Disseminated lymphangiomas as a cutaneous manifestation of Noonan syndrome.

Lymphangioma is a known, but rare manifestation of Noonan syndrome. We present the case of disseminated and circumscribed cutaneous lymphangiomas in the context of Noonan syndrome. Oral rapamycin is a promising treatment in these extensive and morbidity-causing cases.

Association between a stromal cell-derived factor 1 (SDF-1/CXCL12) gene polymorphism and microvascular disease in systemic sclerosis.

OBJECTIVE: To investigate the possible implication of SDF1-3' polymorphism in systemic sclerosis (SSc) susceptibility or clinical phenotype, or both. METHODS: 150 patients with SSc and 150 controls were enrolled. Skin involvement, autoantibodies, interstitial lung disease, pulmonary arterial hypertension (PAH), scleroderma renal crisis, past and/or current skin ulcers were assessed. Genotyping was performed by PCR-RFLP. RESULTS: Genotype distribution and allele frequency were similar in SSc and controls. SDF1-3'A allele and SDF1-3'GA/AA genotype frequencies were significantly higher in SSc-PAH than in SSc-non-PAH (33.3% vs 18.3%, p = 0.01) and in SSc with skin ulcers than in SSc without ulcers (27.3% vs 16.9%, p = 0.03). The SDF1-3'A allele influenced the predisposition to SSc-related PAH (OR = 2.52, 95% CI 1.11 to 5.69, p = 0.02) and skin ulcers (OR = 2.31, 95% CI 1.18 to 4.52, p = 0.01). After adjustment for age and gender, the SDF1-3'A allele remained a susceptibility factor for the SSc-related vascular manifestations (PAH: OR = 2.37, 95% CI 1.04 to 5.42, p = 0.04; ulcers: OR = 2.33, 95% CI 1.78 to 4.62, p = 0.01). CONCLUSION: The SDF1-3'A allele is significantly associated with microvascular involvement in SSc.

Uninephrectomy increases kidney beta2-microglobulin: can it play a role in the progression of kidney damage?

Beta2-microglobulin (beta2M) is highly accumulated by the kidneys of normal rats. The aim of this study was to verify if uninephrectomy can modify the renal uptake of labeled beta2M. For this purpose the radioactivity of plasma and those of the remaining kidney, liver and urine have been measured in uninephrectomized rats (NX) and in controls (C) at different times after the injection as i.v. bolus of 131I-beta2M. The experiments were performed in 114 Sprague-Dawley male rats. Fifty seven animals underwent right nephrectomy, the other animals being the C. NX and their C were divided in 3 groups, studied 2, 4 and 6 weeks after nephrectomy, respectively. Part of the animals were sacrificed 12 min after the injection of labeled beta2M (peak-time, i.e. time of highest kidney accumulation of 131I-beta2M in the normal rat) and part 10 min later. The results demonstrate that: - uninephrectomy increases plasma retention of 131I-beta2M - kidney uptake (total and per gram) is always higher in NX - liver uptake (much lower than that of kidney) is not influenced by uninephrectomy - urine excretion of radioactivity is minimal in both NX and C. The behavior of beta2M is similar to that we previously observed with alpha1-microglobulin and lysozyme. The higher kidney content of some low mw proteins after uninephrectomy could play a role in the progressive reduction of renal function determined by the reduction of renal mass.

Comparison of radiochemical purity control methods for 99Tcm radiopharmaceuticals used in hospital radiopharmacies.

The free fraction of pertechnetate in 99Tcm radiopharmaceuticals has to be tested for quality control reasons in line with the European Pharmacopoeia. Such quality control is often performed by miniaturized chromatographic methods. There are several recommended methods in the literature for quality control of the same radiopharmaceuticals, though it is unlikely that all methods are equivalent. Some of these methods were compared, taking into account different parameters (spot size, time required, analytical artifacts, true separation and shape of the chromatographic peaks, ease of handling), to verify the best method for the control of each radiopharmaceutical. It would appear that instant thin layer chromatography silica gel is the best support for these miniaturized methods, using MEK as solvent to check DTPA, DMSA, gluconate, pyrophosphate, medronate and phytate; NaCl 20% solution is the best solvent for IDA derivatives, human albumin and albumin particles (microspheres, macroaggregates).

Cardiac and pleuropulmonary AL amyloid imaging with technetium-99m labelled aprotinin.

Antiproteases are known to be present in amyloid deposits. We evaluated the possibility of using an anti-serine protease (aprotinin) labelled with technetium-99m (TcA), usually employed as a cortical renal tracer, for the imaging of amyloid deposits. Because of the known high uptake of TcA by the kidneys, we limited our analysis to extra-abdominal amyloid localizations. We report the scintigraphic findings observed in 24 patients with light chain amyloidosis (AL) and one with a hereditary form who were known or suspected to have extra-abdominal involvement. Planar scans obtained 100min after i.v. TcA administration showed myocardial accumulation in 11 patients, pleuropulmonary accumulation in nine, pericardial accumulation in two and localization in the neck region (thyroid, salivary glands and tongue) in eight. TcA scintigraphy was negative in five patients without clinical or laboratory evidence of extra-abdominal involvement, as well as in 12 control group patients with cardiac and renal diseases. These preliminary results indicate TcA to be a low-cost, readily available radiopharmaceutical for imaging of extra-abdominal involvement in AL type amyloidosis.

Biodistribution and pharmacokinetic screening in humans of monoclonal antibody AR-3 as a possible immunoscintigraphy agent in patients with pancreatic cancer.

This pharmacokinetic study was performed in order to assess the potential usefulness of the murine monoclonal antibody (MoAb) AR-3-IgG1 as an immunoscintigraphy agent for pancreatic cancer. This MoAb, which defines a mucin-like antigen (CAR-3) expressed by a large fraction of pancreatic cancers, shows in fact favourable in vivo localizing properties in the experimental animal model of human tumor xenograft. 131I-AR-3-IgG1 was injected i.v. into 5 patients with suspected pancreatic cancer. Whole-body maps and spot views of the abdominal area were recorded with a computerized gamma-camera, and specific regions of interest drawn over the liver and spleen helped to define the kinetics of activity in these organs. Blood samples taken from 0.1-144 hours post-injection and daily urine collections over the same interval served to define the kinetics of plama distribution and removal of activity from the body. Different multicompartmental models were tested to fit the experimental data, assuming as the starting hypothesis that there was to be significant nonspecific tracer accumulation in the liver, spleen and bone marrow, as already observed for the majority of radioiodinated murine MoAbs injected into humans. Surgery confirmed pancreatic cancer in 3 out of the 5 patients (chronic pancreatitis and periampullary cancer in one each); in all these 3 patients immunostaining with the MoAb AR-3 demonstrated the presence of the CAR-3 antigen (with a cytoplasmic and endoluminal/secretory pattern of distribution). Nonspecific radioactivity accumulation in the liver, spleen and bone marrow was extremely low, linked essentially to the blood pool effect of circulating activity in these organs.(ABSTRACT TRUNCATED AT 250 WORDS)

Human biodistribution, dosimetry and clinical use of technetium(III)-99m-Q12.

UNLABELLED: Technetium(III)-99m-Q12, trans-(1,2-bis(dihydro-2,2,5,5-tetramethyl- 3(2H)furanone-4-methyleneimino)ethane)bis(tris(3-methoxy-1-propyl) - phosphine)technetium(III)-99m, is a nonreducible complex of Tc(III) which is herein evaluated as a myocardial perfusion imaging agent. METHODS: The biodistribution and dosimetry of 99mTc-Q12 were assessed in 10 normal volunteers, while its potential clinical use was evaluated in 70 patients. RESULTS: Safety parameters measured up to 24 hr postinjection demonstrate no clinically significant drug-related adverse reactions. Technetium(III)-99m-Q12 exhibits good heart uptake (2.2% injected dose at 1 hr postinjection under resting conditions) and no detectable myocardial washout or redistribution up to 5 hr postinjection. The biodistribution is characterized by very rapid hepatobiliary clearance which allows effective myocardial imaging at times as short as 15 min postinjection. Blood and plasma clearances and myocardial uptake are rapid, while lung uptake is minimal. The heart-to-lung and heart-to-liver ratios are higher at stress than at rest, independent of the time elapsed between injection and image acquisition, and independent of whether the patient is fasted or fed after tracer administration. A preliminary correlation shows that 46/47 patients with angiographically demonstrated CAD also have perfusion defects demonstrated by 99mTc-Q12. CONCLUSIONS: On the basis of the studies reported herein, 99mTc-Q12 appears to be a promising myocardial perfusion imaging agent.

Preliminary evaluation in humans of Tc-99m-Q3, a new tracer for myocardial perfusion imaging.

Trans[99m-Tc-acac2en(TMPP)2]+, where acac2en is N,N'-ethylenebis(acetylacetone iminate) and TMPP is tris-(3 methoxy propyl) phosphine, (shortened Q3) is a new lipophilic Technetium-99m-labelled compound developed for myocardial perfusion imaging. Encouraging data were obtained in the experimental animal. Aim of this study was to perform a preliminary evaluation of Q3 imaging in humans and to compare it with a reference coronary flow tracer such as Tc-99m microspheres. Eight coronary artery disease patients (males, age 58.5 +/- 10 years) were studied. They were injected with 740 MBq of Q3 and single photon emission computed tomography (SPECT) was performed 90 minutes later. After 3 days 740 MBq of Tc-99m microspheres were injected through a pig-tail catheter in the left ventricle (LV), during heart catheterization, and SPECT was acquired 60 minutes later. Q3 images showed a good target/background activity ratio:LV wall/LV cavity = 4.16 +/- 1.2; myocardium/lung = 3.95 +/- 0.52; the related values with microspheres were 6.36 +/- 2.48 (N.S.) and 4.57 +/- 1.07 (N.S.), respectively. Q3 was cleared by the liver and at the moment of SPECT collection the myocardium/liver activity ratio was 1.54 +/- 0.32. The Q3 LV lateral wall/septum activity ratio showed a good correlation with the corresponding microspheres ratio: Q3 ratio = 0.027 + 0.95 microspheres ratio, r = 0.89, SEE = 1.12, p < 0.005.

In vivo targeting of Hodgkin and Reed-Sternberg cells of Hodgkin's disease with monoclonal antibody Ber-H2 (CD30): immunohistological evidence.

The ability of the Ber-H2 (CD30) monoclonal antibody (mAb) to target in vivo Hodgkin (H) and Reed-Sternberg (R-S) cells was investigated in six patients with advanced Hodgkin's disease (HD). The patients were injected with scaled-up quantities of 'cold' Ber-H2 mixed-up to a small dose of 131I-labelled Ber-H2, and in vivo binding of the antibody to H and R-S cells was assessed by immunohistological analysis of tumour biopsies and immunoscintigraphy. Only 50% of tumour sites were imaged at scintigraphy by the 131I-labelled Ber-H2. In contrast, immunohistological studies on tissue biopsies, taken 24-72 h following the mAb injection, showed that H and R-S cells in all tumour sites, including those that were not imaged by immunoscintigraphy, were specifically and strongly labelled in vivo by the injected Ber-H2, at a dose as low as 30-50 mg of antibody. In vivo binding of a single dose of Ber-H2 mAb to H and R-S cells did not result in any anti-tumour effect. The excellent in vivo targeting of H and R-S cells with the Ber-H2 mAb may have been the result of multiple favourable factors, including: (a) the restricted expression of the CD30 antigen in normal human tissues; (b) the low level of soluble CD30 in the serum of our patients; and (c) the high affinity of the Ber-H2 mAb for the CD30 molecule. The immunohistological results presented in this study provide a strong argument for using the Ber-H2 mAb as a carrier for delivering cytotoxic agents (isotopes or toxins) to neoplastic cells of HD refractory to conventional therapy.

[Renal accumulation of radioiodinated alpha-1-microglobulin increases in the mononephrectomised rat]. / L'accumulation rénale de alpha-1-microglobuline radioiodée augmente chez le rat mononéphrectomisé.

Alpha-1-microglobulin (alpha 1M) is highly accumulated by the kidneys of normal rats. Aim of this study has been to verify if uninephrectomy can modify this behaviour. For this purpose the radioactivity of the remaining kidney and those of plasma and urine have been measured in uninephrectomized rats after IV injection of radioiodinated alpha 1M. The experiments have been performed in 100 Sprague-Dawley male rats. Fifty animals underwent right nephrectomy, the others being the controls. Uninephrectomized rats and their controls have been divided in 3 groups, studied 4, 14 and 28 days after surgery, respectively. All the animals were injected with human alpha 1M labelled with iodine-131. They were sacrificed in part 18 minutes after the injection of labelled alpha 1M (time of highest kidney accumulation in the normal rat), and in part 28 minutes after the injection. Uninephrectomy increased plasma retention of labelled alpha 1M. Kidney uptake (total and per gram) was always higher in uninephrectomized animals. Similarly, urine radioactivity was higher in uninephrectomized rats. These results demonstrate that uninephrectomy remarkably increases the accumulation of alpha 1M in the remaining kidney.

In vivo detection of somatostatin receptors in patients with functionless pituitary adenomas by means of a radioiodinated analog of somatostatin ([123I]SDZ 204-090).

The recent availability of a Tyr3-substituted octreotide (SDZ 204-090) for radioiodination has allowed somatostatin (SRIH) receptor binding to be studied in vivo, and receptor-positive tumors of different origins to be visualized with a gamma-camera. This prompted us to investigate whether this compound could be used for external imaging of functionless pituitary adenomas displaying SRIH receptors. Eight patients with functionless pituitary adenomas, three patients with acromegaly, and three with macroprolactinoma were injected iv with 123I-labeled Tyr3-octreotide and then scanned with a gamma-camera. Positive scans were obtained in the three acromegalics and in two of the eight patients with functionless pituitary tumors. The patients with macroprolactinoma had negative scans. The diagnosis of functionless pituitary adenomas was confirmed by light and electron microscopic examination as well as immunocytochemical studies. In vitro binding of [125I]Tyr11-SRIH to cell membranes was evaluated in four functionless and three GH-secreting adenomas removed from seven of the patients. All of the GH-secreting as well as one of the four functionless adenomas had high affinity SRIH-binding sites, without differences in number or affinity, whereas SRIH-binding sites were not detected in the others. Positive scans were observed only in patients bearing tumors with high affinity SRIH-binding sites. In conclusion, [123I]Tyr3-octreotide appears to be a promising tool for singling out, in vivo, patients with functionless pituitary tumors displaying SRIH receptors who might potentially benefit from octreotide treatment.

Updating the procedure for metaiodobenzylguanidine labelling with iodine radioisotopes employed in industrial production.

The classical procedure used for the preparation of [125I]- and [131I]metaiodobenzylguanidine (MIBG) is the solid-phase isotopic exchange between MIBG and radioiodide. This reaction requires 1.5 hours at 160 degrees C to obtain maximum total labelling yields of 75-80%. Recently, the importance of rapid procedures for the preparation of 123I-MIBG has been highlighted. A highly efficient procedure for the industrial production of 123I-MIBG using ascorbic acid, tin sulfate and copper sulfate pentahydrate in 0.01 M sulfuric acid is reported. Sequential radio-TLC analysis of the labelling mixture shows that the labelling yield reaches 98% within 45 min at 100 degrees C. The specific activity of the 123I-MIBG produced in this manner is on the order of 100 Ci/mmol.

Human gliomas radioimmunoimaging with 131-I BC-2 murine IgG: preliminary report.

Ten patients with intracranial malignancies were studied by radioimmunoscintigraphy with I-131 BC-2 MoAb. Sensitivity and specificity of radioimmunoimaging were determined and compared with the results obtained with computed X-ray tomography and magnetic resonance imaging. BC-2 MoAb is a murine IgG1 anti-tenascin, which is not expressed by adult normal brain and has been found in large amount in gliomas and/or cerebral metastases, as well as other human tumors. Gamma-camera images obtained at 1 to 4 days exhibited increasing uptake of BC-2 in eight tumors, with varying degrees of contrast with the surrounding normal brain. Two lesions resulted negative to RIS: a meningioma and an oligodendroglioma. Specific tumor uptake of I-131 BC-2 was determined, by external gamma imaging, and ranged from 0.002 up to 0.007 percent of injected dose. Nonspecific uptake in the tumor was determined injecting 99m-Tc-FO23C5 (an isotype-matched control IgG1) in four patients and it was lower than 0.0001% ID. I-131 BC-2 tumor/nontumor ratios, measured using the geometric mean on digital images, ranged from 3 to 7.5:1. This study demonstrates that the tumor uptake of BC-2 in patients with glioma was due to specific processes.