Pyruvate‐lactate exchange and glucose uptake in human prostate cancer cell models. A study in xenografts and suspensions by hyperpolarized [1‐13C]pyruvate MRS and [18F]FDG‐PET

Reprogramming of energy metabolism in the development of prostate cancer can be exploited for a better diagnosis and treatment of the disease. The goal of this study was to determine whether differences in glucose and pyruvate metabolism of human prostate cancer cells with dissimilar aggressivenesses can be detected using hyperpolarized [1‐¹³C]pyruvate MRS and [¹⁸F]FDG‐PET imaging, and to evaluate whether these measures correlate. For this purpose, we compared murine xenografts of human prostate cancer LNCaP cells with those of more aggressive PC3 cells. [1‐¹³C]pyruvate was hyperpolarized by dissolution dynamic nuclear polarization (dDNP) and [1‐¹³C]pyruvate to lactate conversion was followed by ¹³C MRS. Subsequently [¹⁸F]FDG uptake was investigated by static and dynamic PET measurements. Standard uptake values (SUVs) for [¹⁸F]FDG were significantly higher for xenografts of PC3 compared with those of LNCaP. However, we did not observe a difference in the average apparent rate constant k_pl of ¹³C label exchange from pyruvate to lactate between the tumor variants. A significant negative correlation was found between SUVs from [¹⁸F]FDG PET measurements and k_pl values for the xenografts of both tumor types. The k_pl rate constant may be influenced by various factors, and studies with a range of prostate cancer cells in suspension suggest that LDH inhibition by pyruvate may be one of these. Our results indicate that glucose and pyruvate metabolism in the prostate cancer cell models differs from that in other tumor models and that [¹⁸F]FDG‐PET can serve as a valuable complementary tool in dDNP studies of aggressive prostate cancer with [1‐¹³C]pyruvate.     

MRI evaluation of vulvar squamous‐cell carcinoma in fresh radical local excision specimens for cancer localization and prediction of surgical tumor‐free margins

In the surgical treatment of vulvar squamous‐cell carcinoma (VSCC), tumor‐free margins of 8 mm or more are considered adequate. However, limited perioperative information on the tumor‐free margins other than the surgeon's own estimation is available. The purpose of this study was therefore to investigate the feasibility of ex vivo MRI in localizing VSCC and to assess the surgical tumor‐free margins in fresh radical local excision (RLE) specimens to guide the surgeon during resections. Nine patients with biopsy‐proven VSCC scheduled for RLE were prospectively included. Intact fresh specimens were scanned using a 7 T preclinical MR‐scanner. Whole mount H&E‐stained slides were obtained every 3 mm and correlated with ex vivo MRI. A pathologist annotated VSCC and minimal tumor‐free margins (3 o'clock, 9 o'clock, basal) on the digitalized histological slides. An observer with knowledge of histology (the non‐blinded annotation) and a radiologist blinded to histology (the blinded annotation) separately performed annotation of the same features on ex vivo MRI. Linear correlation and agreement of the ex vivo MRI measurements with histology were assessed. Diagnostic performance for VSCC localization and identification of margins less than 8 mm was expressed as positive and negative predictive values (PPV, NPV). In 153 matched ex vivo MRI slices, the observer correctly identified 79/91 margins as less than 8 mm (PPV 87%) and 110/124 margins as 8 mm or greater (NPV 89%). The radiologist correctly annotated absence of VSCC in 73/81 (NPV 90%) and presence in 65/72 (PPV 90%) slices. Sixty‐four of 90 margins were correctly identified as less than 8 mm (PPV 71%) and 83/102 margins as 8 mm or greater (NPV 81%). Both non‐blinded and blinded annotations were linearly correlated and demonstrated good agreement with histology. Accurate localization of VSCC and measurements of the surgical tumor‐free margins in fresh RLE specimens using ex vivo MRI seems feasible. High diagnostic performance in VSCC localization and identification of margins less than 8 mm suggest ex vivo MRI to be clinically applicable.     

A large retrospective single-centre study to define the best image acquisition protocols and interpretation criteria for white blood cell scintigraphy with 99mTc-HMPAO-labelled leucocytes in musculoskeletal infections

Purpose

The diagnosis of infection is often based on clinical, pathological and microbiological results. However, these investigations lack specificity. White blood cell (WBC) scintigraphy is considered the gold standard nuclear imaging technique for diagnosing infections in bone and soft tissues (except spondylodiscitis). However, image acquisition and interpretation criteria differ amongst centres throughout the world, leading to differences in reported results. The aim of this study was to identify the most accurate WBC scintigraphy acquisition and interpretation protocols for diagnosis of bone and soft tissue infections.

Methods

Included in this retrospective study were 297 patients with suspected bone or soft tissue infection who underwent WBC scintigraphy with ^99mTc-HMPAO-labelled leucocytes between 2009 and 2012. Sensitivity, specificity, accuracy, and positive and negative predictive values of WBC scintigraphy were determined for two different dual time point acquisition protocols (fixed-time acquisition and time decay-corrected acquisition) and five image interpretation methods (visual and semiquantitative with four different reference regions of interest). Final diagnosis was based on pathological and microbiological reports, and when these were not available, on clinical follow-up of at least 6 months.

Results

The best acquisition protocol was 4 h and 20 – 24 h dual time-point acquisition with time decay-corrected acquisition. When using this acquisition protocol, visual qualitative interpretation led to a sensitivity of 85.1 %, a specificity of 97.1 %, a diagnostic accuracy of 94.5 %, a positive predictive value of 88.8 % and a negative predictive value of 95.9 %. For semiquantitative analysis, the best results were found when lesion-to-reference ratios were calculated with the contralateral side as the reference tissue, except for osteomyelitis and infected osteosynthesis, for which the contralateral bone marrow was found to be the best reference tissue. Results of the semiquantitative analyses per se were not better than for visual analysis. In the optimal analysis protocol, scans are first visually evaluated, and if this gives equivocal results, semiquantitative analysis is performed. This strategy resulted in an improved sensitivity of 97.9 %, a specificity of 91.8 % and a diagnostic accuracy of 93.1 %.

Conclusion

WBC scintigraphy for bone and soft-tissue infection is best performed using a dual acquisition protocol at 4 h and at 20–24 h after injection, in which the acquisition time of the scans is corrected for decay. In most patients, visual analysis is sufficient and leads to high diagnostic accuracy. When interpretation by visual analysis is inconclusive, semiquantitative analysis adds accuracy. Based on our results, we propose a flow chart for analysing WBC scintigraphy in musculoskeletal infections.     

Myocardial perfusion reserve in spared myocardium: correlation with infarct size and left ventricular ejection fraction

Purpose

Left ventricular ejection fraction (LVEF) after myocardial infarction is considered to be determined by the size of the infarction and residual function of the spared myocardium. Myocardial perfusion reserve (MPR) has been shown to be a strong prognostic factor in patients with ischaemic heart failure, even stronger than LVEF. In the present study, the interrelationship between MPR, LVEF and infarct size was investigated.

Methods

In total, 102 patients with a prior history of myocardial infarction were included. All underwent rest and stress ¹³N-ammonia and gated ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) positron emission tomography (PET) for evaluation of myocardial ischaemia and viability. FDG polar maps were used to determine the size of the infarction. The LVEF was obtained by gated ¹⁸F-FDG PET or another available method within 3 months of the PET scan. MPR was obtained per segment in the spared myocardium.

Results

The mean age of the subjects was 68?±?12 years. Global MPR was 1.63?±?0.51. The mean LVEF was 36?±?10 % and mean infarct size 23.72?±?14.8 %. A linear regression model was applied for the analysis considering the LVEF as a dependent variable. All risk factors, mean stress flow, infarct size and MPR were entered as variables. The infarct size (p?<?0.001) and MPR (p?=?0.04) reached statistical significance. In a multivariate model MPR had a stronger correlation with LVEF than infarct size.

Conclusion

In patients with a prior history of myocardial infarction, LVEF is not just related to infarct size but also to MPR in the spared myocardium.