Partial-volume correction in dynamic PET-CT: effect on tumor kinetic parameter estimation and validation of simplified metrics.

BACKGROUND: Partial-volume effects generally result in an underestimation of tumor tracer uptake on PET-CT for small lesions, necessitating partial-volume correction (PVC) for accurate quantification. However, investigation of PVC in dynamic oncological PET studies to date is scarce. The aim of this study was to investigate PVC's impact on tumor kinetic parameter estimation from dynamic PET-CT acquisitions and subsequent validation of simplified semi-quantitative metrics. Ten patients with EGFR-mutated non-small cell lung cancer underwent dynamic 18F-fluorothymidine PET-CT before, 7 days after, and 28 days after commencing treatment with a tyrosine kinase inhibitor. Parametric PVC was applied using iterative deconvolution without and with highly constrained backprojection (HYPR) denoising, respectively. Using an image-derived input function with venous parent plasma calibration, we estimated full kinetic parameters VT, K1, and k3/k4 (BPND) using a reversible two-tissue compartment model, and simplified metrics (SUV and tumor-to-blood ratio) at 50-60 min post-injection. RESULTS: PVC had a non-linear effect on measured activity concentrations per timeframe. PVC significantly changed each kinetic parameter, with a median increase in VT of 11.8% (up to 25.1%) and 10.8% (up to 21.7%) without and with HYPR, respectively. Relative changes in kinetic parameter estimates vs. simplified metrics after applying PVC were poorly correlated (correlations 0.36-0.62; p < 0.01). PVC increased correlations between simplified metrics and VT from 0.82 and 0.81 (p < 0.01) to 0.90 and 0.88 (p < 0.01) for SUV and TBR, respectively, albeit non-significantly. PVC also increased correlations between treatment-induced changes in simplified metrics vs. VT at 7 (SUV) and 28 (SUV and TBR) days after treatment start non-significantly. Delineation on partial-volume corrected PET images resulted in a median decrease in metabolic tumor volume of 14.3% (IQR - 22.1 to - 7.5%), and increased the effect of PVC on kinetic parameter estimates. CONCLUSION: PVC has a significant impact on tumor kinetic parameter estimation from dynamic PET-CT data, which differs from its effect on simplified metrics. However, it affected validation of these simplified metrics both as single measurements and as biomarkers of treatment response only to a small extent. Future dynamic PET studies should preferably incorporate PVC. TRIAL REGISTRATION: Dutch Trial Register, NTR3557 .

Validation of [18F]FLT as a perfusion-independent imaging biomarker of tumour response in EGFR-mutated NSCLC patients undergoing treatment with an EGFR tyrosine kinase inhibitor.

BACKGROUND: 3'-Deoxy-3'-[18F]fluorothymidine ([18F]FLT) was proposed as an imaging biomarker for the assessment of in vivo cellular proliferation with positron emission tomography (PET). The current study aimed to validate [18F]FLT as a perfusion-independent PET tracer, by gaining insight in the intra-tumoural relationship between [18F]FLT uptake and perfusion in non-small cell lung cancer (NSCLC) patients undergoing treatment with a tyrosine kinase inhibitor (TKI). Six patients with metastatic NSCLC, having an activating epidermal growth factor receptor (EGFR) mutation, were included in this study. Patients underwent [15O]H2O and [18F]FLT PET/CT scans at three time points: before treatment and 7 and 28 days after treatment with a TKI (erlotinib or gefitinib). Parametric analyses were performed to generate quantitative 3D images of both perfusion measured with [15O]H2O and proliferation measured with [18F]FLT volume of distribution (V T ). A multiparametric classification was performed by classifying voxels as low and high perfusion and/or low and high [18F]FLT V T using a single global threshold for all scans and subjects. By combining these initial classifications, voxels were allocated to four categories (low perfusion-low V T , low perfusion-high V T , high perfusion-low V T and high perfusion-high V T ). RESULTS: A total of 17 perfusion and 18 [18F]FLT PET/CT scans were evaluated. The average tumour values across all lesions were 0.53 ± 0.26 mL cm- 3 min- 1 and 4.25 ± 1.71 mL cm- 3 for perfusion and [18F]FLT V T , respectively. Multiparametric analysis suggested a shift in voxel distribution, particularly regarding the V T : from an average of ≥ 77% voxels classified in the "high V T category" to ≥ 85% voxels classified in the "low V T category". The shift was most prominent 7 days after treatment and remained relatively similar afterwards. Changes in perfusion and its spatial distribution were minimal. CONCLUSION: The present study suggests that [18F]FLT might be a perfusion-independent PET tracer for measuring tumour response as parametric changes in [18F]FLT uptake occurred independent from changes in perfusion. TRIAL REGISTRATION: Nederlands Trial Register (NTR), NTR3557 . Registered 2 August 2012.

Repeatability of quantitative 18F-FLT uptake measurements in solid tumors: an individual patient data multi-center meta-analysis.

INTRODUCTION: 3'-deoxy-3'-[18F]fluorothymidine (18F-FLT) positron emission tomography (PET) provides a non-invasive method to assess cellular proliferation and response to antitumor therapy. Quantitative 18F-FLT uptake metrics are being used for evaluation of proliferative response in investigational setting, however multi-center repeatability needs to be established. The aim of this study was to determine the repeatability of 18F-FLT tumor uptake metrics by re-analyzing individual patient data from previously published reports using the same tumor segmentation method and repeatability metrics across cohorts. METHODS: A systematic search in PubMed, EMBASE.com and the Cochrane Library from inception-October 2016 yielded five 18F-FLT repeatability cohorts in solid tumors. 18F-FLT avid lesions were delineated using a 50% isocontour adapted for local background on test and retest scans. SUVmax, SUVmean, SUVpeak, proliferative volume and total lesion uptake (TLU) were calculated. Repeatability was assessed using the repeatability coefficient (RC = 1.96 × SD of test-retest differences), linear regression analysis, and the intra-class correlation coefficient (ICC). The impact of different lesion selection criteria was also evaluated. RESULTS: Images from four cohorts containing 30 patients with 52 lesions were obtained and analyzed (ten in breast cancer, nine in head and neck squamous cell carcinoma, and 33 in non-small cell lung cancer patients). A good correlation was found between test-retest data for all 18F-FLT uptake metrics (R2 ≥ 0.93; ICC ≥ 0.96). Best repeatability was found for SUVpeak (RC: 23.1%), without significant differences in RC between different SUV metrics. Repeatability of proliferative volume (RC: 36.0%) and TLU (RC: 36.4%) was worse than SUV. Lesion selection methods based on SUVmax ≥ 4.0 improved the repeatability of volumetric metrics (RC: 26-28%), but did not affect the repeatability of SUV metrics. CONCLUSIONS: In multi-center studies, differences ≥ 25% in 18F-FLT SUV metrics likely represent a true change in tumor uptake. Larger differences are required for FLT metrics comprising volume estimates when no lesion selection criteria are applied.

Is ultrasound-guided fine-needle aspiration cytology of adequate value in detecting breast cancer patients with three or more positive axillary lymph nodes?

This study evaluated the accuracy of ultrasound-guided fine-needle aspiration cytology of the sonographically most suspicious axillary lymph node (US/FNAC) to select early breast cancer patients with three or more tumour-positive axillary lymph nodes. Between 2004 and 2014, a total of 2130 patients with histologically proven early breast cancer were evaluated and treated in the Noordwest Clinics Alkmaar. US/FNAC was performed preoperatively in all these patients. We analysed the results of US/FNAC retrospectively. Pathological axillary node status (sentinel node biopsy and/or axillary lymph node dissection) was used as reference standard. A total of 634 (29.8 %) of 2130 patients had axillary lymph node metastases on final histology. 248 node positive patients (11.6 %) had three or more positive lymph nodes. The accuracy of US/FNAC to detect three or more positive lymph nodes was 89.8 %, sensitivity was 44.8 %, specificity was 95.7 %, PPV was 58.1 %, and NPV was 92.9 %. This study shows a more than adequate accuracy of preoperative US/FNAC to detect three or more positive lymph nodes (89.8 %). However, when US/FNAC was chosen as the only axillary staging method, 6.4 % of all patients (false negative group) would have been undertreated and 3.8 % of all patients (false positive group) would have been overtreated according to the ACOSOG Z0011 criteria.

A systematic review on [(18)F]FLT-PET uptake as a measure of treatment response in cancer patients.

Imaging biomarkers have a potential to depict the hallmarks of cancers that characterise cancer cells as compared to normal cells. One pertinent example is 3'-deoxy-3'-(18)F-fluorothymidine positron emission tomography ([(18)F]FLT-PET), which allows non-invasive in vivo assessment of tumour proliferation. Most importantly, [(18)F]FLT does not seem to be accumulating in inflammatory processes, as seen in [(18)F]-fludeoxyglucose, the most commonly used PET tracer for assessment of cell metabolism. [(18)F]FLT could therefore provide additional information about the tumour biology before, during and after treatment. This systematic review focuses on the use of [(18)F]FLT-PET tumour uptake values as a measure of tumour response to therapeutic interventions. The clinical studies which evaluated the role of [(18)F]FLT-PET as a measure of tumour response to treatment are summarised and the evidence linking [(18)F]FLT-PET tumour uptake values with clinical outcome is evaluated.

CT-perfusion versus [(15)O]H2O PET in lung tumors: effects of CT-perfusion methodology.

PURPOSE: Nowadays, PET and dynamic contrast enhanced CT or MRI are used to assess tumor blood perfusion. Although [(15)O]H2O PET is the gold standard, it is hardly available for routine clinical practice, due to the short half-life of (15)O. However, the lack of uniformity in scanning and analytic methods limits the use of CT perfusion (CTP) in clinical trials and practice. This study compares [(15)O]H2O PET with CT based perfusion in lung tumors and assesses the effects of various CTP postprocessing and analytical methods on the CTP results using [(15)O]H2O PET as the reference technique. METHODS: Various CTP analysis and image postprocessing methods were assessed. Furthermore, parametric images were obtained using the Slope method. Volumes of interests were defined using several different segmentation methods including Hounsfield unit based contouring thresholds, both with and without framewise application of dynamic contouring thresholds to exclude lung tissue or intravascular contrast. A head-to-head comparison of tumor perfusion obtained by CTP and [(15)O]H2O PET was performed using linear regressions, Bland-Altman plots, and an intraclass correlation coefficient (ICC). In addition, the different postprocessing methods were compared reciprocally. RESULTS: In six lung cancer patients, perfusion assessed using CTP studies combined with the Slope method correlated best with [(15)O]H2O PET (ICC = 0.88; R(2) = 0.89; Y = 0.80). The Mullani-Gould method showed best correlation with the Slope method (ICC ≥ 0.71; R(2) ≥ 0.80; Y = 0.71-1.35). These correlations were obtained using dynamic contouring thresholds and show the influence of CTP postprocessing methods. CONCLUSIONS: Tumor perfusion assessed by CTP in combination with dynamic contouring thresholds using the Slope method correlates well with [(15)O]H2O PET. This suggests that CTP can be used as a method to evaluate tumor perfusion in lung cancer.

The case for ostectomy--a time-tested therapeutic modality in selected periodontitis sites.

Although ostectomy has been proven in numerous studies to be an effective means of reducing pocket depth, some clinicians still question its merits. To determine the efficacy of ostectomy for the treatment of periodontitis, 870 pairs of presurgical and postsurgical radiographs of sites treated by ostectomy were examined. The postsurgical radiographs, taken 5 to 30 years postoperatively, revealed distinct lamina dura and demonstrated that ostectomy is an effective and predictable technique for intercepting the progressive loss of attachment in selected sites with periodontitis.

Surgical alternatives in regenerative therapy of the periodontium.

Surgical alternatives in regenerative therapy are presented, along with an explanation of the author's rationale and indications for treatment. These alternatives are lesion, site, and patient dependent. The techniques are described and illustrated in several cases to support the thesis that a multifaceted approach to regeneration is necessary.

Surgical pocket reduction.

It is not possible within the scope of this paper to describe in any detail each of the aforementioned procedures. These can be found in the various textbooks and journals on clinical periodontology. Instead, the objectives of treatment, the spectrum of techniques available, and the rationale for their use have been described. Periodontal surgery should be performed only under certain conditions: the patient must be physically and mentally competent to undergo any type of surgery, and should understand and agree to the procedure and to postoperative management. Finally, periodontal surgery should only be considered when nonsurgical therapy will not accomplish the desired result. When periodontal surgery for pocket elimination is performed for selected defects that have been properly evaluated after a debridement and healing period, and is executed with technical competence and proper postoperative care, it can preserve the dentition affected by periodontal disease.

The influence of prosthetic stem stiffness and of a calcar collar on stresses in the proximal end of the femur with a cemented femoral component.

UNLABELLED: We used three-dimensional finite-element models of the proximal end of the femur to examine the influence of stem material, stem geometry, and the use of a calcar collar on the stresses in and around implanted total hip-replacement femoral components. Anatomical bone geometries and realistic prosthetic geometries were considered. A slender titanium-alloy stem with a collar allows creation of calcar stresses of approximately 80 per cent of the anticipated normal levels. A similar stem of cobalt-chromium alloy creates calcar stresses of 67 per cent of these normal values. Stem designs without a collar were shown to generate no more than 40 per cent of normal values while larger, stiffer stems were seen to create less than 30 per cent of normal values, with or without a collar. Proximal cement stresses were increased by the use of titanium-alloy stems, but were reduced to low levels by a functioning collar. The highest cement stresses in the system were found near the tip of the stem, where titanium-alloy stems create lower stresses than do corresponding cobalt-chromium-alloy stems. The achievability of calcar loading with a titanium prosthesis was demonstrated in in vitro strain-gauge tests. CLINICAL RELEVANCE: Loosening of the femoral stem and calcar resorption are problems that are seen in many long-term clinical series of total hip prostheses. In order to reduce the incidence of these problems, the goal of the designer of a prosthesis is to reduce cement and cement interface stresses around the femoral stem and to create stress distributions in the bone that will prevent resorption.(ABSTRACT TRUNCATED AT 250 WORDS)