Scientific misconduct.
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Ethics, Research↗
Biomedical subjects
D I Rosenthal
Publications and source records attributed to D I Rosenthal.
ICAM-5 (telencephalin) gene expression in head and neck squamous carcinoma tumorigenesis and perineural invasion!
ICAM-5 (telencephalin) is an intercellular adhesion molecule reported to be expressed only in the somatodendritic membrane of telencephalic neurons. We recently identified high ICAM-5 expression in a cDNA array study of head and neck neoplasms with a propensity for perineural invasion. To determine the association of this gene in tumorigenesis and perineural invasion, we analyzed the expression and functional status of ICAM-5 mRNA transcripts in 30 different human cancer cell lines and 25 head and neck squamous carcinoma specimens by reverse-transcriptase polymerase chain reaction (cell lines and specimens) and in vitro functional assays (cell lines). ICAM-5 transcripts were detected in 28 (93%) of 30 cell lines derived from primary head and neck, colon, thyroid, cervical, pancreatic, skin, and adenoid cystic carcinomas. In cell lines, small interfering RNA blocked ICAM-5 expression and inhibited cell proliferation. Treatment with the phosphatidylinositol 3'-kinase (PBK) inhibitor LY294002 resulted in ICAM-5 down-regulation. In tissue specimens, none of the 25 histologically normal oral mucosal specimens had detectable ICAM-5 level, whereas 16 (64%) of the 25 matched primary squamous carcinomas showed expression. Carcinoma specimens high ICAM-5 expression had a high incidence of perineural invasion. Our study indicates that ICAM-5 may play a role in tumorigenesis and perineural invasion, most likely through the P13K/Akt-signaling pathway.
Adult↗
Oral buspirone causes a shift in the dose-response curve between the elevated-plus maze and Vogel conflict tests in Long-Evans rats: relation of brain levels of buspirone and 1-PP to anxiolytic action.
Most studies concerning the effects of oral buspirone in the rat elevated plus-maze (EPM) test, spontaneous motor activity (SMA) test, and Vogel conflict (VC) test have used Sprague-Dawley or Wistar rats. Although it has been documented that the behavior of Long-Evans rats is more sensitive to detection of anxiolytics when compared to the aforementioned strains, the effects of oral buspirone have not been fully characterized in the Long-Evans strain in the EPM and VC tests. Thus, we studied the effects of orally administered buspirone (0.03-10.0 mg/kg) in the EPM, SMA, and VC (0.3-60.0 mg/kg) tests in Long-Evans rats. In a separate experiment, brain and plasma concentrations of buspirone and 1-(2-pyrimidinyl)-piperazine (1-PP) were determined after oral administration of buspirone (0.3 and 10 mg/kg) to relate the behavioral effects of buspirone with brain and plasma concentrations of buspirone and 1-PP. Our results showed that buspirone exhibited an inverted-U-shaped dose-response curve in both the EPM and the VC tests. In the EPM, buspirone produced anxiolytic activity in a low, narrow dose-range (0.03, 0.1, 0.3 mg/kg, p.o.) with maximum efficacy at 0.3 mg/kg, whereas in the VC test, significant anxiolytic activity was observed in a high, narrow dose-range (10, 30 mg/kg, p.o.) with maximum efficacy occurring at 10 mg/kg. In the SMA test, buspirone (10 mg/kg, p.o.) significantly decreased horizontal activity and vertical movements suggestive of sedation. Also, one hour following oral doses of buspirone (0.3 and 10 mg/kg), both buspirone and 1-PP concentrations were higher in brain when compared with those in plasma. Additionally, the concentrations of 1-PP were always higher in brain and in plasma compared with the concentrations of buspirone. Of particular interest is our finding of the shift in the dose-response curve between the EPM and VC tests. This shift in the dose-response curve is discussed in relation to brain levels of buspirone and 1-PP levels and their anxiolytic action.
Administration, Oral↗
Paraffinoma of the knee.
We present the case of a 90-year-old man with a swollen, painful knee and a history of paraffin injections. Radiography showed soft tissue streaky and nodular calcifications without erosions. MR imaging showed globular areas of low signal intensity on T1- and T2-weighted images which became even more hypointense on STIR sequences, and an infiltrative hypointense region containing areas of high signal on T1-weighted, T2-weighted and STIR images. Biopsy confirmed soft tissue foreign body granulomata, fibrous reaction and areas of inflammation. We believe this to be the first report of MR imaging of paraffinoma outside the breast.
Aged↗
Pyrazolecarboxamide human neuropeptide Y5 receptor ligands with in vivo antifeedant activity.
1-Aryl-3-carboxamido-5-alkylpyrazoles were prepared based on a hit found in high-throughput screening of our corporate compound library in an assay measuring affinity for the human neuropeptide Y5 receptor. 1-(3-Trifluoromethylphenyl)-3-[N-(5-quinolinyl)carboxamido]-5-methylpyrazole (31) bound to the human neuropeptide Y5 receptor with a 80 nM IC(50 )and was shown to inhibit cumulative food consumption 43.2% 2-6 h after ip dosing in a fasting-induced feeding model in rats.
Animals↗
Increased abdominal visceral fat is associated with reduced bone density in HIV-infected men with lipodystrophy.
OBJECTIVE: To examine the relationship between bone density and changes in regional and whole body composition in HIV-infected men with and without lipodystrophy. DESIGN: Cross-sectional, observational study of HIV-infected men with and without lipodystrophy and matched HIV-negative controls. SETTING: Tertiary care academic medical institution. PATIENTS: A total of 59 men, belonging to three different groups: HIV-positive men with lipodystrophy (n = 21), HIV-positive men without lipodystrophy (n = 20), and age-matched and body mass index-matched HIV-negative controls (n = 18). METHODS: Bone density, markers of bone turnover and indices of calcium metabolism were measured in all subjects. Quantitative computed tomography was used both to determine volumetric bone density of the spine and to quantify abdominal visceral fat. Dual energy X-ray absorptiometry was used to determine whole body composition and bone density. Statistical comparisons were performed according to lipodystrophy categorization and protease inhibitor exposure. RESULTS: Men with HIV-associated lipodystrophy had reduced lumbar spine bone density compared with both HIV-infected non-lipodystrophic men [mean +/- SD, 132 +/- 29 versus 154 +/- 30 mg/cm(3); P = 0.02] and HIV-negative controls [mean +/- SD 132 +/- 29 versus 148 +/- 18) mg/cm(3); P = 0.04]. Lumbar spine bone density was reduced significantly in HIV lipodystrophy patients independently of protease inhibitor use. In an analysis among all HIV-infected subjects, increased visceral abdominal fat area was associated with decreased lumbar spine bone density (r, -0.47; P = 0.002). The association between visceral fat and bone density remained significant (P = 0.007) after controlling for age, body mass index, lowest body weight, protease inhibitor use, and extremity fat in a multivariate regression model. Markers of bone turnover were not related to bone density or lipodystrophy status. CONCLUSIONS: Lumbar spine bone density is reduced in association with increased visceral fat in HIV-infected men with lipodystrophy. Further studies are needed to determine the mechanisms of osteopenia in HIV lipodystrophy and whether increased marrow fat occurs in such patients and affects bone density.
Absorptiometry, Photon↗
Phase I study of paclitaxel given by seven-week continuous infusion concurrent with radiation therapy for locally advanced squamous cell carcinoma of the head and neck.
PURPOSE: Paclitaxel is one of the most active agents for squamous cell carcinoma of the head and neck (SCCHN) and an in vitro radiosensitizer. The dose-response relationship for paclitaxel may depend more on exposure duration than on peak concentration. This National Cancer Institute-sponsored phase I trial was designed to determine the feasibility of combining continuous-infusion (CI) paclitaxel with concurrent radiation therapy (RT). PATIENTS AND METHODS: Patients with previously untreated stage IVA/B SCCHN were eligible. Primary end points were determination of the maximum-tolerated dose, dose-limiting toxicity, and pharmacokinetics for paclitaxel given by CI (24 hours a day, 7 days a week for 7 weeks) during RT (70 Gy/7 weeks). RESULTS: Twenty-seven patients were enrolled and assessable for toxicity. Nineteen of the patients who completed > or = 70 Gy were assessable for response. Grade 3 skin and mucosal acute reactions occurred at 10.5 mg/m(2)/d, but uninterrupted treatment was possible in five of six patients. At 17 mg/m(2)/d, skin toxicity required a 2-week treatment break for all three patients. The mean paclitaxel serum concentration at dose levels > or = 6.5 mg/m(2)/d exceeded that reported to achieve in vitro radiosensitization. Initial locoregional control was achieved in 14 (58%) of 24 of patients treated to 70 Gy, and control persisted in nine (38%). CONCLUSION: CI paclitaxel with concurrent RT is a feasible and tolerable regimen for patients with advanced SCCHN and good performance status. Preliminary response and survival data are encouraging and suggest that further study is indicated. The recommended phase II dose of paclitaxel by CI is 10.5 mg/m(2)/d with RT for SCCHN.
Adult↗
Doses near the surface during total-body irradiation with 15 MV X-rays.
An extended source-surface distance (SSD) is often employed in total-body irradiation (TBI) to obtain fields sufficiently large to encompass the total body. It is clinically desirable to administer a uniform dose to all tissues, including the surface, especially to counteract the skin-sparing of high-energy X-rays. The electrons generated from the air contribute more to the dose near the surface at extended distances than at regular SSDs. However, if further increase of the dose at shallow depths is desired a spoiler can be employed. Monte Carlo simulations were used to study these effects for the electron component of the beam and the parameters needed for the pencil-beam dose calculation of this component. Measurements were performed to confirm these studies. The energy spectrum of electrons generated in air is independent of SSD. All the electrons in the beam, however, originate from the spoiler when one is used. The spectrum of these electrons is nearly independent of the SSD. The pencil-beam dose kernels were calculated using the derived electron spectra. To calculate doses in the buildup region with and without a spoiler, we use one pencil-beam kernel for the electrons generated in air and one for the electrons generated from the spoiler. Measured depth-dose data agreed with the calculation results.
Air↗
A phase I study of cranial radiation therapy with concomitant continuous infusion paclitaxel in children with brain tumors.
BACKGROUND: The prognosis of children with high-grade astrocytomas of the central nervous system is grim and has not been substantially improved by conventional chemoradiotherapy. We performed a multi-institutional phase I study to determine the toxicities and tolerance of concurrent external beam radiation of the brain and a unique dose-schedule of paclitaxel as a radiation sensitizer. PROCEDURE: Paclitaxel was delivered intravenously as a continuous 24 h/day, 7 days/week infusion during the entire 6-week course of fixed schedule standard radiation therapy. The dose of paclitaxel was escalated in patient cohorts in standard phase I design. RESULTS: Eleven patients (eight brain stem gliomas, one glioblastoma multiforme, and two gliomatosis cerebri) were treated. Dose-limiting toxicity was encountered in the two patients treated at 6 mg/(m(2)/24 h), both of whom developed severe obstipation requiring prolonged hospitalization. CONCLUSIONS: We have shown in this first study of its kind that paclitaxel can be administered safely to children as a 6-week continuous infusion concurrent with cranial irradiation. The maximally tolerated and recommended phase II dose is 4 mg/(m(2)/day). The benefits of taxanes as clinical radiation sensitizers for children with high-grade gliomas, if any, remain to be determined.
Adolescent↗
Treatment of epithelioid hemangioendothelioma of bone using a novel combined approach.
Radiofrequency (RF) treatment has been used for a variety of malignant and benign conditions. However, treatment of a bone malignancy has yet to be reported. The authors present a 21-year old woman with multifocal epithelioid hemangioendothelioma (EH) treated by a combination of surgical excision, chemotherapy and four RF ablations. Follow-up radiographs of the RF-treated sites reveal no evidence of recurrent disease 71, 58, 49 and 33 months, respectively, after treatment.
Adult↗
Intra-articular lipoma with osteochondroid metaplasia in the knee joint.
We describe a case of lipoma with osteochondroid metaplasia in the knee joint. Although the location of the lesion and radiographic findings were unusual, computed tomography and magnetic resonance imaging were useful in characterizing adipose, cartilaginous and osseous tissue components within the lesion.
Humans↗
The dose distribution of medium energy electron boosts to the laryngectomy stoma.
An en face, medium energy electron boost of approximately 10 Gy is often given to stomal and peristomal tissues. Because the boost is considered a simple treatment, CT-based treatment planning is rarely used. Further, the results of such a plan might be inaccurate, as the complex dose distribution surrounding the stoma air cavity is poorly modeled by many treatment planning systems. We constructed three phantoms-two with a central vertical cavity to mimic the size and shape of the stoma and proximal trachea and one with a cavity inclined at 45 degrees to the horizontal to better simulate anatomy. These were used to investigate the dose distribution surrounding the stoma. In all cases, the entrance to the stoma opening was centered in a field defined by a 7-cm circular cutout and the phantom was irradiated at a source-surface distance (SSD) of 100 cm with either vertically incident 9- or 12-MeV electrons. Film measurements were made at a range of depths below and lateral to the cavity. For the vertical cavity phantoms, diode measurements were performed and isodose plans using CT scans of the phantoms were generated on a modern treatment planning system. For these two phantoms, the combined effects of lateral scatter from surrounding material and reduced equivalent thickness for electrons which pass directly through the cavity increases the dose within a centimeter of the bottom of cavity by as much as 50% for 9 MeV and 70% for 12 MeV. In material at the shallower ("superior") end of the inclined cavity, a 40-50% overdose was noted. The dose increase is geometry dependent and is not predicted by the available treatment planning system. The potential of such a dose increase to affect normal tissues such as the neopharynx should be considered.
Electrons↗
Primary treatment of chondroblastoma with percutaneous radio-frequency heat ablation: report of three cases.
Chondroblastomas are benign cartilaginous lesions; however, intervention is necessary to stop progression and alleviate pain. The authors evaluated three patients in whom minimally invasive percutaneous radio-frequency heat ablation was used to treat pathologically proven chondroblastoma to determine whether this treatment demonstrated long-term success. The authors found that this approach may be an effective alternative to surgical intervention in some cases.
Adolescent↗
Effects of testosterone and exercise on muscle leanness in eugonadal men with AIDS wasting.
Loss of lean body and muscle mass characterizes the acquired immunodeficiency syndrome (AIDS) wasting syndrome (AWS). Testosterone and exercise increase muscle mass in men with AWS, with unclear effects on muscle composition. We examined muscle composition in 54 eugonadal men with AWS who were randomized to 1) testosterone (200 mg im weekly) or placebo and simultaneously to 2) resistance training or no training in a 2 x 2 factorial design. At baseline and after 12 wk, we performed assessments of whole body composition by dual-energy X-ray absorptiometry and single-slice computed tomography for midthigh cross-sectional area and muscle composition. Leaner muscle has greater attenuation. Baseline muscle attenuation correlated inversely with whole body fat mass (r = -0.52, P = 0.0001). This relationship persisted in a model including age, body mass index, testosterone level, viral load, lean body mass, and thigh muscle cross-sectional area (P = 0.02). Testosterone (P = 0.03) and training (P = 0.03) increased muscle attenuation. These data demonstrate that thigh muscle attenuation by computed tomography varies inversely with whole body fat and increases with testosterone and training. Anabolic therapy in these patients increases muscle leanness.
Adult↗
Gaucher disease. New approaches to an ancient disease.
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Gaucher Disease↗
Radiological imaging for the diagnosis of bone metastases.
Primary neoplasms of the skeleton are rare, but metastatic involvement is, unfortunately, a common occurrence. This is particularly true for certain primary tumors. Skeletal metastases are clinically significant because of associated symptoms, complications such as pathological fracture and their profound significance for staging, treatment and prognosis. Detection of bone metastases is, thus, an important part of treatment planning. The frequency with which metastases are detected varies considerably with the type of primary tumor and with the methodology utilized for detection. Four main modalities are utilized clinically: plain film radiography, CT scan, nuclear imaging and magnetic resonance imaging. In this discussion, we will review literature on the radiology of skeletal metastases with respect to lesion detection, assessment of response to treatment and possible therapeutic implications. The bulk of the discussion will focus on MRI and nuclear studies since most of the recent advances have been made in these areas.
Bone Neoplasms↗
Re-evaluating gadolinium(III) texaphyrin as a radiosensitizing agent.
Gadolinium(III) texaphyrin (Gd-tex) was recently proposed as a radiosensitizing agent that combines preferential tumor uptake with detection of drug localization by magnetic resonance imaging (S. W. Young et al., Proc. Natl. Acad. Sci. USA, 93: 6610-6615, 1996). In view of the initial report on this compound, four radiobiology laboratories undertook independent efforts to further study radiosensitization by Gd-tex. In addition to repeating the previously reported studies on Gd-tex in HT-29 cells, we tested five other human tumor cell lines (U-87 MG, U251-NCI, SW480, A549, and MCF-7). These studies included a Gd-tex treatment period of 24 h before irradiation (as in the original publication), with concentrations of Gd-tex ranging from 20-500 microM. In neither the HT-29 cells nor any of the other five human cell lines did we see radiation sensitization by Gd-tex. Two cell lines (MCF-7 and U-87 MG) were further tested for radiosensitization by Gd-tex under hypoxic conditions. No radiosensitization was observed in either case. Finally, the radiation response of two tumor lines were assessed in vivo. Neither HT-29 xenografts in severe combined immunodeficient (SCID) mice nor RIF-1 tumors growing in C3H mice demonstrated radiosensitization after Gd-tex treatment before single or fractionated doses of radiation. Our results raise questions about the efficacy of Gd-tex as a radiosensitizing agent.
Animals↗
Beam spoilers versus bolus for 6 MV photon treatment of head and neck cancers.
When parallel opposed 6-MV x-ray beams are used for treatment of head and neck tumors, superficial tissues and lymphatics at shallow depths of < or =4 to 6 mm may be at cancer risk but receive less than full radiation dose. In these cases, the use of either a beam spoiler or bolus material can increase dose to superficial tissues. The potential benefit of a beam spoiler relative to bolus is preservation of skin-sparing characteristics for cases in which the skin surface does not require full dose. In this study, we evaluate the application of a beam spoiler and compare it to bolus for standard treatments of head and neck tumors. Measurements of both depth dose in-water and in-air profiles were made with a beam spoiler for a 6-MV photon beam. The measurements were combined with Monte Carlo calculations to obtain the energy spectrum of the spoiler-generated electrons. An in-house pencil beam treatment-planning algorithm was used to calculate the dose distribution with spoiler. The dose distribution in the buildup region was then studied with and without the spoiler for a typical head and neck treatment with parallel-opposed beams. Dose distributions and partial-volume dose histograms (PVDH) demonstrate the benefits provided by spoilers for the head and neck treatments and the limitations of their use. The beam spoiler is useful in treating the superficial lymphatics in the buildup region near head and neck tumors. Guidelines for use of beam spoiler versus bolus are discussed.
Head and Neck Neoplasms↗