Mona-Elisabeth Revheim

Combined positron emission tomography/computed tomography in sunitinib therapy assessment of patients with metastatic renal cell carcinoma.

AIM To assess the clinical benefit of combined functional imaging with [(18)F]2-fluoro-2-deoxy-d-glucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) in patients with metastatic renal cell carcinoma (mRCC) treated with the tyrosine kinase inhibitor sunitinib. MATERIALS AND METHODS Fourteen patients with mRCC were prospectively enrolled in this study. All patients underwent PET/CT before receiving at least two cycles of sunitinib treatment. Three months after the onset of sunitinib treatment, a second PET/CT was carried out. The metabolic response evaluated from the PET (standard uptake value; SUV) was compared with the CT component of the PET/CT. The Response Evaluation Criteria in Solid Tumours criteria were used to assess the CT response and modified European Organization for Research and Treatment of Cancer criteria were used to assess the PET response. RESULTS Three main results were obtained: (1) Patients with relatively low 18F-FDG uptake before treatment (SUV<5) had a longer progression-free survival than those with a relatively high 18F-FDG uptake (P=0.006). (2) Patients with a partial metabolic response or stable metabolic disease after two courses of sunitinib had improved prognosis as compared with those with progressive metabolic disease (P=0.031). (3) There was a clear discrepancy between PET and CT as a tool for the evaluation of treatment response after two courses of sunitinib. PET indicated progressive disease in three patients, a partial response in six patients and stable disease in four patients. In contrast, CT concluded with progression in only one patient and stable disease in all other patients. CONCLUSION In patients with mRCC, a high baseline 18F-FDG uptake indicates aggressive disease, and the degree of reduction in 18F-FDG uptake after sunitinib treatment adds valuable prognostic information. Hence, the inclusion of PET results seems to improve the clinical counselling of patients with mRCC. Larger studies are needed to confirm these findings.

Dynamic 18F-FDG-PET for monitoring treatment effect following anti-angiogenic therapy in triple-negative breast cancer xenografts

Abstract Introduction. Dynamic 18F-FDG PET allows the study of glucose distribution in tissues as a function of time and space. Using pharmacokinetics, the temporal uptake pattern of 18F-FDG may be separated into components reflecting perfusion and metabolism. Bevacizumab is an angiogenesis inhibitor which prevents the growth of new blood vessels, and may potentially lead to normalization of the blood circulation in the tumor. The purpose of the study was to explore the use of dynamic PET as a tool for monitoring treatment effect, reflected by changes in perfusion and metabolism. Materials and Methods. Twelve athymic nude mice, bearing the bilateral triple-negative human breast cancer xenograft MAS98.12 were treated with bevacizumab (5 mg/kg i.p.). Dynamic PET data was acquired prior to and 24 and 72 hours after treatment for 1 hour after injection of 10 MBq 18F-FDG and fitted with a FDG two-tissue compartment model. The changes in the rate constants k1, k3, MRFDG and the vascular fraction νB were assessed. To evaluate the effect of treatment regimes, 30 mice, randomized in 5 groups, received either vehicle (0.9% NaCl), bevacizumab (5 mg/kg i.p.), doxorubicin (8 mg/kg i.v.) or bevacizumab and doxorubicin either together, or doxorubicin 24 hours after bevacizumab treatment. Tumor volume was measured twice a week. Results. The perfusion-related rate parameter k1 and the metabolic rate constant k3 decreased significantly 24 hours after treatment. This decrease was followed by an increase, albeit non-significant, at 72 hours post treatment. Doxorubicin given 24 hours after bevacizumab showed less antitumor effect compared to concomitant treatment. Conclusions. Dynamic PET can detect changes in tumor perfusion and metabolism following anti-angiogenic therapy in mouse xenograft models. Longitudinal dynamic PET, used to assess the efficacy of anti-angiogenic treatment, can identify the time frame of potential tumor vasculature re-normalization and allow optimal timing of supplementary therapy (radiation or chemotherapy).

Carotid Plaque Inflammation Assessed with 18F-FDG PET/CT is Higher in Symptomatic Compared with Asymptomatic Patients

Background Carotid artery plaque inflammation is thought to be an important marker of plaque vulnerability and increased stroke risk. Aim The main aim of this study was to assess the level of agreement between 2-deoxy-2-[18F] fluoro-D-glucose (18F-FDG) uptake on PET (positron emission tomography) scan in carotid plaques, with cerebrovascular symptoms, carotid plaque ultrasound echogenicity and histological assessments of plaque inflammation. Methods Thirty-six patients with ≥70% carotid stenosis scheduled for carotid endarterectomy underwent a Colour Duplex ultrasound, 18F-FDG PET/CT and blood tests less than 24 h prior to surgery. Plaques were defined as symptomatic when associated with ipsilateral cerebral ischemic symptoms within 30 days prior to inclusion. Plaques were assessed histologically following endarterectomy. The level of agreement between 18F-FDG uptake (mean SUVmax and SUVmax), and target-to-background ratio, symptoms, plaque echolucency, and histological evidence of inflammation was assessed. Results The amount of 18F-FDG uptake in plaques and the amount of inflammation on histological assessment were significantly correlated (r = 0·521, P = 0·003). 18F-FDG uptake was significantly higher in symptomatic plaques with median SUVmax 1·75 (1·26–2·04) in symptomatic, and 1·43 (1·15–2·28) in asymptomatic patients (P = 0·03). 18F-FDG uptake was also positively correlated with echolucency on Doppler ultrasound (P = 0·03). Conclusion 18F-FDG uptake on PET/CT correlated with histological assessments of inflammation and was higher in patients with symptomatic compared with asymptomatic carotid artery plaques. These results support the use of 18F-FDG PET/CT in the detection inflammation in carotid atherosclerosis, which may be of help in the detection of vulnerable plaques.

Intermittent and continuous imatinib in a human GIST xenograft model carrying KIT exon 17 resistance mutation D816H.

Abstract Background. Acquired resistance to imatinib is frequently caused by secondary KIT mutations. We have investigated the effects of imatinib in mice with human gastrointestinal stromal tumour (GIST) xenograft which harbours a primary exon 11 deletion mutation and a secondary imatinib resistance mutation D816H in exon 17. Such mutations are commonly present in imatinib-resistant GIST in humans. Material and methods. The mice were randomly allocated to receive imatinib either continuously or intermittently. Dynamic 18F-FDG PET was performed and blood volume fraction (vB), rate transfer constants (k1, k2, k3) and metabolic rate of 18F-FDG (MRFDG) were computed using a three-compartment model. Tumours were evaluated for the mitotic rate and the expression of HIF-1α , caspase-3 and glucose transporters (GLUTs). Results. Both intermittent and continuous imatinib delayed tumour growth significantly compared to controls, significantly in favour of the latter. k1 (representing perfusion, vascular permeability and binding of 18F-FDG to the GLUTs) was significantly higher in the intermittent group compared to the continuous group, as was tumour GLUT-3 expression. k3 (representing internalisation of 18F-FDG to the cells) and MRFDG were significantly lower. Conclusion. Imatinib delays GIST xenograft growth despite the presence of the D816H resistance mutation. The schedule of imatinib administration may influence tumour glucose uptake rate and metabolic rate.

Multimodal functional imaging for early response assessment in GIST patients treated with imatinib

Gastrointestinal stromal tumour (GIST) is the most common soft-tissue sarcoma, with reported annual incidence of 14 – 20 cases per million [1,2]. Approxi mately half of the patients will relapse within fi ve years despite complete surgical resection [3]. Standard chemotherapy and radiotherapy are not effective, but the majority of patients with locally advanced or metastatic GIST respond to the tyrosine kinase inhibitor (TKI) imatinib [4], however, are seldomly cured [5]. Approximately 15% of GISTs are prima rily imatinib-resistant and most responders develop secondary resistance to imatinib [5]. Adverse effects of imatinib are dose-dependent and espe-cially patients with large tumour burden and poor general condition are exposed. Early treatment assessment may contribute to a more individualised treatment regime, avoiding ineffective treatment and unnecessary toxicity. Traditionally, computed tomography (CT) and the response evaluation criteria in solid tumours (RECIST) [6] have been used for the assessment of treatment response in GIST patients. Based solely on measurements of tumour size, functional and metabolic responses are not included. When imaged by

Respiratory gated and prolonged acquisition 18F-FDG PET improve preoperative assessment of colorectal liver metastases

Background Detection of small liver metastases from colorectal cancer by 18F-FDG PET/CT is hampered by high physiologic uptake in the liver parenchyma and respiratory movements during image acquisition. Purpose To investigate whether two tailored 18F-FDG PET liver acquisitions (prolonged liver acquisition time [PL-PET] and repeated breath-hold respiratory gated liver acquisition [RGL-PET]) would improve detection of colorectal liver metastases, when added to a standard whole body PET (WB-PET). Material and Methods Twenty consecutive patients referred to our hospital for surgical treatment of colorectal liver metastases diagnosed with contrast-enhanced CT underwent preoperative 18F-FDG PET/CT tailored for detection of liver metastases. Concordance between preoperative imaging results and true findings (histology and/or follow-up imaging) as well as changes in clinical management, based on 18F-FDG PET/CT findings, were documented. Background noise, defined as the standard deviation measured in a reference region within the normal liver parenchyma, was compared between the three 18F-FDG PET/CT protocols. Results WB-PET, PL-PET, and RGL-PET showed suspicious liver lesions in 18 out of 20 patients. Compared to WB-PET alone, the combination of PL-PET and RGL-PET showed additional lesions in the liver in seven out of the 18 patients. The combination of all three PET acquisitions changed clinical management in four patients. Two patients with negative PET results were later found to have benign liver lesions. Conclusion The addition of tailored liver-specific 18F-FDG PET/CT protocols (PL-PET and RGL-PET) to a WB-PET, improved the detection of intrahepatic colorectal metastases, compared to WB-PET alone. Such add-ons can change clinical patient management of potentially resectable colorectal liver metastases.

A Man with Abdominal Pain: Enough Evidence for Surgery?

A 53-year-old man experienced periodic abdominal discomfort and a decreased capacity to work. His primary physician ordered a broad range of laboratory tests as part of the initial workup. The results revealed a greatly increased adrenocorticotropic hormone (ACTH)7 concentration of >1250 pg/mL (>278 pmol/L) [reference interval <46 pg/mL (<10.2 pmol/L)]. Cortisol was within the reference interval. Repeat measurements 4 weeks later confirmed the increased ACTH. Investigators rapidly excluded 2 well-known conditions associated with increased ACTH concentrations: Cushing disease (ACTH-producing pituitary tumor) and Addison disease (adrenal insufficiency) (1, 2). An investigation for an ectopic source of ACTH was begun (3). Over the next 18 months, the patient underwent a plethora of imaging studies. A series of conventional studies failed to provide an explanation for the increased ACTH, and ultimately a positron emission tomography/computed tomography (PET/CT) scan using a relatively new radiotracer, 68Ga-labeled 1,4,7,10-tetraazacyclododecane- N,N ′, N ′′, N ′′′ - tetraacetic acid-d-Phe1-Tyr3-octreotide (68Ga-DOTATOC), was performed (4). A 3.3-cm area in the head of the pancreas with an increased uptake of radiotracer was observed (Fig. 1). In light of the persistently increased ACTH concentration, this finding raised the suspicion of a pancreatic ACTH-secreting neuroendocrine tumor, a rare ectopic source of ACTH (3). Although MRI and conventional CT evaluations did not confirm the presence of a tumor, the patient was offered immediate surgical treatment. The patient declined the offer and subsequently sought second and third opinions at medical facilities in 2 different countries. In both facilities, a neuroendocrine tumor was deemed the likely cause of his problems, and surgery was again suggested. Wishing minimally invasive treatment, the patient contacted the Interventional Centre at our hospital, which offers laparoscopic resection of the pancreas. Fig. 1. 68Ga-DOTATOC PET/CT scan from June 2009 showing increased uptake of radiotracer in the processus uncinatus of the pancreas (arrow), with a maximum standardized uptake value (SUVmax) of 9. Physiological accumulation in the liver (L) and kidneys (K). ### QUESTIONS TO CONSIDER 1. Why …

Translocational renal cell carcinoma (t(6;11)(p21;q12) with transcription factor EB (TFEB) amplification and an integrated precision approach: a case report

IntroductionRenal cell carcinoma with the distinct type of t(6;11)(p21;q12) translocation (transcription factor EB) is a rare neoplasm. In the present case study, we show for the first time an autophagy signature in a patient with transcription factor EB renal cell carcinoma. We attempted to characterize the mutational and expressional features of a t(6;11)(p21;q12) renal cell carcinoma, in an effort to address the potential for molecular guidance of personalized medical decision for a case in this renal cell carcinoma category.Case presentationWe report the case of a 42-year-old white man who had a late relapse of his renal cell carcinoma. The first diagnosis of clear cell renal carcinoma was derived from a histological examination; analyzing the metastasis and going back to the primary tumor it turned out to be a transcription factor EB-renal cell carcinoma. The treatment plan included local radiation and systemic therapy. As part of the multimodal approach, tumor samples for genetic assessment were obtained. However, there is no recommended standard therapy for transcription factor EB-renal cell carcinoma. Despite four lines of medical treatment with targeted therapy and one checkpoint inhibitor, all attempts to prolong the patient’s survival failed.ConclusionsDuring the course of this unusual disease, we gained insights which, to the best of our knowledge, were unknown before in the expression of the gene signature linked to autophagy. This might in part explain the resistance to conventional targeted therapy acknowledged in our patient.

Growth rates of pulmonary metastases after liver transplantation for unresectable colorectal liver metastases

The previously reported SECA study demonstrated a dramatic 5‐year survival improvement in patients with unresectable colorectal liver metastases (CLM) treated with liver transplantation (LT) compared with chemotherapy. The objective of this study was to assess whether immunosuppressive therapy accelerates the growth of pulmonary metastases in patients transplanted for unresectable CLM.

Dynamic 18 F-FDG PET for Assessment of Tumor Physiology in Two Breast Carcinoma Xenografts

PurposeTo compare dynamic 2-deoxy-2-[18 F]fluoro-D-glucose positron emission tomography (18 F-FDG PET) parameters in two selected human breast cancer xenografts and to evaluate associations with immunohistochemistry and histology.ProceduresDynamic 18 F-FDG PET of luminal-like MAS98.06 and basal-like MAS98.12 xenografts was performed, and the compartmental transfer rates (k1,k2,k3), blood volume fraction (vB) and metabolic rate of 18 F-FDG(MRFDG) were estimated from pharmacokinetic model analysis. After sacrifice, analyses of hypoxia (pimonidazole), proliferation (Ki-67), vascularization (CD31), glucose transport receptor (GLUT1) and necrosis (HE) was performed. The level of hexokinase 2 (HK2) was estimated from Western blot analysis.ResultsThe 18 F-FDG uptake curves for the two xenografts were significantly different (p < 0.05). k1 and vB were higher for MAS98.12 (p < 0.01), while k3 was higher for MAS98.06 (p < 0.01). MAS98.12 had a higher fraction of stromal tissue and higher microvessel density (MVD), and it was less necrotic and hypoxic than MAS98.06. MAS98.12 had stronger positive GLUT1 staining and lower Ki-67 than MAS98.06. In both models significant correlations were found between k1 and the GLUT1 score, between k3 and the level of HK2, and between vB and MVD.ConclusionsSignificant differences in dynamic 18 F-FDG parameters between the two human breast cancer xenografts were found. The differences could be explained by underlying histological and physiological characteristics.