Radioembolization with yttrium-90 resin microspheres for neuroendocrine tumor liver metastases

PURPOSE

We aimed to evaluate the effectiveness and safety of radioembolization with yttrium-90 (⁹⁰Y) microspheres in cases with unresectable neuroendocrine tumor liver metastases (NETLMs).

METHODS

Thirty patients (mean age, 55 years) underwent resin-based ⁹⁰Y radioembolization for unresectable NETLM at a single institution between April 2008 and June 2013. Post-treatment tumor response was assessed by cross-sectional imaging using the Response Evaluation Criteria in Solid Tumors (RECIST). Prognostic variables that affected survival were determined.

RESULTS

The mean follow-up was 23.0±19.4 months and the median overall survival was 39 months (95% CI, 12.6–65.4 months), with one- and two-year survival rates of 71% and 45%, respectively. Imaging follow-up using RECIST at three-month intervals demonstrated partial response in 43%, complete remission in 3%, stable disease in 37%, and progressive disease in 17% of patients. Extent of tumor involvement was found to have a statistically significant influence on overall survival (P = 0.03). The existence of extrahepatic disease at the time of radioembolization, radiographic response, age, and primary neuroendocrine tumor site were not significant prognostic factors.

CONCLUSION

The current study demonstrates the effectiveness and safety of radioembolization for the treatment of unresectable NETLMs. We identified that the extent of tumor involvement has a significant effect on overall survival. The use of imaging methods reflecting metabolic activity or cellularity such as scintigraphy or diffusion-weighted MRI would be more appropriate, for the response evaluation of liver metastases after radioembolization.Neuroendocrine tumors (NETs) are a heterogenous group of slow-growing and hormon-releasing malignant tumors. Even though primary NETs originate from a number of locations, 40%–70% of all carcinoids arise in the small intestine and appendix (1, 2). The most common site for metastasis is the liver. Neuroendocrine tumor liver metastasis (NETLM) results in hormone-secretion-related symptoms leading to carcinoid syndrome, pressure on structures, or liver replacement (1–4). Patients with liver metastasis have a five-year survival rate of less than 20% (5). Over the years, improvements in local treatments yielded better control of the symptoms and survival rates, yet only 10% of the patients have limited illness and are eligible for surgery (6). Patient symptomatology and survival can be improved by transarterial treatments like embolization and chemoembolization (6). Limitations of these techniques include the short duration of the effects and the controversial approaches regarding the optimal timing and sequence of the procedures due to the variability of tumor progression (7, 8). Long-term survival benefit was not achieved with systemic chemotherapy (9–11) and treatment with somatostatin analogues is mostly associated with symptomatic relief; there is no clear knowledge of their effect on survival of patients who have carcinoid tumor and metastasis (12).Selective internal radiation therapy (SIRT) has been used to treat unresectable primary and secondary liver cancers for over a decade. Yttrium-90 (⁹⁰Y) is a pure high-energy β emitter with a mean tissue penetration of 2.5 mm. The radioactive microspheres prefer tumoral vascular distribution, so that normal liver tissue is relatively spared and high doses are directed to the tumoral tissue (13). Also, radioembolization-related acute and subacute toxicities are seemingly more tolerable than the ones related to other hepatic embolization procedures (14–16). In this study, we aimed to evaluate the effectiveness and safety of ⁹⁰Y microspheres in cases with unresectable NETLMs.     

Evaluation of Depression and Anxiety Levels in Mothers of Babies' Following Due to Premature Retinopathy

AIM

There are significant increases in the survival rates of premature babies owing to rapid developments in medical technology. As the number of premature babies that can survive in neonatal intensive care increases, so does the frequency of complications due to prematurity. The aim of this study was to investigate the depressive and anxiety symptom levels, and factors affecting these, in mothers of infants who were followed up owing to a diagnosis of premature retinopathy (ROP).

Comparison of Short-Time Fourier Transform and Eigenvector MUSIC Methods Using Discrete Wavelet Transform for Diagnosis of Atherosclerosis

In this paper, a more effective use of Doppler techniques is presented for the purpose of diagnosing atherosclerosis in its early stages using the carotid artery Doppler signals. The power spectral density (PSD) graphics are obtained by applying the short-time Fourier transform (STFT)-Welch and the Eigenvector MUSIC methods to the discrete wavelet transform (DWT) of Doppler signals. The PSDs for the fourth approximation component (A4) of both methods estimated that the patients with atherosclerosis in its early phase had lower maximum frequency components. On the other hand, the healthy subjects had higher maximum frequency components. The area under the curve (AUC), which belongs to the receiver operating characteristic (ROC) curve for the frequency level of the maximum PSDs of the A4 approximation obtained from the STFT modeling, is computed as 0.97. The AUC for the MUSIC modeling is computed as 0.996. The AUC belonging to the ROC curve for the higher maximum frequency component is computed as 0.87. The AUC belonging to the ROC curve for the test parameter of the frequency level of the maximum PSDs derived from the MUSIC modeling is determined to be 0.882. The results of this study clearly demonstrate that it is possible to distinguish between the healthy people and the patients with atherosclerosis by using the frequency level of the maximum PSDs for the A4 approximation. Furthermore, it is concluded that the power of Eigenvector-MUSIC method in terms of the resolution of the high frequencies is better than that of the STFT methods.     

Role of contrast-enhanced 3D magnetic resonance portography in evaluating portal venous system compared with color Doppler ultrasonography

Aim The purpose of this study was to evaluate the capability of contrast-enhanced three-dimensional (3D) MR portography in detecting abnormal findings associated with the portal venous system compared with the results of color Doppler ultrasonography (CDUS). Materials and methods MR portography findings were retrospectively compared with the results of CDUS examinations in 161 patients, who were suspected of having portal venous system abnormalities. Portal venous vessels were divided into main 5 groups including the main portal vein, its left and right intrahepatic branches, splenic vein and superior mesenteric vein. Imaging findings were classified as normal, occluded, or partially thrombosed. Results of clinical and imaging follow-up examinations including CDUS, MR portography or angiography, if available, were used as a proof of final diagnosis. The potential sites of varicose veins and collateral vessels were also examined by both imaging methods. Results Vascular abnormalities were identified in 79 of 161 patients. There was a statistically significant agreement between the results of MR portography and CDUS in evaluating portal venous system (κ = 0.871, P < 0.05). The sensitivity of MR portography was slightly superior to CDUS in detecting partially thrombosis and occlusion in the main portal venous vessels. In addition, MR portograms were superior to CDUS in the management of patients with portal hypertension by identifying portosystemic collaterals more adequately, and clearly demonstrated portal venous vessels that cannot be visualized at CDUS. Conclusion Results of present study indicates that contrast-enhanced 3D MR portography is well suited and superior to CDUS in the management of patients with portal hypertension.     

Cystine-glutamate transporter SLC7A11 mediates resistance to geldanamycin but not to 17-(allylamino)-17-demethoxygeldanamycin

The cystine-glutamate transporter SLC7A11 has been implicated in chemoresistance, by supplying cystine to the cell for glutathione maintenance. In the NCI-60 cell panel, SLC7A11 expression shows negative correlation with growth inhibitory potency of geldanamycin but not with its analog 17-(allylamino)-17-demethoxygeldanamycin (17-AAG), which differs in the C-17 substituent in that the the methoxy moiety of geldanamycin is replaced by an amino group. Structure and potency analysis classified 18 geldanamycin analogs into two subgroups, "17-O/H" (C-17 methoxy or unsubstituted) and "17-N" (C-17 amino), showing distinct SLC7A11 correlation. We used three 17-O/H analogs and four 17-N analogs to test the role of the 17-substituents in susceptibility to SLC7A11-mediated resistance. In A549 cells, which are resistant to geldanamycin and strongly express SLC7A11, inhibition of SLC7A11 by (S)-4-carboxyphenylglycine or small interfering RNA increased sensitivity to 17-O/H, but had no effect on 17-N analogs. Ectopic expression of SLC7A11 in HepG2 cells, which are sensitive to geldanamycin and express low SLC7A11, confers resistance to geldanamycin, but not to 17-AAG. Antioxidant N-acetylcysteine, a precursor for glutathione synthesis, completely suppressed cytotoxic effects of 17-O/H but had no effect on 17-N analogs, whereas the prooxidant ascorbic acid had the opposite effect. Compared with 17-AAG, geldanamycin led to significantly more intracellular reactive oxygen species (ROS) production, which was quenched by addition of N-acetylcysteine. We conclude that SLC7A11 confers resistance selectively to 17-O/H (e.g., geldanamycin) but not to 17-N (e.g., 17-AAG) analogs partly as a result of differential dependence on ROS for cytotoxicity. Distinct mechanisms could significantly affect antitumor response and organ toxicity of these compounds in vivo.     

Acute transient encephalopathy after weekly paclitaxel infusion

Paclitaxel is highly active against a variety of solid tumors including breast lung, ovarian and head and neck cancer. Although peripheral neurotoxicity is well-known side effect, central nervous system (CNS) toxicity-related standard dose of paclitaxel is extremely uncommon, because paclitaxel dose not cross the blood–brain barrier and is not detectable in the cerebrospinal fluid. We present a patient with advanced stage breast carcinoma who developed acute and spontaneous resolving encephalopathy after weekly dose of paclitaxel. The patient did not have brain metastasis, or prior whole-brain irradiation, or any type of neurosurgery. Radiological imaging studies showed no abnormalities. CNS toxicity of paclitaxel should be kept in mind in patients without a previous history of brain metastasis or brain irradiation and even with low weekly doses.     

Prevalence of thyroid dysfunction in untreated cancer patients: a cross-sectional study

The relationship between thyroid disease and cancer (and cancer therapies) has been under investigation for years. Factors that increase the risk for thyroid disease include iodine deficiency, autoimmune disorders, old age, and pregnancy. The screening policy for thyroid disease in the healthy population is not precisely defined, and the frequency of thyroid dysfunction in untreated cancer patients has not been investigated in any great detail. This study was designed to compare the prevalence of thyroid dysfunction in 457 untreated cancer patients at the time of initial diagnosis to that of 373 age- and sex-matched subjects who were healthy and cancer-free (control group). Thyroid dysfunction was found in 29.5?% (135/457) of the cancer patients, while only 15.4?% (56/373) of the control group had thyroid dysfunction (p?=?0.0001). The most prevalent abnormality was euthyroid sick syndrome (14.0?%, 64/457). Overt and subclinical hyperthyroidism and overt hypothyroidism were observed more frequently in cancer patients than the control group, and these differences were all statistically significant. Thyroid dysfunction was more frequent in patients with poor performance scores and those over the age of 50?years. These data indicate that alterations in thyroid hormone metabolism are twice as common in patients with untreated cancer than in control subjects. Those alterations may lead to delayed diagnosis, suboptimal treatment, and a poorer prognosis. In all, this study suggests that screening with thyroid function tests is strongly recommended in all newly diagnosed cancer patients.     

Evaluation of individual and combined neurotoxicity of the immunosuppressants cyclosporine and sirolimus by in vitro multinuclear NMR spectroscopy

Neurotoxicity, a crucial side effect of immunosuppressive therapy with cyclosporine, also has been demonstrated in vitro for sirolimus, a novel macrolide immunosuppressant, which is under clinical investigation in combination with cyclosporine. NMR spectroscopy was used to study the separate and combined effects of cyclosporine and sirolimus on cerebral metabolism, both in brain cells and in perfused rat brain slices. The high-energy phosphate metabolism was already affected significantly at cyclosporine concentrations as low as 100 micrograms/liter: phosphocreatine was reduced by 10 +/- 2% [half-maximal inhibition concentration (IC50) = 1850 +/- 600 micrograms/liter], and nucleoside triphosphate was reduced by 11 +/- 5% (IC50 = 1110 +/- 420 micrograms/liter; n = 4, P <.05). At 500 micrograms/liter cyclosporine, N-acetylaspartate and glutamate were decreased by 13 +/- 7% (IC50 = 1100 +/- 330 micrograms/liter) and 22 +/- 9% (IC50 = 360 +/- 220 micrograms/liter; n = 4, P <.05), respectively. As evaluated using an algorithm based on Loewe isobolograms, combination of cyclosporine and sirolimus resulted in a synergetic reduction of high-energy phosphate metabolites. Addition of sirolimus to the perfusion medium increased brain slice concentrations of cyclosporine. It is concluded that cyclosporine significantly reduced high-energy phosphate metabolism in brain tissue at in vivo relevant concentrations. Combination with sirolimus resulted in synergism, which, in part, is explained by a greater distribution of cyclosporine into the brain tissue in the presence of sirolimus.