Evaluation of systemic targeting of RET oncogene-based MTC with tumor-selective peptide-tagged Ad vectors in clinical mouse models.

Significant advantage of targeted antitumoral treatment consists in the possibility to restrict maximum therapeutic efficacy to the malignant cell population by reducing toxicity in healthy tissues. Using different clinical models for aggressive medullary thyroid carcinoma (MTC), we have recently identified peptide ligands that bind highly selective to tumor cells. By linking the most convincing SRESPHP peptide to an adenoviral (Ad) vector expressing the MTC-related oncogene inhibitor RETΔTK, gene transfer was specifically directed to neoplastic tissue after systemic virus administration. We show that peptide-mediated delivery of RETΔTK significantly enhanced apoptosis, resulting in a strong inhibition of orthotopic and xenograft tumor growth. Conversely, tumors treated with controls expanded their initial size without notable cell death. According to the therapeutic effect, strong virus accumulation was found exclusively in thyroid carcinomas. Strikingly, application of native tropism depleted viral vector linked to tumor-selective peptide was accompanied by a substantial reduction of Ad binding to the liver. Of note, single systemic injection of a low dose (10e8 pfu/mouse) of MTC-specific Ad.RETΔTK induced regression of multiple tumors at different sites in all treated animals. In sum, our results open up the possibility for an efficient cancer cell-specific therapy of primary MTC, their migrating populations and potentially metastases.

A comparison of the skin permeation of three topical 0.5% fluorouracil formulations with that of a 5% formulation.

BACKGROUND: Topical fluorouracil has proven efficacy in the treatment of actinic keratosis. The systemic absorption of various topical formulations of fluorouracil varies, however, and may be affected by the concentration and delivery system used. OBJECTIVE: This study compared the flux and percutaneous absorption of 3H-labeled fluorouracil from three 0.5% fluorouracil formulations incorporated into a porous microsphere delivery system with those from a commercially available 5% fluorouracil formulation. METHODS: Penetration of all formulations through the skin was sampled every 3 hours for 24 hours using full-thickness human cadaver skin samples mounted in a Bronaugh flow-through diffusion cell apparatus. Total absorption was defined as the sum of the amount of cumulative flux through the skin over 24 hours and the amount retained in the skin at 24 hours. RESULTS: The flux through the skin of the 5% fluorouracil formulation was 20 to 40 times greater (normalized, 2-4 times greater) than that of the 0.5% fluorouracil formulations. A higher percentage of absorbed fluorouracil was retained in the skin after 24 hours with the 0.5% formulations (86%-92%) than with the 5% formulation (54%). CONCLUSION: These findings suggest that the 0.5% formulations are associated with less flux through the skin than the 5% formulation and, therefore, potentially less systemic exposure.

A pharmacokinetic evaluation of 0.5% and 5% fluorouracil topical cream in patients with actinic keratosis.

BACKGROUND: Systemic absorption of topical fluorouracil, although usually low, may vary as a result of the specific skin disease, product formulation, and other factors. OBJECTIVE: The present study was conducted to determine the pharmacokinetic profile and tolerability of a new topical 0.5% fluorouracil cream formulation compared with that of a currently available topical formulation of 5% fluorouracil cream. METHODS: This was an open-label, parallel-group study in which patients with actinic keratosis (AK) were randomized to treatment with either topical 0.5% fluorouracil once daily or topical 5% fluorouracil twice daily for up to 28 days. RESULTS: Twenty-one patients (all white; mean age, 64 years) participated in the study, 11 receiving topical 0.5% fluorouracil and 10 receiving topical 5% fluorouracil. Ten patients receiving 0.5% fluorouracil and 7 patients receiving 5% fluorouracil completed the 28-day study. Plasma concentrations of fluorouracil were detectable in 3 of 10 patients treated with 0.5% fluorouracil and 9 of 10 patients treated with 5% fluorouracil; fluorouracil was detected in the urine of 5 and 9 patients, respectively. Despite the one-tenth difference in drug concentration between formulations, the cumulative amount excreted in the urine of the 0.5% fluorouracil group was approximately one fortieth that of the 5% fluorouracil group. This difference may be a result of variations in vehicle formulations. At least 1 adverse event was reported by 4 of 11 patients in the 0.5% fluorouracil group and all 10 patients in the 5% fluorouracil group. The most common adverse event, facial irritation, was evident with both formulations but reached a plateau during treatment with 0.5% fluorouracil. All patients treated with 0.5% fluorouracil tolerated the full course of therapy, whereas 3 patients in the 5% fluorouracil group discontinued treatment early. No serious treatment-related adverse events were reported. CONCLUSIONS: These data suggest that 0.5% fluorouracil has minimal systemic absorption and is well tolerated in patients with AK.

Efficacy of continuous sequential transdermal estradiol and norethindrone acetate in relieving vasomotor symptoms associated with menopause.

OBJECTIVE: This study was undertaken to evaluate the efficacy and tolerability of a combination estradiol plus norethindrone acetate transdermal delivery system given in a continuous sequential regimen with transdermal estradiol versus placebo in the treatment of vasomotor symptoms of menopause. STUDY DESIGN: This was a 12-week double-blind trial of 220 healthy postmenopausal women with > or = 8 moderate to severe hot flushes and sweating episodes per day. Women were randomly assigned to wear transdermal placebo patches or a transdermal patch releasing 50 microg/d 17beta-estradiol alone (Vivelle) for days 1 to 14 of each cycle and a combination patch releasing 50 microg/d 17beta-estradiol plus 1 of 3 dosage levels (140, 250, or 400 microg/d) of norethindrone acetate (CombiPatch) for days 15 through 28. RESULTS: There was a significant (P <.001) reduction by the second week in the mean number of daily hot flushes from baseline to end point with all 3 doses of estradiol plus norethindrone acetate compared with placebo. Significant (P <.001) reductions in the mean intensity of hot flushes and sweating were also noted with estradiol plus norethindrone acetate compared with placebo. The incidences of adverse events with all 3 doses of estradiol plus norethindrone acetate and with placebo were comparable. CONCLUSION: An estradiol plus norethindrone acetate transdermal delivery system administered in a continuous sequential regimen with transdermal estradiol was well tolerated and effective for the treatment of moderate to severe vasomotor symptoms in postmenopausal women.

A randomized comparison of continuous combined transdermal delivery of estradiol-norethindrone acetate and estradiol alone for menopause. CombiPatch Study Group.

OBJECTIVE: To determine whether a continuous estradiol-norethindrone acetate transdermal delivery system reduces incidence of endometrial hyperplasia in postmenopausal women more than transdermal estradiol (E2) alone. METHODS: Six hundred twenty-five postmenopausal women were assigned randomly to one of four treatments, transdermal E2 50 microg/day, or transdermal E2-norethindrone acetate with 50 microg E2 and 140, 250, or 400 microg/day of norethindrone acetate. Follow-up visits to collect information on safety and efficacy were scheduled at 3, 6, 9, and 12 months after initiation of treatment. Endometrial biopsy for histologic evaluation was done at baseline and upon exit from the study (completion or withdrawal). Endometrial histology was evaluated by two independent gynecologic pathologists. In the event of a disparate reading, a third gynecologic pathologist evaluated the tissue using predetermined criteria. RESULTS: Endometrial hyperplasia was found in 37.9% (39 of 103) in the E2 alone group versus 0.8% (one of 123), 1% (one of 98), and 1.1% (one of 89) in the E2-norethindrone acetate 50-140, 50-250, and 50-400 groups, respectively (P < .001). Uterine bleeding was less frequent in the E2-norethindrone acetate 50-140 group than other treatments. The mean number of hot flushes per day decreased to less than one in each treatment group at endpoint. The E2-norethindrone acetate combination patch showed skin tolerance comparable to that of E2 alone. CONCLUSION: Continuous transdermal delivery of E2 combined with norethindrone acetate effectively prevented endometrial hyperplasia in healthy postmenopausal women. Continuous combined transdermal delivery systems provide increased dosing flexibility and might improve convenience and compliance with hormone replacement therapy.

Detection of Mycobacterium tuberculosis in gastric aspirates collected from children: hospitalization is not necessary.

OBJECTIVE: To compare the yields of gastric aspirates collected for culture of Mycobacterium tuberculosis from children evaluated as outpatients versus inpatients and to determine factors associated with a positive culture. METHODS: Retrospective study of 100 children <12 years of age with tuberculosis diagnosed at a pediatric referral hospital or in one of two tuberculosis control programs in California. RESULTS: Of the 100 children who had tuberculosis, 80 had at least one gastric aspirate collected. M tuberculosis was isolated from 33 (41%) of the 80 children who had a gastric aspirate; 4 children had a positive culture from an aspirate subsequent to the first. Inpatients had a higher proportion of positive gastric aspirates than that of children who had aspirates collected as outpatients (48% vs 37%); however, this difference was not statistically significant. Resistance to isoniazid was found in three isolates (9%) of children all of whose presumptive source case had a susceptible strain of M tuberculosis. Characteristics that were associated with an approximately 50% yield from gastric aspirates were identification of a source case, age <2 years, birth in the United States, symptomatic tuberculosis, and pulmonary disease. CONCLUSIONS: The culture of M tuberculosis from gastric aspirates of children in the outpatient setting has a yield comparable to aspirates collected from hospitalized children. Collection of gastric aspirates in the outpatient setting will reduce both the cost and the inconvenience of the procedure. Although the yield from gastric aspirates is relatively low, important information including drug susceptibility patterns may be obtained. tuberculosis, gastric aspirate, children.

[Quality criteria in pancreatic sonography ]. / Qualitätskriterien der Pankreassonographie.

The quality of pancreatic sonography is determined not only by the technical equipment used and by the experience of the interpreter but also by the variable anatomical and nutritional status of the patients examined. The sonograms obtained from 211 consecutively examined patients were analyzed with regard to the quality of pancreatic imaging. Direct visualization of the parenchyma of the pancreatic head and body was found in 47%. In an additional 36%, unequivocal localization of the pancreatic area was possible by delineating the peripancreatic vessels. 17% of the studies were non-diagnostic due to over-lying intestinal gas in obese patients and cases of extensive scarring. This percentage can be reduced by a modified examination technique. The use of alternative radiological methods is, therefore, obligatory in less than 10%.

[Successful transplantation of a two year old child's kidney to an adult (author's transl)]. / Niere eines 2-jährigen Kindes als erfolgreiches Transplantat für einen Erwachsenen.

The successful transplantation of a single kidney of a two year old child to a 38 year old recipient is reported. The size of the kidney increased 400% and the function 340% over a period of 23 months. Adequate function of the transplant was accomplished through growth and considerable compensatory hypertrophy despite intercurrent rejection reactions.

[Acute left decompensation--significance of thoracic bed roentgenography for assessing pulmonary venous pressure (author's transl)]. / Akute Linksdekompensation--Stellenwert der Thoraxbettaufnahme für die Beurteilung des pulmonalvenösen Druckes.

25 thoracic bed x-ray films from 20 intensive-care patients were classified roentgenologically according to three degrees of severity of left decompensation, and compared with the end-diastolic pulmonary arterial pressure. Very good correlation was seen in 60% of the cases and a satisfactory agreement in 30%, whereas a discrepancy compared with haemodynamic parameters was observed in about 10% of the patients. Possibilities of explaining discrepancies are discussed within the framework of error analysis.

[The radiological differential diagnosis of small bowel disease (author's transl)]. / Radiologische Differentialdiagnose von Dünndarmerkrankungen.

The flow diagram of Goldberg and Sheft for the differential diagnosis of diseases of the small bowel was modified (using as its basis mucosal swelling, width of lumen, secretion). Its accuracy was then tested retrospectively in 61 patients. Examination of the small bowel was performed after the administration of a single large dose of contrast medium. A surprisingly high accuracy of 90% was found in 41 pathologically proven cases; all normal patients were correctly identified. The method therefore appears to be extremely promising. More detailed identification is not always possible because of similar reaction of the small bowel to various influences; it may be possible on some occasions, or when taking account of further radiological signs, or of the clinical and laboratory findings.

[Sonography for clarify complications after renal transplantation (author's transl)]. / Die Sonographie zur Abklärung von Komplikationen nach Nierentransplantation.

The diagnostic value of the ultrasound method was studied via 170 individual examinations in 75 patients. The method is particularly well suited for an accurate determination of the location and size of the transplanted kidney and for demonstrating perirenal growing and displacing processes such as cystic lymphangiomas, haematomas and abscesses. In addition, ultrasound supplies information on the area covered by lacunae. However, the use of the method for diagnosing casting-off reactions is limited on account of the great variability of the dimensional parameters. It can be used without risk in followup studies of patients with transplanted kidneys, since it is a non-invasive method. It deserves preference among the possible methods of investigation, especially when growing and displacing processes have to be identified.

[Parathyroid hormone and 25-hydroxycholecalciferol concentrations in the serum of patients with kidney transplantations and their radiological correlation]. / Parathormon- und 25-Hydroxycholekalziferol-Konzentrationen im Serum nierentransplantierter Patienten und ihr röntgenologisches Korrelat.

In 40 renal transplant patients the serum concentration of parathyroid hormone, 25-hydroxycholecalciferol, calcium and inorganic phosphate were estimated. The results of these biochemical studies were compared to X-ray soft tissue and bone pathologic findings. The serum immunoreactive parathyroid hormone (iPTH) was normal in 37 patients and increased in 3 cases. 19 (47.5%) renal transplant recipients showed decreased serum 25-hydroxycholecalciferol levels. In 23 out of 40 patients (57.5%) serum phosphate was lower than 3.0 mg/100 ml. X-ray soft tissue changes were observed in 28 (70%) and bone changes in 18 (45%) patients; both frequencies were higher when compared to occurrence during regular dialysis treatment. Features of hyperparathyroid osteopathy were frequently observed in renal transplant recipients. Femoral head necroses were predominant in men, whereas osteomalacia with Looser's zones were found mainly in women. The pathogenesis of X-ray bone changes in patients with renal transplants seems to be multifactorial and related to the duration of secondary hyperparathyroidism before renal transplantation as well as to phosphate depletion and 25-hydroxycholecalciferol deficiency.

[The diagnostic scope of ultrasonography in renal pathology (author's transl)]. / Der Informationsumfang des Ultraschallverfahrens bei pathologischen Nierenprozessen.

The accuracy of ultrasonography in the diagnosis of different pathological renal conditions is evaluated. Correlations were established to the findings on intravenous urography and selective angiography. Ultrasonography is suitable for the determination of the exact size and site of the kidney and, therefore, should be used routinely in the follow-up of renal transplant recipients. The ability to differentiate between solid and cystic lesions is of partcular value. Moreover, perirenal changes are easily recognizable. The limits of B-mode sonography lie in the interpretation of central expanding lesions with a diameter of under 3 cm. This non-invasive method should be used selectively in the diagnosis of renal disease, whereas angiography should be limited to the classification of equivocal ultrasound findings and in the case of solid tumours.

[Differential diagnosis of space-occupying lesions of kidneys (comparison between IVP, angiography and ultra-sound) (author's transl)]. / Zur Differentialdiagnose renaler Raumforderungen (Vergleichende Untersuchungen Zum Informationsumfang von Ausscheidungsurographie, Angiographie und Ultraschall)

On 77 IVP's it can be shown that correct assessment of the identity of space-occupying lesions of the kidneys is difficult (correct diagnosis in 39% of cystic and 10% of solid conditions). Improvement can be expected from early tomography of IVP's by improved pictures of the parenchyma, mainly with ultra-sound which separates cystic from solid conditions. Correlation of these techniques appears sufficient for cystic processes. Angiography is indicated for solid tumors and doubtful ultra-sound findings.