Current barriers and recommendations on the diagnosis of transthyretin amyloid cardiomyopathy: a Delphi study.

Objectives: This study has been conducted to investigate the non-invasive diagnostic journey of patients with a transthyretin amyloid cardiomyopathy (aTTR-CM) in Turkey, identify the challenges and uncertainties encountered on the path to diagnosis from the perspectives of expert physicians, and develop recommendations that can be applied in such cases. Methods: This study employed a three-round modified Delphi method and included 10 cardiologists and five nuclear medicine specialists. Two hematologists also shared their expert opinions on the survey results related to hematological tests during a final face-to-face discussion. A consensus was reached when 80% or more of the panel members marked the "agree/strongly agree" or "disagree/strongly disagree" option. Results: The panelists unanimously agreed that the aTTR-CM diagnosis could be established through scintigraphy (using either 99mTc-PYP, 99mTc-DPD, or 99mTc-HMPD) in a patient with suspected cardiac amyloidosis (CA) without a further investigation if AL amyloidosis is ruled out (by sFLC, SPIE and UPIE). In addition, scintigraphy imaging performed by SPECT or SPECT-CT should reveal a myocardial uptake of Grade ≥2 with a heart-to-contralateral (H/CL) ratio of ≥1.5. The cardiology panelists recommended using cardiovascular magnetic resonance (CMR) and a detailed echocardiographic scoring as a last resort before considering an endomyocardial biopsy in patients with suspected CA whose scintigraphy results were discordant/inconclusive or negative but still carried a high clinical suspicion of aTTR-CM. Conclusion: The diagnostic approach for aTTR-CM should be customized based on the availability of diagnostic tools/methods in each expert clinic to achieve a timely and definitive diagnosis.

A personalized Monte Carlo study of tumor and critical organ doses for trans-arterial radioembolization patients.

Trans-arterial radioembolization (TARE) is an intra-arterial treatment method for liver malignancies. In this procedure, the therapeutic tumor dose is significant for predicting the treatment effectiveness while the dose absorbed in an organ at risk provides an understanding of its tolerance to radiation. This study proposes a Monte Carlo (MC) approach for determining absorbed organ doses for patients undergoing TARE treatment. The technique is based on the use of a voxel-based partial body model generated for each patient from his/her anatomical image data to represent the critical body structures more realistically. These structures are first segmented from image slices to create an image block which is then incorporated into a radiation transport package (MCNP6.2) to perform MC simulations. When used along with the parameters specific to a patient's treatment, such as lung-shunt factor, tumor-to-normal liver ratio, fractional uptakes, and administered activity, this approach allowed more accurate simulation of radiation interactions and hence provided absorbed doses specific to a TARE patient. The MC method also calculated the absorbed doses in organs or tissues that were close to target tissues for which the Medical Internal Radiation Dose Committee (MIRD) formalism makes no predictions. MIRD calculations were found to overestimate the absorbed doses by as much as 11% in lungs, 5% in liver, and 20% in tumor volumes. This raises concerns about the treatment's efficacy when estimating the correct activity to be administered to a patient. When each patient simulation was repeated with a90Y source spectrum to reflect the distribution of varying beta energies, the liver and the lungs were observed to receive relatively lower doses than those obtained with monoenergetic beta particles. Thus, it can be stated that the approach adopted in this study offers a more precise model of the patient's critical tissues and serves as a personalized dosimetric tool for TARE treatment planning.

The role of F-18 FDG PET/CT in differentiating benign from malignant pulmonary masses and accompanying lymph nodes.

INTRODUCTION: The aim of this study was to evaluate the usefulness of SUVmax and lesion size to differentiate benign and malignant lesions of the lung and accompanying mediastinal lymph node on F-18 FDG PET/CT imaging. MATERIALS AND METHODS: A retrospective analysis was carried out on 100 patients with suspected lung cancer who were recommended for PET/CT scans for diagnosis and staging. The results of the SUVmax, lesion size and patient's age were compared with histopathology which was considered to be the 'gold standard' and sensitivity and specificity were calculated respectively. Lymph nodes greater than 1 cm in patients with benign pathology were evaluated and the SUVmax values were recorded. RESULT: Of the 100 patients, 38 were found to have benign, whereas 62 had malignant on histopathology. The SUVmax was significantly more elevated in malign masses (13.1 ± 6.4) than in benign masses (8 ± 5.7) (p< 0.05). The dimensions of malignant masses (4.5 ± 2.5 cm) were larger than benign ones (3 ± 1.6 cm) (p< 0.05). SUVmax of 7.6 was determined as the cut-off value, while the sensitivity and specificity were 82% and 55% respectively. The sensitivity was 87% and specificity was 45% for the lesion sizes in differentiation of the malignant and benign lesions. CONCLUSIONS: There are significant overlaps between benign and malignant lesions and specialists must be aware of the various pathological conditions that can give false positives and negatives.

Role of Tc-99m pertechnetate for remnant scintigraphy, post-thyroidectomy, and serum thyroglobulin and antithyroglobulin antibody levels in the patients with differentiated thyroid cancer.

AIM: Postoperative scanning may help to identify patients with differentiated thyroid cancer (DTC); however, low dose I-131 can lead to stunning and suboptimal response to ablative therapy. The aim of this retrospective study is to compare postablative I-131 scintigraphy with post-thyroidectomy Tc-99m pertechnetate scintigraphy, serum thyroglobulin (Tg) and antithyroglobulin antibody (TgAb) levels in patients with DTC. METHODS: Patients who had undergone surgical thyroidectomy for DTC were evaluated retrospectively. All patients had undergone Tc-99m pertechnetate and postablative I-131 scans. Serum Tg and TgAb levels were measured in all subjects. Preablative pertechnetate scans of the thyroid bed were viewed blindly and then directly compared with postablative I-131 scans and Tc-99m pertechnetate scintigraphy was compared with serum Tg and TgAb levels. RESULTS: One hundred and seventy-four patients (146 women, 28 men) with a mean age of 48.7 ± 13.1 (range 12-84) years who had undergone surgical thyroidectomy for DTC were evaluated retrospectively. Of 174 patients, 6 (3%) had negative I-131 and also Tc-99m pertechnetate scintigraphy results. Of the remaining 168 positive I-131 scans, 131 (75%) were positive in at least one site on the pertechnetate scan, 19 (11%) were considered to have equivocal uptake and 18 (11%) were negative. For the per-site analysis, pertechnetate sites were considered to be accurately determined if they showed concordant uptake at sites that correlated precisely with those seen on the postablation I-131 scans. There were a total of 356 positive foci on I-131 scans. Of these, 273 foci (77%) were unequivocally positive on pertechnetate scintigraphy, 41 (11%) showed equivocal uptake and 42 (12%) foci could not be detected. There were statistically significant differences (p < 0.0001) between the negative and positive foci in terms of Tg levels on pertechnetate sites. CONCLUSIONS: A positive pertechnetate scan is, therefore, sufficient to guide progression to I-131 ablation in most patients. Pertechnetate scintigraphy may be of particular benefit if it is considered desirable to avoid use of I-131 in post-thyroidectomy remnant imaging. Tg level is an important parameter in the detection of remnant thyroid tissue in patients with DTC.

Is there any relation between PET-CT SUVmax value and prognostic factors in locally advanced breast cancer?

PURPOSE: To investigate the relation between PET-CT SUVmax value and prognostic factors in locally advanced breast cancer. METHODS: Data of 73 patients were retrospectively analyzed. Relations between SUVmax value, clinical stage, tumor grade and breast cancer molecular subtypes were analyzed by using one-way ANOVA and x(2) tests. Correlations between age, ki-67 scores and SUVmax were evaluated by using Pearson's correlation test. A p value <0.05 was considered statistically significant. RESULTS: Median SUVmax values for clinical stages 1, 2 and 3 were 5 (range 2.1-4.1), 10.6 (range 2.9-19.6), and 12.2 (range 3.2-23.3), respectively. Statistically significant difference was noticed between stage 1 and 2 (p=0.014) and stage 1 and 3 (p=0.001). Median SUVmax values of triple negative, luminal A, luminal B and non-luminal HER2 positive groups were 14.4 (range 6.6-23.3), 8.2 (range 2.1-18.2), 10.1 (range 3.5-19.6), and 14 (range 4.1-22.9), respectively. Statistically significant differences were noticed in SUVmax values between triple-negative and luminal A groups (p=0.005) and between non-luminal HER2 positive and luminal A groups (p=0.02). Median SUVmax values of grade 1, 2 and 3 were 5.7 (range 2.1-18.2), 9.5 (range 2.2-21.3), and 11.6 (range 3.5-23), respectively. Statistically significant difference was noticed only between SUVmax values of grade 1 and 3 (p=0.035). There was negative correlation between age and SUVmax value (r=-0.23, p=0.047) and positive correlation between ki-67 and SUVmax value (r=0.43, p=0.016). CONCLUSION: There were significant positive relations between PET-CT SUVmax value and clinical stage, tumor grade, and certain breast cancer molecular subtypes (triple-negative and non-luminal HER2 positive groups. Moreover, positive correlation was found between SUVmax value and ki-67 and negative correlation between SUVmax value and age.

Evaluation of factors affecting tumor response and survival in patients with primary and metastatic liver cancer treated with microspheres.

OBJECTIVE: Radioembolization with the yttrium-90 (Y-90) microspheres is being used increasingly more often in the treatment of patients with primary or metastatic liver cancer. Although technetium-99m macroaggregated albumin (Tc-99m MAA) scintigraphy performed following diagnostic angiography has an important role in predicting the effectiveness of treatment and in dose estimation, the number of studies using quantitative assessment of Tc-99m MAA scintigraphy is limited in this field. In the present study, the aim was to assess whether a tumor dose is required to obtain objective tumor response and to check whether this threshold value is predictive in terms of tumor response, survival, and liver toxicity by using Tc-99m MAA single-photon emission computed tomography (SPECT) images. MATERIALS AND METHODS: Overall, 54 patients (20 women and 34 men; median age: 60 years) who underwent Y-90 Resin (SIR-Spheres) and Glass (TheraSphere) microsphere treatment with a diagnosis of unresectable liver cancer between August 2010 and April 2013 were included in the study. The mean doses to normal liver and tumor were estimated for each patient using Tc-99m MAA SPECT images and the medical internal radiation dosimetry method. The responses were assessed according to Response Evaluation Criteria In Solid Tumors (RECIST) and European Organisation for Research and Treatment of Cancer (EORTC) criteria. Kaplan-Meier survival curves and univariate Cox regression analysis were used in survival analysis. The relationship between treatment response and other parameters included was assessed using logistic regression analysis. The variables with a P value less than 0.01 in univariate analysis were assessed with multivariate analysis. RESULTS: Fifty-four Y-90 microsphere treatments (eight by using a Y-90 glass microsphere and 46 by using a Y-90 resin microsphere) were performed. In the multivariate analysis, the only parameter related to response was tumor dose (P<0.01). With a tumor dose of 280 Gy or higher, objective tumor response was observed in 59 and 77% of the patients according to RECIST and EORTC criteria, respectively, and the tumor control rate was found to be 95% according to both criteria. In addition, it was found that only tumor dose was correlated with progression-free survival (PFS) (P<0.001) and overall survival (OS) (P=0.018). When the tumor dose was 280 Gy or higher, median PFS increased from 2 to 10.7 months (P<0.001), whereas median OS increased from 9 to 17.6 months (P=0.018). However, reversible ≥ G2 liver toxicity was observed in 3.7% (2/54) of the patients within 3 months after radioembolization with a median normal liver dose of 40 Gy (10-102 Gy). There was reversible ≥ G3 liver toxicity in 3.7% (2/54) of patients, but no G4 liver toxicity was observed. Clinical radiation hepatitis and treatment-induced liver failure were not observed in any of these patients. CONCLUSION: Tc-99m MAA SPECT has a predictive value in terms of response to radioembolization, PFS, and OS. Dosimetry based on Tc-99m MAA SPECT images can be used in the selection of patients and, in particular, to adaptation of treatment plan in selected patients.

Yttrium-90 radioembolization in patients with unresectable liver metastases: determining the factors that lead to treatment efficacy.

INTRODUCTION: Locoregional treatments, such as radioembolization, can be used to treat patients with unresectable liver metastases. We aimed to determine the progression-free survival and factors that predict survival of patients with liver metastases whose response to selective internal radiation therapy (SIRT) with Y-90 was assessed by positron emission tomography-computed tomography (PET-CT). PATIENTS: Our study included 78 liver cancer patients who were treated with Y-90 radioembolization. RESULTS: The post-treatment response rates were as follows: 7 patients (9%) had stable disease (SD), 26 patients (33.3%) had a partial response (PR), 4 patients (5.1%) had a complete response (CR). The median hepatic progression-free survival (HPFS) was 4.4 months while median overall survival was 10.1 months. Univariate analysis revealed that HPFS is significantly affected by international normalized ratio (INR) levels and age (Hazard Ratio(HR)=0.54 (95%CI:0.30-096), P=0.034, HR=1.03(95%CI:1.00-1.05), P=0.051). However, only INR levels retained significance with multivariate analysis (HR=0.53 (95%CI:0.30-0.93), P=0.028), while age had limited significance (HR =1.02 (95% CI:1.00-1.05), P=0.051). CONCLUSIONS: We determined that Y-90 radioembolization is effective as a salvage therapy in patients with predominant liver metastases. For the first time, we showed that age and INR values reflecting the functional hepatic reserve can be used as positive predictive factors for HPFS.

In vivo fluorescence imaging is well-suited for the monitoring of adenovirus directed transgene expression in living organisms.

PURPOSE: We tested a new light detection cooled charge-coupled device (CCD) for in vivo assessment of noninvasive, whole-body fluorescence optical imaging of adenovirus directed enhanced green fluorescent protein (AdEGFP) expression. PROCEDURES: AdEGFP was injected i.v. into BALB/c mice via tail vein. Whole-body fluorescence optical imaging of AdEGFP expression was performed using a Kodak 2000MM Image Station before and after vector administration. RESULTS: EGFP expression was exclusively detected around the abdominal cavity, and the fluorescent signal peaked at day 4 and then remained detectable for at least 30 days. Ex vivo fluorescence imaging confirmed that EGFP expression was restricted to the liver, and transgene expression was homogeneously diffused into all four lobes. CONCLUSIONS: These findings demonstrate that in vivo fluorescence imaging provides functional data indicating the approximate location, magnitude, and duration of AdEGFP expression.

Densitometric analysis of the human first tarsometatarsal joint.

The first tarsometatarsal (TMT) joint has a complex role in regulating joint pressure in the midfoot. Despite its importance, there have been only a few studies of the functional morphology and biomechanical function of this joint. Here we report about the densitometric pattern of the subchondral bone layer of the articulating elements of the human first TMT joint. We studied dry bones of the first metatarsal and medial cuneiform bones in 64 human cadavers to establish the pattern of the density distribution and to correlate it with the biomechanical function of the joint. The articular surfaces of both the bones were analyzed planimetrically. Half of the specimens (n=32) were sectioned in the sagittal plane and the other 32 articulations were in the transverse plane. In all the sections, the subchondral bone density of the first TMT joint was measured. We found that in sagittal slices the dorsal area of the lateral parts and intermediate parts in females and the dorsal area of the lateral parts, the medial parts and intermediate parts in males were denser than the plantar area and that its density decreased towards the plantar area. The dorsal parts of transverse slices in males were the densest and its density decreased towards the plantar part. In the dorsal, middle and plantar parts in females in transverse slices, the lateral and intermediate areas were denser than the medial areas (P<0.05). There was no significant difference between the bone densities of females and males.

Effect of exercise on blood pressure in rats with chronic NOS inhibition.

Regular training lowers blood pressure in hypertensive humans and other animals. We investigated the response to 4 weeks of treadmill exercise training in hypertensive male Wistar rats receiving the nitric oxide synthase inhibitor N(omega)-nitro- L-arginine methyl ester ( L-NAME). The rats were on either a short- (4 weeks) or long-term (10 weeks) L-NAME treatment protocol and were subjected to running exercise that started concomitantly in the short-term group and in the 6th week in the long-term group. Four weeks of exercise training induced a fall in mean arterial pressure in both the short- [mean (SEM) 137.6 (4.0) mmHg] and long-term hypertensive groups [161.4 (2.3) mmHg] compared to their sedentary hypertensive controls [160.4 (3.3) mmHg and 176.8 (8.9) mmHg, respectively]. Exercise also increased muscle nitric oxide synthase activity in both of the trained hypertensive groups. Muscle nitrite levels were higher in the exercising short-term hypertensive group compared to both the sedentary control and the sedentary hypertensive groups, and were not different between the sedentary and exercising long-term hypertensive groups. Increased wall thickness of the aortic and mesenteric vessels was observed in the hypertensive groups, but was prevented in the exercising long-term hypertensive group. In rat, exercise reduces the elevated blood pressure in L-NAME-induced hypertension via increasing nitric oxide synthase activity. Changes in vessel structure with exercise training may also be involved in the blood-pressure-lowering effects.