Biomedical subjects

Paul Zhang

Publications and source records attributed to Paul Zhang.

8 recordsLinked to original sources

PubMed2006

Oxygen levels in normal and previously irradiated human skin as assessed by EF5 binding.

The oxygen status of skin is a controversial topic. Skin is radiosensitive, suggesting it is well-oxygenated. However, it can be further sensitized with nitroimidazole drugs, implying that it is partially hypoxic. Skin oxygen levels are difficult to measure with either electrodes or the hypoxia-monitoring agent (3)H-misonidazole. For the latter, binding has previously been reported to be high in murine skin, but this could be attributed to either non-oxygen-dependent variations in nitroreductase activity, drug metabolism, and/or actual oxygen gradients. We obtained tumor and skin from patients given EF5, a 2-nitroimidazole tissue hypoxia monitor. We performed immunohistochemical studies using highly specific monoclonal antibodies for the hypoxia-dependent production of EF5 tissue adducts. Some tissue sections were counterstained using either Ki67 for proliferation or CD31 for vessels. We found that the human dermis is well-oxygenated, the epidermis is modestly hypoxic and portions of some sebaceous glands and hair follicles are moderately to severely hypoxic. Normal and irradiated skin had similar oxygenation patterns. Control studies demonstrated that these observations are not due to tissue variations in nitroreductase activity. The importance of the highly heterogeneous distribution of oxygen in skin requires further study, but recent investigations suggest that skin hypoxia may have important clinical ramifications including mediating cellular transformation.

Aged↗

PubMed2006

EF5 binding and clinical outcome in human soft tissue sarcomas.

PURPOSE: To study the 2-nitroimidazole agent EF5 as a surrogate for measuring hypoxia in a series of patients with soft tissue sarcomas, and to determine whether hypoxia measured with this technique was associated with patient outcome. METHODS AND MATERIALS: Patients with soft tissue sarcomas of the head and neck, extremity, trunk, or retroperitoneum for whom surgical excision was the initial treatment of choice, were given 21 mg/kg EF5 24-48 hours before surgery. Biopsy specimens were stained for EF5 binding with fluorescence-labeled monoclonal antibodies, and the images were analyzed quantitatively. Endpoints included the relationship between EF5 binding, clinically important prognostic factors, and patient outcome. RESULTS: Two patients with recurrent and 14 patients with de novo sarcomas were studied. There were seven low-grade, one intermediate-grade, and eight high-grade tumors. No relationship was found between EF5 binding and patient age, sex, hemoglobin level, or tumor size. In de novo tumors, the presence of mitoses and histologic grade were positively correlated with hypoxia. High-grade and -stage de novo tumors had higher levels of EF5 binding compared with low-grade and -stage tumors. Patients with de novo tumors containing moderate to severe hypoxia (> or = 20% EF5 binding), high grade, or > or = 7% mitoses were more likely to develop metastases. CONCLUSIONS: Further studies in a larger cohort of patients are necessary to determine whether hypoxia, as measured by EF5 binding, is an independent prognostic factor for outcome in high-grade sarcomas. Such data should be useful to identify high-risk patients for clinical trials to determine whether early chemotherapy will influence the occurrence of metastasis.

Adult↗

PubMed2004

Hypoxia and Photofrin uptake in the intraperitoneal carcinomatosis and sarcomatosis of photodynamic therapy patients.

PURPOSE: Response to photodynamic therapy depends on adequate tumor oxygenation as well as sufficient accumulation of photosensitizer in the tumor. The goal of this study was to investigate the presence of hypoxia and retention of the photosensitizer Photofrin in the tumors of patients with intra-abdominal carcinomatosis or sarcomatosis. EXPERIMENTAL DESIGN: Tumor nodules from 10 patients were studied. In nine of these patients, hypoxia was identified in histological sections of biopsied tumor after administration of the hypoxia marker 2-(2-nitroimidazol-1[H]-yl)-N-(2,2,3,3,3-pentafluoropropyl)acetamide (EF5). In separate tumor nodules from 10 patients, Photofrin uptake was measured by fluorescence after tissue solubilization. RESULTS: Hypoxia existed in the tumors of five patients, with three of these patients demonstrating at least one severely hypoxic nodule. Physiological levels of oxygen were present in the tumors of four patients. An association between tumor size and hypoxia was not evident because some tumor nodules as small as approximately 2 mm in diameter were severely hypoxic. However, even these tumor nodules contained vascular networks. Three patients with severely hypoxic tumor nodules exhibited moderate levels of Photofrin uptake of 3.9 +/- 0.4 to 3.9 +/- 0.5 ng/mg (mean +/- SE). The four patients with tumors of physiological oxygenation did not consistently exhibit high tumor concentrations of Photofrin: mean +/- SE drug uptake among these patients ranged from 0.6 +/- 0.8 to 5.8 +/- 0.5 ng/mg. CONCLUSIONS: Carcinomatosis or sarcomatosis of the i.p. cavity may exhibit severe tumor hypoxia. Photofrin accumulation in tumors varied by a factor of approximately 10x among all patients, and, on average, those with severe hypoxia in at least one nodule did not demonstrate poor Photofrin uptake in separate tumor samples. These data emphasize the need for reconsideration of the generally accepted paradigm of small tumor size, good oxygenation, and good drug delivery because this may vary on an individual tumor basis.

Appendiceal Neoplasms↗

PubMed2004

Modern pathological evaluation of soft tissue sarcoma specimens and its potential role in soft tissue sarcoma research.

The vast majority of soft tissue tumors (STT), especially sarcomas, should be examined according to a national standard for pathologic evaluation, including a national consensus on a grading system and elements of a synoptic pathology report. The margins should be separated into fascial margins and other surgically cut margins. If questions about the diagnosis arise, a second opinion should be sought from an expert in sarcoma pathology. Whenever possible, tissue should be frozen for potential molecular diagnosis and additional tissue banked for research. Finally, there is a need for a national registry for rare sarcoma types.

Biological Specimen Banks↗

PubMed2003

Intranodal administration of peptide-pulsed mature dendritic cell vaccines results in superior CD8+ T-cell function in melanoma patients.

PURPOSE: We evaluated the feasibility, safety, and immunogenicity of mature, peptide-pulsed dendritic cell (DC) vaccines administered by different routes. PATIENTS AND METHODS: We performed a randomized, phase I, dose-escalation study in 27 patients with metastatic melanoma receiving four autologous peptide-pulsed DC vaccinations. Patients were randomly assigned to an intravenous (IV), intranodal (IN), or intradermal (ID) route of administration (ROA). For each route, primary end points were dose-limiting toxicity, maximum-tolerated dose, and T-cell sensitization. Sensitization was evaluated through tetramer staining, in vitro peptide recognition assays, and delayed-type hypersensitivity (DTH) responses. RESULTS: Twenty-two (81.5%) of 27 patients completed all four vaccinations. Vaccinations were well tolerated; a few patients exhibited grade 1 to 2 toxicities including rash, fever, and injection site reaction. All routes of administration induced comparable increases in tetramer-staining CD8+ T cells (five of seven IV, four of seven IN, and four of six ID patients). However, the IN route induced significantly higher rates for de novo development of CD8+ T cells that respond by cytokine secretion to peptide-pulsed targets (six [85.7%] of seven IN patients v two [33%] of six ID patients v none [0%] of six IV patients; P =.005) and de novo DTH (seven [87.5%] of eight IN patients v two [33.3%] of six ID patients v one [14.3%] of seven IV patients; P =.01) compared with other routes. CONCLUSION: Administration of this peptide-pulsed mature DC vaccine by IN, IV, or ID routes is feasible and safe. IN administration seems to result in superior T-cell sensitization as measured by de novo target-cell recognition and DTH priming, indicating that IN may be the preferred ROA for mature DC vaccines.

Administration, Cutaneous↗

PubMed2003

A simple formula for sample size calculation in equivalence studies.

Bioequivalence and clinical equivalence can be claimed based on the two one-sided test approach or the confidence interval approach. Consequently the power function of the equivalence test can be derived from either noncentral t-distribution or central t-distribution. The sample size is then determined from the power function either by numerical method or closed formulas. In this paper, we propose a simple formula for sample size calculation based on central t-distribution. The proposed formula has better properties than those currently available and it can be easily applied in all equivalence studies.

Confidence Intervals↗

PubMed2002

Overexpression of p16INK4A in liquid-based specimens (SurePath) as marker of cervical dysplasia and neoplasia.

Human papillomavirus (HPV) is recognized as a causal agent for cervical carcinomas. Assimilation of HPV oncogenes E6 and E7 into the host DNA promotes upregulation of cyclin dependent kinase inhibitor (CDKI) p16(INK4A), detectable by monoclonal antibody in the developing cervical cancer cells. The aim of this study was to 1) develop a protocol for p16(INK4A) immunocytochemical staining on SurePath preparations, and 2) determine its utility as an HPV marker on a spectrum of cervical reactive and neoplastic lesions. Seventy-two specimens consisting of 28 nonneoplastic/nondysplastic cases (NN), one reactive glandular cells (RGC), 27 low-grade squamous intraepithelial lesions (LSIL), 10 high-grade squamous intraepithelial lesions (HSIL), one squamous cell carcinoma (SCCA), four atypical glandular cells (AGUS), and two adenocarcinomas (ADCA) were reprepped by SurePath and antibody to p16(INK4A) applied at 1:100 dilution using the Dako Envision + System on the Dako Autostainer. Expression of p16(INK4A) within the nucleus principally and cytoplasm of at least 10-15 cells was considered positive. All initial Papanicolaou-stained discrepant cases (p16(INK4A) positivity of NN and RGC cases and lack of reactivity in LSIL, HSIL, and AGUS) were reviewed. Nine of ten (90%) HSIL, one (100%) SCCA, 21/27 (78%) LSIL, and some reactive and inflammatory specimens demonstrated the presence of p16(INK4A). Reevaluation of discrepant cases revealed that several were underinterpreted (four NN were LSIL, one RGC was AGUS) or overinterpreted (one LSIL was NN). Following reassessment, false-positive staining was present in only 1/25 (1.4%) NN. Six of 30 (20%) LSIL lacked p16(INK4A) positivity. One of 10 (10%) HSIL had no staining. Two of four AGUS did not react with p16(INK4A) antibody. Both SCCA (1) and ADCA (2) had positive expression. This study confirms the intimate relationship between p16(INK4A) and HPV cytopathic effect. The p16(INK4A) immunocytochemical stain can be applied to liquid-based cervical preparations. This technique offers a more objective approach to deciphering "gray areas" of gynecologic cytopathology.

Adult↗

PubMed2002

Additive effect of drospirenone/17-beta-estradiol in hypertensive postmenopausal women receiving enalapril.

BACKGROUND: Aldosterone has been implicated in the pathogenesis of progressive cardiovascular disease. Drospirenone (DRSP) is a novel progestin with aldosterone receptor antagonist activity developed for hormone replacement therapy (HRT) as DRSP/17beta-estradiol (DRSP/ E2). We investigated the additive effect of DRSP/E2 versus placebo on 24-h ambulatory blood pressure (BP) in postmenopausal women with hypertension treated with enalapril maleate (ENA). METHODS: This was a double-blind, randomized, two-parallel group trial. Twenty-four nonsmoking postmenopausal women receiving 10 mg of ENA twice a day before study were randomized to DRSP/E2 + ENA (n = 12) or placebo (P) + ENA (n = 12) for 14 days. Twenty-four-hour ambulatory BP, plasma renin activity, and serum aldosterone were determined at baseline and on day 14. RESULTS: Compared to placebo, 24-h mean [SD] BP in the DRSP/E2 + ENA group decreased significantly from baseline (139/80 mm Hg), systolic (-9 [51 mm Hg, P = .014) and diastolic (-5 [4] mm Hg, P = .007). Essentially no change from baseline (139/83 mm Hg) in systolic or diastolic 24-h ambulatory BP were observed in the P + ENA group. Aldosterone (mean [SD]) increased from baseline by 2.6 [4.5] ng/dL in the DRSP/E2 + ENA group, and decreased by 0.3 [5.5] ng/dL in the P + ENA group (P = .08) consistent with an antimineralocorticoid effect. CONCLUSIONS: Our results suggest a significant additive BP-lowering effect of DRSP/E2 on both systolic and diastolic BP in hypertensive postmenopausal women receiving ENA, consistent with an antimineralocorticoid effect. DRSP/E2, a HRT with antimineralocorticoid effects, could offer a novel potential mechanism for reducing cardiovascular end points in postmenopausal women.

Aldosterone↗