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.

Count-rate analysis from clinical scans in PET with LSO detectors.

The purpose of optimising the acquisition parameters in positron emission tomography is to improve the quality of the diagnostic images. Optimisation can be done by maximising the noise equivalent count rate (NECR) that in turn depends on the coincidence rate. For each bed position the scanner records coincidences and singles rates. For each patient, the true, random and scattered coincidences as functions of the single count rate(s) are determined by fitting the NEMA (National Electrical Manufacturers Association) 70 cm phantom count rate curves to measured clinical points. This enables analytical calculation of the personalised PNECR [pseudo NECR(s)] curve, linked to the NECR curve. For central bed positions, missing activity of approximately 70% is estimated to get maximum PNECR (PNECR(max)), but the improvement in terms of signal-toz-noise ratio would be approximately 15%. The correlation between patient weight and PNECR(max) is also estimated to determine the optimal scan duration of a single bed position as a function of patient weight at the same PNEC. Normalising the counts at PNECR(max) for the 70 kg patient, the bed duration for a 90 kg patient should be 230 s, which is approximately 30% longer. Although the analysis indicates that the fast scanner electronics allow using higher administered activities, this would involve poor improvement in terms of NECR. Instead, attending to higher bed duration for heavier patients may be more useful.

A multicentric phase II clinical trial on intra-arterial hepatic radiotherapy with 90yttrium SIR-spheres in unresectable, colorectal liver metastases refractory to i.v. chemotherapy: preliminary results on toxicity and response rates.

BACKGROUND: In patients locally progressing after two lines of chemotherapy, some locoregional approaches showed encouraging results in terms of local control of disease. The aim of our study was to evaluate toxicity, clinical response and quality of life in 48 patients with unresectable colorectal liver metastases submitted to selective internal radiotherapy (SIRT). MATERIALS AND METHODS: Up to now 35 patients with unresectable colorectal liver metastases, refractory to two lines of chemotherapy, underwent intra-arterial infusion of resin microspheres with yttrium-90 (SIR-spheres). Pre-treatment evaluation included a CT scan, blood tests, a PET scan and arteriography of celiac trunk, hepatic and superior mesenteric artery; extrahepatic uptakes and pulmonary shunts more than 10% were excluded by a Scinti-scan. The gastroduodenal artery was embolized before the SIR-spheres injection. Other exclusion criteria were liver dysfunction and anatomical vascular anomalies. The clinical response was evaluated by CT-scan following the RECIST criteria. Median follow-up was 4 months. RESULTS: Median number of metastases was 4 (range, 1-15), 38% of cases presenting hepatic involvement < 25%. The median SIRT dose delivered was 1.7 GBq. Median pulmonary shunt was 6%. No operative mortality occurred; early toxicity (within 48 hours) was 20.6%, shown as fever, acute pain and leucocytosis. The late toxicity was 24.1% with chronic pain, jaundice and nausea being the most frequent. All the toxic events were graded 2 or 3 according to the WHO scale. Preliminary results were available in terms of clinical response after 6 weeks: 12.5% had a partial response, 75% a stable disease, while progression of disease, was observed in 12.5% of the patients. CONCLUSION: SIRT is a safe treatment in terms of acute and late toxicity. Intra-arterial microspheres could represent a good therapeutic option for patients with progressing liver metastases only, after two lines of systemic chemotherapy.

A comparison of scintigraphy, thermography, ultrasound and phlebography in grading of clinical varicocele.

Varicocele, a varicosity of the pampiniform plexus, usually on the left side, is a common urologic problem. It may be associated with symptoms of local discomfort or abnormal spermatogenesis. Internal spermatic vein phlebography is the "gold standard" investigative technique, but it is invasive. Noninvasive studies include: labeled blood-pool scintigraphy, thermography and ultrasound. Two hundred sixty-three patients were investigated with various combinations of these modalities. The degree of abnormality for each modality was graded semiquantitatively and the results compared. In addition, the results of semen analysis were correlated to imaging results. Ninety-six patients were investigated with all four tests (scintigraphy, thermography, ultrasound and phlebography). The correlation of positive phlebography to positive scintigraphy was 98%, to thermography 100% and to ultrasound 98%. The concordance (grade for grade) was 71% for scintigraphy, 68% for thermography and 62% for ultrasound. There was no obvious correlation between abnormalities of semen analysis and grading of varicocele. We conclude that the diagnostic accuracy and grading of severity by noninvasive techniques (including scintigraphy) compare very favorably with that of phlebography. Moreover, scintigraphy allows the noninvasive evaluation of reflux through the internal spermatic vein, which may be useful in planning therapy.

Kinetics of interstitially administered monoclonal antibodies for purposes of lymphoscintigraphy.

The clearance rates of radiolabeled murine monoclonal intact IgG, F(ab')2 Fab and of an IgM following subcutaneous administration were evaluated in normal mice and rats using nuclear imaging and counting techniques. These studies suggest no significant difference in clearance rate exists between intact IgG and its F(ab')2 fragment, and little difference between these moieties and intact IgM. Fab is cleared considerably faster than the others, however. While significant differences in clearance rates exist, the magnitude of the differences are not as large as those following intravenous injection particularly when ambulation by the animal is allowed. When ambulation is allowed, clearance rates of all classes and fragments are accelerated and quite similar. Injection into the subcutaneous tissues of the footpad results in consistently faster clearance than an injection into the subcutaneous tissues of the abdomen. Ambulation considerably increased the clearance of antibodies, presumably by increasing lymph flow. These studies imply that the choice of intact antibody versus fragments for kinetic reasons may be less critical (particularly if ambulation is allowed) by the subcutaneous as compared with the intravenous delivery route. This kinetic information should be useful in designing imaging protocols with radiolabeled antibodies administered subcutaneously for purposes of imaging disease processes involving the lymphatics.

Alterations of iodine-131 MIBG biodistribution in an anephric patient: comparison to normal and impaired renal function.

Iodine-131 metaiodobenzylguanidine (MIBG) is an effective agent for the scintigraphic portrayal of pheochromocytomas of all types. Iodine-131 MIBG is a relatively stable radiopharmaceutical that is primarily excreted in the urine. Therefore, impaired renal function would be expected to alter [131I]MIBG pharmacokinetics which would thus affect blood levels, as well as scintigraphy. An 18-yr-old anephric male presented with hypertension and suspected pheochromocytoma. We have compared the [131I]MIBG scintigraphy and blood clearance kinetics in this anephric patient, two patients with renal insufficiency and four patients with normal renal function. The degree of renal insufficiency was directly correlated to the CPM/image (an index of whole-body retention) on all 3 days of imaging and the slower clearance of radioactivity from the blood. The relative distribution of radioactivity between the plasma and cell fractions was greatest in the patients with renal insufficiency. We therefore suggest that attention be paid to plasma creatinine levels prior to the administration of [131I] MIBG to permit accurate interpretation of scintigraphy. In addition, the effect of renal insufficiency on radiation dosimetry should be considered. It may thus be prudent to reduce the administered dose of [131I]MIBG given to anephric or renally insufficient patients to decrease radiation dose.

Iodine-131 metaiodobenzylguanidine scintigraphy for the location of neuroblastoma: preliminary experience in ten cases.

Ten patients with histologically proven neuroblastoma were studied by [131I]MIBG scintigraphy. Tumor uptake of the radiopharmaceutical showed a spectrum varying from no uptake in one case, to slight uptake in two, moderate uptake in two and intense uptake in five cases. Iodine-131 MIBG scintigraphy was more effective in demonstrating the extent of neuroblastoma spread than were conventional bone scan and CT in one patient, equal to these modalities in four cases, almost equal in two cases and significantly inferior in three cases. These preliminary results suggest that [131I]MIBG scintigraphy is useful in detecting the presence and delineating the distribution of neuroblastoma and may, in certain cases, have therapeutic potential.

Artifacts, anatomical and physiological variants, and unrelated diseases that might cause false-positive whole-body 131-I scans in patients with thyroid cancer.

The whole body 131-I scan remains an important component in the postoperative treatment of patients with well-differentiated thyroid cancer. Because normal thyroid tissue remnants and residual or metastatic foci of well-differentiated thyroid cancer have the unique ability to concentrate, organify, and store 131-I, the whole body scan provides a depiction of those tissues that can be ablated with therapeutic doses of 131-I. Over time, it has become obvious that the whole body scan may also reveal foci of 131-i uptake owing to a wide variety of other causes. We provide a detailed pathophysiological classification of the artifacts, anatomic and physiological variants, and nonthyroidal diseases that may give rise to false-positive whole body scans in postoperative patients with thyroid cancer. These include ectopic foci of normal thyroid tissue; nonthyroidal physiological sites (eg, choroid plexus, salivary glands, gastric mucosa, urinary tract); contamination by physiological sections; ectopic gastric mucosa; other gastrointestinal abnormalities; urinary tract abnormalities; mammary abnormalities; serous cavities and cysts; inflammation and infection; nonthyroidal neoplasms; and currently unexplained causes. This article also provides a detailed review of the widely scattered English language literature in which these phenomena were originally described.

Increased prolactin reserve in alcoholics.

The prolactin response to oral metoclopramide (10 mg) was investigated in 53 chronic alcoholics (26 with alcoholic cirrhosis and 27 without evidence of liver disease) from two to seven days after alcohol suspension. The response appeared significantly higher in patients than in healthy controls and was not related to the presence of liver disease. This finding may depend on the deactivation of the dopaminergic activities secondary to alcohol suspension; alternatively, ethanol could have a direct action on prolactin secretion.

Usefulness of 99m-Tc-sestamibi scintimammography in suspected breast cancer and in axillary lymph node metastases detection.

AIMS: To evaluate the usefulness of 99m-Tc-sestamibi scintimammography (SSM) in the detection of T1-2, N0-1, M0 breast cancer (BC) and axillary node (AN) metastases. PATIENTS AND METHODS: A series of 239 women (median age 55 years) who had already been selected for breast biopsy underwent both mammography (MG) and SSM before surgery. The final diagnosis confirmed in 207 (86.6%) patients, and benign breast lesions in 32 (13.4%). RESULTS: Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of MG and SSM in BC detection were 88.9% vs 87.9%, 62.5% vs 93.8% (P<0.01), 93.9% vs 98.9%, 46.5% vs 54.5%, and 85.4% vs 88.7%, respectively. Age did not affect (P=NS) SSM sensitivity, and in premenopausal patients (n=80 (33.5%)) its specificity was 100%. Overall sensitivity and specificity of SSM for assessing AN involvement were 82.3% and 94.1%, respectively. In patients with <3 AN metastases (n=33 (53.2%)) SSM sensitivity was 69.7%, and only one out of six patients with a single AN metastasis had a positive scan. CONCLUSIONS: In patients with suspicious MG undergoing biopsy, SSM should be considered before surgery because of its high specificity, especially in younger patients. At present, its usefulness in detection of AN metastases is still modest and does not allow a correct pre-operative staging of patients with BC.

Sequential salivary scintigraphy in Sjögren's syndrome: proposal for a new method of evaluation.

Thirty-seven non-elderly primary Sjögren's syndrome (I SS) patients, and 27 controls complaining of xerostomia and/or recurrent or persistent swelling of at least one parotid or submandibular gland due to other selected disorders, were studied. A new scintigraphic score (scsc) is proposed for a standardised semiquantitative evaluation of salivary involvement by qualitative sequential salivary scintigraphy (SSS), and is compared with two other well-known methods generally used for this purpose. The scsc proved to be much more suitable for such an evaluation: the other criteria did not allow us either to classify or to score a great number of cases. Furthermore, the scsc allowed us to obtain better SSS sensitivity (89.2%) and specificity (96.3%) values for I.SS (33 of the 37 I SS patients and 26 of the 27 controls were correctly classified by discriminant analysis, for scsc values greater than 8). This was made possible by the different "weights" which we assigned to the various glandular and oral parameters in the scsc determination.

Sestamibi scintimammography in pT1 breast cancer: alternative or complementary to X-ray mammography?

The aim of this study was to compare the results obtained using X-ray mammography (MG) and 99mTc-sestamibi scintimammography (SSM) in patients with breast lesions < or = 2 cm. One hundred and thirty-four women (median age 52 years, range 32-78), who had already been selected for open breast biopsy, underwent both MG and SSM prior to surgery. Final pathology showed 27 (20.1%) benign breast lesions and 107 (79.9%) breast cancers (pT1a=5 [4.7%], pT1b=50 [46.7%], pT1c=52 [48.6%]). The sensitivity, positive predictive value, negative predictive value and accuracy were 81.3%, 97.6%, 55.6% and 83.6% for SSM and 83.2%, 89.9%, 48.6% and 79.1% for MG, respectively. The results were similar (p=NS), but patients with breast cancer (BC) undetected by MG were significantly (p<0.05) younger than those in which the tumor was correctly diagnosed, while the age did not affect SSM sensitivity. SSM was more (p<0.05) specific than MG in BC detection both in the overall group of patients (92.6% vs 63.0%) and in those with < or = 10 mm breast lesions (94.7% vs 63.2%). In conclusion, in patients with suspected BC sized < or = 2 cm, SSM may help in surgical planning because of its high specificity, and should be considered complementary to MG, especially in younger women.

Cyclic AMP excretion in urines of patients with subarachnoid hemorrhages.

Urinary excretion of cAMP was closely monitored for several days in 74 patients with subarachnoid hemorrhages. A rise in urinary cAMP up to 45 microM/24h was observed (normal values being 1 to 5 microM/24h). Patients with associated metabolic disorders were excluded from this study. We have found a correlation between the severity of the clinical conditions, recovery from acute disorder and cAMP excretion, thus suggesting that an increase of urinary cAMP level is related to the extent and the evolution of the acute cerebral damage.

[Pituitary prolactin reserve in acute exacerbation of chronic respiratory insufficiency]. / La riserva prolattinica ipofisaria nell'insufficienza respiratoria cronica riacutizzata.

The level of pituitary prolactin reserve (PPR) was studied in 56 patients with chronic respiratory failure (CRF) in the acute stage after injections of metoclopramide and Thyrotropin Releasing Hormone (TRH). PPR was low in 90% of the subjects in both groups so that the pathogenic mechanism is more likely to be hypophyseal than hypothalamic and due to the reduced synthesis of PRL by the pituitary gland as a result of inadequate ATP synthesis and/or functional alterations to the receptors or pituitary cells following hypoxaemia and hypercapnia.

[Excessive prolactinemic response to sulpiride in patients with mild essential hypertension. Index of diminished hypothalamic dopaminergic activity]. / Eccessiva risposta prolattinemica alla sulpiride in pazienti con ipertensione essenziale lieve. Indice di diminuita attività dopaminergica ipotalamica.

Plasma prolactin concentrations and prolactinaemic response to sulpiride, a prolactin releaser with pituitary dopamine receptor blocking activity, were examined in 16 subjects with mild essential hypertension and in 20 patients with long-sustained essential hypertension. When compared with 16 normotensive controls only the former showed raised plasma renin activity (P < 0.001) and higher plasma prolactin levels either after two-hour ambulation (P < 0.05) or at supine rest (P < 0.05). The average of maximal sulpiride-induced prolactin values was 157 +/- 53 ng/ml (mean +/- SD) in the mild hypertensive, significantly different from 60.2 +/- 21.4 ng/ml (mean +/- SD) as resulted in the controls (P < 0.001). In contrast, patients with sustained hypertension had a mean level of 60.2 +/- 21.4 ng/ml (mean +/- SD), indifferent from the one of the normal volunteers. It is suggested that the excessive prolactinaemic response to sulpiride detected in patients with mild hypertension reflects a reduced hypothalamic dopaminergic activity and that such an alteration may assume some pathogenetic relevance in the natural history of essential hypertension. Further, in the mild hypertensive a positive prolactin-renin correlation was found (r = + 0.76; P < 0.01), so suggesting that in these patients a peripheral sympathetic overactivity is associated to an impaired central dopamine control. The individuation of such cases may be important since they could benefit by dopamine agonists as L-dopa and bromocriptine.

[Cyclic adenosine monophosphate (3'5' cAMP) in the alcohol withdrawal syndrome. Clinico-pathogenetic perspectives]. / L'adenosinmonofosfato ciclico (3'5' AMP-c) nella sindrome da astinenza alcoolica (S.A.A.). Prospettive clinico-patogenetiche.

The cyclic adenosine monophosphate (AMP-c) excreted in the urine over a 24 hour period was systematically measured in 40 patients suffering from alcohol withdrawal syndrome (AWS) in varying degrees from slight to delirium tremens. In almost all patients the level of excreted AMP-c was high bul returned to normal when the clinical picture together with arterial pressure and cardiac frequency, was normalised. This shows the primary importance of the central sympathetic-adrenergic system in the pathogenesis of AWS and the value of monitoring urinary AMP-c excretion during the syndrome.

[Prolactin in the alcohol withdrawal syndrome. Role of the dopaminergic system]. / La prolattina nella sindrome da astinenza alcolica. Ruolo del sistema dopaminergico.

The basal prolactinemia and the prolactinic reserve were investigated in 30 chronic alcoholics, during the alcohol withdrawal syndrome. In 80% of these patients, the prolactinic reserve was extremely low, while in 16,66% of them was normal or near the lowest limits, recognizing in the exaggerated dopaminergic central activity the responsible pathogenetic mechanism. The dopaminergic hyperactivity fits into a general context of the sympathetic-adrenergic hypertonia, which notoriously plays a primary pathogenetic role in the pathogenesis of the alcohol withdrawal syndrome. In 5 patients with an inhibited prolactin response, a normalization of the prolactin reserve was registered in a test (the same methoclopramide test) carried out after 2-3 months of abstinence from alcoholic beverages, as an evidence of the normalization of the central dopaminergic activity and of a dopaminergic hyperactivity during the alcohol withdrawal syndrome.

[Insulin, peptide C and glucide tolerance in chronic alcoholic hepatopathies]. / Insulina, peptide C e tolleranza glucidica nelle epatopatie alcoliche croniche.

Changes in blood glucose and insulin metabolism, both under basal conditions and after glucose and glucagon stimulus, were studied in 95 patients with chronic alcoholic hepatopathy. Peptide C was also determined in 19 patients. A high incidence of islet-cell insufficiency was noted. Stress is laid on the multiplicity of the pathogenetic mechanisms responsible for blood glucose and insulin changes during chronic alcoholic hepatopathy, particularly liver cell damage, hyperglucagonaemia, organic and/or functional islet-cell insufficiency, and peripheral insulin resistance. It is felt that the last two of these are of major importance, whereas liver cell damage is of secondary significance, at any rate as far as glucose and insulin turnover is concerned.

[Prolactin in chronic alcoholic liver diseases with and without gynecomastia]. / La prolattina nelle epatopatie alcoliche croniche con e senza ginecomastia.

The Authors, after having examined the factors responsible for the hyperprolactinemia in the cirrhotic, confirm the lack of a relationship between the increase in the prolactinic reserve and gynecomastia and between the amount of the prolactinic reserve and the degree of liver disorder. While hyperestrinism and the false transmitters lost most of their pathogenetic importance, other factors such as GABA, the Serotonin and the VIP, offered a new pathogenetic prospective. The prolactin reserve was studied in 63 patients affected by cirrhosis and in 25 affected by fibrosis and hepatic fibrosteatosis, pointing out an increase in the prolactin reserve in 61% of cirrhotic patients and an absence of pathological reports in patients affected by fibrotic hepatopathies. These data confirm the low pathogenetic responsability to be strictly ascribed to ethanol and the preminent role of liver cirrhosis and portal hypertension in the prolactin turnover.

[Changes in the circadian rhythm of urinary cyclic adenosine monophosphate during the alcoholic withdrawal syndrome and related neurobiological correlations]. / Alterazioni del ritmo circadiano dell'adenosinmonofosfato ciclico urinario in corso di sindrome da astinenza alcolica e relative correlazioni neurobiologiche.

Urinary cyclic adenosine monophosphate (AMP-c) was measured morning and evening in 35 patients with alcohol withdrawal syndrome (AWS). 65% of the patients revealed a higher night time than day time concentration of AMP-c in the urine, reflecting increased sympathetic adrenergic activity. The circadian rhythm was lost in 88.55% of the 35 patients. The pathogenic factors and mechanisms involved in AWS are discussed and the contribution of sympathetic adrenergic hyperactivity to the onset of the withdrawal syndrome with its concomitant depression of the cholinergic and GABAergic systems is emphasised. Finally it is suggested that insomnia and the loss of REM sleep may also contribute to the onset of the condition.