Levent Kabasakal

Evaluation of PSMA PET/CT imaging using a 68Ga-HBED-CC ligand in patients with prostate cancer and the value of early pelvic imaging.

PurposeThe aim of the study was to evaluate the diagnostic value of the prostate-specific membrane antigen (PSMA) ligand 68Ga-HBED-CC (PSMA PET/CT) in patients with prostate cancer and evaluate the value of early imaging of the pelvis. Materials and methodsThe files of 28 patients were retrospectively evaluated. All patients had a histopatological confirmation of prostate cancer. PSMA PET/CT images were obtained at 5 and 60 min after injection from all patients. ResultsIntense pathologic radiotracer uptake was observed in 23 patients (77%) at the site of primary tumour. Lymph node metastases were detected in 10 patients (36%) and bone metastases were detected in seven patients (25%). Bone scan (n=25) results revealed metastatic bone lesions in four patients, equivocal results in nine patients and normal results in 12 patients. PSMA PET/CT confirmed bone metastases in all four patients. Pathologic radiotracer uptake in PSMA PET/CT scans was observed only in one patient among those who had equivocal bone scans. PSMA PET/CT showed additional bone lesions in two patients who had a normal bone scan. When we compared early and late pelvic images we found no difference in the number of lesions detected. The maximum standardized uptake value (SUVmax) for primary tumour, lymph nodes and bone metastases was significantly higher in late images. ConclusionPSMA PET/CT imaging seems to be a valuable imaging modality for evaluation of primary prostate cancer and it seems to have potential for the detection of lymph node and bone metastases. Early images 5 min p.i. can help to better distinguish between urinary bladder (before tracer accumulation occurs) and tumour lesions.

68 Ga-PSMA PET/CT imaging of metastatic clear cell renal cell carcinoma

Prostate-specific membrane antigen (PSMA) is a type II transmembrane protein with high expression in prostate carcinoma cells. Glu-NH-CO-NH-Lys-(Ahx)-[Ga(HBED-CC)] (GaPSMA) has been suggested as a novel tracer that can detect prostate carcinoma relapses and metastases with high contrast by targeting PSMA [1]. Besides prostate cancer, PSMA has been shown to be expressed in the neovasculature of various solid malignant tumours including clear cell renal cell carcinoma (ccRCC) [2, 3]. RCC is a potentially lethal cancer with aggressive behaviour, and has a propensity for distant metastatic spread. The common sites of metastases from ccRCC include lungs (33 – 72 %), intraabdominal lymph nodes (3 – 35 %) and brain (7 – 13 %) [4]. Bone metastases are also a frequent complication in patients with ccRCC [4]. We present to our knowledge the first reported case of a patient with a diagnosis of ccRCC with Ga-PSMA uptake. A 65-yearold woman, status post-nephrectomy, underwent GaPSMA (b) and F-FDG (a) PET/CT for staging. GaPSMA PET/CT showed multiple pathological bone lesions with intense uptake of the tracer in the seventh cervical vertebra and acromion of the left scapula (c, d, e; SUVmax=35 for PSMA, 7.2 for FDG), sternum (f, g, h; SUVmax=28.3 for PSMA, 5.15 for FDG), and right tuber ischiadicum (i, j, k; SUVmax 34.1 for PSMA, 5.3 for FDG). F-FDG PET/CT provided lower visual detectability of the bone metastasis. This case indicates the clinical utility of Ga-PSMA for the imaging of RCC.

The Effects of Riluzole on Neurological, Brain Biochemical, and Histological Changes in Early and Late Term of Sepsis in Rats

OBJECTIVE One of the underlying mechanisms of sepsis is thought to be the oxidative damage due to the generation of free radicals. Glutamate, the major excitatory amino acid in the brain, is known to play an important role in blood brain barrier (BBB) permeability, brain edema, and oxidative damage in pathological conditions. Riluzole, a glutamate release inhibitor, has been shown to have neuroprotective effects in several animal models. The aim of our study was to investigate the putative protective effect of riluzole against sepsis-induced brain injury. METHODS Sepsis was induced by cecal ligation and puncture in Wistar albino rats. Sham operated (control) and sepsis groups received either saline or riluzole (6 mg/kg, s.c.) 30 min after the surgical procedure, and every 12 h as continuing treatment. The effect of riluzole on the survival rate, weight loss, fever, leukocyte count, brain edema, BBB permeability, oxidative damage, and histological observations were evaluated for early (6 h) and late (48 h) phase of sepsis. RESULTS Riluzole, when administered 6 mg/kg s.c., diminishes the sepsis-induced augmentation in weight loss, body temperature, brain edema, increase in BBB permeability, oxidative damage, and brain injury that is observed histologically. Besides increasing the survival rate in sepsis, it has also improved neurological examination scores and the prognosis of the disease. CONCLUSION According to the results of this study, riluzole appears to have a protective effect for sepsis-induced encephalopathy.

Treatment of iodine-negative thyroglobulin-positive thyroid cancer: differences in outcome in patients with macrometastases and patients with micrometastases.

PurposeDuring the follow-up of patients with well-differentiated thyroid carcinoma, some patients have elevated serum thyroglobulin (Tg) levels without any evidence of radioiodine accumulation on diagnostic whole-body scan (d-WBS). The treatment strategy in these patients is considered a clinical dilemma, with some groups recommending blind use of high-dose radioiodine therapy. The aim of this study was to evaluate whether or not high doses of radioiodine have beneficial effects in these patients.MethodsTwenty-seven patients were included in the study. All patients had negative d-WBS and elevated levels of Tg. All received high doses of radioiodine. The mean follow-up period was 6.3±5.8 years. There were 11 patients with macrometastases and 16 with micrometastases.ResultsPost-treatment WBS revealed radioiodine accumulation in 19 of 24 (79%) patients. Serum Tg levels were decreased in 8 of 16 (50%) patients. Among patients with micrometastases, five out of seven (71%) demonstrated a decrease in serum Tg levels. Among patients with macrometastases, three out of nine (33%) demonstrated a decrease in Tg values and three (33%) have died due to metastatic thyroid cancer.ConclusionRadioiodine treatment may have a beneficial therapeutic effect in patients who have elevated levels of serum Tg and negative d-WBS. This is especially true in those patients with micrometastases; in patients with macrometastases, a beneficial effect of this approach may be observed less frequently.

Ictal and interictal SPECT findings in childhood absence epilepsy

The purpose of this study was to investigate the informative value of single photon emission tomography (SPECT) in relation to the pathophysiological functioning of the brain during absence seizures and the origin of ictal discharges in idiopathic generalized epilepsies (IGEs). Six patients with childhood absence epilepsy (CAE) were selected for the study and two consecutive SPECT sessions were performed concomitant with EEG recordings revealing normal results and during hyperventilation (HV) studies where the ictal discharges were induced either alone or accompanied by clinical absence seizures. All six patients had ictal discharges in their EEGs during HV and two of them also had clinical absences. SPECT findings during HV revealed an overall increase in the cerebral blood flow (CBF) with significantly higher values as compared to the baseline data. There was no indication for any focal origin in either the interictal or the ictal SPECT findings. Results of the study were supportive for the concept of subcortical origin for the absence seizures and they were also promising for the diagnostic value of ictal SPECT in epileptic cases with undetermined origin as to whether they were localization-related or generalized.

Correlation of technetium-99m MIBI and thallium-201 retention in solitary cold thyroid nodules with postoperative histopathology

Abstract.A comparative prospective study of technetium-99m methoxyisobutylisonitrile (MIBI) and thallium-201 with early (15 min) and delayed (90 min for MIBI, 3 h for 201Tl) imaging in the differentiation of thyroid lesions is presented. Forty patients with cold thyroid nodules visualised on 99mTc-pertechnetate scan and with dyskaryotic or atypical epithelial cells verified by fine-needle aspiration biopsy underwent MIBI and 201Tl scintigraphy at 3-day intervals. Subsequent thyroidectomies were carried out in all patients. Semiquantitative analysis was performed using a lesion to non-lesion ratio on early (ER) and delayed images (DR). Additionally, a retention index (RI) was calculated using the formula RI=(DR– ER) × 100/ER. The reproducibility of the method for the early and delayed measurements was tested by analysing intra- and inter-observer variability and repeatability coefficients. Histopathologically, the nodules were found to be well-differentiated thyroid cancer in 21 patients and benign in 19 patients. There was no significant difference in the ER between malignant and benign lesions for either 201Tl or MIBI (P>0.05). However, for both agents significant differences were found between malignant and benign lesions with regard to DR (P<0.01 for 201Tl and P<0.001 for MIBI) and RI (P<0.001 for both agents). Statistical comparison of the two agents showed no significant differences (P>0.05) except with regard to DR and RI in malignant nodules (P<0.05). A receiver operating characteristic analysis was performed to determine threshold levels for the differentiation of malignant from benign nodules. Following this analysis, ER, DR and RI levels of 1.03, 1.54 and 2 for MIBI and ≤1.42, 1.24 and 5 for 201Tl were selected. Using these threshold levels, the sensitivity, specificity and accuracy of the study were 90.5%, 36.8% and 65% for ER MIBI, 61.9%, 94.7% and 77.5% for DR MIBI, 95.2%, 89.4% and 92.5% for RI MIBI, 85.7%, 47.3% and 67.5% for ER 201Tl, 80.9%, 73.6% and 77.5% for DR 201Tl, and 90.5%, 94.7% and 92.5% for RI 201Tl. In conclusion, the DR for MIBI and 201Tl is superior to the ER in detecting malignant nodules, and the RI for both MIBI and 201Tl is more valuable than the DR in differentiating malignant from benign thyroid nodules.

Local delivery of chitosan/VEGF siRNA nanoplexes reduces angiogenesis and growth of breast cancer in vivo.

Vascular endothelial growth factor (VEGF) is the important angiogenic factor associated with tumor growth and metastasis in a wide variety of solid tumors. The aim of this study is to investigate the tumor suppressive effect of chitosan/small interfering RNA (siRNA)-VEGF nanoplexes in the rat breast cancer model. Chitosan/siRNA nanoplexes (siVEGF-A, siVEGFR-1, siVEGFR-2) and NRP-1 were prepared in a 15 to1 ratio and injected (intratumorally) into the breast-tumor-bearing Sprague-Dawley rats. Tumor volumes were measured during 21 days. To investigate the effect of chitosan/siRNA nanoplexes on VEGF expression in tumors, VEGF was analyzed with immunohistochemistry and western blotting. The mRNA levels of VEGF in tumor samples were determined with real-time PCR (RT-PCR). After siRNA treatment, a marked reduction in tumor volumes was measured in complex-injected rats (97%). Free siRNA injection showed lower tumor inhibition. Reduction of VEGF protein was also shown with western blotting and immunohistochemistry. Similar results were obtained with RT-PCR also. These results indicate that the chitosan/siRNA targeting to VEGF nanoplexes have a remarkably suppressive effect on VEGF expression and tumor volume in breast cancer model of rats.

Normal distribution pattern and physiological variants of 68Ga-PSMA-11 PET/CT imaging.

Purpose68Ga-PSMA-11 is a novel PET tracer suggested to be used for imaging of advanced prostate cancer. In this study, we aimed to present a detailed biodistribution of 68Ga-PSMA-11, including physiological and benign variants of prostate-specific membrane antigen (PSMA) imaging. Materials and methodsWe carried out a retrospective analysis of 40 patients who underwent PSMA PET/computed tomography (CT) imaging and who had no evidence of residual or metastatic disease on the scans. In addition, 16 patients who underwent PSMA PET/CT imaging with any indication other than prostate cancer were included in the study to evaluate physiological uptake in the normal prostate gland. The median, minimum–maximum, and mean standardized uptake value (SUV) values were calculated for visceral organs, bone marrow and lymph nodes, and mucosal areas. Any physiological variants or benign lesions with 68Ga-PSMA-11 were also noted. Results68Ga-PSMA-11 uptake was noted in the kidneys, parotid and submandibular glands, duodenum, small intestines, spleen, liver, and lacrimal glands, and mucosal uptake in the nasopharynx, vocal cords, pancreas, stomach, mediastinal blood pool, thyroid gland, adrenal gland, rectum, vertebral bone marrow, and testes. Celiac ganglia showed slight 68Ga-PSMA-11 uptake in 24 of 40 patients without the presence of any other pathologic lymph nodes in abdominal and pelvic areas. Variable uptake of 68Ga-PSMA-11 was observed in calcified choroid plexus, a thyroid nodule, an adrenal nodule, axillary lymph nodes and celiac ganglia, occasional osteophytes, and gallbladder. The patient group with PSMA PET/CT for indications other than prostate cancer (n=16) showed a slight radiotracer uptake in normal prostate gland (SUVmax: 5.5±1.6, range: 3.5–8.3). ConclusionThis study shows normal distribution pattern, range of SUVs, and physiological variants of 68Ga-PSMA-11. In addition, several potential pitfalls were documented to prevent misinterpretations of the scan.

Technetium-99m ethylene dicysteine: a new renal tubular function agent

Abstract. Technetium-99m ethylene dicysteine (EC), a metabolite of ethylene cysteine dimer (ECD), is a new technetium-labelled renal tubular function tracer introduced as an alternative to ortho-iodohippurate (OIH) and with imaging qualities similar to 99mTc-mercaptoacetyltriglycine (MAG3). The elimination of 99mTc-EC is principally via active tubular transport. It is available in lyophilised kit form which can be easily prepared at room temperature, and the compound remains stable for at least 8 h. Both in normal individuals and in patients, plasma clearance of 99mTc-EC has been reported to be around 0.75 of OIH clearance. Thus there is a very strict correlation between 99mTc-EC and OIH clearance, and several algorithms are available to estimate OIH clearance from 99mTc-EC clearance. The renal extraction ratio of 99mTc-EC is 0.70. The distribution volume of 99mTc-EC is twice that of 99mTc-MAG3 (20% of body weight) and slightly higher than that of OIH. The plasma protein-bound fraction of 99mTc-EC (30%) is significantly lower than that of 99mTc-MAG3 and OIH. The same applies to red blood cell binding of 99mTc-EC (5.7%). There is negligible uptake in the liver and intestines. Within 1 h 70% of 99mTc-EC is excreted in the urine. 99mTc-EC provides the same scintigraphic information as 99mTc-MAG3. The lower liver activity makes 99mTc-EC particularly attractive in patients with renal failure. The 99mTc-EC clearance can be accurately estimated from a single plasma sample obtained at 54 min after injection. In conclusion, 99mTc-EC is a suitable renal imaging agent and for some applications is even more attractive than OIH: it provides an index of tubular function and yields high-quality images. The labelling procedure is easy, radiochemical purity is high and the complex is stable for a long time. The extent to which 99mTc-EC is adopted for clinical use will ultimately depend upon its cost and availability.

Changes in caveolin-1 expression and vasoreactivity in the aorta and corpus cavernosum of fructose and streptozotocin-induced diabetic rats

Hyperglycemia is a common defining feature in the development of endothelial dysfunction which plays a key role in the pathogenesis of both type 1 and type 2 diabetes. Caveolin-1 is the main structural component of caveolae which might be involved in the pathophysiology of macrovascular complications of diabetes. In this study we aimed to observe the effect of caveolin-1 on functional responses of aorta and corpus cavernosum in the streptozotocin and fructose-induced diabetes groups. Type 1 diabetes was induced by intraperitoneal administration of streptozotocin (60 mg/kg),. Type 2 diabetes by adding fructose in the rats drinking water (10% (w/v)) for 8 weeks. For insulin treatment; rats were treated with insulin (6 U/kg) for 8 weeks. In Type I and Type II diabetic groups the contractile responses of corpus cavernosum strips to phenylephrine (EC(50):1.82 x 10(-5)M;1.47 x 10(-5)M, respectively)and relaxation responses to acetylcholine (EC(50):7.5 x 10(-5)M;4.48 x 10(-5)M, respectively)were significantly impaired. Contractile responses of aorticstrips to phenylephrine in diabetic groups were markedly decreased (EC(50):3.7.10(-7)M;2.61.10(-7)M respectively) and dose-dependent relaxation responses to acetylcholine were also attenuated (EC(50):3.23.10(-6)M; 2.0.10(-6)M respectively). Treatment with insulin improved the functional responses in the aorta and corpus cavernosum. Protein expression of caveolin-1 was increased in the aorta and corpus cavernosum of the diabetic groups, but this increase seen in the streptozotocin group was more significant than the fructose group. Our findings indicate that an attenuation of the functional responses in both diabetes groups were probably associated with an enhanced expression of caveolin-1, and therefore a decrease in the eNOS activity with a concomitant decrease in NO synthesis.