18F-FDG PET/CT in lymphomas: assessment difficulties due to illness characteristics, and comparison with literature data

Fluor-18-deoxy-glucose (18F-FDG or FDG) positron emission tomography - computer tomography (PET/CT) has recently become integrated into the clinical routine of patients with lymphoma in Hungary. The basic condition of risk-adapted treatment of these patients is the exact staging and early objective evaluation of the effectiveness of therapy. Between 1 May 2007 and 31 October 2010, 1862 18F-FDG PET/CT examinations were conducted for lymphoma patients at the PET/CT Center in Debrecen. This is more than 15% of the total examined patient population, and this rate shows a slight increase with each year. Based on the experience obtained from lymphoma patients by routine metabolic PET/CT scans we analyzed the difficulties of the evaluation in different time frames of patients' management. It is well known that FDG uptake of lymphomas depends on multiple factors. Although most histological subtypes are associated with uptake of FDG, the intensity of the tracer uptake is different. Different intensity of FDG uptake of the same type of lymphoma following therapeutic procedures might cause difficulties in the evaluation of the scans ensuring that primary staging by PET/CT is highly required for precise measurement and reliable comparison of data. Extranodal involvement was detected in ~40% of the patients with variable rate of prevalence. Extranodal involvement is associated with great diversity and in most cases it is not characteristic of the illness and might appear in different forms and in any organs. Additionally, because accompanying disease may produce false positive results, detailed clinical data and precise case history is highly required.     

Immunohistochemical detection of oncoprotein 18 (Op18) in malignant lymphomas

Summary Expression of oncoprotein 18 (Op18), an intracellular phosphoprotein up-regulated in many malignant cell types, was evaluated in a series of normal lymphoid tissue and malignant lymphomas. In normal tonsils and reactive lymph nodes, the majority of Op18-positive cells were present in the germinal centres, whereas cells in the mantle zone were essentially negative and the interfollicular areas showed occasional positive cells. Double staining for PCNA and Op18 revealed that Op18 expression only to some extent was correlated with cell proliferation, as determined by PCNA expression.Non-Hodgkin's lymphomas exhibited a variable Op18 expression, and in Hodgkin's disease, Reed-Sternberg and Hodgkin cells frequently expressed Op18 with a strong staining intensity. Using Op18-PCNA double staining in malignant lymphomas, Op18 expression could also be partially dissociated from cell proliferation. By using confocal microscopy, the intracellular localization of Op18 was studied, demonstrating diffuse reactivity in the cytoplasm in interphase cells and during mitosis, whereas nuclei and condensed chromosomes were negative. In conclusion, Op18 was expressed at variable levels in most, perhaps all, proliferating lymphocytes in benign lymphoid tissue as well as in malignant lymphomas. However, the Op18 protein was also detected in a significant fraction of apparently non-cycling normal and neoplastic lymphocytes.     

Clinical value of (18)F-FDG PET/CT in postoperative monitoring for patients with colorectal carcinoma

Objective: To evaluate the clinical value of ¹⁸F-FDG PET/CT in postoperative monitoring for patients with colorectal carcinoma. Methods: 66 postoperative patients with colorectal carcinoma underwent whole-body FDG PET/CT. The final histopathological and formal clinical follow-up findings were used as gold standard to determine the sensitivity and specificity of FDG PET/CT and enhanced CT of the same periods. Results: The sensitivity and specificity of FDG PET/CT in detecting recurrence are 96.30%, 94.87% (while enhanced CT are 70.37% and 87.18% respectively). The sensitivity and specificity in detecting metastasis are 95.35%, 82.61% (enhanced CT are 61.90%, 75.00%). SUVmax was significantly higher in malignant lesions [range 4.16–22.00, mean ± standard deviation (x ± s) 8.06 ± 4.30] than in benign ones (range1.18–6.25, x ± s 2.82 ± 1.02). Conclusion: At present, whole-body ¹⁸F-FDG PET/CT is an advanced diagnostic imaging technique in detecting loco-regional recurrence and metastasis in postoperative patients with colorectal carcinoma for its higher sensitivity and specificity.     

Diagnostic Efficacy of 18F-FDG PET/MRI in Peripheral Nerve Injury Models

The aim of this study was to evaluate the diagnostic efficacy of ¹⁸F-FDG PET/MRI in two different peripheral neuropathic pain models using the injured rat sciatic nerves. Twelve rats, with operation on left sciatic nerves, were evenly divided into three groups: sham surgery (control group), crushing injury and chronic constriction injury (CCI) (experimental groups). The nerve damage was assessed at 3 weeks postoperatively using following methods: paw withdrawal threshold values (RevWT), maximum standardized uptake values on PET/MRI images (SUVR), and counting the number of myelinated axons in proximal and distal sites of nerve injury (MAxR). The results were quantified and statistically analyzed. Compared to the control group, the crushing injury demonstrated significant differences in RevWT (p < 0.0001) and SUVR (p = 0.027) and the CCI group demonstrated significant differences in RevWT (p < 0.0001), SUVR (p = 0.001) and MAxR (p = 0.048). There were no significant differences between the two experimental groups for all assessments. Correlation analysis demonstrated that RevWT and SUVR assessments were highly correlated (r = -− 0.710, p = 0.010), and SUVR and MAxR were highly correlated (r = 0.611, p = 0.035). However, there was no significant correlation between RevWT and MAxR. The PET scan may be a valuable imaging modality to enable noninvasive, objective diagnosis of neuropathic pain caused by peripheral nerve injury. Also, MRI fused with PET may help clarify the anatomic location of soft tissue structures, including the peripheral nerves.

     

A Dual Tracer 18F-FCH/18F-FDG PET Imaging of an Orthotopic Brain Tumor Xenograft Model

Early diagnosis of low grade glioma has been a challenge to clinicians. Positron Emission Tomography (PET) using ¹⁸F-FDG as a radio-tracer has limited utility in this area because of the high background in normal brain tissue. Other radiotracers such as ¹⁸F-Fluorocholine (¹⁸F-FCH) could provide better contrast between tumor and normal brain tissue but with high incidence of false positives. In this study, the potential application of a dual tracer ¹⁸F-FCH/¹⁸F-FDG-PET is investigated in order to improve the sensitivity of PET imaging for low grade glioma diagnosis based on a mouse orthotopic xenograft model. BALB/c nude mice with and without orthotopic glioma xenografts from U87 MG-luc2 glioma cell line are used for the study. The animals are subjected to ¹⁸F-FCH and ¹⁸F-FDG PET imaging, and images acquired from two separate scans are superimposed for analysis. The ¹⁸F-FCH counts are subtracted from the merged images to identify the tumor. Micro-CT, bioluminescence imaging (BLI), histology and measurement of the tumor diameter are also conducted for comparison. Results show that there is a significant contrast in ¹⁸F-FCH uptake between tumor and normal brain tissue (2.65 ± 0.98), but with a high false positive rate of 28.6%. The difficulty of identifying the tumor by ¹⁸F-FDG only is also proved in this study. All the tumors can be detected based on the dual tracer technique of ¹⁸F-FCH/ ¹⁸F-FDG-PET imaging in this study, while the false-positive caused by ¹⁸F-FCH can be eliminated. Dual tracer ¹⁸F-FCH/¹⁸F-FDG PET imaging has the potential to improve the visualization of low grade glioma. ¹⁸F-FCH delineates tumor areas and the tumor can be identified by subtracting the ¹⁸F-FCH counts. The sensitivity was over 95%. Further studies are required to evaluate the possibility of applying this technique in clinical trials.     

18F-FDG PET和治疗量131I全身扫描对分化型甲状腺癌根治术后转移灶检测的临床价值评估

目的：探讨18F-FDG PET显像和131I-全身扫描（131I-WBS）SPECT显像对分化型甲状腺癌（DTC）术后转移灶的临床诊断价值。方法：对57例外科术后拟行131I治疗的DTC患者行18F-FDG PET全身显像和131I-WBS扫描,观察和记录在糖代谢和碘代谢中DTC转移灶的定位及数量变化,并同时测定甲状腺球蛋白（Tg）,促甲状腺激素释放激素（TSH）等实验室检查项目。结果：57例DTC患者18F-FDG PET显像发现真阳性20例、假阳性3例、真阴性31例、假阴性3例,其灵敏度为87.0%,特异性为91.2%。而131I-WBS扫描发现真阳性13例、假阳性2例、真阴性34例、假阴性8例,其灵敏度为61.9%,特异性为94.4%。PET显像和131I-WBS扫描共检出阳性病灶73个,其中淋巴结32个,肺5个,纵隔6个,骨26个,其他部位4个。PET显像发现43个阳性病灶（58.9%）,而131I-WBS检出30个（41.1%）。当Tg水平〉10μg/L时,随着Tg在血清含量的增高,两种显像方法的对DTC转移灶的阳性检出率亦随之升高。结论：两种检查对DTC术后转移灶的监测和131I的治疗具有良好的互补性,18F-FDG PET显像在Tg阳性和131I-WBS阴性的患者的转移灶检出上更具有优势,有重要的临床指导意义。     

BCG in the immunotherapy of malignant lymphomas

Summary The effectiveness of a nonspecific immunostimulation in related human or animal diseases incited us to do a study of nonspecific immunotherapy by BCG in Hodgkin's disease, and then in other malignant lymphomas. Seventy patients, each one fulfilling at least 2 criteria of poor prognosis, were initially put in complete remission by a combination of radio-chemotherapy, followed by a reinforcing chemotherapy. These patients were then randomized into two groups. The first group received no further treatment; the second received BCG in weekly cutaneous scarifications. Eight patients were excluded from the study. The rate of relapses is significantly lower in the treated group. The results are discussed. Other therapeutic studies are necessary to fix the indications and modalities of this immunotherapy.Communication to the Medical Oncology Society, Nice, December 7, 1976     

Prognostic Value of 18F-FDG PET/CT in Surgical Non-Small Cell Lung Cancer: A Meta-Analysis

Background

The identification of surgical non-small cell lung cancer (NSCLC) patients with poor prognosis is a priority in clinical oncology because of their high 5-year mortality. This meta-analysis explored the prognostic value of maximal standardized uptake value (SUV_max), metabolic tumor volume (MTV) and total lesion glycolysis (TLG) on disease-free survival (DFS) and overall survival (OS) in surgical NSCLC patients.

Materials and Methods

MEDLINE, EMBASE and Cochrane Libraries were systematically searched until August 1, 2015. Prospective or retrospective studies that evaluated the prognostic roles of preoperative 18F-FDG PET/CT with complete DFS and OS data in surgical NSCLC patients were included. The impact of SUV_max, MTV or TLG on survival was measured using hazard ratios (HR). Sub-group analyses were performed based on disease stage, pathological classification, surgery only and cut-off values.

Results

Thirty-six studies comprised of 5807 patients were included. The combined HRs for DFS were 2.74 (95%CI 2.33–3.24, unadjusted) and 2.43 (95%CI: 1.76–3.36, adjusted) for SUV_max, 2.27 (95%CI 1.77–2.90, unadjusted) and 2.49 (95%CI 1.23–5.04, adjusted) for MTV, and 2.46 (95%CI 1.91–3.17, unadjusted) and 2.97 (95%CI 1.68–5.28, adjusted) for TLG. The pooled HRs for OS were 2.54 (95%CI 1.86–3.49, unadjusted) and 1.52 (95%CI 1.16–2.00, adjusted) for SUV_max, 2.07 (95%CI 1.16–3.69, unadjusted) and 1.91 (95%CI 1.13–3.22, adjusted) for MTV, and 2.47 (95%CI 1.38–4.43, unadjusted) and 1.94 (95%CI 1.12–3.33, adjusted) for TLG. Begg’s test detected publication bias, the trim and fill procedure was performed, and similar HRs were obtained. The prognostic role of SUV_max, MTV and TLG remained similar in the sub-group analyses.

Conclusions

High values of SUV_max, MTV and TLG predicted a higher risk of recurrence or death in patients with surgical NSCLC. We suggest the use of FDG PET/CT to select patients who are at high risk of disease recurrence or death and may benefit from aggressive treatments.     

Morphology and index of nucleoli in malignant lymphomas

The significance of morphology and the number of lymphocyte nucleoli was evaluated by electronmicroscopic sections of malignant lymphomas. It was not only the number and the size of nucleoli which characterized malignant lymphomas differing in histological respect, but above all the different morphology of the nucleoli. The prognostic significance of the nucleolus can be illustrated, if malignant lymphomas of a low grade malignancy with a preponderance of micronucleoli and a low nucleolar index are compared with a significantly higher nucleolar index and markedly increased macronucleoli. These differences are further supplemented by additional morphological properties of nucleoli in malignant lymphomas.     

Effectiveness of PET/CT with 18F-fluorothymidine in the staging of patients with squamous cell head and neck carcinomas before radiotherapy

Aim

The aim of our study was to compare the staging of the disease declared before anticancer treatment was begun with the staging that was found after the planning PET/CT scanning with ¹⁸F-FLT was performed.

Background

PET/CT in radiotherapy planning of head and neck cancers can facilitate the contouring of the primary tumour and the definition of metastatic lymph nodes.

Materials and methods

Between November 2010 and November 2013, 26 patients suffering from head and neck carcinomas underwent planning PET/CT examination with ¹⁸F-FLT. We compared the staging of the disease and the treatment strategy declared before and after ¹⁸F-FLT-PET/CT was performed.

Results

The findings from ¹⁸FLT-PET/CT led in 22 patients to a change of staging: in 19 patients it led to upstaging of the disease and in 3 patients it led to downstaging of the disease. In one patient, a secondary malignancy was found.

Conclusions

We have confirmed in this study that the use of ¹⁸F-FLT-PET/CT scanning in radiotherapy planning of squamous cell head and neck carcinomas has a great potential in the precise evaluation of disease staging and consequently in the precise determination of target volumes.     

Correlation of Perfusion MRI and 18F-FDG PET Imaging Biomarkers for Monitoring Regorafenib Therapy in Experimental Colon Carcinomas with Immunohistochemical Validation

ObjectivesTo investigate a multimodal, multiparametric perfusion MRI / ¹⁸F-fluoro-deoxyglucose-(¹⁸F-FDG)-PET imaging protocol for monitoring regorafenib therapy effects on experimental colorectal adenocarcinomas in rats with immunohistochemical validation.ResultsRegorafenib significantly (p<0.01) suppressed PF (81.1±7.5 to 50.6±16.0 mL/100mL/min), PV (12.1±3.6 to 7.5±1.6%) and PS (13.6±3.2 to 7.9±2.3 mL/100mL/min) as well as TTB (3.4±0.6 to 1.9±1.1) between baseline and day 7. Immunohistochemistry revealed significantly (p<0.03) lower tumor microvascular density (CD-31, 7.0±2.4 vs. 16.1±5.9) and tumor cell proliferation (Ki-67, 434.0 ± 62.9 vs. 663.0 ± 98.3) in the therapy group. Perfusion MRI parameters ΔPF, ΔPV and ΔPS showed strong and significant (r = 0.67-0.78; p<0.01) correlations to the PET parameter ΔTTB and significant correlations (r = 0.57-0.67; p<0.03) to immunohistochemical Ki-67 as well as to CD-31-stainings (r = 0.49-0.55; p<0.05).ConclusionsA multimodal, multiparametric perfusion MRI/PET imaging protocol allowed for non-invasive monitoring of regorafenib therapy effects on experimental colorectal adenocarcinomas in vivo with significant correlations between perfusion MRI parameters and ¹⁸F-FDG-PET validated by immunohistochemistry.     

18F-FDG PET Metabolic Parameters and MRI Perfusion and Diffusion Parameters in Hepatocellular Carcinoma: A Preliminary Study

Objectives

Glucose metabolism, perfusion, and water diffusion may have a relationship or affect each other in the same tumor. The understanding of their relationship could expand the knowledge of tumor characteristics and contribute to the field of oncologic imaging. The purpose of this study was to evaluate the relationships between metabolism, vasculature and cellularity of advanced hepatocellular carcinoma (HCC), using multimodality imaging such as ¹⁸F-FDG positron emission tomography (PET), dynamic contrast enhanced (DCE)-MRI, and diffusion weighted imaging(DWI).

Materials and Methods

Twenty-one patients with advanced HCC underwent ¹⁸F-FDG PET, DCE-MRI, and DWI before treatment. Maximum standard uptake values (SUV_max) from ¹⁸F-FDG-PET, variables of the volume transfer constant (K^trans) from DCE-MRI and apparent diffusion coefficient (ADC) from DWI were obtained for the tumor and their relationships were examined by Spearman’s correlation analysis. The influence of portal vein thrombosis on SUV_max and variables of K^trans and ADC was evaluated by Mann-Whitney test.

Results

SUV_max showed significant negative correlation with K^trans _max (ρ = −0.622, p = 0.002). However, variables of ADC showed no relationship with variables of K^trans or SUV_max (p>0.05). Whether portal vein thrombosis was present or not did not influence the SUV _max and variables of ADC and K^trans (p>0.05).

Conclusion

In this study, SUV was shown to be correlated with K_trans in advanced HCCs; the higher the glucose metabolism a tumor had, the lower the perfusion it had, which might help in guiding target therapy.     

Implications of False Negative and False Positive Diagnosis in Lymph Node Staging of NSCLC by Means of 18F-FDG PET/CT

Background

Integrated ¹⁸F-fluorodeoxyglucose positron emission tomography/computed tomography (¹⁸F-FDG PET/CT) is widely performed in hilar and mediastinal lymph node (HMLN) staging of non-small cell lung cancer (NSCLC). However, the diagnostic efficiency of PET/CT remains controversial. This retrospective study is to evaluate the accuracy of PET/CT and the characteristics of false negatives and false positives to improve specificity and sensitivity.

Methods

219 NSCLC patients with systematic lymph node dissection or sampling underwent preoperative PET/CT scan. Nodal uptake with a maximum standardized uptake value (SUVmax) >2.5 was interpreted as PET/CT positive. The results of PET/CT were compared with the histopathological findings. The receiver operating characteristic (ROC) curve was generated to determine the diagnostic efficiency of PET/CT. Univariate and multivariate analysis were conducted to detect risk factors of false negatives and false positives.

Results

The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy of PET/ CT in detecting HMLN metastases were 74.2% (49/66), 73.2% (112/153), 54.4% (49/90), 86.8% (112/129), and 73.5% (161/219). The ROC curve had an area under curve (AUC) of 0.791 (95% CI 0.723-0.860). The incidence of false negative HMLN metastases was 13.2% (17 of 129 patients). Factors that are significantly associated with false negatives are: concurrent lung disease or diabetes (p<0.001), non-adenocarcinoma (p<0.001), and SUVmax of primary tumor >4.0 (p=0.009). Postoperatively, 45.5% (41/90) patients were confirmed as false positive cases. The univariate analysis indicated age > 65 years old (p=0.009), well differentiation (p=0.002), and SUVmax of primary tumor ≦4.0 (p=0.007) as risk factors for false positive uptake.

Conclusion

The SUVmax of HMLN is a predictor of malignancy. Lymph node staging using PET/CT is far from equal to pathological staging account of some risk factors. This study may provide some aids to pre-therapy evaluation and decision-making.     

No diagnostic impact of routinely use of respiratory gating to characterize lung nodules with 18F-FDG PET/CT

Purpose

To evaluate diagnostic impact of routinely use of respiratory gated (RG) ¹⁸FDG PET/CT to distinguish benign and malignant lung nodules.