Angelo Castello

Clinical characteristics of patient selection and imaging predictors of outcome in solid tumors treated with checkpoint-inhibitors

The rapidly evolving knowledge on tumor immunology and the continuous implementation of immunotherapy in cancer have recently led to the FDA and EMA approval of several checkpoint inhibitors as immunotherapic agents in clinical practice. Anti-CTLA-4, anti-PD-1, and anti-PDL-1 antibodies are becoming standard of care in advanced melanoma, as well as in relapsed or metastatic lung and kidney cancer, demonstrating higher and longer response compared to standard chemotherapy. These encouraging results have fostered the evaluation of these antibodies either alone or in combination with other therapies in several dozen clinical trials for the treatment of multiple tumor types. However, not all patients respond to immune checkpoint inhibitors, hence, specific biomarkers are necessary to guide and monitor therapy. The utility of PD-L1 expression as a biomarker has varied in different clinical trials, but, to date, no consensus has been reached on whether PD-L1 expression is an ideal marker for response and patient selection; approximately 20–25% of patients will respond to immunotherapy with checkpoint inhibitors despite a negative PD-L1 staining. On the other hand, major issues concern the evaluation of objective response in patients treated with immunotherapy. Pure morphological criteria as commonly used in solid tumors (i.e. RECIST) are not sufficient because change in size is not an early and reliable marker of tumor response to biological therapies. Thus, the scientific community has required a continuous adaptation of immune-related response criteria (irRC) to overcome the problem. In this context, metabolic information and antibody-based imaging with positron emission tomography (PET) have been investigated, providing a powerful approach for an optimal stratification of patients at staging and during the evaluation of the response to therapy. In the present review we provide an overview on the clinical characteristics of patient selection when using imaging predictors of outcome in solid tumors treated with checkpoint-inhibitors.

Myocardial blood flow and left ventricular functional reserve in hypertrophic cardiomyopathy: a 13NH3 gated PET study

IntroductionIschemia in hypertrophic cardiomyopathy (HCM) is caused by coronary microvascular dysfunction (CMD), which is detected by measuring myocardial blood flow (MBF) with PET. Whether CMD may be associated with ischemic left ventricular (LV) dysfunction is unclear. We therefore assessed LV ejection fraction (EF) reserve in HCM patients undergoing dipyridamole (Dip) PET.MethodsResting and stress 13NH3 dynamic as well as gated PET were performed in 34 HCM patients. Segmental MBF and transmural perfusion gradient (TPG = subendocardial / subepicardial MBF) were assessed. LVEF reserve was considered abnormal if Dip LVEF decreased more than 5 units as compared to rest.ResultsEighteen patients had preserved (group A) and 16 abnormal LVEF reserve (group B; range −7 to −32). Group B patients had greater wall thickness than group A, but resting volumes, LVEF, resting and Dip MBF, and myocardial flow reserve were similar. Group B had slightly higher summed stress score and summed difference score in visual analysis than group A, and a significantly higher summed stress wall motion score. In group B, resting TPG was slightly lower (1.31 ± 0.29 vs. 1.37 ± 0.34, p <0.05), and further decreased after Dip, whilst in group A it increased (B = 1.20 ± 0.39, p < 0.0001 vs. rest and vs. A = 1.40 ± 0.43). The number of segments per patient with TPG <1 was higher than in group A (p < 0.001) and was a significant predictor of impaired LVEF reserve (OR 1.86, p < 0.02), together with wall thickness (OR 1.3, p < 0.02).ConclusionAbnormal LVEF response is common in HCM patients following Dip, and is related to abnormal TPG, suggesting that subendocardial ischemia might occur under Dip and cause transient LV dysfunction. Although in vivo this effect may be hindered by the adrenergic drive associated with effort, these findings may have relevance in understanding exercise limitation and heart failure symptoms in HCM.

Role of molecular imaging in the management of patients affected by inflammatory bowel disease: State-of-the-art

AIM To present the current state-of-the art of molecular imaging in the management of patients affected by inflammatory bowel disease (IBD). METHODS A systematic review of the literature was performed in order to find important original articles on the role of molecular imaging in the management of patients affected by IBD. The search was updated until February 2016 and limited to articles in English. RESULTS Fifty-five original articles were included in this review, highlighting the role of single photon emission tomography and positron emission tomography. CONCLUSION To date, molecular imaging represents a useful tool to detect active disease in IBD. However, the available data need to be validated in prospective multicenter studies on larger patient samples.

68Ga-PSMA Positron Emission Tomography/Computerized Tomography for Primary Diagnosis of Prostate Cancer in Men with Contraindications to or Negative Multiparametric Magnetic Resonance Imaging: A Prospective Observational Study

Purpose: 68Ga labeled prostate specific membrane antigen positron emission tomography/computerized tomography may represent the most promising imaging modality to identify and risk stratify prostate cancer in patients with contraindications to or negative multiparametric magnetic resonance imaging. Materials and Methods: In this prospective observational study we analyzed 68Ga labeled prostate specific membrane antigen positron emission tomography/computerized tomography in a select group of patients with persistently elevated prostate specific antigen and/or Prostate Health Index suspicious for prostate cancer, negative digital rectal examination and at least 1 negative biopsy. The cohort comprised men with equivocal multiparametric magnetic resonance imaging (Prostate Imaging‐Reporting and Data System, version 2 score of 2 or less), or an absolute or relative contraindication to multiparametric magnetic resonance imaging. Sensitivity, specificity and CIs were calculated compared to histopathology findings. ROC analysis was applied to determine the optimal cutoff values of 68Ga labeled prostate specific membrane antigen uptake to identify clinically significant prostate cancer (Gleason score 7 or greater). Results: A total of 45 patients with a median age of 64 years were referred for 68Ga labeled prostate specific membrane antigen positron emission tomography/computerized tomography between January and August 2017. The 25 patients (55.5%) considered to have positive positron emission tomography results underwent software assisted fusion biopsy. We determined the uptake values of regions of interest, including a median maximum standardized uptake value of 5.34 (range 2.25 to 30.41) and a maximum‐to‐background standardized uptake value ratio of 1.99 (range 1.06 to 14.42). Mean and median uptake values on 68Ga labeled prostate specific membrane antigen positron emission tomography/computerized tomography (ie the maximum standardized uptake value or the maximum‐to‐background standardized uptake value ratio) were significantly higher for Gleason score 7 lesions than for Gleason score 6 or benign lesions (p <0.001). On ROC analysis a maximum standardized uptake value of 5.4 and a maximum‐to‐background standardized uptake value ratio of 2 discriminated clinically relevant prostate cancer with 100% overall sensitivity in each case, and 76% and 88% specificity, respectively. Conclusions: Our findings support the use of 68Ga labeled prostate specific membrane antigen positron emission tomography/computerized tomography for primary detection of prostate cancer in a specific subset of men.

Is it time to change our vision of tumor metabolism prior to immunotherapy

Dear Editor, We read with interest the manuscript entitled BMetabolic characteristics of programmed cell death-ligand 1-expressing lung cancer on 18F-fluorodeoxyglucose positron emission tomography/computed tomography^ recently published from Takada et al. [1]. The paper provides new features that should change the way of looking at checkpoint inhibitors, tumor metabolism and response to immunotherapy. In particular, the most interesting aspect and currently the major theme in the paper is represented by the markedly increased glycolytic metabolism in tumors having a high PD-L1 expression. When measured on 18F–FDG PET as maximum standardized uptake value (i.e. SUVmax), tumor metabolism, smoking habitude and pleural invasion result as independent predictors of PD-L1 protein expression in non-small cell lung cancer (NSCLC) tissue specimens. It is now accepted that SUVmax has a prognostic significance in NSCLC, as confirmed by different meta-analyses [2]. An enhanced metabolic activity in malignant cancerous cells in fact predicts a higher risk of disease recurrence or death and has been associated with several oncogenic pathways in patients with NSCLC [3, 4]. Takada et al. [1] add Banother brick in the wall^ by documenting a significant correlation between tumor SUVmax and PD-L1 protein expression (Fig. 1). This finding should not be surprising, since the logical consequence of tumors having a high PDL1 expression is accompanied by the presence of inactive or inefficient immune system response in the surrounding environment, leading to immune tolerance toward malignant cells that would necessarily face no limits to their proliferation and progression. The logical equation might be therefore reported as:

Non-small cell lung carcinoma: understanding cancer microenvironment to drive immunotherapy and patients’ selection

Lung cancer is still the first cause of cancer-related death worldwide with non-small cell lung carcinoma (NSCLC) determining approximately 85% of all cases (1). Almost half of lung cancers present with metastases at the diagnosis.

The Complexity and Fractal Geometry of Nuclear Medicine Images

Irregularity in shape and behavior is the main feature of every anatomical system, including human organs, tissues, cells, and sub-cellular entities. It has been shown that this property cannot be quantified by means of the classical Euclidean geometry, which is only able to describe regular geometrical objects. In contrast, fractal geometry has been widely applied in several scientific fields. This rapid growth has also produced substantial insights in the biomedical imaging. Consequently, particular attention has been given to the identification of pathognomonic patterns of “shape” in anatomical entities and their changes from natural to pathological states. Despite the advantages of fractal mathematics and several studies demonstrating its applicability to oncological research, many researchers and clinicians remain unaware of its potential. Therefore, this review aims to summarize the complexity and fractal geometry of nuclear medicine images.

18F-FDG PET/CT for response assessment in Hodgkin lymphoma undergoing immunotherapy with checkpoint inhibitors

Abstract Our aim was to evaluate Hodgkin Lymphoma (HL) response to checkpoint inhibitors with 18F-FDG PET/CT. Forty three refractory or relapsed HL patients were investigated before immunotherapy, 8 weeks and 17 weeks after administration of either nivolumab or pembrolizumab. The median follow-up was 19 months. Best clinical response was complete response (CR) in 26 patients, partial response (PR) in 5 patients, stable disease (SD) in 8 patients, and progression disease (PD) in 4 patients. At the early assessment, Deauville Score (DS) resulted significantly different in responder group compared to nonresponders. SUVmax was significantly lower in responders, while there was no relevant modification in the tumor burden. At interim evaluation, DS well differentiated responder group. A significant decrease in glucose metabolism and tumor burden parameters was observed in responder patients, who presented with a longer progression-free survival then nonresponders. 18F-FDG PET/CT provides a reliable indication of treatment response under checkpoints inhibitors, even at an early assessment.

Immunotherapy in non-small-cell lung cancer: potential predictors of response and new strategies to assess activity

The treatment algorithm of advanced non-small-cell lung cancer is rapidly evolving. This result is mostly related to the availability in clinical practice of checkpoint inhibitors targeting the programmed death-1 (PD-1) and its ligands (PD-Ls) immunosuppressive pathway. Although patients selection in the first-line setting relies essentially on high levels of PD-L1 tumor expression, treatment choice in pretreated patients is more challenging and, although clinical and biological characteristics might be of help, there is an urgent need for novel tools to better identify sensitive and resistant patients. In this context, the integration of molecular markers and immune-PET imaging might represent a potentially effective strategy to refine patient selection.

Incidental identification of osteoid osteoma by 68Ga-PSMA PET/CT

An osteoid osteoma (OO) is a rare osteoblastic benign bone tumor representing approximately 14% of all bone tumors. It usually arises from cortico-diaphyseal and metaphyseal regions of long bones, mostly in the lower limbs, and affects prevalently children and young male adults [1]. Clinical presentation depends on the site of the tumor. However, most patients experience continuous night-time pain, which is relieved by salicylates or non-steroidal anti-inflammatory drugs. OO is characterized by a well-vascularized Bnidus^ centrally, surrounded by a zone of thickened cortex and bone sclerosis. Bone scintigraphy and computed tomography (CT) are the main and complementary imagingmodalities for the diagnosis of OO [2], athough magnetic resonance imaging (MRI) and X-rays can also be used. Recently, new hybrid imaging as single-photon emission computed tomography-computed tomography (SPECT-CT), F–FDG PET/CT, and F–Fluoride PET/CT might improve the accuracy in the diagnosis of the benign lesion [3, 4]. Ga-PSMA PET/CT is increasingly used in prostate cancer for staging and restaging, but increased PSMA activity has been reported in other different non-prostate malignancies and in normal organs (e.g., kidney, duodenum, parotid and submandibular salivary glands, spleen, lacrimal glands, and liver) [5]. To our knowledge, this is the first case detecting high PSMA uptake in OO, suggesting a possible PSMA expression related to osteoblast activity.