Arifudin Achmad

Predicting cetuximab accumulation in KRAS wild-type and KRAS mutant colorectal cancer using 64Cu-labeled cetuximab positron emission tomography.

Overexpression of epidermal growth factor receptor (EGFR) is common in colorectal cancer. However, cetuximab as an EGFR‐targeting drug is useful only for a subset of patients and currently no single predictor other than V‐Ki‐ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation status has been established. In the present study, we investigated cetuximab accumulation in colorectal tumors and major organs using 111In‐DOTA‐cetuximab. We also evaluated the potential of positron emission tomography (PET) imaging of 64Cu‐DOTA‐cetuximab. Colorectal tumor xenografts with a different EGFR expression level and KRAS mutation status were subjected to in vivo biodistribution study and PET imaging at 48 h post‐injection of radiolabeled cetuximab. The EGFR expression levels on colorectal tumors were determined by ex vivo immunoblotting and ELISA. We found that KRAS wild‐type tumors had significantly higher 111In‐DOTA‐cetuximab accumulation than KRAS mutant tumors (P < 0.001). Based on KRAS mutation status, a strong correlation was found between 111In‐DOTA‐cetuximab tumor uptake and EGFR expression level (KRAS wild type: r = 0.988; KRAS mutant: r = 0.829), and between 64Cu‐DOTA‐cetuximab tumor uptake with EGFR expression level (KRAS wild type: r = 0.838; KRAS mutant: r = 0.927). Significant correlation was also found between tumor uptake of 111In‐DOTA‐cetuximab and 64Cu‐DOTA‐cetuximab (r = 0.920). PET imaging with 64Cu‐DOTA‐cetuximab allowed clear visualization of tumors. Both radiolabeled cetuximab had effectively visualized cetuximab accumulation in colorectal tumors with a wide variety of EGFR expression levels and different KRAS mutation status as commonly encountered in the clinical setting. Our findings suggest that this radioimmunoimaging therefore can be clinically translated as an in vivo tool to predict cetuximab accumulation in colorectal cancer patients prior to cetuximab therapy. (Cancer Sci 2012; 103: 600–605)

Effects of Intratumoral Inflammatory Process on 18F-FDG Uptake: Pathologic and Comparative Study with 18F-Fluoro-α-Methyltyrosine PET/CT in Oral Squamous Cell Carcinoma

The accurate depiction of both biologic and anatomic profiles of tumors has long been a challenge in PET imaging. An inflammation, which is innate in the carcinogenesis of oral squamous cell carcinoma (OSCC), frequently complicates the image analysis because of the limitations of 18F-FDG and maximum standardized uptake values (SUVmax). New PET parameters, metabolic tumor volume (MTV) and total lesion glycolysis (TLG), as well as 18F-fluoro-α-methyltyrosine (18F-FAMT), a malignancy-specific amino acid–based PET radiotracer, are considered more comprehensive in tumor image analysis. Here, we showed the substantial effects of the intratumoral inflammatory process on 18F-FDG uptake and further study the possibility of MTV and TLG to predict both tumor biology (proliferation activity) and anatomy (pathologic tumor volume). Methods: 18F-FDG and 18F-FAMT PET images from 25 OSCC patients were analyzed. SUVmax on the tumor site was obtained. PET volume computerized-assisted reporting was used to generate a volume of interest to obtain MTV and TLG for 18F-FDG and total lesion retention (TLR) for 18F-FAMT. The whole tumor dissected from surgery was measured and sectioned for pathologic analysis of tumor inflammation grade and Ki-67 labeling index. Results: The high SUVmax of 18F-FDG was related to the high inflammation grade. The SUVmax ratio of 18F-FDG to 18F-FAMT was higher in inflammatory tumors (P < 0.05) whereas the corresponding value in tumors with a low inflammation grade was kept low. All 18F-FAMT parameters were correlated with Ki-67 labeling index (P < 0.01). Pathologic tumor volume predicted from MTV of 18F-FAMT was more accurate (R = 0.90, bias = 3.4 ± 6.42 cm3, 95% confidence interval = 0.77–6.09 cm3) than that of 18F-FDG (R = 0.77, bias = 8.1 ± 11.17 cm3, 95% confidence interval = 3.45–12.67 cm3). Conclusion: 18F-FDG uptake was overestimated by additional uptake related to the intratumoral inflammatory process, whereas 18F-FAMT simply accumulated in tumors according to tumor activity as evaluated by Ki-67 labeling index in OSCC.

Determining patient selection tool and response predictor for outpatient 30 mCi radioiodine ablation dose in non-metastatic differentiated thyroid carcinoma: a Japanese perspective

The lack of isolation ward throughout Japan has long been limiting the 131I radioactive iodine (RAI) ablation for differentiated thyroid cancer (DTC) cases. The 30 mCi RAI ablation was only recently permitted for outpatient basis. However, no patient selection tool nor response predictor has been proposed. This study evaluated factors to find response predictor and determinant for the suitable patients. The retrospective study reviewed 47 eligible non-metastatic papillary DTC patients whose had first 30 mCi RAI ablation after total thyroidectomy. Age, gender, clinical stage, risk category, and pre-ablation serum thyroglobulin (Tg) level were among covariates analyzed to determine the patient selection factors; while the thyroid bed uptake on initial whole body scan (WBS) was later also included in determining RAI ablation response. Thirteen (28%) patients had a low risk (T1-2) while 23 (49%) and 11 (23%) had an intermediate (T3) or high risk (T4), respectively. Twenty-five patients were responders, and 22 were non-responders. All factors were similar between responders and non-responders except pre-ablation serum Tg level (p < 0.001). In multivariate analysis, pre-ablation serum Tg level was the only significant factor for both patient selection (odd ratio (OR) = 1.52, 95% confidence interval (CI) = 1.13-2.06) and response predictor (OR = 1.48; 95% CI = 1.12-1.95). With the cut-off of 5.4 ng/mL, pre-ablation serum Tg level predicts RAI ablation response with 92% specificity and 73% sensitivity. Pre-ablation serum Tg level may help patient selection and predict the response to outpatient 30 mCi RAI ablation among post total thyroidectomy non-metastatic DTC patients.

Can 18F-fluorodeoxyglucose positron emission tomography predict the response to radioactive iodine therapy in metastatic differentiated thyroid carcinoma?

Background131I radioactive iodine therapy (RAI) has been commonly applied for metastatic differentiated thyroid cancer (DTC) and played an adjunctive role to total thyroidectomy. However, there is no reliable method to predict therapeutic response to RAI in metastatic DTC. Several studies showed potential use of 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) in lesion detection or therapeutic response prediction of DTC. Thus we aimed to evaluate the feasibility of 18F-FDG PET for the prediction of therapeutic response to RAI in patients with metastatic DTC. MethodsWe retrospectively evaluated 29 adult patients with metastatic DTC who underwent RAI after total thyroidectomy. 18F-FDG PET/CT was performed within three months before RAI, and the maximum, average and sum of each maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV) and total lesion glycolysis (TLG) were assessed. Therapeutic response to RAI was categorized into the progressive disease (PD) or non-progressive disease (Non-PD), based on the Response Evaluation Criteria in Solid Tumor (RECIST) 1.1 using pre- and post-therapeutic computed tomography (CT) or magnetic resonance imaging (MRI) images. The area under curve (ROC) analyses were performed to evaluate their predictive potentials of therapeutic response to RAI.ResultsAmong 29 patients (12 men; median age, 62.4 y.o.; range, 26–81), eight patients were classified into PD and 21 were into Non-PD. PD patients showed a significantly higher maximum, average and sum SUVmax, MTV and TLG before RAI, compared to the Non-PD group (p < 0.05). Among all the 18F-FDG PET/CT parameters, maximum SUVmax showed the highest sensitivity and positive predictive value (PPV) in predicting treatment response to RAI. With a cutoff value of 9.12, the highest area under curve (AUC) of 0.98 was obtained to differentiate between PD and Non-PD patients.Conclusions18F-FDG PET/CT before RAI was a useful predictor of therapeutic response to RAI, and maximum SUVmax was the most sensitive parameter.

The diagnostic performance of 18F-FAMT PET and 18F-FDG PET for malignancy detection: a meta-analysis

BackgroundThis meta-analysis aims to compare the diagnostic performance of l-3-18F-α-methyl tyrosine (18F-FAMT) positron emission tomography (PET) and 2-deoxy-2-[18F]fluoro-d-glucose (18F-FDG) PET for malignancy detection.MethodsThe workflow of this study follows Cochrane Collaboration Guidelines of a systematic review of diagnostic test accuracy studies. An electronic search was performed for clinical diagnostic studies directly comparing 18F-FAMT and 18F-FDG PET for malignant tumors. Study quality, the risks of bias and sources of variation among studies were assessed using the QUADAS (Quality Assessment of Diagnostic Accuracy Studies) assessment tool. A separate meta-analysis was performed for diagnostic performance based on visual assessment and diagnostic cut-off values. Whenever possible, a bivariate random-effect model was used for analysis and pooling of diagnostic measures across studies.ResultsElectronic search revealed 56 peer-reviewed basic science investigations and clinical studies. Six eligible studies (272 patients) of various type of cancer were meta-analyzed. The 18F-FAMT diagnostic accuracy for malignancy was higher than 18F-FDG based on both visual assessment (diagnostic odd ratio (DOR): 8.90, 95% confidence interval (CI) [2.4, 32.5]) vs 4.63, 95% CI [1.8, 12.2], area under curve (AUC): 77.4% vs 72.8%) and diagnostic cut-off (DOR: 13.83, 95% CI [6.3, 30.6] vs 7.85, 95% CI [3.7, 16.8], AUC: 85.6% vs 80.2%), respectively. While the average sensitivity and specificity of 18F-FAMT and 18F-FDG based on visual assessment were similar, 18F-FAMT was significantly more specific than 18F-FDG (p < 0.05) based on diagnostic cut-off values.Conclusions18F-FAMT is more specific for malignancy than 18F-FDG, while their sensitivity is comparable. 18F-FAMT PET is equal to 18F-FDG PET in diagnostic performance for malignancy detection in several cancer types.