Validation of a coupled electromagnetic and thermal model for estimating temperatures during magnetic nanoparticle hyperthermia.

PURPOSE: Alternating magnetic field (AMF) tissue interaction models are generally not validated. Our aim was to develop and validate a coupled electromagnetic and thermal model for estimating temperatures in large organs during magnetic nanoparticle hyperthermia (MNH). MATERIALS AND METHODS: Coupled finite element electromagnetic and thermal model validation was performed by comparing the results to experimental data obtained from temperatures measured in homogeneous agar gel phantoms exposed to an AMF at fixed frequency (155 ± 10 kHz). The validated model was applied to a three-dimensional (3D) rabbit liver built from computed tomography (CT) images to investigate the contribution of nanoparticle heating and nonspecific eddy current heating as a function of AMF amplitude. RESULTS: Computed temperatures from the model were in excellent agreement with temperatures calculated using the analytical method (error < 1%) and temperatures measured in phantoms (maximum absolute error <2% at each probe location). The 3D rabbit liver model for a fixed concentration of 5 mg Fe/cm3 of tumor revealed a maximum temperature ∼44 °C in tumor and ∼40 °C in liver at AMF amplitude of ∼12 kA/m (peak). CONCLUSION: A validated coupled electromagnetic and thermal model was developed to estimate temperatures due to eddy current heating in homogeneous tissue phantoms. The validated model was successfully used to analyze temperature distribution in complex rabbit liver tumor geometry during MNH. In future, model validation should be extended to heterogeneous tissue phantoms, and include heat sink effects from major blood vessels.

Evaluation of 70-150-µm doxorubicin-eluting beads for transcatheter arterial chemoembolization in the rabbit liver VX2 tumour model.

AIM: To evaluate the pharmacokinetic profile (PK) and embolization effect of 70-150-µm doxorubicin eluting beads (DEBs) following intra-arterial injection (i.a.) in the rabbit liver VX2 tumour model. MATERIALS AND METHODS: In this ACUC-approved study, 25 white New Zealand rabbits were randomly assigned into a small DEB group (SDB, n = 7, 70-150-µm DEBs), large DEB group (LDB, n = 7, 100-300-µm DEBs), untreated controls (n = 7), and doxorubicin controls (n = 4, without tumour, received i.a. 12.5 mg doxorubicin). Plasma PK was assessed up to 180 min post-injection. Drug tissue and liver enzyme levels, radiologic tumor response and histopathologic tumour necrosis were assessed at 7 days. RESULTS: Mean tumour doxorubicin concentrations were 922.83 nM (SD = 722.05) and 361.48 nM (SD = 473.23) for the SDB and LDB, respectively (p = 0.005). There was no statistically significant difference in tumour doxorubicinol, plasma doxorubicin and doxorubicinol PK values. More beads were observed in the SDB tumours (p = 0.01). Liver enzymes increased and gradually declined over the observation period, with significantly higher values in the SDB. CONCLUSION: In this preclinical study, plasma PK of i.a.-injected 70-150-µm DEBs was not different than that of 100-300-µm DEBs. More beads and higher tissue doxorubicin levels were observed in the SDB tumours. KEY POINTS: • Small and large doxorubicin-eluting beads show similar plasma pharmacokinetic profiles. • Higher tissue doxorubicin levels were observed in the small bead group. • Liver enzymes were overall significantly higher in the small bead group.

Image-guided thermal therapy with a dual-contrast magnetic nanoparticle formulation: A feasibility study.

PURPOSE/OBJECTIVE: The aim of this study was to develop and investigate the properties of a magnetic iron oxide nanoparticle-ethiodised oil formulation for image-guided thermal therapy of liver cancer. MATERIALS AND METHODS: The formulation comprises bionised nano-ferrite (BNF) nanoparticles suspended in ethiodised oil, emulsified with polysorbate 20 (BNF-lip). Nanoparticle size was measured via photon correlation spectroscopy and transmission electron microscopy. In vivo thermal therapy capability was tested in two groups of male Foxn1(nu) mice bearing subcutaneous HepG2 xenograft tumours. Group I (n = 12) was used to screen conditions for group II (n = 48). In group II, mice received one of BNF-lip (n = 18), BNF alone (n = 16), or PBS (n = 14), followed by alternating magnetic field (AMF) hyperthermia, with either varied duration (15 or 20 min) or amplitude (0, 16, 20, or 24 kA/m). Image-guided fluoroscopic intra-arterial injection of BNF-lip was tested in New Zealand white rabbits (n = 10), bearing liver VX2 tumours. The animals were subsequently imaged with CT and 3 T MRI, up to 7 days post-injection. The tumours were histopathologically evaluated for distribution of BNF-lip. RESULTS: The BNF showed larger aggregate diameters when suspended in BNF-lip, compared to clear solution. The BNF-lip formulation produced maximum tumour temperatures with AMF >20 kA/m and showed positive X-ray visibility and substantial shortening of T1 and T2 relaxation time, with sustained intratumoural retention up to 7 days post-injection. On pathology, intratumoural BNF-lip distribution correlated well with CT imaging of intratumoural BNF-lip distribution. CONCLUSION: The BNF-lip formulation has favourable thermal and dual imaging capabilities for image-guided thermal therapy of liver cancer, suggesting further exploration for clinical applications.

The role of PET/CT in the management of cervical cancer.

OBJECTIVE. Cervical cancer is the second most common malignancy in women worldwide and the third most common cause of cancer mortality in the United States. The aim of this article is to describe cervical cancer and outline the value of (18)F-FDG PET/CT in the management of cervical malignancy. CONCLUSION. The value of PET/CT has been found in staging and treatment strategy for cervical cancer. FDG PET/CT facilitates decision-making and radiation treatment planning and provides important information about treatment response, disease recurrence, and long-term survival.

Association between puberty and weight, height and body mass index in a developing community.

OBJECTIVE: To evaluate the epidemiology of pubertal development of girls in a developing community. METHODS: The cross-sectional study was undertaken in July 2005, on 788 healthy 7-16 years old girls in Gorgan, the most populous city of Golestan province in northern Iran. Physical examination, was performed and height, weight and body mass index were noted. Pubertal stages were assessed by clinical examination according to the methods of Marshall and Tanner, while the mean menarcheal age was calculated by using the status quo method. The data was treated with analysis of variance Pearson's linear regression and SPSS version 16.0. RESULTS: The mean age, weight, height and BMI +/- standard deviation of the studied girls were 10.32 +/- 2.48 years, 35.07 +/- 11.30 kg, 140.11 +/- 14.62 cm, and 17.34 +/- 3.55 kg/m2 respectively. Menarche had occurred with the mean menarcheal age being 12.15 +/- 1.11 years. The mean age at the onset of breast development was 10.55 +/- 1.57 years. There was no significant association between mean height, weight and BMI and the menarcheal age and pubertal stage. CONCLUSION: Based on the epidemiology of pubertal development of girls in the study, there seems to be a case for creating particular guidelines for pubertal development assessment for each type of society in addition to the standard international guidelines in this regard.

Imaging of Colorectal Liver Metastasis.

Colorectal cancer (CRC) is one of the most common cancers in the world. The most important determinant of survival and prognosis is the stage and presence of metastasis. The liver is the most common location for CRC metastasis. The only curative treatment for CRC liver metastasis (CRLM) is resection; however, many patients are ineligible for surgical resection of CRLM. Locoregional treatments such as ablation and intra-arterial therapy are also available for patients with CRLM. Assessment of response after chemotherapy is challenging due to anatomical and functional changes. Antiangiogenic agents such as bevacizumab that are used in the treatment of CRLM may show atypical patterns of response on imaging. It is vital to distinguish patterns of response in addition to toxicities to various treatments. Imaging plays a critical role in evaluating the characteristics of CRLM and the approach to treatment. CT is the modality of choice in the diagnosis and management of CRLM. MRI is best used for indeterminate lesions and to assess response to intra-arterial therapy. PET-CT is often utilized to detect extrahepatic metastasis. State-of-the-art imaging is critical to characterize patterns of response to various treatments. We herein review the imaging characteristics of CRLM with an emphasis on imaging changes following the most common CRLM treatments.

Appropriateness of referrals for single-photon emission computed tomography myocardial perfusion imaging (SPECT-MPI) in a developing community: a comparison between 2005 and 2009 versions of ACCF/ASNC appropriateness criteria.

INTRODUCTION: Appropriateness of referrals for myocardial perfusion imaging (MPI) in developing countries has not been extensively studied. Our study was conducted to describe the ordering practices of physicians and appropriateness of MPI referrals in Iran. METHOD: We prospectively applied 2005 and 2009 versions of the Appropriateness Use Criteria published by the American College of Cardiology Foundation (ACCF) and the American Society of Nuclear Cardiology (ASNC) to 291 consecutive patients (age 55.3 ± 10.3 years) who underwent SPECT-MPI. For this purpose, we convened a panel, consisting of two academic cardiologists, one academic clinician in internal medicine, and one academic clinician in nuclear medicine. The panelists were invited for a face-to-face meeting to judge appropriateness of SPECT-MPI and independently assign a specific indication (scenario), whenever possible, for each case in accordance with ACCF/ASNC appropriateness scenarios. RESULTS: Based on the 2005 ACCF/ASNC criteria, SPECT-MPI studies were judged appropriate for 211 (72.5%), uncertain for 36 (12.4%), inappropriate for 32 (11.0%), and unclassifiable for 12 (4.1%) referrals. The same figures based on the 2009 version were 219 (75.3%), 15 (5.2%), 49 (16.8%), and 8 (2.7%) patients, respectively. Overall agreement between the 2005 and 2009 versions was good (κ 0.63). Lack of chest pain and age below 60 years were significant indicators increasing the likelihood of inappropriate referrals by 2.9-3.4 fold. Absence of diabetes mellitus and hypertension, a normal lipid profile, lack of a past history of myocardial infarction or cardiovascular interventions (CABGs or PCI), as well as lack of application and exercise ECG stress test as the gate keeper (keeping abnormal ETT or inability of the patient to perform exercise as the appropriate indication for SPECT-MPI referral) were significant indicators, decreasing the odds of appropriate referrals. Generally a higher percentage of referrals with inappropriate indications had normal MPI. CONCLUSION: Our study provides an evidence for the fact that SPECT-MPI ordering practices in our developing community largely parallel the ACCF/ASNC recommendations. The implementation of appropriateness criteria is feasible in clinical settings and might provide an alternative to utilization management.

Imaging neuroendocrine tumors: Characterizing the spectrum of radiographic findings.

Neuroendocrine tumors (NET) are a group of neoplasms with neuroendocrine differentiation affecting a wide range of organs. Functional NETs present with symptoms due to the particular hormone produced. Functional NETs are usually small at diagnosis and therefore can be challenging to diagnose. In contrast, non-functioning NETs are generally larger and present with mass effect. Imaging plays an indispensable role in diagnosis, staging and management of patients with NETs. The optimal modality and technique for imaging of NETs depend on the location of primary and metastatic lesions. Regardless of the imaging modality, dynamic contrast-enhanced imaging is essential for evaluation of NETs. In general, CT scan is typically the primary imaging modality for evaluating NETs. MRI is used as a complementary modality, being superior to other modalities to assess liver metastasis. Nuclear medicine imaging is also widely used in NET assessment.

Cytotoxicity of 111In-oxine on mesenchymal stem cells: a time-dependent adverse effect.

BACKGROUND: Radioactive labeling with indium (In) tracers has been among the most widely used methods for tracking stem cells. As the first experiment on human stem cells, we designed a study to continuously follow the influence of In labeling on stem cell viability during the 2-week period of postlabeling. METHODS: After culturing mesenchymal stem cells (MSCs), we divided the cells into six samples, each of which contained 1x10 MSCs. The first sample was considered as the control. The remaining five samples (samples 2-6) were labeled with the following doses of In-oxine, respectively: 0.76, 1.64, 3.48, 5.33, and 7.16 MBq/10 MSCs. To evaluate the effects of In-oxine labeling on cellular viability and count, all samples were examined immediately after labeling (2 h) as well as 24, 48 h, and 5, 7, and 14 days postlabeling. RESULTS: No statistically significant relationship was found between labeling efficiency and administered dose. Associations between the specific activity and radiotracer dosage was significant (P=0.001, r=0.9). In addition, a negative correlation was noted between radiotracer dosage and viability during the 2-week period of follow-up. CONCLUSION: Cytotoxic effects of In on human stem cells is a time-dependent phenomenon and hence, assessment of the stem cell viability immediately after labeling (which is frequently made in clinical trials) is unable to detect adverse effects of this radiopharmaceutical on the integrity of stem cells. Even low doses of In-oxine are accompanied by significant cell loss in a 2-week period. Although it has been confirmed that nuclear medicine techniques are the most sensitive methods for stem cell tracking, we recommend that the application of this tracking technique should be treated with great reserve, and if necessary, as little of In-oxine as possible should be added to the cells (or only a limited portion of the cells should be labeled) to minimize cell death.

99mTc-MIBI whole body scintigraphy and P-glycoprotein for the prediction of multiple drug resistance in multiple myeloma patients.

Multi-drug resistance (MDR) is a major challenge in the treatment of multiple myeloma (MM). There is low sensitivity of technetium-99m methoxy isobutyl isonitrile ((99m)Tc-MIBI) whole body scan (WBS) in the detection of active MM lesions, because (99m)Tc-MIBI is washed out from malignant cells in the presence of P-glycoprotein (PGP). The objective of the present cohort study was to evaluate of (99m)Tc-MIBI WBS in the prediction of MDR in MM patients during a course of one year follow up. Thirty four patients with MM (25 male, 9 female of mean age 54.12+/-11.46 years) entered the study. Thirteen patients had no previous history of treatment and 21 had a history of previous chemo-radiotherapy. The diagnosis and staging of the disease were based upon routine laboratory and clinical criteria like bone marrow plasma cell count, serum M component, calcium, albumin, beta(2)-microglobulin. Measurements of PGP and WBS using (99m)Tc-MIBI were performed before initialization of treatment and the response to treatment was assessed one year later. The baseline (99m)Tc-MIBI WBS were considered positive for the detection of active lesions when at least one area of non-physiologic increased activity was noted. The follow up (99m)Tc-MIBI WBS was positive for MDR when the patient had active disease but normal WBS. Our results showed that for WBS, the sensitivity, specificity, positive predictive value, negative predictive value and accuracy in active state for the diagnosis of MDR were 38.9%, 62.5%, 70%, 31.2% and 46.1%, respectively. Also the above values for the detection of MDR, using PGP values were 50%, 50%, 69.2%, 30.8% and 50%, respectively. The relative risk of resistant to multiple regimens of chemotherapy after one year follow up in patients with negative to patients with positive (99m)Tc-MIBI WBS was 1.02 (0.60-1.72). In conclusion, we found a low sensitivity of WBS and of PGP in the detection of MDR in patients with active MM. However, both WBS and PGP have 70% and 69% positive predictive value for MDR.

Theranostic application of lipiodol for transarterial chemoembolization in a VX2 rabbit liver tumor model.

The goal of this study was to investigate the role of Lipiodol as a tumor-specific imaging biomarker to determine therapeutic efficacy of cTACE and investigate its inter-dependency with tumor perfusion using radiological-pathological correlation in an animal model of liver cancer. METHODS: A total of N=36 rabbits were implanted in the left lobe of the liver with VX2 tumors, treated with cTACE using doxorubicin suspended in Lipiodol, and randomly sacrificed at 24 h, 7 days, or 20 days post-TACE. Unenhanced and contrast-enhanced CT scans including a perfusion protocol were obtained before cTACE and immediately before sacrifice. Tumor vascularity and Lipiodol deposition within tumors and hepatic tissue (non-target deposits) were quantified using 3D quantitative assessment tools and measurements of arterial flow, portal flow, and perfusion index (PI). After sacrifice histologic staining, including hematoxylin and eosin (H&E), CD31, and Oil Red O (ORO) were performed on tumor and liver samples to evaluate necrosis, microvascular density (MVD), and Lipiodol retention over time. Transmission electron microscopy (TEM) was performed to assess Lipiodol deposition and clearance over time. RESULTS: All cTACE procedures were carried out successfully except for one, which was excluded from further analysis. Twenty-four hours post-TACE, tumor PI (p=0.04) was significantly decreased, which was maintained at 7 days (p=0.003), but not at 20 days (p=0.4). A strong correlation (R2 = 0.894) was found between the volume of enhancing tumor tissue at baseline and Lipiodol-positive tumor volume post-TACE. Both ORO and TEM showed deposition of Lipiodol across all imaging time points within the VX2 tumors. However, gradual and ultimately near-complete Lipiodol washout was observed over time in the non-tumoral liver. MVD decreased between 24 h and 7 days post-TACE, and then increased 20 days post-TACE (both p<0.01). CONCLUSIONS: Our data provide radiology-pathology evidence for the function of Lipiodol as a theranostic, tumor-specific drug delivery agent because it is both imageable and tumor-seeking, whereby it is preferentially taken up and retained by tumor cells. Those tumor-specific functions also enable Lipiodol to act as an imaging biomarker for the therapeutic efficacy of cTACE. Together with volumetric quantification of tumor vascularization on CT, Lipiodol could be used as a predictor of a patient's response to cTACE and contribute to the therapeutic management of patients with liver cancer.

Radio-iodine therapy and Helicobacter pylori infection.

BACKGROUND: Helicobacter pylori is the most important cause of gastritis and related morbidities. Following consumption, radioactive iodine accumulates considerably in the stomach. On the basis of this observation, we decided to determine whether the high radiation induced by radio-iodine in the stomach is effective in the eradication of this infection. METHODS: All consecutive patients with differentiated thyroid carcinoma, who were referred for radio-iodine therapy [dose 117.1 +/- 24.4 mCi (4.3 +/- 0.9 GBq), range 100-200 mCi (3.7-7.4 GBq)], were enrolled. To detect H. pylori infection, the urease breath test (UBT) was performed 1-2 h before radio-iodine consumption and the test was repeated 2 months later. RESULTS: Of 88 patients, 71 had pre-treatment positive UBT. Of these, 23 patients had negative post-treatment result, which means a significant reduction (26.1%, 95% CI 16.8-35.5%) in the number of positive UBT results in our treated population (32.4% of UBT-positive cases became UBT-negative). CONCLUSIONS: Considering the high prevalence of reinfection in developing countries, the therapeutic benefit would have been more considerable if the second UBT had been done with a lag time of less than 2 months. Although radio-iodine therapy is not a logical method for the treatment of patients suffering from H. pylori, our finding provides indirect evidence about the radiosensitivity of bacteria, the future clinical applications of which need to be further evaluated. Also this finding can be useful for the food industry, where radiation is used widely to sterilize food. Regarding the possibility of H. pylori suppression, we recommend not using UBT for screening for the infection for at least within 2 months following radio-iodine therapy.

Assessment of the accuracy of lacrimal scintigraphy based on a prospective analysis of patients' symptomatology.

BACKGROUND: Dacryoscintigraphy is a noninvasive method frequently used for assessment of the lacrimal drainage system. Sometimes conflicting results with patients' complaints are obtained, which have no clear explanation. In our hypothesis, follow-up of patients evaluated with dacryoscintigraphy could be helpful in determining possible explanations for these conflicting results. METHOD: Thirty-eight consecutive patients (76 eyes) who had not previously undergone dacryocystorhinostomy or probing were entered in the study. Following instillation of 4 MBq (99m)Tc-pertechnetate, a routine procedure of dacryoscintigraphy was performed. After a mean follow-up time of 1.2 +/- 0.3 years (range 0.9-1.6 years), all patients were reassessed clinically. RESULTS: Using initial patients' symptoms as the gold standard, the sensitivity, specificity, NPV, and PPV of dacryoscintigraphy were calculated to be 82.1%, 75%, 60%, and 90.1%, respectively. The kappa value as a measure of agreement was 0.52. Considering the follow-up study as the gold standard, the sensitivity, specificity, NPV, and PPV were calculated as follows, respectively: 96.3%, 90.4%, 96.3%, and 90.4%. The kappa value was 0.86. There were three initially symptom-free eyes with obstructive pattern on the scans, which developed epiphora on the follow-up. In fact, these eyes were initially classified as false positive, but follow-up assessment showed that they were true-positive scans in a subclinical state. CONCLUSION: Despite certain drawbacks inherent to the technique, dacryoscintigraphy provides valuable independent information and allows more accurate management decisions. In some patients, data obtained from lacrimal scintigraphy could be predictive, and it makes possible determination of subclinical nasolacrimal duct obstructions.

Impact of DAT-SPECT on Management of Patients Suspected of Parkinsonism.

OBJECTIVE: To evaluate the value of I-2ß-carbomethoxy-3ß-(4-iodophenyl)-N-(3-fluoropropyl) nortropane (I-FP-CIT) dopamine transporter single photon emission computed tomography (DAT-SPECT) to change management strategies of patients suspected of parkinsonism. METHOD: This was an institutional review board-approved, retrospective study. DAT-SPECT scans ordered by movement disorder specialist and neurologists from 2011-2014 were reviewed. Clinical data and radiological reports of 173 patients suspected of parkinsonism were reviewed. The DAT-SPECT scan results were correlated with clinical assessment and treatment changes. RESULTS: A total of 173 patients (104 male and 69 female subjects; age, 64.4 ± 12.6 years) suspected of parkinsonism were included. Median duration of symptoms was 36 months (range, 1-480 months). Scans were most often requested when there was diagnostic uncertainty in clinical features (59.6%, 103/173) or to differentiate one other disease from parkinsonism such as Parkinson disease (PD) versus essential tremor (23.7%, 41/173), PD versus drug-induced parkinsonism (8.7%, 15/173), or PD versus psychogenic (6.4%, 11/173) or vascular (1.7%, 3/173) disorders. Patients were classified, according to the DAT-SPECT scanning results, as those with abnormal DAT-SPECT findings (59%, 102/173) and those with normal DAT-SPECT findings (41%, 71/173). In patients with normal DAT-SPECT findings, follow-up management data were available in 76.1% (54/71). The management changed in 39.4% (28/54) after DAT scan with starting a new appropriate medications or supportive therapy in 4.2% (3/28), withholding inappropriate dopaminergic treatment in 11.3% (8/28), or continuing observation in 23.9% (17/28). In patients with abnormal DAT-SPECT findings, follow-up management data were available in 78.4% (80/102). There was change in management of 37.3% (38/80), a new PD treatment was started in 89.5% (34/38). The dose of medication was adjusted in 5.3% (2/38), although the original treatment was not changed. Parkinson disease treatment was stopped in 2.6% (1/38) and discontinued in 2.6% (1/38) based on clinical decision of neurologists despite abnormal DAT-SPECT findings. CONCLUSIONS: DAT-SPECT findings impacted treatment decisions in 44.7% of patients suspected of Parkinsonism.

A correlative study comparing current different methods of calculating left ventricular ejection fraction.

BACKGROUND: Left ventricular ejection fraction (EF) is a major determinant of survival in patients with coronary artery disease (CAD). Comparative accuracy of numerous modalities in calculating EF is not well investigated. METHOD: We compared EF as calculated by rest and post-stress Cedars automated quantitative gated SPECT (AQGS), rest and post-stress semi-automatically processed gated SPECT (MQGS), echocardiography and contrast ventriculography (LVG) to those determined by rest and post-stress cavity-to-myocardium ratio (CMR) in 109 patients. Gated SPECT was performed based on a 2-day protocol using Tc-MIBI. RESULTS: Mean EF in LVG, echo, post-stress CMR, rest CMR, post-stress AQGS, rest AQGS, post-stress MQGS and rest MQGS were 41.8%+/-12.1, 44.8%+/-11.8, 38.1%+/-10.7, 35.7%+/-12.1, 44.5%+/-15.1, 46.9%+/-14.7, 40.1%+/-14.3 and 43.5%+/-14.3 respectively. Although significant differences were observed between some of these methods, good and excellent linear correlations were present among values (all Pearson correlations >0.63). Considering LVG as the 'gold standard', we defined two groups: EF <35% (class 1) and >35% (class 2). Discriminant analysis showed that SPECT has the ability to predict patients' classes. In 4/18 of patients with normal SPECT (on both visual and quantitative analyses, SSS <4), EF on QGS showed a significant decrease on post-stress compared with rest. CONCLUSION: There is a good correlation in calculating EF by LVG, QGS and echocardiography, regardless of EF value. Whenever QGS is impossible, CMR is a reliable indirect indicator of EF. Gating of both phases (and when impossible, CMR of both phases) has an additional value in diagnosis of CAD.

Evaluation of relationship between clinical and colonoscopic features in patients with active ulcerative colitis.

OBJECTIVE: To develop a system to score disease activity based on clinical manifestations in patients with active ulcerative colitis and to assess the relationship of this score with endoscopic disease severity as assessed by colonoscopy. METHODS: In a pilot study of 43 patients, nine clinical variables were examined by univariate analysis. Six factors that correlated with disease severity included age, well-being, defecation frequency, bloody stool, extraintestinal manifestations (Ext) and hemoglobin (Hb). Multivariate analysis resulted in the generation of a new activity index for the prediction of disease severity. Validation of this index was performed on 88 patients with definite diagnosis of ulcerative coli-tis based on previous histological examination. RESULTS: The activity index is derived as follows: (18 x bloody stool) + (20 x defecation frequency) + (5 x Ext) + (15 x Hb) - (well-being x 17) + (age x 2) + 158. Values below 280, between 280 and 310 and above 310 corresponded to mild, moderate and severe disease, respectively. The model classified disease severity correctly in 71% of cases. CONCLUSION: This activity index may be useful for noninvasive evaluation of disease severity in patients with ulcerative colitis.

[On-levothyroxine measurement of thyroglobulin is not a reliable test for the follow-up of patients at high risk for remnant/recurrent differentiated thyroid carcinoma].

INTRODUCTION: At present the most widely accepted tool for follow-up management of differentiated thyroid cancer (DTC) patients is serum thyroglobulin (Tg) measurement. It is not uncommon for the serum Tg level to be measured while the patient is taking thyroid hormones (on-treatment Tg measurement). The purpose of the study was to evaluate the accuracy of on-treatment measurement of serum Tg in detecting remnant/recurrent or metastatic disease in high-risk DTC patients. MATERIAL AND METHODS: We retrospectively analysed the medical records of 26 high-risk DTC patients and compared the on-treatment and off-treatment Tg levels of these patients. All patients were anti-Tg negative. Using off-treatment measurement of Tg as the gold standard, the results of on-treatment measurement of Tg in the diagnosis of remnant/recurrent disease were analysed for sensitivity, specificity, negative predictive value (NPV) and positive predictive value (PPV). RESULTS: The median serum Tg level under thyroid hormone suppressive therapy (on-treatment Tg) was 16.5 ng/ml and after withdrawal of thyroid hormone suppressive therapy (off-treatment Tg) was 95.0 ng/ml (P value = 0.001). In 6 patients (23%) the on-treatment Tg level missed the recurrence of the disease. Regarding the off-treatment Tg as the gold standard, the sensitivity, specificity, PPV and NPV of the on-treatment Tg measurement were 72.7%, 100%, 100%, and 40% respectively. CONCLUSION: Normal serum Tg level without TSH-stimulation (on-treatment) is not diagnostically reliable in the follow-up of DTC patients with a high probability of residual/recurrent or metastatic disease.

Papillary Breast Lesions: Association with Malignancy and Upgrade Rates on Surgical Excision.

Intraductal papilloma falls under the category of benign breast mass. However, recent studies show that it can harbor occult carcinoma. The management of benign intraductal papilloma remains controversial because of its nonspecific radiologic and histological findings, as well as its association with surrounding malignant pathology. The purpose of this study is to investigate upgrade rates of a benign intraductal papilloma on surgical excision and the need for surgical excision of papillary lesions diagnosed at core needle biopsy. A retrospective review of a single institution's pathology database between 2011 and 2015 identified 43 core biopsies with benign papilloma. We followed the upgrade rates of these lesions on surgical excision. There were 90 biopsies with the diagnosis of benign intraductal papilloma. The average age was 55.2 (range from 24-87 years old). Forty-three had benign intraductal papilloma; 28 of the 43 core biopsies had surgical excision. Two (7.1%) had an upgrade from benign intraductal papilloma to intraductal papilloma with atypia. One (3.6%) had an upgrade to ductal carcinoma in situ. None had invasive cancer. Surgical findings were in agreement with core biopsies in 25 (89.3%) of 28 cases (κ = 0.80, P < 0.0001). Core biopsies have a statistically significant correlation with pathologies on surgical excision in detecting atypia in breast lesion as demonstrated by κ = 0.80. However, the study shows benign intraductal papillomas on core biopsy have an upgrade rate of 10.7 per cent after undergoing surgical excision. As such, we recommend a more aggressive approach including surgical excision of all benign intraductal papillary lesions.

Preclinical Benefit of Hypoxia-Activated Intra-arterial Therapy with Evofosfamide in Liver Cancer.

PURPOSE: To evaluate safety and characterize anticancer efficacy of hepatic hypoxia-activated intra-arterial therapy (HAIAT) with evofosfamide in a rabbit model. EXPERIMENTAL DESIGN: VX2-tumor-bearing rabbits were assigned to 4 intra-arterial therapy (IAT) groups (n = 7/group): (i) saline (control); (ii) evofosfamide (Evo); (iii) doxorubicin-lipiodol emulsion followed by embolization with 100-300 µm beads (conventional, cTACE); or (iv) cTACE and evofosfamide (cTACE + Evo). Blood samples were collected pre-IAT and 1, 2, 7, and 14 days post-IAT. A semiquantitative scoring system assessed hepatocellular damage. Tumor volumes were segmented on multidetector CT (baseline, 7/14 days post-IAT). Pathologic tumor necrosis was quantified using manual segmentation on whole-slide images. Hypoxic fraction (HF) and compartment (HC) were determined by pimonidazole staining. Tumor DNA damage, apoptosis, cell proliferation, endogenous hypoxia, and metabolism were quantified (γ-H2AX, Annexin V, caspase-3, Ki-67, HIF1α, VEGF, GAPDH, MCT4, and LDH). RESULTS: cTACE + Evo showed a similar profile of liver enzymes elevation and pathologic scores compared with cTACE. Neither hematologic nor renal toxicity were observed. Animals treated with cTACE + Evo demonstrated smaller tumor volumes, lower tumor growth rates, and higher necrotic fractions compared with cTACE. cTACE + Evo resulted in a marked reduction in the HF and HC. Correlation was observed between decreases in HF or HC and tumor necrosis. cTACE + Evo promoted antitumor effects as evidenced by increased expression of γ-H2AX, apoptotic biomarkers, and decreased cell proliferation. Increased HIF1α/VEGF expression and tumor glycolysis supported HAIAT. CONCLUSIONS: HAIAT achieved a promising step towards the locoregional targeting of tumor hypoxia. The favorable toxicity profile and enhanced anticancer effects of evofosfamide in combination with cTACE pave the way towards clinical trials in patients with liver cancer. Clin Cancer Res; 23(2); 536-48. ©2016 AACR.