760 research outputs found
Somatostatin receptor scintigraphy in patients with carcinoid tumors
In 80% to 90% of patients with carcinoids, tumor sites can be detected with [111In-DTPA-D-Phe1]-octreotide scintigraphy. Unexpected, additional localizations are reported in one-third to two-thirds of patients. In a group of 52 patients, we analyzed the results of various combinations of octreotide scintigraphy and conventional imaging. Octreotide scintigraphy, alone or in combination with other imaging modalities, led to the detection of more tumor sites than any combination of conventional imaging techniques. The combination of octreotide scintigraphy, chest radiography, and ultrasonography of the upper abdomen led to the detection of lesions in all patients in whom they could be demonstrated by any imaging means, with a sensitivity of 87% in terms of the number of detected lesions. The calculated cost for this imaging regimen was higher than for the combination of conventional imaging as applied in our group. However, the benefit was the detection of at least one lesion in 11% of patients in whom with conventional imaging no abnormalities were found. Moreover, if the results from our patient group were extrapolated to a group of 100 patients, the advantage in terms of the number of extra lesions detected would be 65 extra lesions per 100 patients. The detection of more tumor sites in patients who are known to have one tumor localization with conventional imaging may be essential when deciding whether to perform surgery. Octreotide scintigraphy can be used to localize tumors, direct the choice of medical therapy, and (expected in the near future) select patients for radiotherapy. The impact on patient management is fourfold: Octreotide scintigraphy may detect resectable tumors that would be unrecognized with conventional imaging techniques; it may prevent surgery in patients whose tumors have metastasized to a greater extent than can be detected with conventional imaging; it may direct the choice of therapy in patients with inoperable tumors; and in the future it may be used to select patients for radionuclide therapy
Thyroid hormone uptake by rat hepatocytes in primary culture
Iodide is taken up by the thyroid follicular cell,
oxydized and bound to thyroglobulin at the apical
membrane facing the colloid in the follicular lumen.
Iodinated colloid is subsequently engulfed by the
follicular cell and hydrolysed, liberating thyroxine
and triiodothyronine from their peptide linkage to
thyroglobulin. Iodothyronines are then secreted into
the blood stream. These and other steps in the synthesis
and secretion of thyroid hormones are conditioned
by the extent of thyroid stimulation by pituitary
thyrotropin. The synthesis and release of thyrotropin
is stimulated by the hypothalamic thyrotropinreleasing
hormone, while thyroid hormone inhibits
these processes (Larsen, 1982). In this way, a negative
feedback mechanism is formed between the thyroid
and pituitary.
The main product secreted by the human thyroid is
thyroxine (mean 115 nmol/day per 70 kg body weight).
Other products are triiodothyronine (mean 9 nrnol/day,
which accounts for 20% of the total daily production)
and reverse triiodothyronine (mean 2 nmol/day; 6%)
(Chopra, 1976; Chopra et al., 1978a; Visser, 1980).
From these figures it will be clear that synthesis of
the latter iodothyronines occurs mainly outside the
thyroid gland by monodeiodination of thyroxine, the
so-called peripheral production. In pathophysiological conditions, like iodine deficiency and Graves'
disease, thyroidal secretion of triiodothyronine is
increased relative to that of thyroxine (Izumi and
Larsen, 1977). The relative contribution of different
tissues to the daily production of triiodothyronine
and reverse triiodothyronine is at present unknown.
However, deiodination has been observed in
vitro in almost all tissues studied (see review by
Visser, 1980). Based on circumstantial evidence, it
is generally believed that the liver is the main site
of triiodothyronine synthesise For instance, in
liver cirrhosis triiodothyronine production is decreased,
while apparent reverse triiodothyronine synthesis
is unaltered (Chopra, 1976). The latter finding
is in favour of extra-hepatic thyroxine_.reverse
triiodothyronine conversion. The low serum reverse
triiodothyronine levels in patients with severe,
chronic renal failure may suggest that substantial
amounts of reverse triiodothyronine are produced in
the kidneys (Chopra et al., 1975; Weissel et al.,
1977; Weissel and Stummvoll, 1981)
To serve and protect: Enzyme inhibitors as radiopeptide escorts promote tumor targeting
Radiolabeled octreotide analogs are most successfully being applied today in clinical cancer imaging and treatment. Propagation of this paradigm to other radiopeptide families has been greatly hampered by the inherent poor metabolic stability of systemically administered peptide analogs. We hypothesized that the in vivo coadministration of specific enzyme inhibitors would improve peptide bioavailability and hence tumor uptake. Through single coinjection of the neutral endopeptidase inhibitor phosphoramidon (PA), we were able to provoke remarkable rises in the percentages of circulating intact somatostatin, gastrin, and bombesin radiopeptides in mouse models, resulting in a remarkable increase in uptake in tumor xenografts in mice. Methods: The peptide conjugates [DOTA-Ala1]SS14 (DOTA-Ala-Gly-c[Cys-Lys- Asn-Phe-Phe-Trp-Lys-Thr-Phe- Thr-Ser-Cys]-OH), PanSB1 (DOTAPEG2- DTyr-Gln-Trp-Ala-Val-βAla- His-Phe-Nle-NH2), and DOTA-MG11 (DOTA-DGlu-Al
Considerations concerning a tailored, individualized therapeutic management of patients with (neuro)endocrine tumours of the gastrointestinal tract a
Endocrine tumours of the gastrointestinal tract and pancreas may present
at different disease stages with either hormonal or hormone-related
symptoms/syndromes, or without hormonal symptoms. They may occur either
sporadically or as part of hereditary syndromes. In the therapeutic
approach to a patient with these tumours, excessive hormonal secretion
and/or its effects should always be controlled first. Tumour-related
deficiencies or disorders should also be corrected. Subsequently, control
should be aimed at the tumour growth. Surgery is generally considered as
first-line therapy for patients with localized disease, as it can be
curative. However, in patients with metastatic disease the role of
first-line surgery is not clearly established and other therapies should
be considered, such as non-surgical cytoreductive therapies, biotherapy
(with somatostatin analogues or interferon-alpha), embolization and
chemoembolization of liver metastases, chemotherapy (with single or
multiple dose regimens) and peptide receptor-targeted radiotherapy. The
delicate balance of the use of the different therapeutical options in
patients with endocrine tumours of the gastrointestinal tract and pancreas
emphasizes the importance of team approach and team expertise
Side-Chain Modified [<sup>99m</sup>Tc]Tc-DT1 Mimics:A Comparative Study in NTS<sub>1</sub>R-Positive Models
Radiolabeled neurotensin analogs have been developed as candidates for theranostic use against neurotensin subtype 1 receptor (NTS1R)-expressing cancer. However, their fast degradation by two major peptidases, neprilysin (NEP) and angiotensin-converting enzyme (ACE), has hitherto limited clinical success. We have recently shown that palmitoylation at the ε-amine of Lys7 in [99mTc]Tc-[Lys7]DT1 (DT1, N4-Gly-Arg-Arg-Pro-Tyr-Ile-Leu-OH, N4 = 6-(carboxy)-1,4,8,11-tetraazaundecane) led to the fully stabilized [99mTc]Tc-DT9 analog, displaying high uptake in human pancreatic cancer AsPC-1 xenografts but unfavorable pharmacokinetics in mice. Aiming to improve the in vivo stability of [99mTc]Tc-DT1 without compromising pharmacokinetics, we now introduce three new [99mTc]Tc-DT1 mimics, carrying different pendant groups at the ε-amine of Lys7: MPBA (4-(4-methylphenyl)butyric acid)—[99mTc]Tc-DT10; MPBA via a PEG4-linker—[99mTc]Tc-DT11; or a hydrophilic PEG6 chain—[99mTc]Tc-DT12. The impact of these modifications on receptor affinity and internalization was studied in NTS1R-positive cells. The effects on stability and AsPC-1 tumor uptake were assessed in mice without or during NEP/ACE inhibition. Unlike [99mTc]Tc-DT10, the longer-chain modified [99mTc]Tc-DT11 and [99mTc]Tc-DT12 were significantly stabilized in vivo, resulting in markedly improved tumor uptake compared to [99mTc]Tc-DT1. [99mTc]Tc-DT11 was found to achieve the highest AsPC-1 tumor values and good pharmacokinetics, either without or during NEP inhibition, qualifying for further validation in patients with NTS1R-positive tumors using SPECT/CT.</p
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