Multi-centre phase II clinical trial of yttrium-90 resin microspheres alone in unresectable, chemotherapy refractory colorectal liver metastases.

BACKGROUND: This multi-centre phase II clinical trial is the first prospective evaluation of radioembolisation of patients with colorectal liver metastases (mCRC) who failed previous oxaliplatin- and irinotecan-based systemic chemotherapy regimens. METHODS: Eligible patients had adequate hepatic, haemopoietic and renal function, and an absence of major hepatic vascular anomalies and hepato-pulmonary shunting. Gastroduodenal and right gastric arteries were embolised before hepatic arterial administration of yttrium-90 resin microspheres (median activity, 1.7 GBq; range, 0.9-2.2). RESULTS: Of 50 eligible patients, 38 (76%) had received > or =4 lines of chemotherapy. Most presented with synchronous disease (72%), >4 hepatic metastases (58%), 25-50% replacement of total liver volume (60%) and bilateral spread (70%). Early and intermediate (>48 h) WHO G1-2 adverse events (mostly fever and pain) were observed in 16 and 22% of patients respectively. Two died due to renal failure at 40 days or liver failure at 60 days respectively. By intention-to-treat analysis using Response Evaluation Criteria in Solid Tumours, 1 patient (2%) had a complete response, 11 (22%) partial response, 12 (24%) stable disease, 22 (44%) progressive disease; 4 (8%) were non-evaluable. Median overall survival was 12.6 months (95% CI, 7.0-18.3); 2-year survival was 19.6%. CONCLUSION: Radioembolisation produced meaningful response and disease stabilisation in patients with advanced, unresectable and chemorefractory mCRC.

Natural history and clinical outcome of differentiated thyroid carcinoma: a retrospective analysis of 1503 patients treated at a single institution.

BACKGROUND: The study evaluates clinical presentation and outcome of differentiated thyroid cancer (DTC) on a large series of patients homogeneously managed. PATIENTS AND METHODS: A cohort of 1503 DTC followed according to a standardized protocol entered the study. Main outcome measures were clinical presentation at the diagnosis, survival, morbidity and prognostic risk factors. RESULTS: Median age at diagnosis was 46 years. Papillary cancer and low pathological tumor-node-metastasis stages represented >80% of cases. Cancer specific survival at 5, 10 and 15 years was 98.6%, 94.7% and 87.4%; 10-year disease-free and progression-free survivals were 96.8% and 17.1%, respectively. Cancer-specific mortality rate was 2.5% [95% confidence interval (CI) 1.7% to 3.4%], recurrence rate was 0.6 % while morbidity rate was 12.6% (95% CI 11% to 14%). Response to radioiodine treatment is the strongest predictor of a good outcome in multivariate analysis (hazard ratio 211, P < 0.0001). Other independent predictor variables are sex, age, histology and distant metastases for survival and metastases for morbidity. CONCLUSIONS: A rigorous initial therapeutic approach leads to a better survival and a very low morbidity. Patients who do not respond to radioiodine treatment have a worse prognosis.

A NTCP approach for estimating the outcome in radioiodine treatment of hyperthyroidism.

Radioiodine has been in use for over 60 years as a treatment for hyperthyroidism. Major changes in clinical practice have led to accurate dosimetry capable of avoiding the risks of adverse effects and the optimization of the treatment. The aim of this study was to test the capability of a radiobiological model, based on normal tissue complication probability (NTCP), to predict the outcome after oral therapeutic 131I administration. Following dosimetric study, 79 patients underwent treatment for hyperthyroidism using radioiodine and then 67 had at least a one-year follow up. The delivered dose was calculated using the MIRD formula, taking into account the measured maximum uptake of administered iodine transferred to the thyroid, U0, and the effective clearance rate, Teff and target mass. The dose was converted to normalized total dose delivered at 2 Gy per fraction (NTD2). Furthermore, the method to take into account the reduction of the mass of the gland during radioiodine therapy was also applied. The clinical outcome and dosimetric parameters were analyzed in order to study the dose-response relationship for hypothyroidism. The TD50 and m parameters of the NTCP model approach were then estimated using the likelihood method. The TD50, expressed as NTD2, resulted in 60 Gy (95% C.I.: 45-75 Gy) and 96 Gy (95% C.I.: 86-109 Gy) for patients affected by Graves or autonomous/multinodular disease, respectively. This supports the clinical evidence that Graves' disease should be characterized by more radiosensitive cells compared to autonomous nodules. The m parameter for all patients was 0.27 (95% C.I.: 0.22-0.36). These parameters were compared with those reported in the literature for hypothyroidism induced after external beam radiotherapy. The NTCP model correctly predicted the clinical outcome after the therapeutic administration of radioiodine in our series.

Randomized prospective clinical trial of high-dose epirubicin and dexrazoxane in patients with advanced breast cancer and soft tissue sarcomas.

PURPOSE: We conducted a randomized trial to evaluate primarily the cardioprotective effect of dexrazoxane (DEX) in patients with advanced breast cancer and soft tissue sarcomas (STS) treated with high-dose epirubicin (EPI). We wished also to determine the value of radioimmunoscintigraphy (RIS) in the assessment of anthracycline cardiotoxicity. PATIENTS AND METHODS: Patients with breast cancer (n = 95) or STS (n = 34) received EPI 160 mg/m2 by intravenous (I.V.) bolus every 3 weeks with or without DEX 1,000 mg/m2 I.V. Cardiac monitoring included multigated radionuclide (MUGA) scans with determination of resting left ventricular ejection fraction (LVEF), and RIS with indium 111 antimyosin monoclonal antibodies. RESULTS: In either disease, antitumor response rates, time to progression, and survival did not significantly differ between the two arms. There was little difference in noncardiac toxicity for the two treatment groups. All methods of cardiac evaluation clearly documented the cardioprotective effect of DEX. Four patients developed congestive heart failure (CHF), all in the EPI arm. The decrease in LVEF from baseline was significantly greater in the control group. An abnormal antimyosin uptake was observed early in both arms and progressively increased during treatment. However, this increase was significantly higher in the EPI group (P = .004). CONCLUSION: DEX significantly protects against the development of cardiotoxicity when high single doses of EPI are used. Apparently, there was no evidence of an adverse impact of DEX on antitumor activity. Although RIS is a sensitive technique in detecting anthracycline cardiac damage, its specificity is low and it cannot be considered a primary test for guiding anthracycline treatment.

Short- and long-term effects of 186Re-1,1-hydroxyethylidene diphosphonate in the treatment of painful bone metastases.

UNLABELLED: This study evaluates the short- and long-term therapeutic efficacy of 186Re-1,1-hydroxyethylidene diphosphonate (HEDP) in the palliation of painful bone metastases and the influence of variables before therapy in determining the characteristics of pain palliation. METHODS: Sixty patients with painful bone metastases from different tumor types were treated with 1406 MBq 186Re-HEDP. After treatment, the patients were followed up clinically at weekly intervals for the first month and monthly thereafter up to 1 y, until death or pain relapse. Pain response was graded as complete, partial, minimal, or absent using the Wisconsin test scoring system. Duration of pain relief, performance status, tumor markers, serum alkaline phosphatase levels, hematologic toxicity, and metastatic bone progression were also evaluated. RESULTS: Overall, 80% of individuals experienced prompt relief of pain, with 31% complete, 34% partial, and 15% minimal responses. Transient World Health Organization grade 1-2 hematologic toxicity was apparent, with a decrease in the mean platelet (32%) and mean leukocyte (18%) counts at 3 and 4 wk, respectively. The degree of pain response did not correlate with any pretreatment variable. The duration of pain relief ranged from 3 wk to 12 mo and correlated positively with the degree of response (P = 0.02) and negatively with pretreatment scintigraphic scores and alkaline phosphatase levels (P = 0.02). CONCLUSION: 186Re-HEDP is effective for fast palliation of painful bone metastases from various tumors. The effect tends to last longer if patients are treated early in the course of their disease.

99mTc-MIBI scintimammography using a dedicated nuclear mammograph.

UNLABELLED: This study reports on a prototype single-photon emission mammograph (SPEM) dedicated to 99mTc-hexakis-2-methoxyisobutile isonitrile (MIBI) scintimammography. Main technical features are reported together with physical performance. Preliminary patient data are also reported. METHODS: The SPEM detector head is composed of a CsI(T1) scintillating array coupled to a Hamamatsu R3292 position-sensitive photomultiplier tube with crossed-wire anode. The high-resolution collimator is 35-mm thick with a 1.7-mm hole diameter and a 0.2-mm septal thickness. The electronic acquisition system is composed of five integrated cards with computation based on high-speed programmable microprocessors. The readout electronics include correction maps for on-line energy correction and spatial uniformity. The small size of the detector head allows the use of mechanical breast compression to minimize detection distance and tissue scatter. After physical SPEM performance evaluation in vivo scintimammography was performed in 29 patients and was compared with a state-of-the-art Anger camera. RESULTS: The SPEM showed an intrinsic spatial resolution of 2 mm, an energy resolution of 23% FWHM at 122 keV and spatial uniformities of 18% (integral) and 13.5% (differential). The SPEM imaged one 0.4-cm carcinoma missed by the Anger camera and resolved as separate lumps an irregular focal uptake on the Anger camera image. The remaining cases yielded concordant results. CONCLUSION: The SPEM prototype presented in this study shows adequate physical characteristics for 99mTc-MIBI scintimammography.

Technetium-99m-MIBI scintigraphy in the assessment of neoadjuvant chemotherapy in breast carcinoma.

UNLABELLED: Presurgical neoadjuvant chemotherapy (PSNC) is the treatment of choice for patients with locally advanced breast carcinoma (LABC). Accurate assessment of tumor response is important in planning subsequent treatments. Conventional response assessment by mammography and clinical evaluation is not fully reliable. This study evaluates the diagnostic yield of serial 99mTc-MIBI scintigraphy in the assessment of LABC response to PSNC. METHODS: Twenty-nine patients affected by LABC underwent clinical, mammographic and 99mTc-MIBI scintigraphy before and after 3 cycles of FEC (500 mg/m2 5-fluorouracil, 50 mg/m2 epirubicin and 400 mg/m2 cyclophosphamide) on Days 1 and 8. Surgery was planned for 15 days after the third cycle of chemotherapy. Pathological status was obtained after surgery in all patients. RESULTS: Sensitivities (i.e., true-positive ratios) for a correct prediction of tumor presence after PSNC were 65% for scintigraphy, 35% for clinical evaluation and 69% for mammography. Specificities (i.e., true-negative ratios) for a correct prediction of tumor absence after PSNC were 100% for scintigraphy, 67% for clinical evaluation and 33% for mammography. Technetium-99m-MIBI uptake in this series did not correlate with P-170 expression, proliferating cell nuclear antigen, Her-2/neu oncogene protein, antihuman endothelial cell CD31 antigen and estrogenic and progestinic receptor status. CONCLUSION: Technetium-99m-MIBI scintigraphy is effective in monitoring the response to PSNC in LABC patients. Its diagnostic yield is clearly superior to clinical evaluation alone. Scintigraphy performs as does mammography in patients with negative response, but it is clearly superior in patients with positive response.

Ictal single photon emission computed tomography in absence seizures: apparent implication of different neuronal mechanisms.

Absence seizures represent a complex group of epilepsy, characterized by lapse of consciousness with staring. Bilateral, synchronous, and symmetric bursts of 3-Hz spike-and-wave discharges are observed on the electroencephalogram, whereas interictal background activity is normal. This kind of epilepsy has to be differentiated from other generalized epilepsies such as juvenile absence epilepsy and juvenile myoclonic epilepsy. Moreover, absence seizures, together with generalized spike-and-wave discharges, may coexist with other types of epilepsy such as frontal lobe epilepsy, temporal lobe epilepsy, benign epilepsy with centrotemporal spikes, and childhood epilepsy with occipital paroxysms. We have carried out ictal single photon emission computed tomography (SPECT) in 10 patients with clinical evidence of absence seizures with the aim to better understand and to distinguish this kind of seizure as primarily or secondarily generalized to a specific area and to obtain more information on the neuronal mechanisms involved in the different types of seizures, usually not identifiable at the first appearance. During the long follow-up period (9 months to 14 years), 7 of the 10 examined patients underwent interictal SPECT when they became seizure free. Our data permitted, in two patients, the diagnosis of childhood absence seizures; in three patients, they suggested the possibility of later appearance of other seizure types, on the basis of focal hyperperfusion indicating a possible focal firing. In three of the examined patients, the diagnosis of idiopathic localization-related epilepsies mimicking childhood absence seizures could be performed. In the last two patients, the hypothesis of a coexistence of absences with partial and generalized seizures was considered. From our results, it can be presumed that ictal SPECT findings may contribute to the physiopathologic classification of the different types of epilepsies. Moreover, anticonvulsant treatment more appropriate to the different forms of seizures can be used.

A statistical study on left ventricular peak filling rate in diabetes.

The importance of non-invasive evaluation of cardiac function in diabetes is well known and radionuclide angiocardiography has become an accepted diagnostic procedure. While the pathophysiological interpretation of systolic parameters is clear, the meaning and determinants of peak filling rate (PFR) remain rather speculative. In the present study, a "pattern recognition" approach, including principal component analysis and hierarchical cluster analysis, has been adopted in order to evaluate the determinants of PFR in a series of 48 non-selected diabetic patients. The results of the study show that: PFR is inversely dependent on age which is its main determinant when systolic function is preserved; PFR is inversely dependent on combined effects of left ventricular dimensions, angina and wall motion; and the duration of diabetes in itself does not influence PFR. These results lead to the following clinically relevant conclusions: (a) It is unlikely that a young diabetic patient without anginal symptoms will have a significant PFR impairment even if the diabetes has been present for a long time. If such impairment is however present, ventricular latent dysfunction is likely to be the cause even if systolic parameters are still normal; (b) A decrease of PFR in a middle-aged diabetic patient without symptoms and with normal systolic function cannot be equated with latent ventricular dysfunction as it may represent only an age-related physiological change without special diagnostic meaning.

The diagnostic application of radiocolloid liver scintigraphy in breast carcinoma.

The authors have reviewed their experiences in determining the presence of liver metastases in 103 patients by radiocolloid scanning. The sensitivity of liver scanning proved to be quite low if the presence of focal defects in the distribution of the tracer was chosen as the diagnostic criterion. The inclusion of less restrictive criteria such as liver enlargement or irregular distribution of the tracer, resulted in a higher sensitivity without lowering the predictive value of a negative scan. Using the latter diagnostic criterion, sensitivity, specificity and accuracy were in the range of 90%. Abnormal liver scans are common in patients classified at T3-T4 or N+ and their chances of being "true positive" are high. Conversely, abnormal scans are seldom found in patients classified at T1-T2 or N0 and probabilities of "false positive" results are high.

Equilibrium radionuclide angiocardiography to select inotropic therapy in patients with left ventricular aneurysm.

Fourteen patients with postinfarctual ventricular aneurysm underwent equilibrium radionuclide angiocardiography at rest (ERNA) before and after oral digoxin administration in order to evaluate the effects of increasing myocardial contractility upon both ventricular aneurysm mechanical behaviour and global ventricular function. The ejection fraction (EF) was not significantly affected by digoxin therapy. However, digoxin induced changes in EF (delta EF) correlated inversely with changes in aneurysm size and directly with changes in the extent of the hypokinetic area. Two types of aneurysm were observed: high-compliance aneurysm the size of which increased after digoxin administration while both EF and the extent of the hypokinetic area fell, and low compliance aneurysm for which opposite changes occurred. This different behaviour of ventricular aneurysm may have important practical implications as surgery would be probably more effective than medical treatment in improving resting ventricular function in patients with high-compliance aneurysm.

Right ventricular wall motion and performance in stabilized chronic respiratory failure evaluated by equilibrium radionuclide angiocardiography.

Equilibrium radionuclide angiocardiography (ERNA) was performed at rest in 30 patients with chronic respiratory failure (CRF) in order to evaluate right ventricular performance and wall motion. The usual indices of left ventricular performance were also recorded and correlated with right ventricular parameters. Only CRF patients without clinical, electrocardiographic or echocardiographic criteria suggestive of congenital, valvular, hypertensive or ischemic heart disease were studied. A RV dyskinesis was detected in 5 of the 30 patients, occurring however only in stage II-III CRF, as if a longstanding RV pressure overload were necessary for a RV dyskinesis to develop. No significant differences were found between patients with and without RV dyskinesis for all the functional ERNA parameters (i.e. LVEF, RVEF, PER, PFR). On the other hand, a significant correlation between the stage of the CRF and RVEF was observed.

Cerebral blood flow and volume in symptom-free migraineurs: a SPECT study.

Both CBF and CBV were evaluated by gamma-camera SPECT in 14 patients with classic migraine, all studied while symptom-free. Nuclear data were correlated with CT and MRI. A decreased regional CBF was observed in 13 of the 14 patients. The decreased perfusion was localized in the frontal lobe in 6 patients, the temporal lobe in one, the parietal lobe in 11 and the occipital lobe in 5 patients. The parieto-occipital cortex was involved more often than the frontal cortex; the association of hypoperfusion with parieto-occipital cortex was quite high. The right parieto-occipital regions were affected more often than the left ones. Regional CBV was increased in 8 patients. There was good topographical concordance between decreased CBF and increased CBV, but the increase of CBV was in general more evident at the periphery of the hypoperfusion. It is of interest that the only patient with a normal CBF study had a pathological CBV study. Apparently, CBF derangements are very common in symptom-free patients with classic migraine, a CBF decrease being often accompanied by a CBV increase. In these patients both CT and MRI have a lower diagnostic yield than SPECT.

99mTc-DTPA clearance in bullous emphysema.

The degree of permeability of the alveolar-capillary barrier to low molecular weight solutes has been supposed to depend upon the radius of the epithelial pores. The bullous emphysema is a natural model in which this radius may increase because of the high tension in the bulla. Accordingly, the 99mTc-DTPA clearance may be expected to be faster than normal in lung fields including bullae. Results of the present study in which 99mTc-DTPA clearance was measured in six patients with bullous emphysema, seem to confirm this hypothesis at least to some extent. In fact, either increased or normal 99mTc-DTPA clearances were found over the lung fields including bullae communicating with the bronchial tree. Differences in both the size and the inner tension of the bullae as well as in the anatomical and functional conditions of the surrounding parenchyma are likely to account for such varying behaviour.

Left ventricular diastolic performance at rest in patients with angina and normal systolic function--assessment by equilibrium radionuclide angiography.

The aim of the study was to correlate diastolic function, as evaluated by peak filling rate (PFR) and relative time (TPFR), with the severity of ischemic heart disease, as evaluated by exercise electrocardiography. Accordingly, 83 ischemic patients with effort angina, but normal ejection function at rest and normal left ventricular size, were studied by equilibrium radionuclide angiocardiography within two weeks from the exercise ECG. Diastolic dysfunction, as determined from PFR and, to a lesser extent, from TPFR, is common in patients with ischemic heart disease and normal systolic function. The prevalence and severity of such dysfunction is related more to the severity of the ischemia, as evaluated by the exercise ECG, than to the presence of an old myocardial infarction. Such findings are consistent with the hypothesis that PFR reflects mainly the early diastolic active uncoupling process.

Cerebral blood flow in AIDS-related neurotoxoplasmosis: a preliminary 99mTc-HMPAO SPECT study.

Cerebral blood flow (CBF) was evaluated by gamma camera 99mTc-HMPAO SPECT in 11 patients with AIDS-related neurotoxoplasmosis and correlated with neurological findings and the results of CT and MRI. Evident CBF abnormalities were observed in all patients with involvement of at least two cerebral lobes. In 10 patients the abnormalities were bilateral and in 8 patients basal ganglia were involved; no specific hypoperfusion pattern was however evident. Focal lesions were found in 7 patients by CT (sensitivity: 63.6%) and in 10 patients by MRI (sensitivity: 90.9%). It may be concluded that neurotoxoplasmosis in AIDS patients is associated with a high prevalence of focal cortical and subcortical hypoperfusion but that the scintigraphic findings are not specific; that HMPAO SPECT may show focal hypoperfusion in patients with normal CT studies and/or non-focal MRI abnormalities; that the hypoperfusion may be more extensive than the corresponding MRI lesion(s) and that it may be present even in areas with normal MRI signals; and that more experience and longitudinal studies are needed to assess the possible impact of HMPAO SPECT on follow-up and therapy monitoring.

The influence of age on the pulmonary clearance of 99Tcm-DTPA radioaerosol.

Age-dependent changes of 99Tcm-DTPA radioaerosol transpulmonary clearance have been investigated in 49 healthy volunteers with an age range of 21-63 years. The clearance was uniformly increased in all smokers irrespective of age, but it showed a highly significant (p less than 0.001) decrease in non-smoking patients over 50 years. Several age-related changes in the ageing lung can contribute to this decreased clearance, but the reduced alveolar-capillary surface area available for the transport is probably the key factor. The practical implication of the results is the need to use age-related normal ranges when interpreting 99Tcm-DTPA radioaerosol clearance studies.

The effects of chronic hypoxia on left ventricular peak filling rate evaluated by equilibrium radionuclide angiocardiography.

Left ventricular peak filling rate (PFR) was measured by equilibrium radionuclide angiocardiography (ERNA) in 15 patients with Stage II stabilized chronic respiratory failure (CRF) without evidence of coexisting heart diseases and in 18 patients with coronary artery disease (CAD) without myocardial infarction. The study was designed to assess the effects of severe hypoxia and of ischaemia on the calcium-dependent early diastolic filling. PFR was found to be impaired in both groups of patients (mean = 1.72 EDVs-1 and S.E.M. = 0.07 in CAD; mean = 2.35 EDVs-1 and S.E.M. = 0.14 in CRF) but significantly less (p less than 0.001) in CRF patients while the left ventricular ejection fraction (LVEF) values were not significantly different between the two groups (mean = 60.0% and S.E.M. = 1.4 in CAD; mean = 62.0% and S.E.M. = 1.6 in CRF). As PFR is known to be a sensitive index of left ventricular performance the results obtained in this human model are consistent with findings obtained in animal models suggesting that hypoxia is less efficient than ischaemia in depressing left ventricular function.

Somatostatin receptors in meningiomas: a scintigraphic study using 111In-DTPA-D-Phe-1-octreotide.

111In-octreotide (Octreoscan) planar scintigraphy was performed in 12 patients with suspected meningioma. The scan was positive in 10 patients with meningioma and negative in two patients with acoustic neurinoma assisting in the differential diagnosis. Good quality images were obtained as early as 2 h after injection and there was no increase in diagnostic quality at 24 h. No adverse effects were observed to radiopharmaceutical administration. The following conclusions are drawn: 111In-octreotide is a safe and fast test which can increase the specificity of traditional neuroimaging procedures.

Radiosensitization with low-dose carboplatin enhances pain palliation in radioisotope therapy with strontium-89.

Strontium-89 (89Sr) is currently used for the treatment of painful bone metastases. This study reports the use of low-dose carboplatin as a radiosensitizer in 89Sr radioisotope therapy. The study design comprised two groups: 15 patients treated with 89Sr (148 MBq) followed by carboplatin (100 mg m-2 at 7 and 21 days) and 15 patients treated with 89Sr alone. Their pain response was assessed 8 weeks post-injection. Follow-up was continued for up to 1 year in the survivors. Twenty-seven patients were evaluable. A pain response was observed in 20 of 27 (74%) patients. The pain response in the patients treated with 89Sr and carboplatin was clearly superior to that seen in the patients treated with 89Sr alone (P = 0.025), whereas survival was only marginally better in the combined treatment group (8.1 vs 5.7 months, P = 0.19). No clinically significant adverse effects or myelosuppression by carboplatin were observed. Low-dose carboplatin enhances the effects of 89Sr radioisotope therapy on pain from bone metastases.