV) in single lesions on 18F-FDG PET/CT scans and serum S-100B concentrations are inversely associated with disease-free survival in stage IV melanoma. The aim of this study was to assess the association between biomarkers (S-100B, LDH) and the PET-derived metrics SUVmean/max, metabolic active tumor volume (MATV), and total lesion glycolysis (TLG) in stage IV melanoma in order to understand what these biomarkers reflect and their possible utility for follow-up. METHODS: In 52 stage IV patients the association between PET-derived metrics and the biomarkers S-100B and LDH was assessed and the impact on survival analyzed. RESULTS: S-100B was elevated (>0.15 µg/l) in 37 patients (71%), LDH in 11 (21%). There was a correlation between S-100B and LDH (R2 = 0.19). S-100B was correlated to both MATV (R2 = 0.375) and TLG (R2 = 0.352), but LDH was not. Higher MATV and TLG levels were found in patients with elevated S-100B (p < 0.001) and also in patients with elevated LDH (>250 U/l) (p < 0.001). There was no association between the biomarkers and SUVmean/max. Survival analysis indicated that LDH was the only predictor of melanoma-specific survival. CONCLUSION: In newly diagnosed stage IV melanoma patients S-100B correlates with 18F-FDG PET/CT derived MATV and TLG in contrast to LDH, is more often elevated than LDH (71% vs. 21%) and seems to be a better predictor of disease load and disease progression. However, elevated LDH is the only predictor for survival. The biomarkers, S-100B and LDH appear to describe different aspects of the extent of metastatic disease and of tumornecrosis.

Rational use of 18F-FDG PET/CT in patients with advanced cutaneous melanoma: A systematic review.

18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) is increasingly used in patients with advanced melanoma. Immune checkpoint inhibitors and BRAF/MEK-targeted therapy have transformed the therapeutic landscape of metastatic melanoma. Consequently, a need for markers predicting (early) response to treatment and for monitoring treatment (toxicity) has arisen. This systematic review appraises the current literature evidence for rational use of 18F-FDG PET/CT scans in staging, clinical decision-making, treatment monitoring and follow-up in advanced melanoma. 18F-FDG PET/CT has high overall accuracy for detection of distant metastases and is, combined with cerebral MRI, the preferred imaging strategy for staging metastatic melanoma. In contrast, strong evidence supporting the standard use of 18F-FDG PET/CT for predicting and monitoring therapy response and toxicity is currently lacking. Essential for determining the position of 18F-FDG PET/CT during treatment course in advanced melanoma are well-designed studies with standardized scanning protocols, incorporation of clinical parameters and comparison with contrast-enhanced CT alone.

Correction to: [89Zr]Zr-cetuximab PET/CT as biomarker for cetuximab monotherapy in patients with RAS wild-type advanced colorectal cancer.

Missing Electronic Supplementary Materials.

[89Zr]Zr-cetuximab PET/CT as biomarker for cetuximab monotherapy in patients with RAS wild-type advanced colorectal cancer.

PURPOSE: One-third of patients with RAS wild-type mCRC do not benefit from anti-EGFR monoclonal antibodies. This might be a result of variable pharmacokinetics and insufficient tumor targeting. We evaluated cetuximab tumor accumulation on [89Zr]Zr-cetuximab PET/CT as a potential predictive biomarker and determinant for an escalating dosing strategy. PATIENTS AND METHODS: PET/CT imaging of [89Zr]Zr-cetuximab (37 MBq/10 mg) after a therapeutic pre-dose (500 mg/m2 ≤ 2 h) cetuximab was performed at the start of treatment. Patients without visual tumor uptake underwent dose escalation and a subsequent [89Zr]Zr-cetuximab PET/CT. Treatment benefit was defined as stable disease or response on CT scan evaluation after 8 weeks. RESULTS: Visual tumor uptake on [89Zr]Zr-cetuximab PET/CT was observed in 66% of 35 patients. There was no relationship between PET positivity and treatment benefit (52% versus 80% for PET-negative, P = 0.16), progression-free survival (3.6 versus 5.7 months, P = 0.15), or overall survival (7.1 versus 9.4 months, P = 0.29). However, in 67% of PET-negative patients, cetuximab dose escalation (750-1250 mg/m2) was applied, potentially influencing outcome in this group. None of the second [89Zr]Zr-cetuximab PET/CT was positive. Eighty percent of patients without visual tumor uptake had treatment benefit, making [89Zr]Zr-cetuximab PET/CT unsuitable as a predictive biomarker. Tumor SUVpeak did not correlate to changes in tumor size on CT (P = 0.23), treatment benefit, nor progression-free survival. Cetuximab pharmacokinetics were not related to treatment benefit. BRAF mutations, right-sidedness, and low sEGFR were correlated with intrinsic resistance to cetuximab. CONCLUSION: Tumor uptake on [89Zr]Zr-cetuximab PET/CT failed to predict treatment benefit in patients with RAS wild-type mCRC receiving cetuximab monotherapy. BRAF mutations, right-sidedness, and low sEGFR correlated with intrinsic resistance to cetuximab.

89Zr-trastuzumab PET supports clinical decision making in breast cancer patients, when HER2 status cannot be determined by standard work up.

BACKGROUND: Up-to-date information on human epidermal growth factor receptor 2 (HER2) status in breast cancer (BC) is important, as expression can vary during the course of the disease, necessitating anti-HER2 therapy adjustments. Repeat biopsies, however, are not always possible. In this feasibility trial we assessed whether 89Zr-trastuzumab PET could support diagnostic understanding and aid clinical decision making, when HER2 status could not be determined by standard work up. Additionally, HER2 status on circulating tumour cells (CTCs) was assessed. PATIENTS AND METHODS: 89Zr-trastuzumab PET was performed in patients if disease HER2 status remained unclear after standard work up (bone scan, 18F-FDG PET, CT and if feasible a biopsy). PET result and central pathologic revision of available tumour biopsies were reported to the referring physician. CTC HER2 status prior to PET was evaluated afterwards and therefore not reported. Diagnostic understanding and treatment decision questionnaires were completed by the referring physicians before, directly after and ≥ 3 months after 89Zr-trastuzumab PET. RESULTS: Twenty patients were enrolled: 8 with two primary cancers (HER2-positive and HER2-negative BC or BC and non-BC), 7 with metastases inaccessible for biopsy, 4 with prior HER2-positive and -negative metastases and 1 with primary BC with equivocal HER2 status. 89Zr-trastuzumab PET was positive in 12 patients, negative in 7 and equivocal in 1 patient. In 15/20 patients, 89Zr-trastuzumab PET supported treatment decision. The scan altered treatment of 8 patients, increased physicians' confidence without affecting treatment in 10, and improved physicians' disease understanding in 18 patients. In 10/20 patients CTCs were detected; 6/10 showed HER2 expression. CTC HER2 status was not correlated to 89Zr-trastuzumab PET result or treatment decision. CONCLUSION: 89Zr-trastuzumab PET supports clinical decision making when HER2 status cannot be determined by standard work up. The impact of CTC HER2 status needs to be further explored.

High sensitivity and negative predictive value of sentinel lymph node biopsy in a retrospective early stage oral cavity cancer cohort in the Northern Netherlands.

OBJECTIVES: In cT1-2N0, oral squamous cell carcinoma (OSCC) occult metastases are detected in 23%-37% of cases. Sentinel lymph node biopsy (SLNB) was introduced in head and neck cancer as a minimally invasive alternative for an elective neck dissection in neck staging. Meta-analyses of SLNB accuracy show heterogeneity in the existing studies for reference standards, imaging techniques and pathological examination. The aim of this study was to assess the sensitivity and negative predictive value (NPV) of the SLNB in detecting occult metastases in cT1-2N0 OSCC in a well-defined cohort. DESIGN: Retrospective study. The SLNB procedure consisted of lymphoscintigraphy, SPECT/CT-scanning and gamma probe detection. Routine follow-up was the reference standard for the SLNB negative neck. Histopathological examination of sentinel lymph nodes (SLN) consisted of step serial sectioning, haematoxylin-eosin and cytokeratin AE1/3 staining. SETTING: Two comprehensive oncology centres. PARTICIPANTS: A total of 91 consecutive patients with primary cT1-2N0 OSCC treated by primary resection and neck staging by SLNB procedure between 2008 and 2016. MAIN OUTCOME MEASURES: Sensitivity and negative predictive value. RESULTS: In all cases, SLNs were harvested. A total of 25 (27%) patients had tumour-positive SLNs. The median follow-up was 32 months (range 2-104). Four patients were diagnosed with an isolated regional recurrence in the SLNB negative neck side resulting in an 85% sensitivity and a 94% NPV. CONCLUSION: In our cohort, the SLNB detected occult metastases in early OSCC with 85% sensitivity and 94% NPV. This supports that SLNB is a reliable procedure for surgical staging of the neck in case of oral cT1-2N0 SCC.

[Diagnostic approach and treatment of primary hyperparathyroidism]. / De diagnostiek en behandeling van primaire hyperparathyreoïdie.

- Primary hyperparathyroidism (PHPT) is characterised by elevated serum calcium levels due to elevated levels, or insufficient suppression, of parathyroid hormone (PTH).- The incidence of PHPT has increased in recent years. This is mainly the result of more frequently performed routine measurements of serum calcium, e.g. as part of postmenopausal screening.- The classically described features of PHPT - bones and stones - are not always observed and most patients are asymptomatic.- Diagnosis of PHPT is only established by biochemical testing, not by imaging.- Ultrasound and technetium-99m sestamibi SPECT-CT are the first-choice imaging modalities. These investigations are necessary to localize the parathyroid adenomas and thereby facilitate minimal invasive parathyroidectomy (MIP).

Molecular imaging in ovarian cancer.

Ovarian cancer has a high mortality and novel-targeted treatment strategies have not resulted in breakthroughs for this disease. Insight into the molecular characteristics of ovarian tumors may improve diagnosis and selection of patients for treatment with targeted therapies. A potential way to achieve this is by means of molecular imaging. Generic tumor processes, such as glucose metabolism ((18)F-fluorodeoxyglucose) and DNA synthesis ((18)F-fluorodeoxythymidine), can be visualized non-invasively. More specific targets, such as hormone receptors, growth factor receptors, growth factors and targets of immunotherapy, can also be visualized. Molecular imaging can capture data on intra-patient tumor heterogeneity and is of potential value for individualized, target-guided treatment selection. Early changes in molecular characteristics during therapy may serve as early predictors of response. In this review, we describe the current knowledge on molecular imaging in the diagnosis and as an upfront or early predictive biomarker in patients with ovarian cancer.

A systematic review and meta-analyses of sentinel lymph node identification in breast cancer and melanoma, a plea for tracer mapping.

PURPOSE: Sentinel lymph node biopsy (SLNB) has become a widely accepted staging procedure for both breast carcinoma and melanoma. The aim of our study was to systematically review different SLNB techniques and perform a meta-analysis for corresponding identification and false-negative rates. METHODS: A systematic review of the literature on SLNB in patients with early stage breast carcinoma and melanoma was performed. Only original study groups were included. The SLN identification rate and false negative rate were pooled for patients with breast carcinoma or melanoma according to radiocolloid tracer, blue dye, indocyanine green (ICG), or a combination of a radiocolloid tracer with blue dye or ICG. RESULTS: Between 1992 and 2012, a total of 154 studies (88 breast carcinoma and 66 melanoma) were reported that met our eligibility criteria. These studies included a total of 44,172 patients. The pooled SLN identification rate in breast carcinoma and melanoma patients using solely blue dye was 85% (range: 65-100%) and 84% (range: 59-100%), while for radiocolloid alone it was 94% (range: 67-100%) and 99% (range: 83-100%), respectively. Using a combination of radiocolloid and blue, identification rates were 95% (range 94-95%) and 98% (range: 98-98%). CONCLUSIONS: The current meta-analysis provides data that favors the use of radiocolloid or radiocolloid combined with a blue dye for SLN identification. Performing SLNB with radiocolloid alone is the technique of choice for experienced surgeons, since blue dye has multiple disadvantages. SLNB using ICG as a fluorescent dye seems a promising technique for the near future.

Molecular imaging as a tool to investigate heterogeneity of advanced HER2-positive breast cancer and to predict patient outcome under trastuzumab emtansine (T-DM1): the ZEPHIR trial.

BACKGROUND: Only human epidermal growth factor receptor (HER)2 status determined by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) has been validated to predict efficacy of HER2-targeting antibody-drug-conjugate trastuzumab emtansine (T-DM1). We propose molecular imaging to explore intra-/interpatient heterogeneity in HER2 mapping of metastatic disease and to identify patients unlikely to benefit from T-DM1. PATIENTS AND METHODS: HER2-positive mBC patients with IHC3+ or FISH ≥ 2.2 scheduled for T-DM1 underwent a pretreatment HER2-positron emission tomography (PET)/computed tomography (CT) with (89)Zr-trastuzumab. [(18)F]2-fluoro-2-deoxy-D-glucose (FDG)-PET/CT was performed at baseline and before T-DM1 cycle 2. Patients were grouped into four HER2-PET/CT patterns according to the proportion of FDG-avid tumor load showing relevant (89)Zr-trastuzumab uptake (>blood pool activity): patterns A and B were considered positive (>50% or all of the tumor load 'positive'); patterns C and D were considered negative (>50% or all of the tumor load 'negative'). Early FDG-PET/CT was defined as nonresponding when >50% of the tumor load showed no significant reduction of FDG uptake (<15%). Negative (NPV) and positive predictive values (PPV) of HER2-PET/CT, early FDG response and their combination were assessed to predict morphological response (RECIST 1.1) after three T-DM1 cycles and time-to-treatment failure (TTF). RESULTS: In the 56 patients analyzed, 29% had negative HER2-PET/CT while intrapatient heterogeneity (patterns B and C) was found in 46% of patients. Compared with RECIST1.1, respective NPV/PPV for HER2-PET/CT were 88%/72% and 83%/96% for early FDG-PET/CT. Combining HER2-PET/CT and FDG-PET/CT accurately predicted morphological response (PPV and NPV: 100%) and discriminated patients with a median TTF of only 2.8 months [n = 12, 95% confidence interval (CI) 1.4-7.6] from those with a TTF of 15 months (n = 25, 95% CI 9.7-not calculable). CONCLUSIONS: Pretreatment imaging of HER2 targeting, combined with early metabolic response assessment holds great promise for improving the understanding of tumor heterogeneity in mBC and for selecting patients who will/will not benefit from T-DM1. CLINICALTRIALSGOV IDENTIFIER: NCT01565200.

Targeting breast cancer through its microenvironment: current status of preclinical and clinical research in finding relevant targets.

It is increasingly evident that not only breast cancer cells, but also the tissue embedding these cells: the tumor microenvironment, plays an important role in tumor progression, metastasis formation and treatment sensitivity. This review focuses on the current knowledge of processes by which the microenvironment affects breast cancer, including formation of the metastatic niche, metabolic stimulation, stimulation of tumor cell migration, immune modulation, angiogenesis and matrix remodeling. The number of drugs targeting key factors in these processes is expanding, and the available clinical data is increasing. Therefore current strategies for intervention and prediction of treatment response are outlined. At present, targeting the formation of the metastatic niche and metabolic stimulation by the breast cancer microenvironment, are already showing clinical efficacy. Intervening in the stimulation of tumor cell migration and immune modulation by the microenvironment upcoming fields of great research interest. In contrast, targeting microenvironmental angiogenesis or matrix remodeling appears to be of limited clinical relevance in breast cancer treatment so far. Further research is warranted to optimize intervention strategies and develop predictive tests for the relevance of targeting involved factors within the microenvironment in order to optimally personalize breast cancer treatment.

Prognostic value of the standardized uptake value for (18)F-fluorodeoxyglucose in patients with stage IIIB melanoma.

PURPOSE: FDG PET/CT is an excellent tool to detect melanoma metastases and also allows quantification of FDG uptake using standardized uptake value (SUV). The aim of this study was to prospectively investigate the potential prognostic value of SUV for disease-free survival (DFS) and disease-specific survival (DSS) for patients with stage IIIB melanoma. METHODS: From November 2003 to March 2008, all consecutive patients were included in the present study. Inclusion criteria were: palpable, histology- or cytology-proven lymph node metastases of melanoma, and referred to the University Medical Centre Groningen for FDG PET and CT examination. Patients without distant metastases were evaluated. Multivariable survival analysis was performed to determine whether SUV was associated with DFS and DSS (Cox proportional hazard analysis). RESULTS: In 80 patients (without distant metastases, 65 %) SUV could be measured. Overall 5-year DFS was 41 % (95% CI 26-56 %) and 24 % (95% CI 12-38 %) in patients with a low and high SUVmean (p = 0.02), respectively. Overall 5-year DSS was 48 % (95% CI 31-62 %) and 30 % (95% CI 17-45 %) in patients with a low and high SUVmean (p = 0.04), respectively. In the multivariable analysis, SUVmean was associated with DFS (hazard ratio 1.7; p = 0.048), but was not associated with DSS (hazard ratio 1.6; p = 0.1). The number of positive nodes, extranodal growth and gender were also associated with survival. CONCLUSION: FDG uptake in clinically overt nodal melanoma metastases is inversely associated with DFS. Univariate analysis showed an association with DSS. However, after adjustment for potential confounders this association was no longer significant. If these findings are confirmed in larger studies, SUVmean could potentially be used (in addition to the number of positive nodes, tumour size and extranodal growth) as a factor in deciding on adjuvant systemic treatment.

Use of S-100B to evaluate therapy effects during bevacizumab induction treatment in AJCC stage III melanoma.

AIM: To investigate the feasibility of using bevacizumab to improve the survival of American Joint Committee on Cancer (AJCC) stage III melanoma patients, we investigated how a single bevacizumab treatment affected nodal disease and a panel of biomarkers in clinically fluorodeoxyglucose positron emission tomography (FDG-PET)/computed tomography (CT)-staged, stage III melanoma patients, prior to therapeutic lymph node dissection (TLND). METHODS: Four weeks before TLND, nine patients (median age 50, range 28.8-62.1 years; two male, seven female) with palpable lymph node metastases received 7.5 mg/kg bevacizumab. Before and after this treatment, all patients were assessed by measurements of the maximum standardized uptake value (SUVmax) by FDG-PET scan, and serum S-100B and lactate dehydrogenase (LDH). After TLND, the dissection specimen was analyzed for number of removed lymph nodes, number of metastatic lymph nodes, and tumor necrosis. RESULTS: Median follow-up was 15.5 (2.2-32.9) months. Histopathological analysis revealed tumor necrosis in six patients, of whom five had an S-100B decline and one had an unchanged S-100B level after bevacizumab. The other three patients showed an S-100B increase and no necrosis. Tumor necrosis was correlated with S-100B decrease (P = 0.048). No association was found between necrosis and the markers SUVmax and LDH. No wound healing disturbances were encountered. CONCLUSION: Tumor necrosis in dissection specimens was associated with declining S-100B levels, while elevated S-100B was only found in cases with no necrosis. Bevacizumab might be useful in treating AJCC stage III melanoma patients prior to TLND, and S100-B appears to be a useful marker for assessment of treatment effects.