Diffusion MRI for rectal cancer staging: ADC measurements before and after ultrasonographic gel lumen distension.

OBJECTIVES: To compare Apparent Diffusion Coefficient (ADC) measurements in rectal neoplastic lesions before and after lumen distension obtained with sonography transmission gel. METHODS: From January 2014 to July 2016, 25 patients (average age 63.7, range 41-85, 18 males) were studied for pre-treatment rectal cancer staging using a 1.5T MRI. Diffusion MRI was obtained using echo-planar imaging with b=800 value; all patients were studied acquiring diffusion sequences with and without rectal lumen distension obtained using sonography transmission gel. In both diffusion sequences, two blinded readers calculated border ADC values and small ADC values, drawing regions of interest respectively along tumour borders and far from tumour borders. Mean ADC values among readers - for each type of ADC measurement - were compared using Wilcoxon matched pairs signed rank test. Correlation was assessed using Pearson analysis. RESULTS: Border ADC mean value for diffusion MR sequences without endorectal contrast was 1.122mm2/sec, with 95% Confidence Interval (CI)=1.02-1.22; using gel lumen distension, higher border ADC mean value of 1.269mm2/s (95% CI=1.16-1.38) was obtained. Wilcoxon matched pairs signed rank test revealed statistical difference (p<0.01); a strong Pearson correlation was reported, with r value of 0.69. Small-ADC mean value was 1.038mm2/s (95% CI=0.91-1.16) for diffusion sequences acquired without endorectal distension and 1.127mm2/s (95% CI=0.98-1.27) for diffusion sequences obtained after endorectal gel lumen distension. Wilcoxon analysis did not show statistical difference (p=0.13). A very strong positive correlation was observed, with r value of 0.81. CONCLUSIONS: ADC measurements are slightly higher using endorectal sonographic transmission gel; ROI should be traced far from tumour borders, to minimize gel filled-pixel along the interface between lumen and lesion. Further studies are needed to investigate better reliability of ADC in rectal cancer MRI using sonographic gel intraluminal distension.

Cystic pancreatic neoplasms: diagnosis and management emphasizing their imaging features.

The incidence of cystic pancreatic neoplasms increased in the past decade, due to the recent advances in multidetector computed tomography and magnetic resonance imaging; several pancreatic cysts are incidentally encountered during diagnostic exams performed for non-pancreatic diseases. Indeed, cystic pancreatic tumors are currently considered relatively rare, accounting for approximately 10% of all pancreatic neoplasms. Serous cystadenoma, mucinous cystadenoma, intraductal papillary mucinous neoplasms and solid-pseudopapillary tumor represent about 90% of all pancreatic primary cystic tumours. The non-optimal diagnostic preoperative accuracy in distinguishing benign from malignant cystic lesions ensures that up till now there are no well-defined guidelines regarding the management of cystic pancreatic neoplasms. Imaging findings often do not allow the diagnosis, because there is a considerable overlap among the cystic lesions; the best pre-operative characterization is obtained by the association of all diagnostic procedures available. For their different histology and behavior, cystic pancreatic neoplasms need to be managed according to various factors. In this review, the main elements necessary for their management are assessed--radiological features, tumour dimensions, patients' characteristics, the mode of clinical presentation and the associated oncologic markers. A multidisciplinary approach--including gastroenterologists, radiologists and surgeons--should be adopted in order to perform a differential diagnosis and a correct management.

[Risk factors of serious bleeding among ambulatory patients taking antivitamin K aged 75 and over]. / Les déterminants d'hémorragies graves des sujets ambulatoires âgés de 75ans et plus sous antivitamine K.

The benefits of anti-vitamin K (AVK) drugs have been acknowledged in several indications. Such indications increasing with increasing age, AVK prescriptions also increases with age. At the same time, conditions involving significant bleeding are common in this elderly population. It is thus essential to recognize the determining factors. This study included all patients taking AVK drugs aged 75 years and older who sought emergency care at the Cochin Hospital from January to December 2011 for significant bleeding. These patients were compared with a cohort of patients aged 75 years or older who were taking AVK drugs and who were admitted to the same unit during the same time period for other reasons. The case-control comparison included demographic data, comorbidity factors, multiple medications, emergency measured INR, and CHA2DS2VASC level. The hemorrhagic risk was evaluated by HEMORR2HAGES and HAS-BLED. A total of 34 patients were studied and compared with 70 case-controls. The Charlson comorbidity index was higher in patients than case-controls (P<0.05), with a much higher hemorrhagic risk for scores ≥ 9 (OR=2.5; P<0.05). Multiple medication was also more predominant in patients (P<0.05). The risk of serious hemorrhage was also higher when the hemorrhagic scores were high, especially for HEMORR2HAGES (P<0.0001) and HAS-BLED (P<0.001). The risk of serious hemorrhage in elderly outpatients taking AVK drugs is related to their higher comorbidity and hemorrhagic levels which need to be evaluated before starting or stopping AVK treatment.

Multidetector CT Dentascan evaluation of bone regeneration obtained with deproteinised bovine graft in residual cavity after mandibular cyst enucleation.

PURPOSE: This study compared spontaneous bone healing and regeneration obtained with deproteinised bovine graft in residual cavities after mandibular cyst enucleation using computed tomography (CT) Dentascan. MATERIALS AND METHODS: Eighty patients with a radiological diagnosis of mandibular cyst underwent surgical enucleation. Patients were divided into a control group (spontaneous healing, 40 patients) and a test group (deproteinised bovine graft, 40 patients). All patients underwent follow-up CT Dentascan 12 months after the procedure. For each residual cavity, apical-coronal and mesial-distal distance, average pixel intensity and volume were calculated and results compared between two groups using the t test. RESULTS: The control group showed mean volume, apical-coronal and mesial-distal distance of 703.2 ± 185.3 mm(3), 28.6 ± 9.4 mm and 25 ± 2.84 mm, respectively. In the test group, values were 738.2 ± 189.2 mm(3), 27.5 ± 3.6 mm and 25.3 ± 2.97 mm, respectively. There was no statistically significant difference between groups. Average pixel intensity was 1,102.8 ± 124.3 in the test group and 624.9 ± 133.3 in the control group, with a significant difference between groups (p<0.0001). CONCLUSIONS: The significantly higher average pixel intensity observed in the test group demonstrates the cavalue of treatment with biomaterials to obtain earlier bone regeneration.

Endometrial carcinoma: MR staging and causes of error.

PURPOSE: This study was undertaken to prospectively determine the diagnostic capabilities of magnetic resonance (MR) imaging in detecting myometrial and cervical invasion and lymph node involvement in endometrial carcinoma and to identify the causes of errors in staging endometrial carcinoma. MATERIALS AND METHODS: Twenty consecutive patients with a histological diagnosis of endometrial carcinoma underwent preoperative MR imaging. MR findings were compared with surgical staging, considered as the standard of reference. RESULTS: In assessing myometrial invasion, MR imaging showed 70% accuracy, 80% sensitivity, 40% specificity, 80% positive predictive value (PPV), and 40% negative predictive value (NPV). In detecting cervical invasion, MR imaging had 95% accuracy, 100% sensitivity, 94.4% specificity, 66.7% PPV, and 100% NPV. In evaluating lymph node involvement, MR imaging showed 100% accuracy, sensitivity, specificity, PPV and NPV. Errors in evaluating myometrial invasion were caused by polypoid tumour, adenomyosis and leiomyomas, whereas those in evaluating cervical invasion were caused by dilatation and curettage. CONCLUSIONS: MR imaging is a reliable technique for preoperative evaluation of endometrial carcinoma. Its main limitation is differentiating between stage IA and IB carcinomas, which is not highly important for surgical planning. Cooperation between the gynaecologist and radiologist is mandatory to avoid staging errors.

Pelvic floor imaging: comparison between magnetic resonance imaging and conventional defecography in studying outlet obstruction syndrome.

PURPOSE: This study prospectively compared the diagnostic capabilities of magnetic resonance (MR) imaging with conventional defecography (CD) in outlet obstruction syndrome. MATERIALS AND METHODS: Nineteen consecutive patients with clinical symptoms of outlet obstruction underwent pelvic MR examination. The MR imaging protocol included static T2-weighted fast spin-echo (FSE) images in the sagittal, axial and coronal planes; dynamic midsagittal T2-weighted single-shot (SS)-FSE and fast imaging employing steady-state acquisition (FIESTA) cine images during contraction, rest, straining and defecation. MR images (including and then excluding the evacuation phase) were compared with CD, which is considered the reference standard. RESULTS: Comparison between CD and MR with evacuation phase (MRWEP) showed no significant differences in sphincter hypotonia, dyssynergia, rectocele or rectal prolapse and significant differences in descending perineum. Comparison between CD and MR without evacuation phase (MRWOEP) showed no significant differences in sphincter hypotonia, dyssynergia or enterocele but significant differences in rectocele, rectal prolapse and descending perineum. Comparison between MRWEP and MRWOEP showed no significant differences in sphincter hypotonia, dyssynergia, enterocele or descending perineum but significant differences in rectocele, rectal prolapse, peritoneocele, cervical cystoptosis and hysteroptosis. CONCLUSIONS: MR imaging provides morphological and functional study of pelvic floor structures and may offer an imaging tool complementary to CD in multicompartment evaluation of the pelvis. An evacuation phase is mandatory.

Evaluation of the biliary and pancreatic system with 2D SSFSE, breathhold 3D FRFSE and respiratory-triggered 3D FRFSE sequences.

PURPOSE: The authors compared biliary and pancreatic imaging obtained through 2D single-shot fast spin-echo (SSFSE), breath-hold 3D fast recovery fast spin-echo (FRFSE) and respiratory-triggered 3D FRFSE sequences. MATERIALS AND METHODS: A total of 106 magnetic resonance cholangiopancreatography (MRCP) examinations performed between December 2007 and September 2008 were evaluated with a comparison of 2D SSFSE (thin section and thick slab), breath-hold 3D FRFSE and respiratory-triggered 3D FRFSE sequences. The biliary tract was divided into seven segments: right hepatic duct, left hepatic duct, common hepatic duct, cystic duct, common bile duct, cystic duct junction and biliary-pancreatic confluence. The main pancreatic duct was divided into three segments (head, body and tail). Visualisation of biliary variants was also compared. Two blinded radiologists evaluated segment visibility using a quantitative scale. The Student's t test for paired samples was used for statistical analysis. RESULTS: Compared with 2D SSFSE, respiratory-triggered 3D FRFSE sequences showed better visibility of the right hepatic duct (p=0.0277), the cystic duct (p=0.0081), the cystic duct junction (p=0.0010), the biliary-pancreatic confluence (p=0.0334) and biliary variants (p=0.0198). In the comparison between breath-hold 3D FRFSE and 2D SSFSE, a significant statistical difference was found in visualisation of the cystic duct (p=0.027), the cystic duct junction (p=0.020), the biliary-pancreatic confluence (p=0.0338) and biliary variants (p=0.0311). CONCLUSIONS: Three-dimensional FRFSE offers a significant benefit over conventional 2D imaging.

Power Doppler ultrasonography with time-signal intensity curves in monitoring hepatocellular carcinoma and liver metastases after intralesional therapy.

PURPOSE: Analysis of time-intensity curves allows evaluation of the patterns of lesion enhancement before and after treatment. The aim of this study was to evaluate the diagnostic accuracy of time-intensity curves in monitoring intralesional therapy of focal hepatic lesions. MATERIALS AND METHODS: Twenty patients underwent intralesional therapy with either radiofrequency thermal ablation or percutaneous ethanol injection. Contrast-enhanced power Doppler ultrasound with analysis of time-intensity curves was performed one day before and one day after treatment. Targeted biopsy was then obtained to confirm the imaging findings. RESULTS: Before treatment, all lesions showed time-intensity curves characterised by high peaks of signal intensity and plateaus. Complete tumour necrosis, confirmed by targeted biopsy, was observed in patients showing no intralesional flow signals and time-intensity curves with low peak of signal intensity and absence of plateau after treatment. Biopsy confirmed the presence of residual neoplastic tissue in one patient exhibiting perilesional vascularity, absence of intralesional flow signals, and a time-intensity curve with high peak of signal intensity and plateau. CONCLUSIONS: According to our findings, time-intensity curves characterised by high peak of signal intensity and plateau might reflect the presence of perilesional or intralesional neoplastic tissue and provide important information on the effectiveness of the treatment.

Comparison between daidzein and genistein antioxidant activity in primary and cancer lymphocytes.

The main objective of this study was to compare the protective effect of daidzein and genistein against induced oxidative damage in Jurkat T-cell line and in peripheral blood lymphocytes of healthy subjects. After supplementation of cells with isoflavones (from 2.5 to 20micromol/L in Jurkat T-cell and from 0.01 to 2.5micromol/L in primary lymphocytes, 24h), we determined DNA damage induced by hydrogen peroxide using the comet assay and lipid peroxidation evaluating malondialdehyde (MDA) production after ferrous ion treatment. Supplementation of Jurkat cells and primary lymphocytes with both isoflavones significantly increased DNA protection from oxidative damage at concentrations between 0.1 and 5micromol/L (P<0.05), and with just daidzein, at concentrations higher than 2.5micromol/L, there was a decrease in the production of MDA (P<0.05). Our results seem to support that daidzein is just as effective as genistein in protecting cells against oxidative damage especially with respect to DNA. Moreover, since the protective effect was found at concentrations reachable in plasma after soy consumption (less than 2micromol/L), it can be assumed that the antioxidant activity of isoflavones could really contribute to the healthy properties of soy.

Black tea extract supplementation decreases oxidative damage in Jurkat T cells.

The purpose of this study was to investigate the protective effect of black tea (BT) extract against induced oxidative damage in Jurkat T-cell line. Cells supplemented with 10 or 25 mg/L BT were subjected to oxidation with ferrous ions. Malondialdehyde (MDA) production as marker of lipid peroxidation, DNA single strand breaks as marker of DNA damage, and modification of the antioxidant enzyme activity, glutathione peroxidase (GPX) were measured. Results show the efficacy of BT polyphenols to decrease DNA oxidative damage and to affect GPX activity (P<0.05), while no effect was shown on MDA production. The succeeding investigation of the activity of caffeine and epigallocatechin gallate demonstrated their antioxidant potential with respect to the cellular markers evaluated. In conclusion, this study supports the protective effect of BT against ferrous ions induced oxidative damage to DNA and the ability of BT to affect the enzyme antioxidant system of Jurkat cells.

Application of the CFU-GM assay to predict acute drug-induced neutropenia: an international blind trial to validate a prediction model for the maximum tolerated dose (MTD) of myelosuppressive xenobiotics.

In a previous study of prevalidation, a standard operating procedure (SOP) for two independent in vitro tests (human and mouse) had been developed, to evaluate the potential hematotoxicity of xenobiotics from their direct and the adverse effects on granulocyte-macrophages (CFU-GM). A predictive model to calculate the human maximum tolerated dose (MTD) was set up, by adjusting a mouse-derived MTD for the differential interspecies sensitivity. In this paper, we describe an international blind trial designed to apply this model to the clinical neutropenia, by testing 20 drugs, including 14 antineoplastics (Cytosar-U, 5-Fluorouracil, Myleran, Thioguanine, Fludarabine, Bleomycin, Methotrexate, Gemcitabine, Carmustine, Etoposide, Teniposide, Cytoxan, Taxol, Adriamycin); two antivirals (Retrovir, Zovirax,); three drugs for other therapeutic indications (Cyclosporin, Thorazine, Indocin); and one pesticide (Lindane). The results confirmed that the SOP developed generates reproducible IC90 values with both human and murine GM-CFU. For 10 drugs (Adriamycin, Bleomycin, Etoposide, Fludarabine, 5-Fluorouracil, Myleran, Taxol, Teniposide, Thioguanine, and Thorazine), IC90 values were found within the range of the actual drug doses tested (defined as the actual IC90). For the other 10 drugs (Carmustine, Cyclosporin, Cytosar-U, Cytoxan, Gemcitabine, Indocin, Lindane, Methotrexate, Retrovir, and Zovirax) extrapolation on the regression curve out of the range of the actual doses tested was required to derive IC90 values (extrapolated IC90). The model correctly predicted the human MTD for 10 drugs out of 10 that had "actual IC90 values" and 7 drugs out of 10 for those having only an extrapolated IC90. Two of the incorrect predictions (Gemcitabine and Zovirax) were within 6-fold of the correct MTD, instead of the 4-fold range required by the model, whereas the prediction with Cytosar-U was approximately 10-fold in error. A possible explanation for the failure in the prediction of these three drugs, which are pyrimidine analogs, is discussed. We concluded that our model correctly predicted the human MTD for 20 drugs out of 23, since the other three drugs (Topotecan, PZA, and Flavopiridol) were tested in the prevalidation study. The high percentage of predicitivity (87%), as well as the reproducibility of the SOP testing, confirm that the model can be considered scientifically validated in this study, suggesting promising applications to other areas of research in developing validated hematotoxicological in vitro methods.

Prevalidation of a model for predicting acute neutropenia by colony forming unit granulocyte/macrophage (CFU-GM) assay.

This report describes an international prevalidation study conducted to optimise the Standard Operating Procedure (SOP) for detecting myelosuppressive agents by CFU-GM assay and to study a model for predicting (by means of this in vitro hematopoietic assay) the acute xenobiotic exposure levels that cause maximum tolerated decreases in absolute neutrophil counts (ANC). In the first phase of the study (Protocol Refinement), two SOPs were assessed, by using two cell culture media (Test A, containing GM-CSF; and Test B, containing G-CSF, GM-CSF, IL-3, IL-6 and SCF), and the two tests were applied to cells from both human (bone marrow and umbilical cord blood) and mouse (bone marrow) CFU-GM. In the second phase (Protocol Transfer), the SOPs were transferred to four laboratories to verify the linearity of the assay response and its interlaboratory reproducibility. After a further phase (Protocol Performance), dedicated to a training set of six anticancer drugs (adriamycin, flavopindol, morpholino-doxorubicin, pyrazoloacridine, taxol and topotecan), a model for predicting neutropenia was verified. Results showed that the assay is linear under SOP conditions, and that the in vitro endpoints used by the clinical prediction model of neutropenia are highly reproducible within and between laboratories. Valid tests represented 95% of all tests attempted. The 90% inhibitory concentration values (IC(90)) from Test A and Test B accurately predicted the human maximum tolerated dose (MTD) for five of six and for four of six myelosuppressive anticancer drugs, respectively, that were selected as prototype xenobiotics. As expected, both tests failed to accurately predict the human MTD of a drug that is a likely protoxicant. It is concluded that Test A offers significant cost advantages compared to Test B, without any loss of performance or predictive accuracy. On the basis of these results, we proposed a formal Phase II validation study using the Test A SOP for 16-18 additional xenobiotics that represent the spectrum of haematotoxic potential.

High sensitivity of human epidermal keratinocytes (HaCaT) to topoisomerase inhibitors.

In the panorama of the numerous established cell lines, the human keratinocyte line HaCaT has a very interesting feature, having a close similarity in functional competence to normal keratinocytes. This cell line has been used in many studies as a paradigm for epidermal cells and therefore we selected HaCaT as a cell model for investigating the activity of three antitopoisomerase drugs (Camptothecin, Doxorubicin, Ciprofloxacin) on in vitro cell growth. The effect was evaluated both by a 24-h cytotoxicity test and by a 7-day antiproliferation assay, in which the cell viability was assessed by an MTT (3-(4,5-dimethyl-2-thiazolyl) 2,5-diphenil-2-H-tetrazolium bromide) test. DNA topoisomerase I was also partially purified from a nuclear extract of HaCaT cells, the level of topo I catalytic activity was measured by a pBR322 DNA relaxation assay and then the in vitro effect of antitopoisomerase drugs on the target enzyme was also assessed. The results indicated that the in vitro sensitivity of human epidermal HaCaT cells to antitopoisomerase drugs is comparable to that of many human tumour cell lines. HaCaT cells express a high level of topoisomerase I activity that is significantly inhibited by both Camptothecin and Doxorubicin and to a minor degree by Ciprofloxacin. A high correlation between the cell sensitivity to the antitopoisomerase I drug measured by the MTT test and the in vitro direct inhibition of HaCaT topoisomerase I was observed, suggesting that HaCaT cells can represent a very interesting model both for studying cellular pharmacokinetics of antineoplastic drugs on keratinocytes and for predicting possible secondary effects, exerted by these drugs on cutaneous cells, during treatment with chemotherapy.

Altered DNA-cleavage activity of topoisomerase II from WEHI-3B leukemia cells with specific resistance to ciprofloxacin.

In order to investigate the mechanisms of drug resistance arising in tumor cells, we investigated the capacity of fluoroquinolones to inhibit the in vitro growth of WEHI-3B monomyelocytic leukemia cells and then we established a variant of this line (currently maintained in the absence of drug). The line, named WEHI-3B/CPX, expresses a specific resistance to ciprofloxacin (CPX; resistance index=17.3+/-2.2), and does not show cross-resistance with other fluoroquinolones, camptothecin and topoisomerase II inhibitors such as doxorubicin, etoposide and teniposide. Although a little decrease in intracellular accumulation of CPX is observed in WEHI-3B/CPX cells, these cells do not express MDR or LRP markers, and the resistance is not circumvented by verapamil. Purified nuclear extracts from WEHI-3B and WEHI-3B/CPX cells were tested for topoisomerase I catalytic activity and checking in vitro topoisomerase I sensitivity to CPX and camptothecin inhibition, but no difference was observed. As the treatment with CPX showed that the resistant cell line suffers a significantly lower number of breaks in the DNA molecule we also addressed our investigations to the topoisomerase II-dependent DNA cleavage that, in the resistant clone, was found dramatically less susceptible to be enhanced by CPX both in pre-strand and post-strand DNA passage conditions. WEHI-3B/CPX cells do not express any character of multidrug resistance and represent a rare case of specific drug resistance to CPX. The specific resistance to CPX observed in these cells is related to a functional decrease of topoisomerase II cleavage activity. It could be consequent to a decreased binding affinity of CPX for the topoisomerase II--DNA complex or to a decreased affinity or specificity of topoisomerase II for its DNA cleavage sites.

Diffuse pulmonary tumor microemboli from adenocarcinoma of the colon.

We have presented a rare case of pulmonary tumor microemboli from adenocarcinoma of the colon. The majority of primary tumors are adenocarcinomas, with gastric, breast, and liver carcinomas most frequently identified. Dyspnea and respiratory distress without an obvious cause is common. The history, physical examination, chest roentgenogram, ventilation-perfusion lung scan, and pulmonary angiogram are often not helpful in establishing the diagnosis. Pulmonary hypertension, present in our patient, and cor pulmonale are well described in association with diffuse pulmonary tumor microemboli. The pathologic findings are limited to the intravascular compartment exclusively, frequently in association with thrombus. The true incidence of pulmonary tumor microemboli is not known and may be underestimated. Appropriate management requires a high index of suspicion to establish the diagnosis.

Does the respiratory distress syndrome in twins and singletons run different risks of persistent ductus arteriosus?

The incidence and evolution of patent ductus arteriosus (PDA) was evaluated in twins and preterm singletons with birth weight less than or equal to 1750 g admitted to our Department in 1987 for respiratory distress syndrome (RDS). Screening by echocardiography and Doppler-flow studies (AT MK 600) was performed on the third day of life. Out of 91 neonates who needed intubation and ventilation during this 12-month period (23.8% of admissions), 40 weighed less than 1750 g and of these 40, 14 were twins (35%). Hemodynamically significant PDA was documented in 13 patients; of these, only 5 were preterm singletons and 8 were twins. Two twins weighing less than 1000 g received no therapy for ductus closure; one ductus closed spontaneously, the other had an early demise. Three twins and 2 preterm singletons received indomethacin; one of the twins needed a second cycle for definitive ductus closure. Three twins and three preterm singletons underwent surgery, while one twin died on the 10th postoperative day. Screening and early therapy of PDA during RDS could be of great clinical importance. Twinning seems to play a role in the incidence and evolution of PDA and this needs to be evaluated in further studies.

Primary malignant fibrous histiocytoma of the pleura. A case report.

A rare primary malignant fibrous histiocytoma of the pleura is described. The tumor was found in an elderly male and was followed for more than ten years without treatment. At the terminal stage, the patient developed a malignant pleural effusion, which contained mainly histiocytelike, rounded forms with many bizarre and multinucleated giant tumor cells. The main tumor mass was characterized by dual fibroblastlike and histiocytelike cellular components and a storiform growth pattern. In the solid areas, the tumor cells were mainly fibroblastlike spindle-shaped forms, which produced collagen. The tumor cells in the loose, vascular areas and in the effusion were predominantly histiocytelike, with some exhibiting phagocytic activity. We believe that this is the first reported case of a malignant fibrous histiocytoma of the pleura with a malignant effusion showing a preferential histiocytelike differentiation of tumor cells in the fluid environment.