Standardization in Quantitative Imaging: A Multicenter Comparison of Radiomic Features from Different Software Packages on Digital Reference Objects and Patient Data Sets.

Radiomic features are being increasingly studied for clinical applications. We aimed to assess the agreement among radiomic features when computed by several groups by using different software packages under very tightly controlled conditions, which included standardized feature definitions and common image data sets. Ten sites (9 from the NCI's Quantitative Imaging Network] positron emission tomography-computed tomography working group plus one site from outside that group) participated in this project. Nine common quantitative imaging features were selected for comparison including features that describe morphology, intensity, shape, and texture. The common image data sets were: three 3D digital reference objects (DROs) and 10 patient image scans from the Lung Image Database Consortium data set using a specific lesion in each scan. Each object (DRO or lesion) was accompanied by an already-defined volume of interest, from which the features were calculated. Feature values for each object (DRO or lesion) were reported. The coefficient of variation (CV), expressed as a percentage, was calculated across software packages for each feature on each object. Thirteen sets of results were obtained for the DROs and patient data sets. Five of the 9 features showed excellent agreement with CV < 1%; 1 feature had moderate agreement (CV < 10%), and 3 features had larger variations (CV ≥ 10%) even after attempts at harmonization of feature calculations. This work highlights the value of feature definition standardization as well as the need to further clarify definitions for some features.

Open ventral hernia repair with a composite ventral patch - final results of a multicenter prospective study.

BACKGROUND: This study assessed clinical outcomes, including safety and recurrence, from the two-year follow-up of patients who underwent open ventral primary hernia repair with the use of the Parietex™ Composite Ventral Patch (PCO-VP). METHODS: A prospective single-arm, multicenter study of 126 patients undergoing open ventral hernia repair for umbilical and epigastric hernias with the PCO-VP was performed. RESULTS: One hundred twenty-six subjects (110 with umbilical hernia and 16 with epigastric hernia) with a mean hernia diameter of 1.8 cm (0.4-4.0) were treated with PCO-VP. One hundred subjects completed the two-year study. Cumulative hernia recurrence was 3.0% (3/101; 95%CI: 0.0-6.3%) within 24 months. Median Numeric Rating Scale pain scores improved from 2 [0-10] at baseline to 0 [0-3] at 1 month (P < 0.001) and remained low at 24 months 0 [0-6] (P < 0.001). 99% (102/103) of the patients were satisfied with their repair at 24 months postoperative. CONCLUSIONS: The use of PCO-VP to repair primary umbilical and epigastric defects yielded a low recurrence rate, low postoperative and chronic pain, and high satisfaction ratings, confirming that PCO-VP is effective for small ventral hernia repair in the two-year term after implantation. TRIAL REGISTRATION: The study was registered publically at clinicaltrials.gov ( NCT01848184 registered May 7, 2013).

Multisite Concordance of DSC-MRI Analysis for Brain Tumors: Results of a National Cancer Institute Quantitative Imaging Network Collaborative Project.

BACKGROUND AND PURPOSE: Standard assessment criteria for brain tumors that only include anatomic imaging continue to be insufficient. While numerous studies have demonstrated the value of DSC-MR imaging perfusion metrics for this purpose, they have not been incorporated due to a lack of confidence in the consistency of DSC-MR imaging metrics across sites and platforms. This study addresses this limitation with a comparison of multisite/multiplatform analyses of shared DSC-MR imaging datasets of patients with brain tumors. MATERIALS AND METHODS: DSC-MR imaging data were collected after a preload and during a bolus injection of gadolinium contrast agent using a gradient recalled-echo-EPI sequence (TE/TR = 30/1200 ms; flip angle = 72°). Forty-nine low-grade (n = 13) and high-grade (n = 36) glioma datasets were uploaded to The Cancer Imaging Archive. Datasets included a predetermined arterial input function, enhancing tumor ROIs, and ROIs necessary to create normalized relative CBV and CBF maps. Seven sites computed 20 different perfusion metrics. Pair-wise agreement among sites was assessed with the Lin concordance correlation coefficient. Distinction of low- from high-grade tumors was evaluated with the Wilcoxon rank sum test followed by receiver operating characteristic analysis to identify the optimal thresholds based on sensitivity and specificity. RESULTS: For normalized relative CBV and normalized CBF, 93% and 94% of entries showed good or excellent cross-site agreement (0.8 ≤ Lin concordance correlation coefficient ≤ 1.0). All metrics could distinguish low- from high-grade tumors. Optimum thresholds were determined for pooled data (normalized relative CBV = 1.4, sensitivity/specificity = 90%:77%; normalized CBF = 1.58, sensitivity/specificity = 86%:77%). CONCLUSIONS: By means of DSC-MR imaging data obtained after a preload of contrast agent, substantial consistency resulted across sites for brain tumor perfusion metrics with a common threshold discoverable for distinguishing low- from high-grade tumors.

Applications of PET imaging with the proliferation marker [18F]-FLT.

[18F]-3'-fluoro-3'-deoxythymidine (FLT) is a nucleoside-analog imaging agent for quantifying cellular proliferation that was first reported in 1998. It accumulates during the S-phase of the cell cycle through the action of cytosolic thymidine kinase, TK1. Since TK1 is primarily expressed in dividing cells, FLT uptake is essentially limited to dividing cells. Thus FLT is an effective measure of cell proliferation. FLT uptake has been shown to correlate with the more classic proliferation marker, the monoclonal antibody to Ki-67. Increased cellular proliferation is known to correlate with worse outcome in many cancers. However, the Ki-67 binding assay is performed on a sampled preparation, ex vivo, whereas FLT can be quantitatively measured in vivo using positron emission tomography (PET). FLT is an effective and quantitative marker of cell proliferation, and therefore a useful prognostic predictor in the setting of neoplastic disease. This review summarizes clinical studies from 2011 forward that used FLT-PET to assess tumor response to therapy. The paper focuses on our recommendations for a standardized clinical trial protocol and components of a report so multi center studies can be effectively conducted, and different studies can be compared. For example, since FLT is glucuronidated by the liver, and the metabolite is not transported into the cell, the plasma fraction of FLT can be significantly changed by treatment with particular drugs that deplete this enzyme, including some chemotherapy agents and pain medications. Therefore, the plasma level of metabolites should be measured to assure FLT uptake kinetics can be accurately calculated. This is important because the flux constant (KFLT) is a more accurate measure of proliferation and, by inference, a better discriminator of tumor recurrence than standardized uptake value (SUVFLT). This will allow FLT imaging to be a specific and clinically relevant prognostic predictor in the treatment of neoplastic disease.

Efficacy and tolerability of fitostimoline (vaginal cream, ovules, and vaginal washing) and of benzydamine hydrochloride (tantum rosa vaginal cream and vaginal washing) in the topical treatment of symptoms of bacterial vaginosis.

Two hundred and 91 patients showing signs and symptoms of bacterial vaginosis (BV) were randomized to receive topical treatment with Fitostimoline (vaginal cream and vaginal ovules + vaginal washing) or benzydamine hydrochloride (vaginal cream + vaginal washing) for 7 days. Signs (leucorrhoea, erythema, oedema, and erosion) and symptoms (burning, pain, itching, vaginal dryness, dyspareunia, and dysuria) (scored 0-3) were evaluated at baseline and at the end of treatment; the total symptoms score (TSS) was also calculated. In 125 patients, a bacterial vaginosis was confirmed by vaginal swab test. The primary efficacy variable analysis, that is, the percentage of patients with therapeutic success (almost complete disappearance of signs and symptoms), demonstrated that Fitostimoline ovules and vaginal cream were therapeutically equivalent and that pooled Fitostimoline treatment was not inferior to benzydamine hydrochloride. All the treatments were well tolerated, with only minor local adverse events infrequently reported. The results of this study confirmed that gynaecological Fitostimoline is a safe and effective topical treatment for BV.

Regional P-glycoprotein activity and inhibition at the human blood-brain barrier as imaged by positron emission tomography.

We used positron emission tomography (PET) to evaluate the contribution of P-glycoprotein (P-gp), present at the human blood-brain barrier (BBB), to regional drug distribution in the brain. Eleven healthy volunteers underwent PET imaging with [(11)C]-verapamil before and during cyclosporine A infusion. Regional P-gp inhibition was expressed as cyclosporine A-induced percentage change in the distributional clearance of verapamil (K(1)) in the brain, normalized to the regional blood flow (rCBF). K(1) estimates were similar across gray-matter regions of the brain and lower in the white matter regions, but all these estimates were considerably lower than rCBF. Normalization of K(1) by rCBF diminished the differences in estimates related to gray matter and white matter. In contrast, the K(1) for the pituitary, which is situated outside the BBB, approximated the rCBF. The magnitude of P-gp inhibition was comparable across BBB-protected brain structures. Our results indicate that P-gp and its inhibition equally affect the distribution of drugs (and therefore their neuro-efficacy and toxicity) in the various brain regions protected by the BBB.

Kinetic quantitation of cerebral PET-FDG studies without concurrent blood sampling: statistical recovery of the arterial input function.

Kinetic quantitation of dynamic positron emission tomography (PET) studies via compartmental modeling usually requires the time-course of the radio-tracer concentration in the arterial blood as an arterial input function (AIF). For human and animal imaging applications, significant practical difficulties are associated with direct arterial sampling and as a result there is substantial interest in alternative methods that require no blood sampling at the time of the study. A fixed population template input function derived from prior experience with directly sampled arterial curves is one possibility. Image-based extraction, including requisite adjustment for spillover and recovery, is another approach. The present work considers a hybrid statistical approach based on a penalty formulation in which the information derived from a priori studies is combined in a Bayesian manner with information contained in the sampled image data in order to obtain an input function estimate. The absolute scaling of the input is achieved by an empirical calibration equation involving the injected dose together with the subject's weight, height and gender. The technique is illustrated in the context of (18)F -Fluorodeoxyglucose (FDG) PET studies in humans. A collection of 79 arterially sampled FDG blood curves are used as a basis for a priori characterization of input function variability, including scaling characteristics. Data from a series of 12 dynamic cerebral FDG PET studies in normal subjects are used to evaluate the performance of the penalty-based AIF estimation technique. The focus of evaluations is on quantitation of FDG kinetics over a set of 10 regional brain structures. As well as the new method, a fixed population template AIF and a direct AIF estimate based on segmentation are also considered. Kinetics analyses resulting from these three AIFs are compared with those resulting from radially sampled AIFs. The proposed penalty-based AIF extraction method is found to achieve significant improvements over the fixed template and the segmentation methods. As well as achieving acceptable kinetic parameter accuracy, the quality of fit of the region of interest (ROI) time-course data based on the extracted AIF, matches results based on arterially sampled AIFs. In comparison, significant deviation in the estimation of FDG flux and degradation in ROI data fit are found with the template and segmentation methods. The proposed AIF extraction method is recommended for practical use.

Positron emission tomography imaging of tissue P-glycoprotein activity during pregnancy in the non-human primate.

BACKGROUND AND PURPOSE: Changes in tissue P-glycoprotein (P-gp) activity during pregnancy could affect the pharmacokinetics and thus the efficacy and toxicity of many drugs. Therefore, using positron emission tomography (PET) imaging, we tested whether gestational age affects tissue P-gp activity in the pregnant non-human primate, Macaca nemestrina. EXPERIMENTAL APPROACH: Mid-gestational (day 75 +/- 13, n= 7) and late-gestational (day 150 +/- 10, n= 5) age macaques were imaged after administration of a prototypic P-gp substrate, (11)C-verapamil (13.7-75.4 MBq.kg(-1)), before and during intravenous infusion of a P-gp inhibitor, cyclosporin A (CsA) (12 or 24 mg.kg(-1).h(-1)). Accumulation of radioactivity in the fetal liver served as a reporter of placental P-gp activity. P-gp activity was expressed as CsA-induced percent change in the ratio of the area (0-9 min) under the (11)C-radioactivity concentration-time curve in the tissue (AUC(tissue)) to that in the maternal plasma (AUC(plasma)). KEY RESULTS: The CsA-induced change in AUC(fetal liver)/AUC(maternal)(plasma) of (11)C-radioactivity significantly increased from mid- (35 +/- 25%) to late gestation (125 +/- 66%). Likewise, the CsA-induced change in AUC(maternal brain)/AUC(plasma) increased from mid- (172 +/- 80%) to late gestation (337 +/- 148%). The AUC ratio for the other maternal tissues was not significantly affected. Neither the CsA blood concentrations nor the level of circulating (11)C-verapamil metabolites were significantly affected by gestational age. CONCLUSIONS AND IMPLICATIONS: P-gp activity at the blood-brain barrier and the placental barrier in the macaque increased with gestational age. If replicated in humans, the exposure of the fetus and maternal brain to P-gp substrate drugs, and therefore their efficacy and toxicity, will change during pregnancy.

Haemorrhoidectomy with Ligasure vs conventional excisional techniques: meta-analysis of randomized controlled trials.

OBJECTIVE: To compare the use of LigaSure devices with conventional excisional techniques, circular stapling and use of Harmonic Scalpel in patients with symptomatic haemorrhoids and to review literature on LigaSure technology (Valleylab Inc. USA). METHOD: A literature review was performed using the National Library of Medicine's Pubmed Database using the keywords Ligasure, haemorrhoidectomy, vessel sealing technology. Randomized trials comparing LigaSure with other techniques of excisional haemorrhoidectomy with valid end points were reviewed in the present article and included in a quantitative meta-analysis. RESULTS: There was no significant difference in the proportion of patients cured after Ligasure haemorrhoidectomy or other excisional techniques (P > 0.05). Patients treated with LigaSure had a significantly shorter operative time (P < 0.001), postoperative pain VAS Score (P < 0.001), wound healing time and time-off from work (P < 0.001), than the patients submitted to excisional techniques. Postoperative bleeding did not significantly differ between the two groups (P = 0.056); however, the surgeons observed a reduction of intra- and postoperative bleeding using LigaSure. In comparison to the circular stapler and Harmonic Scalpel the authors found similar postoperative outcomes and a slightly favourable trend for LigaSure regarding postoperative complications, ease of handling and length of the procedure. CONCLUSION: Our meta-analysis shows that Ligasure haemorrhoidectomy is a fast procedure characterized by limited postoperative pain, short hospitalization, fast wound healing and convalescence.

A modification of primary closure for the treatment of pilonidal disease in day-care setting.

AIM: The best surgical technique for treating sacrococcygeal pilonidal disease (PD) is still controversial. We evaluated the outcome of a modified primary closure for the treatment of pilonidal sinus. METHOD: One hundred and fifty-two consecutive patients with PD, who underwent excision and primary closure under local anaesthesia according to our method, participated in this prospective study. The duration of operation and of hospitalization, postoperative pain, time to first mobilization, postoperative complications, time to resumption of work were assessed. RESULTS: The median operative time was 30 min (range: 15-40); the median postoperative pain visual analogue scale score was 1 (range 0-3). All patients were mobilized between 2 and 4 h after surgery and discharged within 10 h. Postoperative complications included eight small debridements of an infected wound (5.3%) and one case of wound dehiscence (0.6%). No recurrence was detected during a median follow-up of 22 months (range: 10-34 months). CONCLUSION: The low complication rate, near total absence of wound dehiscence, the compliance of the patients, the type of anaesthesia and the patient satisfaction makes this method effective. A randomized trial with long-term follow-up is warranted.

Randomized clinical trial of LigaSure and conventional diathermy haemorrhoidectomy.

BACKGROUND: The aim of this randomized prospective trial was to compare LigaSure and conventional diathermy haemorrhoidectomy. METHODS: Two hundred and eighty-four patients with grade III or IV haemorrhoids were randomized to LigaSure or diathermy (Milligan-Morgan) haemorrhoidectomy as a day-case procedure. Operating time, postoperative pain score, hospital stay, postoperative complications, wound healing time and time to return to normal activities were assessed. Thirty-four patients were lost to follow-up. RESULTS: The mean operating time for LigaSure haemorrhoidectomy was significantly shorter than that for diathermy (P = 0.011). Patients treated with LigaSure had significantly less postoperative pain (measured on a visual analogue scale; P = 0.010), a shorter wound healing time (defined as time to absence of swelling; P = 0.012) and less time off work (P = 0.010) than patients who had diathermy. Neither postoperative complications nor mean hospital stay (day-case surgery) were significantly different. CONCLUSION: LigaSure haemorrhoidectomy demonstrates simplicity, reproducibility, a low complication rate, fast wound healing, a quick return to work and reduced postoperative pain.

Hypoxia imaging-directed radiation treatment planning.

Increasing evidence supports the role of the tumor microenvironment in modulating cancer behavior. Tissue hypoxia, an important and common condition affecting the tumor microenvironment, is well established as a resistance factor in radiotherapy. Increasing evidence points to the ability of hypoxia to induce the expression of gene products, which confer aggressive tumor behavior and promote broad resistance to therapy. These factors suggest that determining the presence or absence of tumor hypoxia is important in planning cancer therapy. Recent advances in PET hypoxia imaging, conformal radiotherapy, and imaging-directed radiotherapy treatment planning now make it possible to perform hypoxia-directed radiotherapy. We review the biological aspects of tumor hypoxia and PET imaging approaches for measuring tumor hypoxia, along with methods for conformal radiotherapy and image-guided treatment, all of which provide the underpinnings for hypoxia-directed therapy. As a case example, we review emerging data on PET imaging of hypoxia to direct radiotherapy.

Molecular imaging of regional brain tumor biology.

Energy metabolism measurements in gliomas in vivo are now performed widely with positron emission tomography (PET). This capability has developed from a large number of basic and clinical science investigations that have cross fertilized one another. This article presents several areas that exemplify questions that have been explored over the last two decades. While the application of PET with [(18)F]-2-fluoro-2-deoxyglucose (FDG-PET) has proven useful for grading and prognosis assessments, this approach is less clinically suitable for assessing response to therapy, even though results to date raise very intriguing biological questions. Integration of metabolic imaging results into glioma therapy protocols is a recent and only preliminarily tapped method that may prove useful in additional trials that target DNA or membrane biosynthesis, or resistance mechanisms such as hypoxia. There are exciting future directions for molecular imaging that will undoubtedly be fruitful to explore, especially apoptosis, angiogenesis and expression of mutations of genes, e.g., epidermal growth factor receptor, that promote or suppress cellular malignant behavior.

Correlation of Tc-99m-red blood cell phleboscintigraphy with clinical severity of chronic venous disease.

Equilibrium red blood cell phleboscintigraphy of the lower limbs for the diagnostic management of chronic venous disease has been proposed. The aim of this study was to verify the correlation of the phleboscintigraphic assessment of chronic venous disease with the clinical grading of the severity of the disease, since other diagnostic modalities have been recently demonstrated a poor and only partial correlation. Equilibrium Tc-99m-red blood cell phleboscintigraphy was performed in 27 patients with chronic venous disease. Scintigraphic images of 52 limbs were classified according to a four-class qualitative grading of the severity of the venous disease, and a quantitative scintigraphic index (saphena /femoral ratio) was assigned to each limb. The scintigraphic qualitative grading showed a highly significant correlation with the clinical grading (Rs=0.82, p<0.01), a good interobserver and intraobserver agreement (86.5% and 92.3%, respectively) and more than 90% sensitivity and specificity to identify the categories "minimal or no chronic venous disease" or "more significant disease" (assessed according to the Bayes theorem). Sensitivity and specificity results for the quantitative assessment were not as good. Phleboscintigraphy correlates well with the clinical grading of the severity of chronic venous disease of the lower limbs and may have potential as a valuable diagnostic tool for the noninvasive assessment of chronic venous disease.

Kinetic characterization of hexokinase isoenzymes from glioma cells: implications for FDG imaging of human brain tumors.

Quantitative imaging of glucose metabolism of human brain tumors with PET utilizes 2-[(18)F]-fluorodeoxy-D-glucose (FDG) and a conversion factor called the lumped constant (LC), which relates the metabolic rate of FDG to glucose. Since tumors have greater uptake of FDG than would be predicted by the metabolism of native glucose, the characteristic of tumors that governs the uptake of FDG must be part of the LC. The LC is chiefly determined by the phosphorylation ratio (PR), which is comprised of the kinetic parameters (Km and Vmax) of hexokinase (HK) for glucose as well as for FDG (LC proportional to (Km(glc) x Vmax(FDG))/(Km(FDG) x Vmax(glc)). The value of the LC has been estimated from imaging studies, but not validated in vitro from HK kinetic parameters. In this study we measured the kinetic constants of bovine and 36B-10 rat glioma HK I (predominant in normal brain) and 36B-10 glioma HK II (increased in brain tumors) for the hexose substrates glucose, 2-deoxy-D-glucose (2DG) and FDG. Our principal results show that the KmGlc < KmFDG << Km2DG and that PR2DG < PRFDG. The FDG LC calculated from our kinetic parameters for normal brain, possessing predominantly HK I, would be higher than the normal brain LC predicted from animal studies using 2DG or human PET studies using FDG or 2DG. These results also suggest that a shift from HK I to HK II, which has been observed to increase in brain tumors, would have little effect on the value of the tumor LC.

Determining hypoxic fraction in a rat glioma by uptake of radiolabeled fluoromisonidazole.

The usefulness of radiolabeled nitroimidazoles for measuring hypoxia will be clarified by defining the relationship between tracer uptake and radiobiologically hypoxic fraction. We determined the radiobiologically hypoxic fraction from radiation response data in 36B10 rat gliomas using the paired cell survival curve technique and compared the values to the radiobiologically hypoxic fraction inferred from mathematical modeling of time-activity data acquired by PET imaging of [(18)F]FMISO uptake. Rats breathed either air or 10% oxygen during imaging, and timed blood samples were taken. The uptake of [(3)H]FMISO by 36B10 cells in vitro provided cellular binding characteristics of this radiopharmaceutical as a function of oxygen concentration. The radiobiologically hypoxic fraction determined for tumors in air-breathing rats using the paired survival curve technique was 6.1% (95% CL = 4.3- 8.6%), which agreed well with that determined by modeling FMISO time-activity data (7. 4%; 95% CL = 2.5-17.3%). These results are consistent with the agreement between the two techniques for measuring radiobiologically hypoxic fraction in Chinese hamster V79 cell spheroids. In contrast, the FMISO-derived radiobiologically hypoxic fraction in rats breathing 10% oxygen was 13.1% (95% CL 7.9-8.3%), much lower than the radiobiologically hypoxic fraction of 43% determined from the radiation response data. This discrepancy may be due to the failure of FMISO to identify hypoxic cells residing at or above an oxygen level of 2-3 mmHg that will still confer substantial protection against radiation. The presence of transiently hypoxic cells in rats breathing reduced oxygen may also be under-reported by nitroimidazole binding, which is strongly dependent on time and concentration.

Angiosarcoma of the spleen mimicking rupture. Case report and literature review.

Primary angiosarcoma of the spleen is very rare and only 143 cases have previously been reported. The pathogenesis is unknown. The clinical aspects are variable, but loss of weight, anaemia, splenomegaly and liver metastases are frequently present. The age range is generally 18 to 93 years; only four of the reported patients were under 20 (Chen KTK). The prognosis is very poor in any case and survival isn't more than two years: wherever the spleen undergoes spontaneous rupture the survival should be less than six months. Patients with or without metastatic disease may be treated by chemotherapy but with poor results. Radiotherapy is used for the pain from bone metastasis. We report the clinical case concerning a 79-years-old man with liver metastases and a 5-cm lesion in the spleen, where a subcapsular rupture was suspected.

Propofol, but not etomidate, reduces desflurane-mediated sympathetic activation in humans.

PURPOSE: The administration of desflurane to humans can lead to substantial activation of the neurohumoral axis. Propofol can inhibit the sympathetic response to stress. This study compared the neurocirculatory effects of induction of anesthesia with propofol with those of etomidate on desflurane-mediated sympathetic activation. METHODS: After informed consent, awake baseline recordings of heart rate (HR), mean arterial blood pressure (MAP), and efferent sympathetic nerve activity (SNA, peroneal nerve) were obtained from healthy volunteers randomly assigned to receive either 2.5 mg x kg(-1) propofol (n=8) or 0.3 mg x kg(-1) etomidate (n=7). Two minutes after i.v. induction, desflurane 3.6% was added to the inspired gas, and increased in consecutive minutes to 7% and 10.9%. Ventilation via mask was continued for an additional seven minutes. Normocarbia was maintained while neurocirculatory parameters were continuously recorded. RESULTS: There were no differences between groups at baseline. The administration of desflurane via mask after etomidate led to increases in HR, MAP and SNA. Propofol significantly reduced the MAP response and delayed and attenuated the sympatho-excitation. CONCLUSION: Propofol induction reduced the sympathetic activation and hypertension associated with desflurane.