Zena Wimana

Paget bone disease demonstrated on 68Ga-PSMA ligand PET/CT

We present the case of an 87-year-old man with a history of prostatic adenocarcinoma diagnosed in 2006 and initially treated locally with high intensity focused ultrasound. An increase of prostate-specific antigen (PSA) values was detected recently and a positron emission/ computed tomography (PET/CT) investigation with the Ga-labelled prostate-specific membrane antigen (PSMA) ligand [Glu-NH-CO-NH-Lys(Ahx)-HBED-CC] was performed at our institution [1]. Apart from focal increased uptake in the prostatic bed, a non-expected overexpression of PSMA was found involving the proximal phalanx of the fourth finger of the left hand (a). On the bone scan performed at the time of initial diagnosis, 9 years ago (b), it appeared that an intense Tc-HDP uptake had already been described in the same location, involving the whole phalanx, with an image suggestive for bone Paget disease (PD) [2]. On physical examination the patient had a swollen and non-painful proximal phalanx with restricted finger motility. A plain X-ray of the hands was performed (c) confirming the diagnosis of monostotic PD of the phalanx [3]. PSMA expression in non-prostatic tumor lesions has already been described and seems to be related to an overexpression of PSMA in the endothelial cells of tumor neovasculature, probably stimulated by secreted angiogenic factors [4, 5]. We hypothesize this mechanism could also be the reason for Ga-PSMA uptake in PD, as it is known to present with an abnormal bone remodeling and increased vascularity. AS bone lesions are the most frequent site of metastatic disease in prostate cancer, it is important to be aware of this possible GaPSMA PET/CT false-positive finding.

Imaging Diagnostic and Therapeutic Targets: Human Epidermal Growth Factor Receptor 2

Since the approval of trastuzumab, a humanized monoclonal antibody against the extracellular domain of human epidermal growth factor receptor 2 (HER2), 3 other HER2-targeting agents have gained regulatory approval: lapatinib, pertuzumab, and trastuzumab–emtansine. These agents have revolutionized the management of HER2-positive breast cancer, highlighting the concept that targeted therapies are successful when patients exhibit tumor-selective expression of a molecular target—in this case, HER2. However, response prediction and innate or acquired resistance remain serious concerns. Predictive biomarkers of a response—which could help in the selection of patients who might benefit from a selected targeted therapy—are currently lacking. Molecular imaging with anti-HER2 probes allows the noninvasive, whole-body assessment of HER2 tumor burden and has the potential to improve patient selection, optimize the dose and schedule, and rationalize assessment of the response to anti-HER2 therapies. Furthermore, unlike biopsy-based HER2 assessment, this approach can reveal inter- or intratumoral heterogeneity as well as variations in HER2 expression over time. This review summarizes the available literature and the current status of molecular imaging as a tool for the assessment of HER2 (target) expression or the prediction of an early treatment response in early and advanced HER2-positive breast cancer.

N-Acetylcysteine breaks resistance to trastuzumab caused by MUC4 overexpression in human HER2 positive BC-bearing nude mice monitored by 89 Zr-Trastuzumab and 18 F-FDG PET imaging

Trastuzumab remains an important drug in the management of human epidermal growth factor receptor 2 (HER2) overexpressing breast cancer (BC). Several studies reported resistance mechanisms to trastuzumab, including impaired HER2-accessibility caused by mucin 4 (MUC4). Previously, we demonstrated an increase of Zirconium-89-radiolabeled-trastuzumab (89Zr-Trastuzumab) accumulation when MUC4-overexpressing BC-cells were challenged with the mucolytic drug N-Acetylcysteine (NAC). Hereby, using the same approach we investigated whether tumor exposure to NAC would also enhance trastuzumab-efficacy.Dual SKBr3 (HER2+/MUC4-, sensitive to trastuzumab) and JIMT1 (HER2+/MUC4+, resistant to trastuzumab) HER2-BC-bearing-xenografts were treated with trastuzumab and NAC. Treatment was monitored by molecular imaging evaluating HER2-accessibility/activity (89Zr-Trastuzumab HER2-immunoPET) and glucose metabolism (18F-FDG-PET/CT), as well as tumor volume and the expression of key proteins.In the MUC4-positive JIMT1-tumors, the NAC-trastuzumab combination resulted in improved tumor-growth control compared to trastuzumab alone; with smaller tumor volume/weight, lower 18F-FDG uptake, lower %Ki67 and pAkt-expression. NAC reduced MUC4-expression, but did not affect HER2-expression or the trastuzumab-sensitivity of the MUC4-negative SKBr3-tumors.These findings suggest that improving HER2-accessibility by reducing MUC4-masking with the mucolytic drug NAC, results in a higher anti-tumor effect of trastuzumab. This provides a rationale for the potential benefit of this approach to possibly treat a subset of HER2-positive BC overexpressing MUC4.Trastuzumab remains an important drug in the management of human epidermal growth factor receptor 2 (HER2) overexpressing breast cancer (BC). Several studies reported resistance mechanisms to trastuzumab, including impaired HER2-accessibility caused by mucin 4 (MUC4). Previously, we demonstrated an increase of Zirconium-89-radiolabeled-trastuzumab (89Zr-Trastuzumab) accumulation when MUC4-overexpressing BC-cells were challenged with the mucolytic drug N-Acetylcysteine (NAC). Hereby, using the same approach we investigated whether tumor exposure to NAC would also enhance trastuzumab-efficacy. Dual SKBr3 (HER2+/MUC4-, sensitive to trastuzumab) and JIMT1 (HER2+/MUC4+, resistant to trastuzumab) HER2-BC-bearing-xenografts were treated with trastuzumab and NAC. Treatment was monitored by molecular imaging evaluating HER2-accessibility/activity (89Zr-Trastuzumab HER2-immunoPET) and glucose metabolism (18F-FDG-PET/CT), as well as tumor volume and the expression of key proteins. In the MUC4-positive JIMT1-tumors, the NAC-trastuzumab combination resulted in improved tumor-growth control compared to trastuzumab alone; with smaller tumor volume/weight, lower 18F-FDG uptake, lower %Ki67 and pAkt-expression. NAC reduced MUC4-expression, but did not affect HER2-expression or the trastuzumab-sensitivity of the MUC4-negative SKBr3-tumors. These findings suggest that improving HER2-accessibility by reducing MUC4-masking with the mucolytic drug NAC, results in a higher anti-tumor effect of trastuzumab. This provides a rationale for the potential benefit of this approach to possibly treat a subset of HER2-positive BC overexpressing MUC4.

Tumor Drug Penetration Measurements Could Be the Neglected Piece of the Personalized Cancer Treatment Puzzle

Precision medicine aims to use patient genomic, epigenomic, specific drug dose, and other data to define disease patterns that may potentially lead to an improved treatment outcome. Personalized dosing regimens based on tumor drug penetration can play a critical role in this approach. State‐of‐the‐art techniques to measure tumor drug penetration focus on systemic exposure, tissue penetration, cellular or molecular engagement, and expression of pharmacological activity. Using in silico methods, this information can be integrated to bridge the gap between the therapeutic regimen and the pharmacological link with clinical outcome. These methodologies are described, and challenges ahead are discussed. Supported by many examples, this review shows how the combination of these techniques provides enhanced patient‐specific information on drug accessibility at the tumor tissue level, target binding, and downstream pharmacology. Our vision of how to apply tumor drug penetration measurements offers a roadmap for the clinical implementation of precision dosing.

Value of the 68Ga-DOTATATE PET-CT in the diagnosis of endometriosis. A pilot study

OBJECTIVE The non-invasive diagnosis of endometriosis remains challenging. Recent data suggested that somatostatin might be involved in its pathogenesis. High sensitive visualization of somatostatin receptors expression is possible using PET-CT imaging after the administration of a 68Ga-labeled somatostatin analog (DOTATATE) that will bind to the somatostatin receptor sub-types 2 and 5. The aim of the present study was to assess the usefulness of 68Ga-DOTATATE PET-CT in the diagnosis of endometriosis. STUDY DESIGN This is a prospective, single center pilot study. A pre operative 68Ga-DOTATATE PET-CT was performed in all of the patients who presented with suspected endometriosis and who were scheduled for a laparoscopy. Surgical endometriosis staging and histopathological analysis, including somatostatin receptors SST1, 2 and 5 immunohistochemistry (IHC) of removed specimens, were confronted to the results of the 68Ga-DOTATATE PET-CT. RESULTS 12 patients were included in this study. 68Ga-DOTATATE PET-CT performed pre operatively showed increased pathologic uptake in four patients with a deep infiltrating endometriosis (DIE) recto-vaginal lesion and in another patient with an adenomyoma. Expression of SST1, 2 and 5 receptors in surgical specimens was confirmed by IHC in these five lesions. Neither superficial peritoneal endometriosis, nor ovarian endometrioma were found to show an increased pathologic uptake on 68Ga-DOTATATE PET-CT. IHC analysis confirmed that SST1, 2, and 5 receptors were not present in these lesions. CONCLUSION The results observed in this small size series of patients seem to confirm expression of somatostatin receptors only in recto-vaginal DIE and focal adenomyosis lesions. The usefulness of 68Ga-DOTATATE PET-CT in the diagnosis of this entity is uncertain. Future research should concentrate on studying the role of somatostatin in the pathogenesis of DIE.

Phantom program analysis to assess the variability in PET image quantification between different PET-CT centres

Human primary immunodeficiencies (PIDs) comprise a broad group of inherited disorders characterised by developmental or functional defects of myeloid or lymphoid haemapoietic-derived cells, as well as non-haemapoietic cells involved in protective immunity. More than 150 different forms of PIDs affecting distinct components of the innate and adaptive immune system, such as neutrophils, macrophages, dendritic cells, complement proteins, natural killer cells, and T and B lymphocytes have been described [1]. Clinically, PIDs can be associated with any combination of infectious disease, autoimmunity, auto-inflammatory, allergy and malignancy. The best known PIDs show Mendelian inheritance and first become symptomatic during childhood. However, the field of PIDs is rapidly expanding and PIDs showing non-Mendelian inheritance and/or affecting primarily adult patients is being increasingly recognized. Conventional PIDs are typically seen as rare monogenic conditions associated with detectable immunologic abnormalities, resulting in a broad susceptibility to multiple and recurrent infections caused by weakly pathogenic and more virulent microorganisms. By opposition to these conventional PIDs, nonconventional primary immunodeficiencies as Mendelian conditions manifesting in otherwise healthy patients as a narrow susceptibility to infections, recurrent or otherwise, caused by weakly pathogenic or more virulent microbes are now reported [2]. By now, up to 120 diseasecausing genes have been identified. This molecular characterisation of PIDs has helped to increase our understanding of their physiopathology. The study of these diseases has provided essential insights into the functioning of the immune system with the ultimate goal of facilitating diagnosis and treatment.