Optimal method for metabolic tumour volume assessment of cervical cancers with inter-observer agreement on [18F]-fluoro-deoxy-glucose positron emission tomography with computed tomography.

PURPOSE: Cervical cancer metabolic tumour volume (MTV) derived from [18F]-FDG PET/CT has a role in prognostication and therapy planning. There is no standard method of outlining MTV on [18F]-FDG PET/CT. The aim of this study was to assess the optimal method to outline primary cervical tumours on [18F]-FDG PET/CT using MRI-derived tumour volumes as the reference standard. METHODS: 81 consecutive cervical cancer patients with pre-treatment staging MRI and [18F]-FDG PET/CT imaging were included. MRI volumes were compared with different PET segmentation methods. Method 1 measured MTVs at different SUVmax thresholds ranging from 20 to 60% (MTV20-MTV60) with bladder masking and manual adjustment when required. Method 2 created an isocontour around the tumour prior to different SUVmax thresholds being applied. Method 3 used an automated gradient method. Inter-observer agreement of MTV, following manual adjustment when required, was recorded. RESULTS: For method 1, the MTV25 and MTV30 were closest to the MRI volumes for both readers (mean percentage change from MRI volume of 2.9% and 13.4% for MTV25 and - 13.1% and - 2.0% for MTV30 for readers 1 and 2). 70% of lesions required manual adjustment at MTV25 compared with 45% at MTV30. There was excellent inter-observer agreement between MTV30 to MTV60 (ICC ranged from 0.898-0.976 with narrow 95% confidence intervals (CIs)) and moderate agreement at lower thresholds (ICC estimates of 0.534 and 0.617, respectively for the MTV20 and MTV25 with wide 95% CIs). Bladder masking was performed in 86% of cases overall. For method 2, excellent correlation was demonstrated at MTV25 and MTV30 (mean % change from MRI volume of -3.9% and - 8.6% for MTV25 and - 16.9% and 19% for MTV30 for readers 1 and 2, respectively). This method also demonstrated excellent ICC across all thresholds with no manual adjustment. Method 3 demonstrated excellent ICC of 0.96 (95% CI 0.94-0.97) but had a mean percentage difference from the MRI volume of - 19.1 and - 18.2% for readers 1 and 2, respectively. 21% required manual adjustment for both readers. CONCLUSION: MTV30 provides the optimal correlation with MRI volume taking into consideration the excellent inter-reader agreement and less requirement for manual adjustment.

[18F]Fluciclatide PET as a biomarker of response to combination therapy of pazopanib and paclitaxel in platinum-resistant/refractory ovarian cancer.

BACKGROUND: Angiogenesis is a driver of platinum resistance in ovarian cancer. We assessed the effect of combination pazopanib and paclitaxel followed by maintenance pazopanib in patients with platinum-resistant/refractory ovarian cancer. Integrins αvß3 and αvß5 are both upregulated in tumor-associated vasculature. [18F]Fluciclatide is a novel PET tracer that has high affinity for integrins αvß3/5, and was used to assess the anti-angiogenic effect of pazopanib. PATIENTS AND METHODS: We conducted an open-label, phase Ib study in patients with platinum-resistant/refractory ovarian cancer. Patients received 1 week of single-agent pazopanib (800 mg daily) followed by combination therapy with weekly paclitaxel (80 mg/m2). Following completion of 18 weeks of combination therapy, patients continued with single-agent pazopanib until disease progression. Dynamic [18F]fluciclatide-PET imaging was conducted at baseline and after 1 week of pazopanib. Response (RECIST 1.1), toxicities, and survival outcomes were recorded. Circulating markers of angiogenesis were assessed with therapy. RESULTS: Fourteen patients were included in the intention-to-treat analysis. Complete and partial responses were seen in seven patients (54%). Median progression-free survival (PFS) was 10.63 months, and overall survival (OS) was 18.5 months. Baseline [18F]fluciclatide uptake was predictive of long PFS. Elevated baseline circulating angiopoietin and fibroblast growth factor (FGF) were predictive of greater reduction in SUV60,mean following pazopanib. Kinetic modeling of PET data indicated a reduction in K1 and Ki following pazopanib indicating reduced radioligand delivery and retention. CONCLUSIONS: Combination therapy followed by maintenance pazopanib is effective and tolerable in platinum-resistant/refractory ovarian cancer. [18F]Fluciclatide-PET uptake parameters predict clinical outcome with pazopanib therapy indicating an anti-angiogenic response.

Radiological assessment of Peritoneal Cancer Index on preoperative CT in ovarian cancer is related to surgical outcome and survival.

PURPOSE: To evaluate whether Peritoneal Cancer Index (PCI) assessed on preoperative CT (CT-PCI) can be used as non-invasive preoperative tool to predict surgical outcome, disease-free survival (DFS) and overall survival (OS). MATERIALS AND METHODS: This is a retrospective, observational cohort study performed in a single institution. We considered all patients with diagnosis of ovarian cancer and preoperative CT, who had undergone upfront cytoreductive surgery between 2008 and 2010 and had post-operative clinical follow-up to December 2015. Two radiologists reviewed CT scans and assessed CT-PCI using Sugarbaker's diagram. We assessed the discriminatory capacity of the CT-PCI score on the surgical outcome by ROC curve analysis. DFS and OS were assessed by Kaplan-Meier nonparametric curves and by multivariable Cox-regression analysis. RESULTS: A total of 297 patients were included in the present analysis. CT-PCI was positively correlated with post-operative residual disease [odds ratio (OR) 1.04, 95% CI 1.01-1.07, p = 0.003]. ROC curve analysis returned AUC = 0.64 for the prediction of total macroscopic tumour clearance. In multivariable analysis, patients with no peritoneal disease seen on CT had a significantly longer DFS [Hazard ratio (HR) 2.28, p = 0.007]. Radiological serosal small bowel involvement was an independent predictor for shorter OS (HR 3.01, p = 0.002). CONCLUSION: Radiological PCI assessed on preoperative CT is associated with the probability of residual disease after cytoreductive surgery; however, it has low performance as a triage test to reliably identify patients who are likely to have complete cytoreductive surgery. CT-PCI is positively correlated with both DFS and OS and may be used as an independent prognostic factor, for example in patients with high FIGO stages.

Discovery of pre-therapy 2-deoxy-2-18F-fluoro-D-glucose positron emission tomography-based radiomics classifiers of survival outcome in non-small-cell lung cancer patients.

PURPOSE: The aim of this multi-center study was to discover and validate radiomics classifiers as image-derived biomarkers for risk stratification of non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Pre-therapy PET scans from a total of 358 Stage I-III NSCLC patients scheduled for radiotherapy/chemo-radiotherapy acquired between October 2008 and December 2013 were included in this seven-institution study. A semi-automatic threshold method was used to segment the primary tumors. Radiomics predictive classifiers were derived from a training set of 133 scans using TexLAB v2. Least absolute shrinkage and selection operator (LASSO) regression analysis was used for data dimension reduction and radiomics feature vector (FV) discovery. Multivariable analysis was performed to establish the relationship between FV, stage and overall survival (OS). Performance of the optimal FV was tested in an independent validation set of 204 patients, and a further independent set of 21 (TESTI) patients. RESULTS: Of 358 patients, 249 died within the follow-up period [median 22 (range 0-85) months]. From each primary tumor, 665 three-dimensional radiomics features from each of seven gray levels were extracted. The most predictive feature vector discovered (FVX) was independent of known prognostic factors, such as stage and tumor volume, and of interest to multi-center studies, invariant to the type of PET/CT manufacturer. Using the median cut-off, FVX predicted a 14-month survival difference in the validation cohort (N = 204, p = 0.00465; HR = 1.61, 95% CI 1.16-2.24). In the TESTI cohort, a smaller cohort that presented with unusually poor survival of stage I cancers, FVX correctly indicated a lack of survival difference (N = 21, p = 0.501). In contrast to the radiomics classifier, clinically routine PET variables including SUVmax, SUVmean and SUVpeak lacked any prognostic information. CONCLUSION: PET-based radiomics classifiers derived from routine pre-treatment imaging possess intrinsic prognostic information for risk stratification of NSCLC patients to radiotherapy/chemo-radiotherapy.

What's New in Imaging for Gynecologic Cancer?

Magnetic resonance imaging (MRI) is the optimal modality for local staging of gynecological tumors. Advances in functional MRI with diffusion-weighted and dynamic contrast-enhanced sequences provide more detailed information regarding tumor cellularity, vascularity, and viability. Fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) now has an established role in imaging for gynecological cancers, particularly staging of locally advanced cervical cancers and pre-salvage exenterative therapy in relapsed gynecologic tumors. Novel PET tracers, targeting other aspects of tumor biology, are being evaluated although none are currently in routine clinical use. New PET/MR scanners have the potential to combine the strengths of both modalities in one sitting. This review covers advances in gynecologic imaging concentrating on cervical, endometrial, and ovarian cancers.

Radiopharmaceuticals as probes to characterize tumour tissue.

Tumour cells exhibit several properties that allow them to grow and divide. A number of these properties are detectable by nuclear imaging methods. We discuss crucial tumour properties that can be described by current radioprobe technologies, further discuss areas of emerging radioprobe development, and finally articulate need areas that our field should aspire to develop. The review focuses largely on positron emission tomography and draws upon the seminal 'Hallmarks of Cancer' review article by Hanahan and Weinberg in 2011 placing into context the present and future roles of radiotracer imaging in characterizing tumours.

Immunotherapy-related adverse effects on 18F-FDG PET/CT imaging.

18F-Fluorodeoxyglucose positron emission tomography/CT imaging plays a key role in oncological imaging including in staging, radiotherapy planning, treatment response and recurrence assessment. Immunotherapies represent a major advance in cancer therapy for a number of tumours with resulting survival benefit. However, a wide range of immune related adverse events (irAEs), some of which can be apparent on imaging, have been reported. These involve many organ systems but particularly endocrine, cutaneous and gastrointestinal systems. Early detection of irAEs is essential to aid diagnosis and management of patients and to reduce associated morbidity. In addition, it is important to not mistake treatment related effects for disease.This pictorial review aims to identify common irAEs and changes seen on 18F-fluorodeoxyglucose positron emission tomography/CT.

Interobserver agreement of the visual Herder scale for the assessment of solitary pulmonary nodules on 18F Fluorodeoxyglucose PET/computed tomography.

BACKGROUND: British Thoracic Society guidelines recommend 18F Fluorodeoxyglucose (F-FDG) PET/computed tomography (CT) for solitary pulmonary nodule (SPN) follow-up in high-risk individuals or if the CT Brock score is >10%. Nodule tracer uptake is assessed visually in comparison to the surrounding lung tissue and mediastinal blood pool (Herder score). This score is used to calculate the risk of malignancy and guide patient management. Despite its widespread use, there have been no studies to date looking at interobserver agreement using the Herder scale. PATIENTS AND METHODS: F-FDG PET/CT studies of 100 consecutive patients imaged for the evaluation of SPN were retrospectively analysed. Anonymized images were reviewed independently by three Consultant Nuclear Medicine Radiologists and the Herder score was documented, along with a confidence score graded 1-3, where 1 indicated 'not at all confident' and 3 indicated 'very confident'. Interobserver agreement was assessed using interclass correlation coefficient modelling. RESULTS: There was complete reviewer agreement in 81% cases, and interclass correlation with Cronbach's alpha was excellent at 0.973 (95% confidence interval, 0.962-0.981). The agreement between pairs of reviewers was good and confidence scores using the Herder scale were high, with reviewers giving a confidence score of 3 in an average of 78% of cases. CONCLUSION: Our study suggests excellent interobserver agreement for use of the Herder scale in evaluating SPNs. Reviewer confidence scores were high reflecting high confidence in the use of the Herder scale for evaluating SPN.

Spatial heterogeneity of radiolabeled choline positron emission tomography in tumors of patients with non-small cell lung cancer: first-in-patient evaluation of [18F]fluoromethyl-(1,2-2H4)-choline.

Purpose: The spatio-molecular distribution of choline and its metabolites in tumors is highly heterogeneous. Due to regulation of choline metabolism by hypoxic transcriptional signaling and other survival factors, we envisage that detection of such heterogeneity in patient tumors could provide the basis for advanced localized therapy. However, non-invasive methods to assess this phenomenon in patients are limited. We investigated such heterogeneity in Non-Small Cell Lung Cancer (NSCLC) with [18F]fluoromethyl-(1,2-2H4) choline ([18F]D4-FCH) and positron emission tomography/computed tomography (PET/CT). Experimental design: [18F]D4-FCH (300.5±72.9MBq [147.60-363.6MBq]) was administered intravenously to 17 newly diagnosed NSCLC patients. PET/CT scans were acquired concurrently with radioactive blood sampling to permit mathematical modelling of blood-tissue transcellular rate constants. Comparisons were made with biopsy-derived choline kinase-α (CHKα) expression and diagnostic [18F]fluorodeoxyglucose ([18F]FDG) scans. Results: Oxidation of [18F]D4-FCH to [18F]D4-fluorobetaine was suppressed (48.58±0.31% parent at 60 min) likely due to the deuterium isotope effect embodied within the design of the radiotracer. Early (5 min) and late (60 min) images showed specific uptake of tracer in all 51 lesions (tumors, lymph nodes and metastases) from 17 patients analyzed. [18F]D4-FCH-derived uptake (SUV60max) in index primary lesions (n=17) ranged between 2.87-10.13; lower than that of [18F]FDG PET [6.89-22.64]. Mathematical modelling demonstrated net irreversible uptake of [18F]D4-FCH at steady-state, and parametric mapping of the entire tumor showed large intratumorally heterogeneity in radiotracer retention, which is likely to have influenced correlations with biopsy-derived CHKα expression. Conclusions: [18F]D4-FCH is detectable in NSCLC with large intratumorally heterogeneity, which could be exploited in the future for targeting localized therapy.

The Racoon Eye Sign in the Investigation of Dementia Using 18F-Florbetaben.

Differentiating Alzheimer disease (AD) from other forms of cognitive impairment and from normal aging can be challenging. As a consequence, the diagnosis of AD can be delayed, often occurring too late for meaningful intervention. The role of ß-amyloid plaques in the pathogenesis of AD provides a target for highly sensitive and specific image quantification of amyloid plaque burden using ß-amyloid PET (F-florbetaben). Here we present the case of a 77-year-old woman with increasing memory impairment and striking white matter changes on MRI, with the "racoon eye" sign on F-florebetaben PET imaging.

Osteoporosis Circumscripta on 68Ga-DOTATATE PET CT.

Incidental findings on PET CT studies are common. The distribution of Ga-DOTATATE is dependent on cell surface expression of somatostatin receptors, which may be pathologic or physiologic. Osteoporosis circumscripta is the early lytic phase of Paget disease associated with well-defined osteopenia, most commonly seen within the skull on imaging. The appearance has been well demonstrated on Tc HDP/MDP bone scans. Here, we present the case of a 76-year-old man with a small bowel carcinoid tumor who underwent staging imaging with Ga-DOTATATE PET CT with the incidental finding of osteoporosis circumscripta.

FDG-PET Imaging in Cervical Cancer.

FDG-PET/CT has an established role in the initial staging of locally advanced cervical cancers, particularly in evaluation of nodal disease and distant metastases. It is common practice to perform FDG-PET/CT 3 months postcompletion of chemoradiotherapy as it can predict outcome and be used to tailor management, including adjuvant therapy and follow-up. It is also routinely used prior to pelvic exenterative surgery to ensure there is no disease outside the pelvis. There is growing evidence that FDG-PET-derived parameters are prognostic and could potentially be used to tailor therapy. This review outlines the use of FDG-PET/CT imaging in cervical cancer.

A mathematical-descriptor of tumor-mesoscopic-structure from computed-tomography images annotates prognostic- and molecular-phenotypes of epithelial ovarian cancer.

The five-year survival rate of epithelial ovarian cancer (EOC) is approximately 35-40% despite maximal treatment efforts, highlighting a need for stratification biomarkers for personalized treatment. Here we extract 657 quantitative mathematical descriptors from the preoperative CT images of 364 EOC patients at their initial presentation. Using machine learning, we derive a non-invasive summary-statistic of the primary ovarian tumor based on 4 descriptors, which we name "Radiomic Prognostic Vector" (RPV). RPV reliably identifies the 5% of patients with median overall survival less than 2 years, significantly improves established prognostic methods, and is validated in two independent, multi-center cohorts. Furthermore, genetic, transcriptomic and proteomic analysis from two independent datasets elucidate that stromal phenotype and DNA damage response pathways are activated in RPV-stratified tumors. RPV and its associated analysis platform could be exploited to guide personalized therapy of EOC and is potentially transferrable to other cancer types.

Dexmedetomidine produces its neuroprotective effect via the alpha 2A-adrenoceptor subtype.

Which of the three alpha2-adrenoceptor subtypes of alpha2A, alpha2B, or alpha2C mediates the neuroprotective effect of dexmedetomidine was examined in cell culture as well as in an in vivo model of neonatal asphyxia. Dexmedetomidine dose-dependently attenuated neuronal injury (IC50=83+/-1 nM) in neuronal-glial co-cultures derived from wild-type mice; contrastingly, dexmedetomidine did not exert neuroprotection in injured cells from transgenic mice (D79N) expressing dysfunctional alpha2A-adrenoceptors. An alpha2A-adrenoceptor subtype-preferring antagonist 2-[(4,5-Dihydro-1H-imidazol-2-yl)methyl]-2,3-dihydro-1-methyl-1H-isoindole maleate (BRL44408) completely reversed dexmedetomidine-induced neuroprotection, while other subtype-preferring antagonists 2-[2-(4-(2-Methoxyphenyl)piperazin-1-yl)ethyl]-4,4-dimethyl-1,3-(2H,4H)-isoquinolindione dihydrochloride (ARC239) (alpha2B) and rauwolscine (alpha2C) had no significant effect on the neuroprotective effect of dexmedetomidine in neuronal-glial co-cultures. Dexmedetomidine also protected against exogenous glutamate induced cell death in pure cortical neuron cultures assessed by flow cytometry and reduced both apoptotic and necrotic types of cell death. Likewise this neuroprotective effect was antagonised by BRL44408 but not ARC239 or rauwolscine. Dexmedetomidine exhibited dose-dependent protection against brain matter loss in vivo (IC50=40.3+/-6.1 microg/kg) and improved the neurologic functional deficit induced by the hypoxic-ischemic insult. Protection by dexmedetomidine against hypoxic-ischemic-induced brain matter loss was reversed by the alpha2A-adrenoceptor subtype-preferring antagonist BRL44408; neither ARC239 nor rauwolscine reversed the neuroprotective effect of dexmedetomidine in vivo. Our data suggest that the neuroprotective effect of dexmedetomidine is mediated by activation of the alpha2A adrenergic receptor subtype.

Is hand-sewn anastomosis superior to stapled anastomosis following oesophagectomy?

A best evidence topic was written according to a structured protocol. The question addressed was: In patients undergoing oesophagectomy is stapled anastomosis (STA) superior to hand-sewn anastomosis (HSA) with respect to post-operative outcomes. In total, 82 papers were found suitable using the reported search and 14 of these represented the best evidence to answer the clinical question. The authors, date, journal, study type, population, main outcome measures and results are tabulated. Existing evidence shows that STA is associated with reduced time to anastomotic construction and decreased intra-operative blood loss but increased risk of benign stricture formation compared to HSA. There is no difference between HSA and STA with respect to cardiac or respiratory complications, anastomotic leakage, duration of hospital admission or 30-day mortality. In HSA, increasing surgical experience and intra-operative air leakage testing after anastomotic creation are associated with reduced risk of anastomotic leakage. Further adequately powered studies will enable identification of other local and systemic factors influencing anastomotic healing, which will lead to improved patient and anastomotic technique selection for optimal surgical outcomes.

Xenon and hypothermia combine to provide neuroprotection from neonatal asphyxia.

Perinatal asphyxia can result in neuronal injury with long-term neurological and behavioral consequences. Although hypothermia may provide some modest benefit, the intervention itself can produce adverse consequences. We have investigated whether xenon, an antagonist of the N-methyl-D-aspartate subtype of the glutamate receptor, can enhance the neuroprotection provided by mild hypothermia. Cultured neurons injured by oxygen-glucose deprivation were protected by combinations of interventions of xenon and hypothermia that, when administered alone, were not efficacious. A combination of xenon and hypothermia administered 4 hours after hypoxic-ischemic injury in neonatal rats provided synergistic neuroprotection assessed by morphological criteria, by hemispheric weight, and by functional neurological studies up to 30 days after the injury. The protective mechanism of the combination, in both in vitro and in vivo models, involved an antiapoptotic action. If applied to humans, these data suggest that low (subanesthetic) concentrations of xenon in combination with mild hypothermia may provide a safe and effective therapy for perinatal asphyxia.