Teresa Szyszko

What can gallium-68 PET add to receptor and molecular imaging?

In the last decade there has been a significant increase in the development of radiolabelled peptides for diagnostic applications, especially due to simplified methods of purification. Peptides have fast clearance, rapid tissue penetration, and low antigenicity and can therefore be produced easily and inexpensively. In addition, if the diagnostic scan is positive, the peptides can be labelled with therapeutic radionuclides (yttrium-90, lutetium-177) and used for therapy [1]. Most efforts at labelling peptides have targeted somatostatin and its receptors. Somatostatin is a regulatory peptide widely distributed in the human body. Its action is mediated by membrane-bound receptors (SSTR) that are present in normal human tissues, such as thyroid, brain, gastrointestinal tract (GIT), pancreas, spleen and kidney [2]. They are also abundant in a variety of human tumours, notably neuroendocrine tumours (NET) [3] of which carcinoid tumour and phaeochromocytoma are encountered most in clinical practice. SSTR are also expressed, with variable abundance, in renal cell carcinoma, small cell lung cancer, breast cancer, prostate cancer and malignant lymphoma [4]. Somatostatin itself has a short half-life and is rapidly degraded by enzymes; therefore analogues have been developed which mimic its effects but are resistant to enzyme degradation. There are 5 somatostatin receptor subtypes but only subtypes 2 (SSTR2) and 5 (SSTR5) and to a lesser extent receptor subtype 3 (SSTR3) have a high affinity for commercially available synthetic analogues and even these differ in their affinity for the various receptor subtypes [5].

Arginine Deprivation With Pegylated Arginine Deiminase in Patients With Argininosuccinate Synthetase 1-Deficient Malignant Pleural Mesothelioma: A Randomized Clinical Trial

Importance Preclinical studies show that arginine deprivation is synthetically lethal in argininosuccinate synthetase 1 (ASS1)-negative cancers, including mesothelioma. The role of the arginine-lowering agent pegylated arginine deiminase (ADI-PEG20) has not been evaluated in a randomized and biomarker-driven study among patients with cancer. Objective To assess the clinical impact of arginine depletion in patients with ASS1-deficient malignant pleural mesothelioma. Design, Setting, and Participants A multicenter phase 2 randomized clinical trial, the Arginine Deiminase and Mesothelioma (ADAM) study, was conducted between March 2, 2011, and May 21, 2013, at 8 academic cancer centers. Immunohistochemical screening of 201 patients (2011-2013) identified 68 with advanced ASS1-deficient malignant pleural mesothelioma. Interventions Randomization 2:1 to arginine deprivation (ADI-PEG20, 36.8 mg/m2, weekly intramuscular) plus best supportive care (BSC) or BSC alone. Main Outcomes and Measures The primary end point was progression-free survival (PFS) assessed by modified Response Evaluation Criteria in Solid Tumors (RECIST) (target hazard ratio, 0.60). Secondary end points were overall survival (OS), tumor response rate, safety, and quality of life, analyzed by intention to treat. We measured plasma arginine and citrulline levels, anti–ADI-PEG20 antibody titer, ASS1 methylation status, and metabolic response by 18F-fluorodeoxyglucose positron-emission tomography. Results Median (range) follow-up in 68 adults (median [range] age, 66 [48-83] years; 19% female) was 38 (2.5-39) months. The PFS hazard ratio was 0.56 (95% CI, 0.33-0.96), with a median of 3.2 months in the ADI-PEG20 group vs 2.0 months in the BSC group (P = .03) (absolute risk, 18% vs 0% at 6 months). Best response at 4 months (modified RECIST) was stable disease: 12 of 23 (52%) in the ADI-PEG20 group vs 2 of 9 (22%) in the BSC group (P = .23). The OS curves crossed, so life expectancy was used: 15.7 months in the ADI-PEG20 group vs 12.1 months in the BSC group (difference of 3.6 [95% CI, −1.0 to 8.1] months; P = .13). The incidence of symptomatic adverse events of grade at least 3 was 11 of 44 (25%) in the ADI-PEG20 group vs 4 of 24 (17%) in the BSC group (P = .43), the most common being immune related, nonfebrile neutropenia, gastrointestinal events, and fatigue. Differential ASS1 gene-body methylation correlated with ASS1 immunohistochemistry, and longer arginine deprivation correlated with improved PFS. Conclusions and Relevance In this trial, arginine deprivation with ADI-PEG20 improved PFS in patients with ASS1-deficient mesothelioma. Targeting arginine is safe and warrants further clinical investigation in arginine-dependent cancers. Trial Registration clinicaltrials.gov Identifier: NCT01279967

Selective Internal Radiation Therapy with Yttrium-90 for Unresectable Liver Tumours

Primary and secondary liver tumours are common malignancies that are being treated more aggressively nowadays than decades ago. Surgery is the most effective method of treatment but is only suitable for a minority of patients with well-defined and easily accessible tumours. Surgical resection is contraindicated in patients with massive involvement of the liver or in cases where the disease involves the confluence of vessels at the porta hepatis. These patients may benefit from a variety of ablative and embolic therapies including selective internal radiation therapy (SIRT) with Yttrium-90 microspheres. SIRT has been introduced in the 1980s but the technology has been refined and made more available only recently. The microspheres are injected directly into the hepatic arteries, through a trans-femoral angiographic approach, and are delivered selectively to tumours due to their preferential blood supply by hepatic arteries. SIRT can therefore target small volumes disease with a higher dose of radiation compared with external-beam radiation and is associated the relatively low toxicity and a good response irrespective of tumor origin. Assessment of response to therapy is best performed with metabolic imaging using (18)F-FDG PET scanning. Although it is not considered as a cure, it has been shown to improve quality of life and prolong survival, with the main cause of death being extra-hepatic spread. The technical and clinical demands of patient selection, treatment planning, administration, and clinical follow-up require an interdisciplinary team willing to work cooperatively to achieve the best result for the patient.

Evaluation of hepatic angiography procedures and bremsstrahlung imaging in selective internal radiation therapy: a two-year single-center experience.

The imaging of Bremsstrahlung radiation is performed after hepatic radioembolization to assess the distribution of the injected radioactive material. This review assesses the role of Bremsstrahlung imaging and its relation to the angiographic procedure and technique in hepatic selective internal radiation therapy on 21 patients undergoing this procedure at a single center.

Endoanal magnetic resonance imaging of fistula‐in‐ano: a comparison of stir with gadolinium‐enhanced techniques

Purpose: To compare a STIR sequence with gadolinium‐enhanced techniques on endoanal magnetic resonance (MR) imaging of fistulas‐in‐ano by correlating the findings with those at surgery. Material and Methods: Twenty‐two consecutive patients with clinical suspicion of perianal sepsis were studied using an endoanal coil followed immediately by a phased array coil. T1‐weighted precontrast and postcontrast and STIR images in transverse and coronal planes were produced with each coil and analysed by noting the presence and site of a collection, primary track, the position of any internal opening, and subcutaneous or supralevator extension. An “expert” and also a “trainee” radiologist assessed the images. Operative findings were similarly recorded. The Fisher exact test was used to compare imaging with surgery. Interobserver variation was calculated using a kappa statistic. Results: Of 22 patients with suspected fistulas, 8 were simple, 4 were complex, and 3 were superficial sinuses. Five had no anal pathology, 1 had anal excoriation, and 1 had a polyp. At surgery, 6 intersphincteric, 1 transsphincteric, 8 extrasphincteric, no supralevator collections, and 9 internal openings were noted. The overall sensitivity and specificity for detecting these were 75% and 64%, respectively, for STIR imaging, and 58.3% and 62.8% for gadolinium‐enhanced imaging. There was good agreement between the “trainee” and the “expert” in the interpretation of images (kappa = 0.7). Conclusion: A STIR sequence is more sensitive overall than gadolinium‐enhanced techniques on endoanal magnetic resonance imaging of fistulas‐in‐ano because of increased sensitivity in detecting the internal opening. A combination of endoanal and phased array techniques using STIR imaging sequences is valuable preoperative assessment in both simple and complex cases.

Phase 1 Dose-Escalation Study of Pegylated Arginine Deiminase, Cisplatin, and Pemetrexed in Patients With Argininosuccinate Synthetase 1–Deficient Thoracic Cancers

Purpose Pegylated arginine deiminase (ADI-PEG 20) depletes essential amino acid levels in argininosuccinate synthetase 1 (ASS1) –negative tumors by converting arginine to citrulline and ammonia. The main aim of this study was to determine the recommended dose, safety, and tolerability of ADI-PEG 20, cisplatin, and pemetrexed in patients with ASS1-deficient malignant pleural mesothelioma (MPM) or non–small-cell lung cancer (NSCLC). Patients and Methods Using a 3 + 3 + 3 dose-escalation study, nine chemotherapy-naïve patients (five MPM, four NSCLC) received weekly ADI-PEG 20 doses of 18 mg/m2, 27 mg/m2, or 36 mg/m2, together with pemetrexed 500 mg/m2 and cisplatin 75 mg/m2 which were given every three weeks (maximum of six cycles). Patients achieving stable disease or better could continue ADI-PEG 20 monotherapy until disease progression or withdrawal. Adverse events were assessed by Common Terminology Criteria for Adverse Events version 4.03, and pharmacodynamics and immunogenicity were also evaluated. Tumor response was assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 for NSCLC and by modified RECIST criteria for MPM. Results No dose-limiting toxicities were reported; nine of 38 reported adverse events (all grade 1 or 2) were related to ADI-PEG 20. Circulating arginine concentrations declined rapidly, and citrulline levels increased; both changes persisted at 18 weeks. Partial responses were observed in seven of nine patients (78%), including three with either sarcomatoid or biphasic MPM. Conclusion Target engagement with depletion of arginine was maintained throughout treatment with no dose-limiting toxicities. In this biomarker-selected group of patients with ASS1-deficient cancers, clinical activity was observed in patients with poor-prognosis tumors. Therefore, we recommend a dose for future studies of weekly ADI-PEG 20 36 mg/m2 plus three-weekly cisplatin 75 mg/m2 and pemetrexed 500 mg/m2.

The role of new PET tracers for lung cancer

18F-fluorodeoxyglucose (18F-FDG) positron emission tomography-computed tomography (PET/CT) is established for characterising indeterminate pulmonary nodules and staging lung cancer where there is curative intent. Whilst a sensitive technique, specificity for characterising lung cancer is limited. There is recognition that evaluation of other aspects of abnormal cancer biology in addition to glucose metabolism may be more helpful in characterising tumours and predicting response to novel targeted cancer therapeutics. Therefore, efforts have been made to develop and evaluate new radiopharmaceuticals in order to improve the sensitivity and specificity of PET imaging in lung cancer with regards to characterisation, treatment stratification and therapeutic monitoring. 18F-fluorothymidine (18F-FLT) is a marker of cellular proliferation. It shows a lower accumulation in tumours than 18F-FDG as it only accumulates in the cells that are in the S phase of growth and demonstrates a low sensitivity for nodal staging. Its main role is in evaluating treatment response. Methionine is an essential amino acid. 11C-methionine is more specific and sensitive than 18F-FDG in differentiating benign and malignant thoracic nodules. 18Ffluoromisonidazole (18F-FMISO) is used for imaging tumour hypoxia. Tumour response to treatment is significantly related to the level of tumour oxygenation. Angiogenesis is the process by which new blood vessels are formed in tumours and is involved in tumour growth and metastatic tumour spread and is a therapeutic target. Most clinical studies have focused on targeted integrin PET imaging of which αvβ3 integrin is the most extensively investigated. It is upregulated on activated endothelial cells in association with tumour angiogenesis. Neuroendocrine tumour tracers, particularly 68Ga-DOTA-peptides, have an established role in imaging of carcinoid tumours. Whilst most of these tracers have predominantly been used in the research environment, they offer exciting opportunities for improving staging, characterisation, stratification and response assessment in an era of increased personalised therapy in lung cancer.

Role of 18F-FDG PET imaging in paediatric primary dystonia and dystonia arising from neurodegeneration with brain iron accumulation

PurposeNo current neuroimaging modality offers mechanistic or prognostic information to guide management in paediatric dystonia. We assessed 18F-fluorodeoxyglucose (18F-FDG) PET/computed tomography (CT) brain imaging in childhood primary dystonia (PDS) and neurodegeneration with brain iron accumulation (NBIA) to determine whether it would identify altered metabolism and hence constitute a potentially useful ‘biomarker’ indicating functional disturbances associated with dystonia and severity of the disease. Materials and methodsA total of 27 children (15 PDS and 12 NBIA) underwent brain 18F-FDG PET/CT imaging under anaesthesia during acquisition. The images were assessed visually and the two groups were compared quantitatively with statistical parametric mapping. PET/CT images were spatially transformed to Montreal Neurological Institute standard space. Voxelwise 18F-FDG uptake was normalized to whole-brain uptake. Data of both groups were correlated separately with duration and severity of dystonia as assessed using the Burke–Fahn–Marsden Dystonia Rating Scale (BFMDRS). ResultsVisual inspection did not identify any abnormalities in 18F-FDG uptake within the cerebral cortex, basal ganglia, or thalami in either group. Quantitative analysis identified higher uptake in the posterior cingulate and bilateral posterior putamina but decreased uptake in the occipital cortex and cerebellum in NBIA compared with PDS. The NBIA group had more severe dystonia scores compared with the PDS group. BFMDRS was negatively correlated with age but not with duration of dystonia. ConclusionCompared with PDS, NBIA is dominated by relative overactivity in the putamen and by cerebellar underactivity, patterns that may reflect the increased severity of dystonia in NBIA cases. Hence, there is a potential role for 18F-FDG PET/CT imaging in paediatric dystonia, particularly in the NBIA group.

Respiratory papillomatosis of lung and F-18 FDG PET-CT

Abstract: Recurrent respiratory papillomatosis (RRP) is the most common benign tumor of the larynx in children. Papillomas in RRP are usually benign and are localized to the larynx. Lung involvement is rare. The papillomas in the laryngotracheal and bronchioloalveolar region may undergo malignant degeneration to squamous cell carcinoma and are reported to have a poor prognosis. A 28-year-old woman presented with hemoptysis. She had known RRP in the trachea but no previous lung involvement. A chest radiograph and CT scan revealed multiple nodules, some of which were cavitating and some were with a predominantly cystic appearance. PET/CT showed increased F-18 FDG uptake in these nodules and guided biopsy.

Selective Internal Radiation therapy

Primary and secondary liver tumours are common malignancies associated with unsatisfactory treatment and bad prognosis. Hepatocellular carcinoma (HCC) ranks among the 10 most common cancers worldwide and is the most common primary malignancy of the liver. The geographic distribution of HCC is clearly related to the incidence of hepatitis B virus (HBV) infection with the highest incidence in Southeast Asia and tropical Africa