Alphons H. H. Bongaerts

Assessment of Estrogen Receptor Expression in Epithelial Ovarian Cancer Patients Using 16α-18F-Fluoro-17β-Estradiol PET/CT

The estrogen receptor α (ERα) is expressed in approximately 70% of ovarian cancer tumors. PET of tumor ERα expression with the tracer 16α-18F-fluoro-17β-estradiol (18F-FES) may be valuable to select ovarian cancer patients for endocrine therapy. The aim of this study was to evaluate the feasibility of 18F-FES PET to determine tumor ERα expression noninvasively in epithelial ovarian cancer patients. Methods: 18F-FES PET/CT was performed shortly before cytoreductive surgery. Tumor 18F-FES uptake was quantified for all lesions 10 mm or greater on CT and expressed as maximum standardized uptake value. 18F-FES PET/CT findings were compared with histology and immunohistochemistry for ERα, ERβ, and progesterone receptor. Receptor expression was scored semiquantitatively using H-scores (percentage of positive tumor cells × staining intensity). The optimum threshold to discriminate ER-positive and -negative lesions was determined by receiver-operating-characteristic analysis. Results: In the 15 included patients with suspected ovarian cancer, 32 measurable lesions greater than 10 mm were present on CT. Tumor 18F-FES uptake could be quantified for 28 lesions (88%), and 4 lesions were visible but nonquantifiable because of high uptake in adjacent tissue. During surgery, histology was obtained of 23 of 28 quantified lesions (82%). Quantitative 18F-FES uptake correlated with the semiquantitative immunoscore for ERα (ρ = 0.65, P < 0.01) and weakly with progesterone receptor expression (ρ = 0.46, P = 0.03) and was not associated with ERβ expression (ρ = 0.21, P = 0.33). The optimum threshold to discriminate ERα-positive and ERα-negative lesions was a maximum standardized uptake value greater than 1.8, which provided a 79% sensitivity, 100% specificity, and area under the curve of 0.86 (95% confidence interval, 0.70–1.00). In 2 of 7 patients with cytology/histology available at primary diagnosis and at debulking surgery, immunohistochemical ERα expression had changed over time. 18F-FES PET was in accordance with histology at debulking surgery but not at primary diagnosis, indicating that 18F-FES PET could provide reliable information about current tumor ERα status. Conclusion: 18F-FES PET/CT can reliably assess ERα status in epithelial ovarian cancer tumors and metastases noninvasively. Evaluation of the predictive value of 18F-FES PET/CT for endocrine therapy in epithelial ovarian cancer patients is warranted.

Drug concentration in lung tissue in multidrug-resistant tuberculosis

To the Editor: Multidrug-resistant tuberculosis (MDR-TB) is emerging worldwide, with 3.7% of new cases and 20% of previously treated tuberculosis (TB) cases having MDR-TB. Unfortunately, second-line TB drugs, used for MDR-TB treatment, are less effective than first-line drugs [1]. Sputum culture rather than sputum smear microscopy is recommended to monitor treatment response [1]. Therapeutic drug monitoring (TDM), which may help optimise efficacy and minimise side-effects with the potential to safeguard intestinal absorption of drugs [2], is currently not recommended in World Health Organization (WHO) treatment guidelines [1]. Although TDM yields information on serum drug concentrations, penetration of second-line TB drugs into diseased tissues such as destroyed lung tissue has, to our knowledge, not been addressed in studies [3]. Herein, we report simultaneous blood and tissue concentrations of second-line TB drugs in lung tissue destroyed by MDR-TB. A 13-year-old Somalian, HIV sero-negative female, residing in the Netherlands since 2010, was admitted to our TB Unit (TB Center Beatrixoord, University Medical Center Groningen, Groningen, the Netherlands) in September 2011 with a 3-month history of cough, fever, chest pain and unintentional 14 kg weight loss. TB contacts were denied and she had not received a bacilli Calmette–Guerin vaccination. Apart from almost absent breathe sounds and dullness to percussion over the left lung field her physical examination was normal. Chest radiography showed infiltrates in the left lung, particularly in the left upper lobe. Sputum microscopy revealed acid-fast bacilli, and she was started on TB treatment with isoniazid, rifampicin, pyrazinamide and ethambutol. 2 weeks later, molecular diagnostic tests revealed mutations in both the katG and rpoB genes. MDR-TB was now considered and she was transferred to our hospital (University …

111 In-Trastuzumab Scintigraphy in HER2-Positive Metastatic Breast Cancer Patients Remains Feasible during Trastuzumab Treatment

Human epidermal growth factor receptor (HER)2 imaging with radiolabeled trastuzumab might support HER2-targeted therapy. It is, however, frequently questioned whether HER2 imaging is also possible during trastuzumab treatment as the receptor might be saturated. We studied the effect of trastuzumab treatment on 111In-trastuzumab uptake. Patients received trastuzumab weekly and paclitaxel once every 3 weeks. 111In-trastuzumab was injected on day 1 of cycle 1 and day 15 of cycle 4. Whole-body planar scintigraphy was acquired at different time points postinjection. Tumor uptake and organ distribution between the first and repeated scan series were calculated via residence times. Twenty-five tumor lesions in 12 patients were visualized on both scintigraphy series. Tumor uptake decreased (19.6%; p = .03). The residence times of normal organs remained similar except for the cardiac blood pool (+ 16.3%; p = .014). Trastuzumab treatment decreases tumor 111In-trastuzumab uptake around 20%. HER2 imaging is feasible during trastuzumab treatment.Human epidermal growth factor receptor (HER)2 imaging with radiolabeled trastuzumab might support HER2-targeted therapy. It is, however, frequently questioned whether HER2 imaging is also possible during trastuzumab treatment as the receptor might be saturated. We studied the effect of trastuzumab treatment on 111In-trastuzumab uptake. Patients received trastuzumab weekly and paclitaxel once every 3 weeks. 111In-trastuzumab was injected on day 1 of cycle 1 and day 15 of cycle 4. Whole-body planar scintigraphy was acquired at different time points postinjection. Tumor uptake and organ distribution between the first and repeated scan series were calculated via residence times. Twenty-five tumor lesions in 12 patients were visualized on both scintigraphy series. Tumor uptake decreased (19.6%; p = .03). The residence times of normal organs remained similar except for the cardiac blood pool (+ 16.3%; p = .014). Trastuzumab treatment decreases tumor 111In-trastuzumab uptake around 20%. HER2 imaging is feasible during trastuzumab treatment.

Total Body Metabolic Tumor Response in ALK Positive Non-Small Cell Lung Cancer Patients Treated with ALK Inhibition

Background In ALK-positive advanced NSCLC, crizotinib has a high response rate and effectively increases quality of life and survival. CT measurement of the tumor may insufficiently reflect the actual tumor load changes during targeted therapy with crizotinib. We explored whether 18F-FDG PET measured metabolic changes are different from CT based changes and studied the impact of these changes on disease progression. Methods 18F-FDG PET/CT was performed prior to and after 6 weeks of crizotinib treatment. Tumor response on CT was classified with RECIST 1.1, while 18F-FDG PET response was assessed according to the 1999 EORTC recommendations and PERCIST criteria. Agreement was assessed using McNemars test. During follow-up, patients received additional PET/CT during crizotinib treatment and second generation ALK inhibition. We assessed whether PET was able to detect progression earlier then CT. Results In this exploratory study 15 patients were analyzed who were treated with crizotinib. There was a good agreement in the applicability of CT and 18F-FDG PET/CT using the EORTC recommendations. During first line crizotinib and subsequent second line ALK inhibitors, PET was able to detect progression earlier then CT in 10/22 (45%) events of progression and in the others disease progression was detected simultaneously. Conclusion In advanced ALK positive NSCLC PET was able to detect progressive disease earlier than with CT in nearly half of the assessments while both imaging tests performed similar in the others.

Assessment of Volumetric versus Manual Measurement in Disseminated Testicular Cancer; No Difference in Assessment between Non-Radiologists and Genitourinary Radiologist.

Background The aim of this study was to assess the feasibility and reproducibility of semi-automatic volumetric measurement of retroperitoneal lymph node metastases in testicular cancer (TC) patients treated with chemotherapy versus the standardized manual measurements based on RECIST criteria. Methods 21 TC patients with retroperitoneal lymph node metastases of testicular cancer were studied with a CT scan of chest and abdomen before and after cisplatin based chemotherapy. Three readers, a surgical resident, a radiological technician and a radiologist, assessed tumor response independently using computerized volumetric analysis with Vitrea software® and manual measurement according to RECIST criteria (version 1.1). Intra- and inter-rater variability were evaluated with intra class correlations and Bland-Altman analysis. Results Assessment of intra observer and inter observer variance proved non-significant in both measurement modalities. In particularly all intraclass correlation (ICC) values for the volumetric analysis were > .99 per observer and between observers. There was minimal bias in agreement for manual as well as volumetric analysis. Conclusion In this study volumetric measurement using Vitrea software® appears to be a reliable, reproducible method to measure initial tumor volume of retroperitoneal lymph node metastases of testicular cancer after chemotherapy. Both measurement methods can be performed by experienced non-radiologists as well.

Insights and ImagesDetection of Intra-Abdominal Testicles with 16β-[18F]-Fluoro-5α-Dihydrotestosterone Positron Emission Tomography/Computed Tomography in a Pubertal Boy

L ocalization of impalpable cryptorchid testicles, which carry an increased risk of subfertility and malignancy, can be a challenging endeavor. Here, we describe a novel imaging approach in a 16-year-old pubertal boy, who presented as aneonatewith cryptorchidism,penoscrotal hypospadia, renal failure, and proteinuria. He was clinically diagnosed with Denys-Drash syndrome, confirmed genetically. At the age of 6 years, he received a kidney transplant in the right iliac fossa. Earlier efforts to detect gonadal tissue were unsuccessful: laparoscopy at 2 years of age (because of the thickness of the peritoneum from peritoneal dialysis) and repeated radiological imaging (computed tomography,magnetic resonance imaging). Progression to puberty, including a normal pubertal growth spurt and increasing levels of sex-hormones (testosterone, gonadotropins, and anti-M€ ullerian hormone), confirmed the presence of hormonally active gonads. As androgen receptors are known to be expressed in testicles from prepuberty onward, we decided to try to localize testicular tissue by positron emission tomography imaging with the androgen receptor tracer 16b-[F]-fluoro-5a-dihydrotestosterone (F-FDHT). F-FDHT-positron emission tomography/computed tomography revealed both testicles, at the right side just below the transplanted kidney, and at the left ventral side of the pelvic area (Figure, green arrows = testicular tissue, white arrows: veins). F-FDHT uptake in the testicles was low, probably due to competition with high levels of testosterone in serum. With the boy, options are discussed concerning surgery. n

Detection of Intra-Abdominal Testicles with 16β-[18F]-Fluoro-5α-Dihydrotestosterone Positron Emission Tomography/Computed Tomography in a Pubertal Boy

L ocalization of impalpable cryptorchid testicles, which carry an increased risk of subfertility and malignancy, can be a challenging endeavor. Here, we describe a novel imaging approach in a 16-year-old pubertal boy, who presented as aneonatewith cryptorchidism,penoscrotal hypospadia, renal failure, and proteinuria. He was clinically diagnosed with Denys-Drash syndrome, confirmed genetically. At the age of 6 years, he received a kidney transplant in the right iliac fossa. Earlier efforts to detect gonadal tissue were unsuccessful: laparoscopy at 2 years of age (because of the thickness of the peritoneum from peritoneal dialysis) and repeated radiological imaging (computed tomography,magnetic resonance imaging). Progression to puberty, including a normal pubertal growth spurt and increasing levels of sex-hormones (testosterone, gonadotropins, and anti-M€ ullerian hormone), confirmed the presence of hormonally active gonads. As androgen receptors are known to be expressed in testicles from prepuberty onward, we decided to try to localize testicular tissue by positron emission tomography imaging with the androgen receptor tracer 16b-[F]-fluoro-5a-dihydrotestosterone (F-FDHT). F-FDHT-positron emission tomography/computed tomography revealed both testicles, at the right side just below the transplanted kidney, and at the left ventral side of the pelvic area (Figure, green arrows = testicular tissue, white arrows: veins). F-FDHT uptake in the testicles was low, probably due to competition with high levels of testosterone in serum. With the boy, options are discussed concerning surgery. n

Assessment of Estrogen Receptor Expression in Epithelial Ovarian Cancer Patients Using 16 alpha-F-18-Fluoro-17 beta-Estradiol PET/CT

The estrogen receptor α (ERα) is expressed in approximately 70% of ovarian cancer tumors. PET of tumor ERα expression with the tracer 16α-18F-fluoro-17β-estradiol (18F-FES) may be valuable to select ovarian cancer patients for endocrine therapy. The aim of this study was to evaluate the feasibility of 18F-FES PET to determine tumor ERα expression noninvasively in epithelial ovarian cancer patients. Methods: 18F-FES PET/CT was performed shortly before cytoreductive surgery. Tumor 18F-FES uptake was quantified for all lesions 10 mm or greater on CT and expressed as maximum standardized uptake value. 18F-FES PET/CT findings were compared with histology and immunohistochemistry for ERα, ERβ, and progesterone receptor. Receptor expression was scored semiquantitatively using H-scores (percentage of positive tumor cells × staining intensity). The optimum threshold to discriminate ER-positive and -negative lesions was determined by receiver-operating-characteristic analysis. Results: In the 15 included patients with suspected ovarian cancer, 32 measurable lesions greater than 10 mm were present on CT. Tumor 18F-FES uptake could be quantified for 28 lesions (88%), and 4 lesions were visible but nonquantifiable because of high uptake in adjacent tissue. During surgery, histology was obtained of 23 of 28 quantified lesions (82%). Quantitative 18F-FES uptake correlated with the semiquantitative immunoscore for ERα (ρ = 0.65, P < 0.01) and weakly with progesterone receptor expression (ρ = 0.46, P = 0.03) and was not associated with ERβ expression (ρ = 0.21, P = 0.33). The optimum threshold to discriminate ERα-positive and ERα-negative lesions was a maximum standardized uptake value greater than 1.8, which provided a 79% sensitivity, 100% specificity, and area under the curve of 0.86 (95% confidence interval, 0.70–1.00). In 2 of 7 patients with cytology/histology available at primary diagnosis and at debulking surgery, immunohistochemical ERα expression had changed over time. 18F-FES PET was in accordance with histology at debulking surgery but not at primary diagnosis, indicating that 18F-FES PET could provide reliable information about current tumor ERα status. Conclusion: 18F-FES PET/CT can reliably assess ERα status in epithelial ovarian cancer tumors and metastases noninvasively. Evaluation of the predictive value of 18F-FES PET/CT for endocrine therapy in epithelial ovarian cancer patients is warranted.

Assessment of Estrogen Receptor Expression in Epithelial Ovarian Cancer Patients using 18F-FES-PET/CT

The estrogen receptor α (ERα) is expressed in approximately 70% of ovarian cancer tumors. PET of tumor ERα expression with the tracer 16α-18F-fluoro-17β-estradiol (18F-FES) may be valuable to select ovarian cancer patients for endocrine therapy. The aim of this study was to evaluate the feasibility of 18F-FES PET to determine tumor ERα expression noninvasively in epithelial ovarian cancer patients. Methods: 18F-FES PET/CT was performed shortly before cytoreductive surgery. Tumor 18F-FES uptake was quantified for all lesions 10 mm or greater on CT and expressed as maximum standardized uptake value. 18F-FES PET/CT findings were compared with histology and immunohistochemistry for ERα, ERβ, and progesterone receptor. Receptor expression was scored semiquantitatively using H-scores (percentage of positive tumor cells × staining intensity). The optimum threshold to discriminate ER-positive and -negative lesions was determined by receiver-operating-characteristic analysis. Results: In the 15 included patients with suspected ovarian cancer, 32 measurable lesions greater than 10 mm were present on CT. Tumor 18F-FES uptake could be quantified for 28 lesions (88%), and 4 lesions were visible but nonquantifiable because of high uptake in adjacent tissue. During surgery, histology was obtained of 23 of 28 quantified lesions (82%). Quantitative 18F-FES uptake correlated with the semiquantitative immunoscore for ERα (ρ = 0.65, P < 0.01) and weakly with progesterone receptor expression (ρ = 0.46, P = 0.03) and was not associated with ERβ expression (ρ = 0.21, P = 0.33). The optimum threshold to discriminate ERα-positive and ERα-negative lesions was a maximum standardized uptake value greater than 1.8, which provided a 79% sensitivity, 100% specificity, and area under the curve of 0.86 (95% confidence interval, 0.70–1.00). In 2 of 7 patients with cytology/histology available at primary diagnosis and at debulking surgery, immunohistochemical ERα expression had changed over time. 18F-FES PET was in accordance with histology at debulking surgery but not at primary diagnosis, indicating that 18F-FES PET could provide reliable information about current tumor ERα status. Conclusion: 18F-FES PET/CT can reliably assess ERα status in epithelial ovarian cancer tumors and metastases noninvasively. Evaluation of the predictive value of 18F-FES PET/CT for endocrine therapy in epithelial ovarian cancer patients is warranted.

1627PPET-IMAGING WITH 89ZR-LABELED ANTI-MESOTHELIN (MSLN) ANTIBODY IN PATIENTS WITH PANCREATIC CANCER (PC) OR OVARIAN CANCER (OC)

Aim: The tumor antigen MSLN is frequently overexpressed in PC and OC. A 89Zr-PET study (NCT01832116) with MMOT0530A, an anti-MSLN antibody, was initiated in conjunction with a phase 1 study of the antibody-drug conjugate DMOT4039A (containing MMOT0530A linked to the anti-mitotic agent MMAE, NCT01469793). This imaging study aims to investigate antibody tumor uptake, whole body distribution and organ pharmacokinetics and to explore the relation between uptake and MSLN expression and response to DMOT40392A treatment in patients with unresectable PC or platinum-resistant OC. Methods: Before receiving DMOT4039A, patients were injected with 37 MBq 89Zr-MMOT0530A +/- additional unlabeled MMOT0530A, followed by PET/CT imaging 2, 4 and 7 days post injection (pi). Tracer uptake was quantified with standardized uptake value (SUV) and expressed as mean (±SD). MSLN expression was determined in archival tumor tissue with an exploratory immunohistochemical (IHC) assay. Results: 7 PC and 4 OC patients were included. MSLN expression varied from 0 to 3+. The optimal antibody protein dose resulting in sufficient circulating tracer was 10 mg MMOT0530A and the optimal imaging time was 4 or 7 days pi. Tumor tracer uptake was observed in 37 quantifiable tumor lesions (all patients) with mean SUV of 10.7 (±6.3) on PET 4 days pi. The mean SUV per patient (1-8 lesions/patient) was 10.9 (±5.7), with 9.2 (±4.5) in PC and 11.9 (±7.4) in OC lesions on PET 4 days pi. Within patients, a mean 2.4-fold (±1.10) difference in tumor uptake between lesions was found. Two measurable lesions on diagnostic CT (according to RECIST 1.1) were not visible on PET. Uptake in blood, liver, kidneys, spleen and intestine reflected normal antibody distribution with mean SUV at day 4 pi of 5.6, 7.8, 6.1, 4.1 and 3.2, respectively, while low uptake was observed in muscle, lung, brain and bone (0.6, 1.0, 0.2 and 0.7, respectively). Tracer tumor uptake was lower in the 2 patients with IHC scores 0 and 1. Best response on DMOT4039A was stable disease in ten patients. An association between iPET tumor uptake and clinical response could not be determined. Conclusions: 89Zr-MMOT0530A-PET shows antibody uptake in primary and metastatic PC and OC tumor lesions. This technique can potentially guide antibody-based therapy development.