Search PubMed⌕ Search

Biomedical subjects

M A D'Hallewin

Publications and source records attributed to M A D'Hallewin.

17 recordsLinked to original sources
PubMed2003

Primary photodamage sites and mitochondrial events after Foscan photosensitization of MCF-7 human breast cancer cells.

To determine the initial photodamage sites of Foscan-mediated photodynamic treatment, we evaluated the enzymatic activities in selected organelles immediately after light exposure of MCF-7 cells. The measurements indicated that the enzymes located in the Golgi apparatus (uridine 5'-diphosphate galactosyl transferase) and in the endoplasmic reticulum (ER) (nicotinamide adenine dinucleotide [reduced] [NADH] cytochrome c [cyt c] reductase) are inactivated by the treatment, whereas mitochondrial marker enzymes (cyt c oxidase and dehydrogenases) were unaffected. This indicates that the ER and the Golgi apparatus are the primary intracellular sites damaged by Foscan-mediated PDT in MCF-7 cells. We further investigated whether the specific mitochondria events could be associated with Foscan photoinduced cell death. The dose response profiles of mitochondrial depolarization and cytochrome c release immediately after Foscan-based PDT were very different from that of overall cell death. By 24 h post-PDT the fluence dependency was strikingly similar for both mitochondrial alterations and cell death. Therefore, although mitochondria are not directly affected by the treatment, they can be strongly implicated in Foscan-mediated MCF-7 cell death by late and indirect mechanism.

Adenocarcinoma↗
PubMed2001

Cellular photodestruction induced by hypericin in AY-27 rat bladder carcinoma cells.

In a recent clinical study we showed that hypericin accumulates selectively in urothelial lesions following intravesical administration of the compound to patients. In the present study the efficacy of hypericin as a photochemotherapeutic tool against urinary bladder carcinoma was investigated using the AY-27 cells (chemically induced rat bladder carcinoma cells). The uptake of hypericin by the cells increased by prolonging the incubation time and increasing the extracellular hypericin concentration. Photodynamic treatment of the cells incubated with 0.8 and 1.6 microM hypericin concentrations resulted in remarkable cytotoxic effects the extent of which depended on the fluence rates. Photoactivation of 1.6 microM hypericin by 0.5, 1.0 or 2.0 mW/cm2 for 15 min resulted in 3, 30 and 95% of the antiproliferative effect, respectively. Increasing the photoactivating light dose from 0.45 to 3.6 J/cm2 resulted in a five-fold increase in hypericin photodynamic activity. Irrespective of the fluence rates and irradiation times incubation of the cells with 10 microM hypericin induced rapid and extensive cell death in all conditions. The type of cell death (apoptosis or necrosis) induced by photoactivated hypericin depended largely on the hypericin concentration and the postirradiation time. At lower hypericin concentrations and shorter postirradiation times apoptosis was the prominent mode of cell death; increasing the hypericin concentration and/or prolonging the postirradiation time resulted in increased necrotic cell death. Cell pretreatment with the singlet oxygen quencher histidine, but not with the free-radical quenchers, significantly protected the cells from photoactivated hypericin-induced apoptosis, at least when a relatively low concentration (1.25 microM) was used. This result suggests the involvement of a Type-II photosensitization process. However, cells treated with higher hypericin concentrations (2.5-5 microM) were inadequately protected by histidine. Since hypericin is thus shown to be a potent and efficient photosensitizer, and since the conditions used were the same as when hypericin is used clinically to locate early-stage urothelial carcinoma lesions, hypericin may well become very important for the photodynamic treatment of superficial bladder carcinoma.

Animals↗
PubMed2001

In vivo photodynamic activity of hypericin in transitional cell carcinoma bladder tumors.

In a recent clinical study, we showed that hypericin accumulates selectively in urothelial lesions of the bladder following intravesical administration of the compound in patients. This observation infers that hypericin, a potent photosensitizer, could be used as a selective photodynamic therapy (PDT) tool against superficial bladder cancer. In the present study we investigated the in vivo PDT activity of hypericin in transition cell carcinoma (TCC) tumors of the bladder. Both the distribution and tumor PDT response were carried out using subcutaneous heterotopic AY-27 TCC tumors in syngeneic rats. For both PDT and distribution studies, hypericin (1 or 5 mg/kg) was injected intravenously 0.5, 6 or 24 h before PDT or distribution evaluation. The data show that hypericin is a potent photosensitizer in the treatment of TCC tumors in vivo and that the interval between drug administration and photo-irradiation has a dramatic effect on the PDT outcome. Using a 0.5 h interval between drug administration and photo-irradiation the tumor regrowth study indicated that no tumor mass could me measured 9-10 days after PDT. On the contrary, lengthening the time interval between drug administration and photo-irradiation resulted in a gradual loss of PDT efficiency in these tumors. For instance, while the 6 h drug interval protocol produced a moderate PDT activity in which the tumor sizes decreased to about 50% of their original sizes 11-16 days after photo-irradiation, the 24 h interval protocol was even less effective. The distribution data indicate that the PDT efficiency of hypericin in TCC tumors corresponded to the plasma concentrations rather than to the over all concentrations in the tumor. It is therefore conceivable that the mechanism of PDT efficacy of hypericin in TCC tumors is through indirect (vascular effects) rather than through direct effects (cellular destruction) of hypericin in these tumors. In conclusion, our data indicate that hypericin is a potent photosensitizer against AY-27 TCC tumors and that the PDT efficacy of hypericin is largely determined by photosensitizer distribution in the tumor at the time of photo-irradiation.

Animals↗
PubMed2000

Fluorescence detection of flat bladder carcinoma in situ after intravesical instillation of hypericin.

PURPOSE: We determined the sensitivity and specificity of detecting flat bladder carcinoma in situ through fluorescent detection after intravesical hypericin instillations. MATERIALS AND METHODS: The study included 40 patients, of whom 26 presented with macroscopic visible tumor, 9 had a positive cytology without visible tumor and 5 underwent cystoscopy after bacillus Calmette-Guerin instillations (4) or radiotherapy (1). We instilled 40 ml. of a 8 microM. solution of hypericin intravesically for at least 2 hours. Fluorescence excitation with blue light was effective up to 16 hours after termination of the instillation. RESULTS: All visible papillary tumors showed red fluorescence. In addition, 134 flat fluorescent areas were detected. Analysis of 281 biopsies from flat bladder wall indicated 93% sensitivity and 98.5% specificity for detecting carcinoma in situ. Visible lesions resulting from radiotherapy, chemotherapy or immunotherapy did not show any fluorescent signs and, therefore, did not induce false-positive readings. There were no signs of photobleaching during inspection and resection. CONCLUSIONS: We report a simple yet comprehensive endoscopic method for early detection of bladder cancer, including carcinoma in situ. Hypericin induced fluorescence has a high sensitivity and specificity for detection of bladder transitional cell carcinoma, papillary and flat carcinoma in situ. When carcinoma in situ is suspected, this technique is highly recommended.

Administration, Intravesical↗
PubMed1998

Fluorescence detection of flat transitional cell carcinoma after intravesical instillation of aminolevulinic acid.

Carcinoma in situ (CIS) of the bladder is a confounding disease that is difficult to recognize endoscopically because it is a flat cancer. Many studies have suggested its relationship with subsequent invasive disease. Early recognition of CIS therefore is essential in offering the patient the most appropriate treatment and the highest cure rate. Because white light cystoscopic examination is not sufficient to reveal areas of dysplasia or CIS, random biopsies are recommended. The authors evaluate whether amino levulinic acid (ALA) fluorescence detection could be helpful in diagnosing CIS and if the specificity could be enhanced by reducing the ALA dose. Sixteen patients with papillary bladder cancer, and CIS and dysplasia were given low-dose ALA. Fluorescence detection of the metabolized ALA was performed 3 hours later, with the naked eye, after blue light illumination. Carcinoma in situ or dysplasia was found in 50 biopsies. The sensitivity for detecting CIS was 94% with a specificity of 54%. Carcinoma in situ can be diagnosed with a very high accuracy through fluorescence detection after ALA instillation. Fluorescence detection can be achieved with the naked eye and does not necessitate either complex equipment or specially trained personnel.

Administration, Intravesical↗
PubMed1997

Contemporary non-imaging methods in diagnosis of bladder cancer: a review.

The early diagnosis of bladder cancer is central to the effective treatment of the disease. Presently, the detection of bladder tumors relies on cystoscopy and there are no methods available to easily and specifically identify the presence of bladder cancer cells. A variety of new technologies and potential tumor markers are being studied in bladder cancer and some are being translated into clinical use. It is important to realise that all available results on the diagnostic value of tumor markers do not allow firm clinical recommendations, but tests based on biomarkers will undoubtedly influence the management of bladder cancer in the near future.

Antigens, Neoplasm↗
PubMed1996

Initial evaluation of the bladder tumor antigen test in superficial bladder cancer.

PURPOSE: We analyzed the value of the Bard bladder tumor antigen (BTA*) test for the diagnosis of stage Ta superficial bladder cancer and carcinoma in situ, and compared it to the highly sensitive bladder washing cytology. MATERIALS AND METHODS: The BTA test is a latex agglutination test that qualitatively detects the presence of basement membrane complexes in the urine. A total of 60 patients with superficial bladder cancer underwent voided urine BTA analysis and bladder washing cytologies. RESULTS: Of the patients 65% were correctly diagnosed with the BTA test compared to 32% with bladder washings, which is statistically significant (p < 0.001). CONCLUSIONS: The BTA test is a noninvasive diagnostic tool that is superior to bladder washing cytology for diagnosing superficial bladder cancer.

Adult↗
PubMed1995

Long-term results of whole bladder wall photodynamic therapy for carcinoma in situ of the bladder.

OBJECTIVES: This article evaluates the results of whole bladder wall photodynamic therapy (PDT) for multifocal carcinoma in situ after a mean follow-up time of 3 years. METHODS: Photofrin II was used as a photosensitizer (2 mg/kg) and in situ dosimetry to obtain the best possible central positioning of the light diffuser as well as to know exact dosimetry data (scattered plus nonscattered light). RESULTS: Major classical drawbacks of PDT, such as severe bladder irritative symptoms and bladder shrinking, can be minimized with the help of in situ dosimetry. The success rate after 3-year follow-up is 60%. Fifty percent of the recurrences occurred in the prostatic urethra without evidence of disease of the bladder. CONCLUSIONS: A success rate of 60% is comparable to the results obtained after bacille Calmette-Guérin (BCG). Side effects such as loss of bladder capacity can be minimized with adequate light dosimetry but they are still higher than with BCG (9% versus 1% cystectomy).

Biopsy↗
PubMed1994

In vivo fluorescence detection of human bladder carcinoma without sensitizing agents.

The diagnosis of transitional cell bladder carcinoma and especially carcinoma in situ of the bladder in spinal cord disordered persons is often made difficult by catheters, infections or stone-induced chronic inflammation. Fluorescence tagging of tumors by sensitizing agents such as hematoporphyrin derivatives enhances visualization but presents a number of drawbacks for the patients, even at low doses. We have developed a cystoscopic fiber optic instrument, based on a mercury arc lamp, for in vivo detection of human bladder carcinoma without sensitizing agents. The tissue autofluorescence upon UV excitation (365 nm) is detected and a demarcation contrast ratio for carcinoma in situ and transitional cell carcinoma of 2.6 and 3.2 respectively is obtained. This demarcation ratio is 60 percent higher than the contrast ratio obtained after photosensitizer injection. The integration of a reliable diagnostic method with a known efficient therapeutic technique (Nd YAG laser irridiation) opens the way for cost-effective preventive care of high-risk patients.

Biopsy↗
PubMed1994

Fluorescence imaging of bladder cancer.

Fluorescence tagging of tumors by sensitizing agents such as hematoporphyrin derivatives is an efficient method for diagnosing tumors but presents, even at low doses, a number of serious drawbacks for the patients. We demonstrate a fiberoptic instrument for the diagnosis of bladder cancer, based on a tripled frequency Nd YAG laser, without need for sensitizing agents, based on the autofluorescence of tissues. The contrast demarcation obtained for CIS and TCC respectively is 2.2 and 2.7, which is about 30% higher than what can be obtained after photosensitizing. The integration of the diagnostic method with a reliable therapeutic technique for tumor cell destruction, opens the way for cost-effective preventive care of high risk patients.

Carcinoma in Situ↗
PubMed1993

Clinical fluorescence diagnosis of human bladder carcinoma following low-dose Photofrin injection.

A point-monitoring fluorescence diagnostic system based on a low-energy pulsed laser, fiber transmission optics, and an optical multichannel analyzer was used for diagnosis of patients with bladder malignancies. Twenty-four patients with bladder carcinoma, carcinoma in situ, and/or dysplasia were injected with hematoporphyrin derivative, Photofrin, 0.35 or 0.5 mg/kg body weight, forty-eight hours prior to the investigation. The ratio between the red sensitizer emission and the bluish tissue autofluorescence provided excellent demarcation between papillary tumors and normal bladder wall. Certain cases of dysplasia also could be differentiated from normal mucosa. Benign exophytic lesions such as malakoplakia appeared different from malignant tumors in fluorescence. Flat suspicious bladder mucosa such as seen in infectious diseases or after radiation therapy appeared normal on fluorescence.

Adult↗
PubMed1993

In situ light dosimetry during whole bladder wall photodynamic therapy: clinical results and experimental verification.

Photodynamic therapy (PDT) using Photofrin IIR (PII) as a photosensitizer is currently being evaluated as a new treatment modality for superficial bladder cancer. An optimum therapeutic ratio requires uniform illumination of the whole bladder wall and accurate light dosimetry. The first clinical light dosimetry results (16 patients) are reported, obtained using a system which allows in situ measurement and control of the light fluence at the bladder wall. The true light fluence at the bladder wall (i.e. non-scattered incident light plus scattered light) appeared to be on the average a factor beta = 4.8 +/- 1.2 (mean +/- SD) larger than the non-scattered incident light fluence. The latter is often, but incorrectly, used in reporting light fluence. The factor beta varied between patients with extremes of 2.5 and 7.1. Because such large variations were unexpected, but may have significant clinical consequences, experiments in plastic bladder models were performed to study separately the various factors (e.g. bladder shape, air bubble) affecting the dosimetry in clinical treatments. The results imply that the clinical variations are most likely to be the result of variations in optical properties of the bladder wall mucosa, probably due to the disease and prior treatments. If light dosage is based on non-scattered light only (without in situ light dosimetry, according to a current clinical protocol) the present results indicate variations in the true (total) light fluence between patients by a factor of at least 2. At the least this may cause unnecessary discomfort to a number of patients.

Female↗
PubMed1992

Whole bladder wall photodynamic therapy with in situ light dosimetry for carcinoma in situ of the bladder.

We report on the preliminary results of 12 patients with multifocal carcinoma in situ of the bladder treated with whole bladder wall photodynamic therapy. The total light dose (scattered plus nonscattered light) measured in situ was 100 joules per cm.2 in the first 6 patients (group 1) and 75 joules per cm.2 in the remaining 6 (group 2). These light doses correspond on the average to 27 joules per cm.2 and 15.5 joules per cm.2 nonscattered light as reported by other investigators. Followup ranged from 6 to 22 months (average 11.5). In group 1, 2 tumors recurred after 6 and 9 months, respectively, and 2 other patients had a permanently shrunken bladder without evidence of disease. In group 2, 1 tumor recurred 5 months after photodynamic therapy. In this group the bladder capacity increased on the average to 135% of the pretreatment value 3 months after photodynamic therapy. All recurrences were in patients with a history of invasive bladder cancer (stages T1 and T2). These preliminary results demonstrate the importance of in situ scattered light dosimetry for minimizing local side effects of whole bladder photodynamic therapy.

Aged↗
PubMed1986

The human umbilical vein graft in below-knee femoropopliteal and femorotibial surgery: an eight year experience.

The authors present a series of 175 femoropopliteal (below-knee) and 65 femorotibial reconstructions with the human umbilical vein (HUV) graft performed over an eight year period. With a mean follow-up of 36.7 months (range one month to 84 months) the early patency rate of 89% decreased to 54% after five years. Long-term patency was found to be primarily related to the location of the distal anastomosis and the quality of the outflow, showing a statistically significant decrease after repeat revascularization. Early thrombosis, even in the absence of a technical failure and late aneurysmal degeneration remain the major problems associated with the use of the HUV graft. It is therefore recommended that these reconstructions be preserved for patients with advanced ischemia or a limited life-expectancy.

Adult↗
PubMedDate not supplied

Photodynamic activity of hypericin in human urinary bladder carcinoma cells.

Recently, we reported the selective accumulation of hypericin in transitional cell carcinoma cells following intravesical instillation of hypericin in humans. This observation infers that hypericin, a potent photosensitizer, could be used as a selective PDT (photodynamic therapy) tool against superficial bladder cancer. The aim of the present study was to investigate in vitro whether hypericin exhibits specific affinity for TCC transitional cell carcinoma) bladder cells and to assess its photocytotoxic effect. Three human TCC cell lines (J-82, T-24 and RT-4), a chemically induced rat TCC cell line (NBT-II), but also non-bladder carcinoma cells (HeLa, A431, MCF-7 and MCF-***ADR) and normal cells (HEL229, RPE and PHK), were used in this comparative study. Flow cytometric analysis of cells treated with different hypericin-containing vehicles for various incubation times (2 hours or 24 hours) indicated that short exposure of the cells (2 hours) to hypericin in the absence of serum results in the highest intracellular accumulation of the compound. As expected, prolonging the incubation time increased both the cellular accumulation and photocytoxicity of hypericia. With the exception of the RT-4 and MCF-7 cells (which were less sensitive to hypericin), all the other carcinoma cell lines examined showed equal sensitivity to the photoactivated hypericia, independently of their histological origin (bladder or non-bladder). Moreover, normal cells exhibited the same pattern of hypericin photosensitivity as shown by the cancer cells, indicating that, in cultured cells, hypericin cellular uptake and subsequent photokilling is not selective. This suggests that in vivo factors other than the cancer cells themselves are responsible for the specific accumulation of hypericin in urothelial carcinoma lesions.

Anthracenes↗