Faculty Bibliography

INTRODUCTION/BACKGROUND:Receptor radionuclide therapy is a promising treatment modality for patients with neuroendocrine tumors for whom alternative treatments are limited. The aim of this study was to investigate the incidence of hormonal crises after therapy with the radiolabeled somatostatin analogue [(177)Lu-DOTA(0),Tyr(3)]octreotate ((177)Lu-octreotate). MATERIALS AND METHODS/METHODS:All (177)Lu-octreotate treatments between January 2000 and January 2007 were investigated. Four hundred seventy-six patients with gastroenteropancreatic neuroendocrine tumors and three patients with metastatic pheochromocytoma were included for analysis. RESULTS:Four hundred seventy-nine patients received a total of 1,693 administrations of (177)Lu-octreotate. Six of 479 patients (1%) developed severe symptoms because of massive release of bioactive substances after the first cycle of (177)Lu-octreotate. One patient had a metastatic hormone-producing small intestinal carcinoid; two patients had metastatic, hormone-producing bronchial carcinoids; two patients had vasoactive intestinal polypeptide-producing pancreatic endocrine tumors (VIPomas); and one patient had a metastatic pheochromocytoma. With adequate treatment, all patients eventually recovered. CONCLUSION/CONCLUSIONS:Hormonal crises after (177)Lu-octreotate therapy occur in 1% of patients. Generally, (177)Lu-octreotate therapy is well tolerated.

BACKGROUND:We previously reported the efficacy of a combined treatment of active acromegaly with both long-acting somatostatin analogs (SSA) and pegvisomant (PEG-V). OBJECTIVE:Our objective was to assess long-term efficacy and safety in a larger group of acromegalic patients after a period of 138 (35-149) wk [median (range)]. DESIGN/METHODS:PEG-V was added to high-dose SSA treatment in 32 subjects (13 females) who had not shown a normalization in serum IGF-I concentrations during SSA monotherapy. PEG-V dosage was increased until IGF-I concentration normalized. The maximal dose was 80 mg twice weekly. RESULTS:After dose finding, IGF-I remained within the normal range in all subjects with PEG-V administered once (n = 24) or twice (n = 8) weekly, on a total weekly dose of 60 (40-160) mg. Baseline IGF-I levels were positively correlated with the required dosage of PEG-V (r = 0.48; P = 0.006). PEG-V-dependent liver enzyme disturbances were observed in 11 (6 diabetic) subjects, of which symptomatic gallstones explained two cases. These liver enzyme disturbances were transient in all subjects without discontinuation or dose adaptation of PEG-V. In our series, diabetic patients had a 5.1 times (odds ratio) (confidence interval, 1.02-25.54; P < 0.05) higher risk for developing liver enzyme disturbances. These liver enzyme disturbances seemed to occur earlier. Pituitary adenoma size decreased in four patients. No increase in tumor size was observed in any of the patients. CONCLUSION/CONCLUSIONS:Long-term combined treatment with long-acting SSA and (twice) weekly PEG-V for active acromegaly seems to be effective and safe. Patients with acromegaly and diabetes seem to have a higher risk of developing transient liver enzyme disturbances.

Dopamine D2 receptor scintigraphy of pituitary adenomas is feasible by single-photon emission computed tomography using (123)I-S-(-)-N-[(1-ethyl-2-pyrrolidinyl)methyl]-2-hydroxy-3-iodo-6-methoxybenzamide ((123)I-IBZM) and (123)I-epidepride. (123)I-epidepride is generally superior to (123)I-IBZM for the visualization of D2 receptors on pituitary macroadenomas. However, (123)I-IBZM and (123)I-epidepride scintigraphy are generally not useful to predict the response to dopaminergic treatment in pituitary tumour patients. These techniques might allow discrimination of non-functioning pituitary macroadenomas from other non-tumour pathologies in the sellar region. Dopamine D2 receptors on pituitary tumours can also be studied using positron emission tomography with (11)C-N-raclopride and (11)C-N-methylspiperone.

CONTEXT/BACKGROUND:Adrenocortical carcinoma (ACC) is a rare tumor with a poor prognosis. Despite efforts to develop new therapeutic regimens for metastatic ACC, surgery remains the mainstay of treatment. Interferons are known to exert tumor-suppressive effects in several types of human cancer. DESIGN/METHODS:We evaluated the tumor-suppressive effects of type I interferons (IFN)-alpha2b and IFNbeta on the H295 and SW13 human ACC cell lines. RESULTS:As determined by quantitative RT-PCR analysis and immunocytochemistry, H295 and SW13 cells expressed the active type I IFN receptor (IFNAR) mRNA and protein (IFNAR-1 and IFNAR-2c subunits). Both IFNalpha2b and IFNbeta1a significantly inhibited ACC cell growth in a dose-dependent manner, but the effect of IFNbeta1a (IC50 5 IU/ml, maximal inhibition 96% in H295; IC50 18 IU/ml, maximal inhibition 85% in SW13) was significantly more potent, compared with that of IFNalpha2b (IC50 57 IU/ml, maximal inhibition 35% in H295; IC50 221 IU/ml, maximal inhibition 60% in SW13). Whereas in H295 cells both IFNs induced apoptosis and accumulation of the cells in S phase, the antitumor mechanism in SW13 cells involved cell cycle arrest only. Inhibitors of caspase-3, caspase-8, and caspase-9 counteracted the apoptosis-inducing effect by IFNbeta1a in H295 cells. In H295 cells, IFNbeta1a, but not IFNalpha2b, also strongly suppressed the IGF-II mRNA expression, an important growth factor and hallmark in ACC. CONCLUSIONS:IFNbeta1a is much more potent than IFNalpha2b to suppress ACC cell proliferation in vitro by induction of apoptosis and cell cycle arrest. Further studies are required to evaluate the potency of IFNbeta1a to inhibit tumor growth in vivo.

OBJECTIVE:Clinically non-functioning pituitary adenomas (NFPAs) can express functional dopamine D2 receptors. Therapy with dopamine (DA) agonists may result in a NFPA size reduction. However, DA agonist-sensitive and -resistant NFPAs are clinically indistinguishable. We have studied the correlation between in vivo imaging of D2 receptors using (123)I-epidepride and the radiological response of NFPA to DA in 18 patients. METHODS:Patients were treated with either cabergoline (1-2 mg/week) or quinagolide (150-300 mug/day) for a mean period of 89.7 months (range, 34-187 months). RESULTS:Pituitary uptake of (123)I-epidepride varied from slight uptake classified as grade 0 to very high classified as grade 3. Grade 0 uptake was found in four patients; grade 1 in three; grade 2 in ten, and grade 3 in one. NFPA stabilization or shrinkage with DA agonist therapy showed no significant difference between grade 0, 1, and 2 tumors (mean tumor stabilization or shrinkage: 31, 30, and 36% respectively). However, when we considered a decrease in tumor size ranging from 0 to 20% as tumor stabilization and >20% decrease in tumor size as true shrinkage, one out of four NFPAs with grade 1 uptake, two out of three with grade 1 uptake, and eight out of ten with grade 2 uptake showed tumor shrinkage. CONCLUSION/CONCLUSIONS:In conclusion, there is limited clinical usefulness of dopamine D2 receptor imaging for predicting the clinical efficacy of DA agonist in selected patients with NFPAs. DA agonist therapy in NFPAs can result in tumor stabilization and shrinkage.

UNLABELLED:Therapy using the radiolabeled somatostatin analog [177Lu-DOTA0,Tyr3]octreotate (177Lu-octreotate) (DOTA is 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid) has been used primarily in gastroenteropancreatic neuroendocrine tumors. Here we present the effects of this therapy in a small number of patients with metastasized or inoperable paragangliomas, meningiomas, small cell lung carcinomas (SCLCs), and melanomas. METHODS:Twelve patients with paraganglioma, 5 with meningioma, 3 with SCLC, and 2 with eye melanoma were treated. Three meningiomas were very large and exophytic and all standard treatments had failed. Patients with melanoma had rapidly progressive disease (PD). The intended cumulative dose of 177Lu-octreotate was 22.2-29.6 GBq. Effects of the treatment on tumor size were evaluated using the Southwest Oncology Group criteria. RESULTS:Two of 4 patients with progressive paraganglioma had tumor regression and 1 had stable disease (SD). Of 5 patients with stable paraganglioma, 2 had SD, 2 had PD, and in 1 patient treatment outcome could not be determined. Paraganglioma was stable in 3 patients in whom the disease status at the beginning of therapy was unknown. One of 4 patients with progressive meningioma had SD and 3 patients had PD. One patient with stable meningioma at the beginning of therapy had SD. All patients with SCLC or melanoma died within 5 mo after starting therapy because of tumor progression. Although not statistically significant, a positive trend was found between high uptake on pretherapy somatostatin receptor scintigraphy and treatment outcome. CONCLUSION/CONCLUSIONS:177Lu-octreotate can be effective in patients with paraganglioma and meningioma. Response rates are lower than those in patients with gastroenteropancreatic neuroendocrine tumors. Most meningiomas were very large. Further studies are needed to confirm the treatment outcome because of the limited number of patients. 177Lu-octreotate did not have antitumor effects in patients with small lung carcinoma and melanoma.

PURPOSE/OBJECTIVE:Ways to predict the risk of cardiovascular (CV) events or all-cause mortality have largely been derived from populations in which old and very old subjects were underrepresented. We set out to estimate the incremental prognostic utility of inflammation and atherosclerosis markers in the prediction of all-cause and CV mortality in elderly men. METHODS:In a prospective population-based cohort study, conventional CV risk factors were documented in 403 independently living elderly men. C-reactive protein (CRP) and interleukin (IL)-6 levels were measured. Carotid plaques were assessed by ultrasound. Analyses were performed with proportional hazards analyses, and bootstrapping was used for internal validation. Main outcome was CV and all-cause mortality occurring during 4 years of follow-up. RESULTS:Increasing tertiles of CRP, IL-6, and number of plaques were independently associated with all-cause and CV mortality. With information on age, carotid plaques, IL-6, and CRP yielded good discriminatory power for all-cause and CV mortality: area under the receiver operating characteristic curve (95% confidence interval), 0.76 (0.70-0.82) and 0.74 (0.68-0.80), respectively. Combined use of only IL-6 and plaque burden allowed identification of subjects with low and high mortality risk. The Framingham PROCAM and a Dutch Risk Function poorly predicted mortality risk, similar or worse than a model using age alone. CONCLUSION/CONCLUSIONS:In the old and very old, IL-6 and number of carotid plaques are powerful predictors of mortality risk in the years to come. Conventional risk scores seem to perform unsatisfactorily.

Tumors and metastases that express the somatostatin receptor subtypes sst2 sst3 or sst5 can be visualized in vivo after injection of radiolabeled octapeptide somatostatin analogs, like (111)In-pentetreotide. (111)In-pentetreotide scintigraphy also allows for more accurate staging of the disease by demonstrating tumor sites, which were not shown by conventional imaging. (111)In-pentetreotide scintigraphy may also detect resectable tumors that would have remained unrecognized using conventional radiological imaging techniques; it may prevent surgery with curative intent in those patients whose tumors have metastasized to a greater extend than could be detected with conventional radiological imaging and it may be used to select patients for treatment with the currently available octapeptide somatostatin analogs or with tumor targeted radioactive treatment with radiolabelled somatostatin analogs. (111)In-pentetreotide scintigraphy has also been used to select patients with pituitary tumors for medical treatment with octapeptide analogs, but its clinical usefulness for this purpose seems to be limited. It further allows scar tissue to be differentiated from tumor recurrence after the pituitary surgery or radiotherapy. However, a large variety of lesions in and around the pituitary region also express somatostatin receptors and, therefore, can be visualized by (111)In-pentetreotide scintigraphy.

OBJECTIVE:Cardiac surgery with cardiopulmonary bypass (CPB) is associated with a systemic inflammatory response, which is correlated with outcome. We hypothesized that ventilation according to the open lung concept (OLC) attenuates cytokine release. METHODS:A prospective, single center randomized controlled clinical study containing 62 patients scheduled for elective coronary artery bypass graft and/or valve surgery with cardiopulmonary bypass. Before surgery, patients were randomly assigned to three groups: (1) conventional mechanical ventilation (CV), (2) OLC started after arrival on the ICU (late open lung, LOL), and (3) OLC started directly after intubation (early open lung, EOL). In both OLC groups, recruitment maneuvers were applied until PaO(2)/FiO(2)>50. The CV group received no recruitment maneuvers. Interleukin (IL)-6, IL-8, IL-10, tumor necrosis factor (TNF)-alpha, and interferon (IFN)-gamma were measured preoperatively, immediately after cessation of CPB, and 3h, 5h, 24h, 2, and 3 days after cessation of CPB. RESULTS:CPB caused a significant increase of IL-6, IL-8, and IL-10 in all groups. Thereafter, IL-8 decreased significantly more rapidly in both OLC groups compared to CV. IL-10 decreased significantly more rapidly after CPB only in the EOL group, compared with CV. Three hours after cessation of the CPB, IL-10 was already comparable with preoperative levels in the EOL group, but not in the LOL or CV group. IL-6, TNF-alpha, and IFN-gamma did not differ significantly between groups. CONCLUSIONS:OLC ventilation leads to an attenuated inflammatory response, presumably by reducing additional lung injury after cardiac surgery. Studies on cytokines after cardiac surgery should take these findings into account.