68 Ga-labeled, imatinib encapsulated, theranostic liposomes: Formulation, characterization, and in vitro evaluation of anticancer activity.

Cancer is still a global health problem. Among cancer types, breast cancer is the most frequently diagnosed one, and it causes a high mortality rate if not diagnosed in the early stages. In our study, imatinib encapsulated, nanosized, neutral/cationic liposome formulations were prepared as theranostic agents for breast cancer. After the characterization studies in which all liposomes exhibited proper profile owing to their particle size between 133 and 250 nm, polydispersity index values lower than 0.4, neutral and cationic zeta potential values, and high drug encapsulation efficiency, controlled drug release behaviors with zero-order kinetic were obtained. The higher than 90% radiolabeling efficiency values were obtained thanks to the determination of optimum radiolabeling condition (80°C temperature, 5 mCi radioactivity, and 10 min incubation period). According to the resazurin assay evaluating the cytotoxic profile of liposomes on MCF7 cells, neutral empty liposome was found as biocompatible, while both cationic liposomes (empty and drug-loaded ones) exhibited high nonspecific cytotoxicity at even low drug concentration due to the existence of stearyl amine in the formulations. However, dose-dependent cytotoxic effect and the highest cellular binding capacity were obtained by imatinib loaded neutral liposomes. In conclusion, 68 Ga-radiolabeled, imatinib-loaded, neutral, nanosized liposome formulation is the most promising one as a theranostic agent among all formulations.

What has changed in the last 25 years in osteosarcoma treatment? A single center experience.

BACKGROUND: Osteosarcoma is the most common type of primary malignant bone tumor in the extremities. The main purpose of this study was to determine clinical features, prognostic factors, and treatment results of patients with osteosarcoma at our center. METHODS: We retrospectively analyzed the medical records of children with osteosarcoma between the years 1994-2020. RESULTS: 79 patients were identified (54.4% male, 45.6% female). The most common primary site was the femur (62%). Twenty-six of them (32.9%) had lung metastasis at diagnosis. The patients were treated between 1995- 2013 according to the Mayo Pilot II Study protocol, while the others were treated with the EURAMOS protocol between the years 2013-2020. Sixty-nine patients underwent limb salvage surgery as a local treatment, whereas seven underwent amputation. The median follow-up time was 53 months (2.5-265 months). The event-free survival (EFS) and overall survival (OS) rates at 5 years were 52.1% and 61.5%. The 5-year EFS and OS rates were 69.4% and 80% in females; 37.1% and 45.5% in males (p=0.008/p=0.001). The 5-year EFS and OS rates of the patients without metastasis were 63.2% and 66.3%; with metastasis 28.8% and 51.8% (p=0.002/p=0.05). For good-responders, the 5-year EFS and OS rates were 80.2% and 89.1%; while for poor-responders, 35% and 46.7% (p=0.001). Mifamurtide was used in addition to chemotherapy as of the year 2016 (n=16). The 5-year EFS and OS rates were 78.8% and 91.7%, respectively for the mifamurtide group; 55.1% and 45.9%, respectively for the non-mifamurtide group (p=0.015, p=0.027). CONCLUSIONS: Metastasis at diagnosis and poor response to preoperative chemotherapy were the most important predictors of survival. Females had a better outcome than males. In our study group, the mifamurtide group`s survival rates were significantly higher. Further large studies are needed to validate the efficacy of mifamurtide.

Unusual 68 Ga-DOTATATE Uptake in Primary Nodal Hemangioma of Axillary Lymph Node.

ABSTRACT: 68 Ga-DOTATATE PET/CT is a well-known modality in diagnosis, staging, and in predicting therapy response of neuroendocrine tumors. We present a case of 63-year-old woman with diagnosis of pancreas neuroendocrine tumor showing 68 Ga-DOTATATE uptake in a lymph node in left axilla. It was diagnosed as capillary hemangioma after biopsy. 68 Ga-DOTATATE uptake in bone hemangiomas is well-known; however, its uptake in a nodal hemangioma is worth to know as it might change the clinical perspective.

Unexpected False-positive I-131 Uptake in Patients with Differentiated Thyroid Carcinoma

Objective: Radioiodine is the most specific radionuclide for differentiated thyroid carcinoma (DTC) imaging. Despite its high specificity and sensitivity, false-positive I-131 uptake could be seen on whole body scan (WBS) that may lead to misdiagnosis and unnecessary radioiodine treatment. In this study, we aimed to present the I-131 WBS and concomitant single photon emission computed tomography/computed tomography (SPECT/CT) images of unexpected false-positive radioiodine uptake along with the patients' clinical outcomes and the contribution of SPECT/CT imaging. Methods: I-131 WBSs of 1507 patients with DTC were retrospectively reviewed, and anticipated I-131 uptakes (like in breasts or thymus) were excluded from the study. The unexpected false-positive I-131 uptakes with concomitant SPECT/CT imaging were included in the study. Results: Twenty-one patients had 23 unexpected I-131 uptakes on WBS and concomitant SPECT/CT imaging. The vast majority (87%) of these cases were seen on post-therapeutic I-131 WBS. Most of the false-positive I-131 uptakes could be explained by SPECT/CT and radiologic findings, and were secondary to non-thyroid conditions (bronchiectasis, lung infection, subcutaneous injection into gluteal fatty tissue, aortic calcification, benign bone cyst, vertebral hemangioma, recent non-thyroid surgical procedure site, rotator cuff injury, mature cystic teratoma and ovarian follicle cyst). However, the possible reasons of 9 false-positive I-131 uptakes could not be explained by radiologic findings. Conclusion: We suggest that false-positive I-131 uptake and its underlying mechanisms (inflammation, trapping, increased perfusion, etc.) must be kept in mind in patients with thyroid cancer and unexpected findings must be considered together with serum thyroglobulin levels, SPECT/CT and radiologic findings in order to avoid misdiagnosis and unnecessary radioiodine treatment.

Comparison of gated myocardial perfusion SPECT, echocardiography and equilibrium radionuclide ventriculography in the evaluation of left ventricle contractility.

OBJECTIVES: In this study, we investigated the reliability of gated myocardial perfusion single-photon emission computerized tomography (GSPECT) for the evaluation of left ventricle (LV) function. We compared left ventricle ejection fraction (LVEF) calculated with GSPECT with the values derived from planar equilibrium-gated radionuclide ventriculography (ERVG) and echocardiography (ECHO). STUDY DESIGN: Forty-eight patients with suspected coronary artery disease (CAD), who were referred for evaluation of myocardial perfusion and LV function and underwent two-day 99mTc-MIBI protocol GSPECT and ERVG, were examined retrospectively. LVEF was calculated with GSPECT Myometrix software, and wall motion and thickness were calculated with QGS analysis program. In the ERVG study, LVEF values were calculated using left anterior oblique images. In the GSPECT and ERVG study, wall motion was evaluated visually and scored. LVEF values and wall motion data measured with ECHO were noted. RESULTS: For all cases, there was a significant correlation between LVEF values calculated by GSPECT and ERVG. Numerical LVEF values of 30 patients measured with ECHO showed no significant difference from the values measured with GSPECT. When 240 segments obtained from 48 patients were examined, the correlation between GSPECT and ERVG was 77.5% and between GSPECT and ECHO was 75.4% by visual wall motion analysis. Quantitatively calculated wall motion and thickness scores of segments visually defined as normokinetic were significantly higher than segments visually defined as having contraction defect. CONCLUSION: GSPECT can be used safely in clinical practice for the evaluation of LV function. Quantitatively calculated wall motion and thickness scores are promising methods to verify the visual evaluation.

Joint practice guidelines for radionuclide lymphoscintigraphy for sentinel node localization in oral/oropharyngeal squamous cell carcinoma.

Involvement of the cervical lymph nodes is the most important prognostic factor for patients with oral/oropharyngeal squamous cell carcinoma (OSCC), and the decision whether to electively treat patients with clinically negative necks remains a controversial topic. Sentinel node biopsy (SNB) provides a minimally invasive method of determining the disease status of the cervical node basin, without the need for a formal neck dissection. This technique potentially improves the accuracy of histological nodal staging and avoids over-treating three-quarters of this patient population, minimizing associated morbidity. The technique has been validated for patients with OSCC, and larger-scale studies are in progress to determine its exact role in the management of this patient population. This article was designed to outline the current best practice guidelines for the provision of SNB in patients with early-stage OSCC, and to provide a framework for the currently evolving recommendations for its use. These guidelines were prepared by a multidisciplinary surgical/nuclear medicine/pathology expert panel under the joint auspices of the European Association of Nuclear Medicine (EANM) Oncology Committee and the Sentinel European Node Trial Committee.

EANM-EORTC general recommendations for sentinel node diagnostics in melanoma.

The accurate diagnosis of a sentinel node in melanoma includes a sequence of procedures from different medical specialities (nuclear medicine, surgery, oncology, and pathology). The items covered are presented in 11 sections and a reference list: (1) definition of a sentinel node, (2) clinical indications, (3) radiopharmaceuticals and activity injected, (4) dosimetry, (5) injection technique, (6) image acquisition and interpretation, (7) report and display, (8) use of dye, (9) gamma probe detection, (10) surgical techniques in sentinel node biopsy, and (11) pathological evaluation of melanoma-draining sentinel lymph nodes. If specific recommendations given cannot be based on evidence from original, scientific studies, referral is given to "general consensus" and similar expressions. The recommendations are designed to assist in the practice of referral to, performance, interpretation and reporting of all steps of the sentinel node procedure in the hope of setting state-of-the-art standards for good-quality evaluation of possible spread to the lymphatic system in intermediate-to-high risk melanoma without clinical signs of dissemination.

Sentinel node in breast cancer procedural guidelines.

Procedure guidelines for scintigraphic detection of sentinel node in breast cancer are presented.

Improved efficacy of aerosol delivery to distal airways in pediatric subjects using a new spacer mouth-mask.

Aerosol nebulization is and most effective ways of treating airway diseases especially in children. Failure of inhaled asthma treatment is mainly due to inadequate deposition of drugs in the peripheral area of the lungs. The aim of this study was to compare the efficacy of a traditional mask and that of a new spacer mouth-mask (Nebula, Markos Mefar, Italy) when used with a jet nebulizer, by measuring aerosol deposition in the lungs, oropharynx, upper airways, and gastrointestinal tract. Twelve children without respiratory disease aged between 8 and 13 years were included in the study. Aerosol inhalation was performed using a jet nebulizer with 2 mL of saline solution containing 20 Mci of Tc99m-DTPA. The first group initially performed aerosol inhalation using a traditional facemask and then, one week later, using the new spacer mouth-mask. The second group performed aerosol inhalation using the new spacer mouth-mask first and then, one week later, using a traditional mask. Scintigraphic ventilation images were then obtained, and aerosol deposition in the trachea, oropharynx, lungs and stomach was measured. In the first group, the radioaerosol deposition in the peripheral lung area using the new spacer mouth-mask was greater 97.8 +/- 7.0 vs. 68.5 +/- 7.9 (p = 0.04). On the other hand, the oropharyngeal radioaerosol deposition was greater using the traditional mask: 50.2 +/- 5.2 vs 20.3 +/- 11.8 (p = 0.028). Similarly, in the second group the peripheral lung deposition was greater and the oropharyngeal deposition was less using the new spacer mouth-mask: 97.3 +/- 9.4 vs. 70.2 +/- 11.2 and 20.7 +/- 8.9 vs. 46.3 +/- 16.8 (p = 0.028 and 0.046 respectively). In conclusion, the new design of the spacer mouth-mask allows greater aerosol deposition in the peripheral lung area and less in other parts such as the oropharyngeal area, the central airways and the stomach.

Tc-99m MIBI SPECT in prediction of prognosis in patients with small cell lung cancer.

PURPOSE: The purpose of this study was to evaluate whether the degree of technetium-99m methoxyisobutylisonitrile (MIBI) uptake and its retention in delayed imaging in small cell lung cancer (SCLC) was correlated with the response to multiagent chemotherapy and to investigate if there was a relationship between the survival time of patients with SCLC and Tc-99m MIBI SPECT tumor uptake parameters at the time of diagnosis. METHODS: Between 1998 and by December 2004, 40 patients with SCLC were studied with Tc-99m MIBI SPECT at the time of diagnosis. The patients were classified by a follow-up CT as good responders (complete or partial remission) and poor responders (stable disease or progressive disease). Following i.v. administration of 740 MBq Tc-99m MIBI, SPECT imaging at 30 minutes (early) and 2 hours (delayed) was performed. Regions of interests were placed over the tumors and contralateral normal lung tissue on one transverse section. The uptake ratio of the lesion to that in the contralateral normal lung was obtained from early images (early ratio; ER) as well as delayed images (delayed ratio; DR). The retention index (RI%) was measured as: RI% = [(DR-ER)/ER] x 100. Tc-99m MIBI tumor uptake parameters were compared with chemotherapeutic response and survival time. RESULTS: Of 40 patients, 29 patients were good responders (72.5%) and 11 patients were poor responders (27.5%). RI% of Tc-99m MIBI SPECT in the group of good response was significantly higher than in that with poor response (p < 0.05). On the other hand, there was no significant difference between the two groups with respect to ER or DR values. Four of 40 patients were still alive with disease (10%). The patient survival time varied from 1 to 70 months (mean survival time = 12.9 +/- 13.4 months). There was no significant difference between the survival time of patients with respect to ER or DR of Tc-99m MIBI SPECT imaging. When median RI% was accepted as a cut-off value (-3.85%), patients with higher RI% values had a longer survival time (12 months) when compared with those with low RI% (8 months), p < 0.05. CONCLUSION: Our results suggest that Tc-99m MIBI SPECT could accurately predict the chemotherapy response in patients with SCLC. RI% of Tc-99m MIBI SPECT is recommended to differentiate patients with a poor response to chemotherapy and good responders, and RI% of Tc-99m MIBI SPECT appears as the only parameter that may be useful in predicting the survival of patients with SCLC.

To use MIBI or not to use MIBI? That is the question when assessing tumour cells.

99mTc-sestamibi (MIBI) is a well-known tumour imaging agent. Its retention within tumour cell mitochondria is related to perfusion and to the magnitude of the electrical gradient, reflecting cell viability. Several internal cell factors modulate this uptake; for example, multidrug resistance membrane proteins (Pgp and MRP1) and anti-apoptotic BCl-2 protein of the outer mitochondrial membrane can limit retention of MIBI. At the early stage of cell apoptosis, the electrical driving forces of MIBI uptake are impaired, and influx and accumulation are reduced. It seems clear that MIBI can be used before treatment to detect drug resistance, assess anti-apoptotic status and predict treatment efficacy. Although it has been suggested that MIBI might be used to monitor tumour response to treatment, MIBI is unable to differentiate tumours with ongoing apoptosis from those developing drug resistance.

99mTc-MIBI imaging as a predictor of therapy response in osteosarcoma compared with multidrug resistance-associated protein and P-glycoprotein expression.

UNLABELLED: In vitro studies have demonstrated that (99m)Tc-methoxyisobutylisonitrile ((99m)Tc-MIBI) is a transport substrate of multidrug resistance (MDR)-related proteins. The aim of this clinical study was to evaluate whether (99m)Tc-MIBI scintigraphy was a functional imaging tool for in vivo detection of multidrug resistance-associated protein (MRP) expression in osteosarcoma and to investigate the role of MRP and (99m)Tc-MIBI imaging to predict the clinical outcome. We also examined whether the scintigraphic parameters would help to distinguish the functional capacity of P-glycoprotein (Pgp) and MRP. METHODS: Twenty-four patients with a diagnosis of osteosarcoma were studied before neoadjuvant chemotherapy. Tumor-to-background ratios of both early (10 min) and delayed (1 h) images and the percentage washout rate (WR%) of (99m)Tc-MIBI were calculated. Immunohistochemical analysis of MRP and Pgp was performed on biopsy specimens, and the response to preoperative chemotherapy was assessed by histopathologic examination. RESULTS: Fifteen of 24 osteosarcoma samples in our series (62.5%) showed significant expression of MRP. The level of MRP expression was significantly correlated with the WR% of (99m)Tc-MIBI (r = 0.58, P = 0.003), and the WR% of (99m)Tc-MIBI was significantly faster in patients with high MRP expression than in those with a low MRP score (P = 0.007). The clearance rate of (99m)Tc-MIBI was significantly slower in tumor samples with negative or low expression of both Pgp and MRP (16% +/- 6.2%) when compared with osteosarcomas with high expression of both proteins (31.7% +/- 8.7%) (P = 0.001). There was not a significant difference between the WR% of (99m)Tc-MIBI in tumors with coexpression of both proteins and in tumors with high expression of either Pgp or MRP. Both the rate of MRP expression and the WR% of (99m)Tc-MIBI were significantly correlated with response rate. CONCLUSION: Our results suggest that the WR% of (99m)Tc-MIBI is correlated with MRP expression. Both the WR% of (99m)Tc-MIBI and MRP expression are correlated with therapy response. (99m)Tc-MIBI can be used as a general probe for functional imaging of both Pgp and MRP; however, it is not capable of differentiating the functional status of either MDR-related glycoprotein.

Experience of the Izmir Pediatric Oncology Group on Neuroblastoma: IPOG-NBL-92 Protocol.

This multicentric study aimed to bring neuroblastoma patients together under IPOG-NBL-92 protocol and evaluate the results within the period between 1992 and 2001 in Izmir. Sixty-seven neuroblastoma patients from 4 pediatric oncology centers in Izmir were included in the study. IPOG-NBL-92 protocol modified from German Pediatric Oncology (GPO)-NB-90 protocol was applied: Patients in stage 1 received only surgery, while surgery plus 4 chemotherapy courses (cisplatin, vincristine, ifosfamide) were given in stage 2 and surgery plus 6 chemotherapy courses (cisplatin, vincristine, ifosfamide, epirubicin, cyclophosphamide) were given in stages 3 and 4 patients. In patients who were kept in complete remission (CR), a maintenance therapy of one year was applied. Radiotherapy was given to the primary site following induction chemotherapy plus surgery in stages 3 and 4 patients with partial remission (PR). The stages of the patients were as follows: 5% in stage 1, 39% in stage 3, 49% in stage 4, and 7% in stage 4S. Primary tumor site was abdomen in 88% of cases. CR rates were as 100% in stage 1, 76% in stage 3, 35% in stage 4, and 75% in stage 4S. Relapse was observed in 32% of patients in a median of 19 months. The median follow-up time for survivors was 33 (17-102) months. Five-year OS rate was 31% and the EFS rate was 30% in all patients. Five-year overall and event-free survival rates were 63 and 30% in stage 3, but 6 and 5%, respectively, in stage 4 patients. Univariate analysis established that the age, stage, primary tumor site, and high LDH and NSE levels conferred a significant difference. The IPOG-NBL-92 protocol has proved to be satisfactory with tolerable toxicity and reasonable CR and survival rates. However, more effective treatments suitable to Turkey's social and economic conditions are urgently needed for children over 1 year of age with advanced neuroblastoma.

Treatment results of osteosarcoma of the extremity in children and adolescents at Ege University Hospital.

Twenty-five patients were treated for osteosarcoma of the extremity at Ege University Hospital. Eight of them were metastatic. All patients received cisplatin, doxorubicin, ifosfamide, and methotrexate preoperatively. Twenty-three patients underwent surgery at around week 15 (11-18 weeks). All but one underwent limb-sparing surgery. While good responders continued to receive the same drugs, poor responders were given the same regimen before 1996, but high-dose ifosfamide alone after 1996. For all patients the projected event-free survival (EFS) rates were 63.5% at 2 years and 53% at 5 years. The projected overall survival (OS) rates were 72% at 2 years and 62% at 5 years. For nonmetastatic patients, 5-year EFS and OS rates were 67% as compared with metastatic patients (25 and 50%)(p =. 01 for EFS; p > .05 for OS). The results show that nonmetastatic patients with osteosarcoma of the extremity have favorable prognosis on this therapy regimen, allowing a high rate of limb-sparing surgery.

The role of Tc-99m sestamibi imaging in predicting clinical response to chemotherapy in lung cancer.

Multidrug resistance (MDR) is a major problem in lung cancer. Tc-99m methoxyisobutyl isonitrile (MIBI) has been demonstrated to be a non-invasive marker to diagnose MDRI related P-glycoprotein (Pgp) and multidrug resistance-associated protein (MRP) expression in various solid tumors. The aim of this study was to evaluate the relationship between the degree of Tc-99m MIBI uptake and its retention on delayed images and the response to chemotherapy in lung cancer. Twenty-three patients (1 woman and 22 men, age range 40-67 years) with lung cancer (9 small cell and 14 non-small cell) were examined with Tc-99m MIBI imaging before chemotherapy. After i.v. administration of 740 MBq Tc-99m MIBI, planar and SPECT imaging at 30 minutes and 2 hours was performed. Tumor to normal lung uptake ratio (T/N) and percent retention were measured. Response to chemotherapy was evaluated according to follow-up CT and grouped as complete responders (CR), partial responders (PR) and non-responders (NR). Clinical follow-up and CT evaluation revealed that 12 patients had partial remission, 4 patients had complete remission and 7 patients had no-remission after chemotherapy. Statistically, there was no significant correlation between early (30 min), delayed (2 hr) T/N ratios and percent retention of Tc-99m MIBI with chemotherapeutic response of the lung cancer among the three groups (p > 0.05). Results of the current study imply that Tc-99m MIBI uptake and the retention index may not correlate with chemotherapy response in lung cancer, so that the accuracy of this method needs to be verified in a larger series with additional investigation at the molecular level.

Technetium-99m-DTPA aerosol scintigraphy in amiodarone induced pulmonary toxicity in comparison with Ga-67 scintigraphy.

Amiodarone hydrochloride, which is used in life-threatening cardiac tachyarrhythmia, has been known to cause amiodarone induced pulmonary toxicity (AIPT) as a complication. In this study we aimed to investigate the clinical value of technetium-99m diethylene triamine penta-acetic acid (DTPA) aerosol lung scintigraphy in patients with AIPT in comparison with gallium-67 (Ga-67) scan. The study group included 26 cases, 7 patients with diagnosis of AIPT (Group A), 8 patients receiving amiodarone therapy but without AIPT (Group B) and 11 healthy subjects as a control group (Group C). All patients underwent Ga-67 and Tc-99m-DTPA aerosol scintigraphy in addition to various laboratory tests, Ga-67 scintigraphy was positive in 4 of 7 AIPT patients but quite normal in Group B. A positive correlation was found (r = 0.52, p < 0.05) between kep values determined by Tc-99m-DTPA aerosol scintigraphy and the cumulative dose of amiodarone. The mean kep values were 2.04% +/- 0.85%/min, 1.30% +/- 0.42%/min and 0.86% +/- 0.19%/min for groups A, B and C, respectively. The mean clearance rate of group A was significantly faster than that of normals (p < 0.0005) and group B (p = 0.028). In addition, there was a significant difference between groups B and C (p = 0.015). In conclusion, Ga-67 lung scintigraphy is a useful method for the detection of AIPT but Tc-99m-DTPA aerosol scintigraphy offers better results than Ga-67 scintigraphy. Early changes in Tc-99m-DTPA clearance may be observed in patients receiving amiodarone. The kep value in patients with AIPT is noticeably increased with respect to the control group. With its favorable physical properties, low cost, lower radiation burden and its ability to be used as an objective measure for the pulmonary clearance rate, Tc-99m-DTPA aerosol scintigraphy appears to be promising in patients receiving amiodarone therapy.