Impact of preoperative breast MRI on 10-year survival of patients included in the Swedish randomized multicentre POMB trial.

BACKGROUND: The value of preoperative breast MRI as an adjunct technique regarding its effect on re-excision rates has been a subject of discussion. No survival data regarding preoperative breast MRI are available from randomized studies. METHODS: Ten-year follow-up of the POMB randomized multicentre study was analysed, evaluating MRI and its effect on disease-free survival (DFS) and overall survival (OS). Patients with newly diagnosed breast cancer were randomized to either preoperative MRI or conventional imaging. Kaplan-Meier plots were used to analyse DFS and OS, and Cox regression to estimate hazard ratios (HRs). RESULTS: A total of 440 patients, aged 56 years or less, with newly diagnosed breast cancer were randomized to either preoperative MRI (220) or conventional imaging (220; control). Median follow-up for each group was 10 years. DFS rates were 85.5 and 80.0 per cent for the MRI and control groups respectively (P = 0.099). The risk of relapse or death was 46 per cent higher in the control group (HR 1.46, 95 per cent c.i. 0.93 to 2.29). OS rates after 10 years were 90.9 and 88.6 per cent in the MRI and control groups respectively (P = 0.427). The risk of death was 27 per cent higher in the control group (HR 1.27, 0.71 to 2.29). Locoregional, distant, and contralateral recurrence outcomes combined were increased in the control group (P = 0.048). A subgroup analysis of patients with breast cancer stages I-III showed that preoperative MRI improved DFS compared with conventional imaging, but this did not reach statistical significance (P = 0.057). CONCLUSION: After 10 years of follow-up, preoperative breast MRI as an adjunct to conventional imaging resulted in slightly, but non-significantly, improved DFS and OS. Registration number: NCT01859936 (http://www.clinicaltrials.gov).

Long-term outcome of pT1a-b, cN0 breast cancer without axillary dissection or staging: a prospective observational study of 1543 women.

BACKGROUND: The implementation of screening programmes in Sweden during the mid-1990s increased the number of small node-negative breast cancers. In this era before staging by sentinel node biopsy, routine axillary dissection for staging of early breast cancer was questioned owing to the increased morbidity and lack of perceived benefit. The long-term risk of axillary recurrence when axillary staging is omitted remains unclear. METHODS: This prospective observational multicentre cohort study included Swedish women diagnosed with breast cancer between 1997 and 2002. The patients had clinically node-negative, pT1a-b, grade I-II tumours. No axillary staging or dissection was performed. The primary outcome was ipsilateral axillary recurrence and survival. RESULTS: A total of 1543 patients were included. Breast-conserving surgery (BCS) was performed in 94·0 per cent and the rest underwent mastectomy. After surgery, 58·1 per cent of the women received adjuvant radiotherapy, 11·9 per cent adjuvant endocrine therapy and 31·5 per cent did not receive any adjuvant treatment. After a median follow-up of 15·5 years, 6·4 per cent developed contralateral breast cancer and 16·5 per cent experienced a recurrence. The first recurrence was local in 116, regional in 47 and distant in 59 patients. The breast cancer-specific survival rate was 93·7 per cent after 15 years. There were no differences in overall or breast cancer-specific survival between patients who received adjuvant radiotherapy and those who did not. Only 3·0 per cent of patients had an axillary recurrence, which was isolated in only 1·0 per cent. CONCLUSION: Axillary surgery can safely be omitted in patients with low-grade, T1a-b, cN0 breast cancers. This large prospective cohort with 15-year follow-up had a very low incidence of axillary recurrences and high breast cancer-specific survival rate.

ANTECEDENTES: La puesta en marcha en Suecia, a mediados de los años 90, de los programas de cribaje aumentó el número de cánceres de mama precoces con ganglios negativos. En esa era, antes de la estadificación mediante la biopsia del ganglio centinela, se cuestionó la disección axilar rutinaria para la estadificación del cáncer de mama precoz debido a su aumento de la morbilidad y la falta de percepción de beneficio. El riesgo de recidiva axilar a largo plazo cuando no se omite la estadificación axilar sigue sin estar claro. MÉTODOS: Estudio de cohortes prospectivo, observacional y multicéntrico de las mujeres suecas diagnosticadas de cáncer de mama entre 1997-2002. Se incluyeron las pacientes con ganglios clínicamente no detectables, pT1a-b, grados I-II y no se realizó disección/estadificación axilar en ninguna de ellas. El resultado principal fue la recidiva axilar ipsilateral y la supervivencia. RESULTADOS: Se incluyeron 1.543 pacientes. Se realizó cirugía conservadora de la mama (breast conserving surgery, BCS) en el 94% de las mujeres y en las restantes se practicó una mastectomía. Tras la BCS, el 58% de las mujeres recibió radioterapia adyuvante, el 12% tratamiento endocrino adyuvante y el 32% no recibió ningún tratamiento adyuvante. Tras una mediana de seguimiento de 15,5 años, el 6% desarrolló un cáncer de mama contralateral y un 14% una recidiva. La primera recidiva fue local en 116 pacientes, regional en 47 y a distancia en 59. La supervivencia específica para el cáncer de mama a los 15 años fue del 94%. No hubo diferencias en la supervivencia general o específica por cáncer de mama entre las pacientes que recibieron radioterapia adyuvante y las que no. Solo el 3% de las pacientes presentó una recidiva axilar, de las cuales tan solo el 1% padecieron exclusivamente una recidiva axilar. CONCLUSIÓN: La cirugía axilar se puede omitir con seguridad en los cánceres de mama de bajo grado, T1a-b, cN0. Esta gran cohorte prospectiva con un seguimiento de 15 años muestra que la incidencia de recidivas axilares es muy baja y la supervivencia específica por cáncer de mama muy alta.

Expression of cyclooxygenase-1 and cyclooxygenase-2, syndecan-1 and connective tissue growth factor in benign and malignant breast tissue from premenopausal women.

Stromal factors have been identified as important for tumorigenesis and metastases of breast cancer. From 49 premenopausal women, samples were collected from benign or malignant tumors and the seemingly normal tissue adjacent to the tumor. The factors studied, with real-time polymerase chain reaction (PCR) and immunohistochemistry, were cyclooxygenase-1 and cyclooxygenase-2 (COX-1 and COX-2), syndecan-1 (S-1) and connective tissue growth factor (CTGF). COX-1 and S-1 mRNA levels were higher in the malignant tumors than in normal and benign tissues. The COX-2 mRNA level was lower in the malignant tumor than in the normal tissue, while CTGF mRNA did not differ between the groups. COX-1 immunostaining was higher in stroma from malignant tumors than in benign tissues, whereas COX-2 immunostaining was higher in the malignant tissue. Glandular S-1 immunostaining was lower in malignant tumors compared to benign and normal tissues, and the opposite was found in stroma. Conclusively, mRNA levels of COX-1 and COX-2 were oppositely regulated, with COX-1 being increased in the malignant tumor while COX-2 was decreased. S-1 protein localization switched from glandular to stromal cells in malignant tissues. Thus, these markers are, in premenopausal women, localized and regulated differently in normal/benign breast tissue as compared to the malignant tumor.

Diacylglycerol acyltransferase 1 inhibition with AZD7687 alters lipid handling and hormone secretion in the gut with intolerable side effects: a randomized clinical trial.

AIM: Inhibition of diacylglycerol acyltransferase 1 (DGAT1) is a potential treatment modality for patients with type 2 diabetes mellitus and obesity, based on preclinical data suggesting it is associated with insulin sensitization and weight loss. This randomized, placebo-controlled, phase 1 study in 62 overweight or obese men explored the effects and tolerability of AZD7687, a reversible and selective DGAT1 inhibitor. METHODS: Multiple doses of AZD7687 (1, 2.5, 5, 10 and 20 mg/day, n = 6 or n = 12 for each) or placebo (n = 20) were administered for 1 week. Postprandial serum triacylglycerol (TAG) was measured for 8 h after a standardized 45% fat meal. Glucagon-like peptide-1 (GLP-1) and peptide YY (PYY) were measured and a paracetamol challenge was performed to assess gastric emptying. RESULTS: Dose-dependent reductions in postprandial serum TAG were demonstrated with AZD7687 doses ≥5 mg compared with placebo (p < 0.01). Significant (p < 0.001) increases in plasma GLP-1 and PYY levels were seen at these doses, but no clear effect on gastric emptying was demonstrated at the end of treatment. With AZD7687 doses >5 mg/day, gastrointestinal (GI) side effects increased; 11/18 of these participants discontinued treatment owing to diarrhoea. CONCLUSIONS: Altered lipid handling and hormone secretion in the gut were demonstrated during 1-week treatment with the DGAT1 inhibitor AZD7687. However, the apparent lack of therapeutic window owing to GI side effects of AZD7687, particularly diarrhoea, makes the utility of DGAT1 inhibition as a novel treatment for diabetes and obesity questionable.

Ticagrelor inhibits human platelet aggregation via adenosine in addition to P2Y12 antagonism.

BACKGROUND: Ticagrelor, a P2Y12 antagonist, is an antiplatelet agent approved for the treatment of acute coronary syndromes; it also inhibits adenosine uptake by erythrocytes and other cells. OBJECTIVE: To test whether ticagrelor inhibits platelet aggregation (PA) in whole blood (WB) by increasing the extracellular levels of adenosine, which inhibits PA via the A2A receptor. METHODS: Collagen-induced PA was measured in WB or platelet-rich plasma (PRP) from 50 healthy subjects and two patients with inherited P2Y12 deficiency, in presence/absence of adenosine concentrations that by themselves marginally affected PA in WB, and ZM241385 (A2A antagonist). The effects of ticagrelor, the active metabolite of prasugrel (PAM) (P2Y12 antagonist), and dipyridamole (adenosine uptake inhibitor) on PA and on adenosine clearance in WB were compared. RESULTS: For PA in WB, adenosine contributed to drug-induced inhibition of PA; the adenosine contribution was similar for dipyridamole and ticagrelor but was significantly greater for ticagrelor than for PAM (P < 0.01). For PA in PRP (no adenosine uptake by erythrocytes), adenosine contributed to inhibition of PA in the presence/absence of all tested drugs. ZM241385 reversed the inhibition by adenosine in WB and PRP. Similar results were obtained with WB and PRP from P2Y12 -deficient patients. Adenosine (7.1 µmol L(-1) ) added to WB, was detectable for 0.5 min in the presence of vehicle or PAM, for 3-6 min in the presence of ticagrelor, and for > 60 min in the presence of dipyridamole. CONCLUSION: This study provides the first evidence of an additional antiplatelet mechanism by ticagrelor, mediated by the induced increase of adenosine levels.

Proof of mechanism for the DGAT1 inhibitor AZD7687: results from a first-time-in-human single-dose study.

AIMS: Inhibition of diacylglycerol acyltransferase 1 (DGAT1), which catalyses the final step in triacylglycerol (TAG) assembly, is suggested as a treatment for type 2 diabetes and obesity based on animal data indicating insulin sensitization and weight reduction. This first-time-in-human single ascending dose study explored the safety, tolerability, pharmacokinetics and pharmacodynamics of the selective DGAT1 inhibitor AZD7687. METHODS: Eighty healthy male subjects were enrolled. In each of 10 cohorts, six subjects received the same dose of AZD7687 orally (range across cohorts 1-60 mg) and two placebo. Plasma AZD7687 exposure was measured repeatedly. Postprandial serum TAG excursion was measured during 8 h after a standardized mixed meal with fat energy content of 60% (SMM 60%; five cohorts, 1-20 mg), before (baseline) and after dosing, to assess effects on gut DGAT1 activity. RESULTS: AZD7687 markedly reduced postprandial TAG excursion with a steep concentration-effect relationship. Incremental TAG AUC (area under the serum concentration vs. time curve) following SMM 60% was decreased >75% from baseline at doses ≥5 mg (p < 0.0001 vs. placebo). Serum levels of diacylglycerol, specifically measured with mass spectrometry, did not increase after AZD7687 administration. Nausea, vomiting and diarrhoea were reported with increasing doses and they limited dose escalation. Lowering of SMM fat content to 45 or 30% in five cohorts gradually reduced the frequency of gastrointestinal symptoms at a given dose of AZD7687. CONCLUSIONS: The attenuating effect of AZD7687 on postprandial TAG excursion provides proof of mechanism with respect to gut DGAT1 inhibition. However, dose and diet-related gastrointestinal side effects may impact further development of DGAT1 inhibitors.

Amelioration of lipid-induced insulin resistance in rat skeletal muscle by overexpression of Pgc-1ß involves reductions in long-chain acyl-CoA levels and oxidative stress.

AIMS/HYPOTHESIS: To determine if acute overexpression of peroxisome proliferator-activated receptor, gamma, coactivator 1 beta (Pgc-1ß [also known as Ppargc1b]) in skeletal muscle improves insulin action in a rodent model of diet-induced insulin resistance. METHODS: Rats were fed either a low-fat or high-fat diet (HFD) for 4 weeks. In vivo electroporation was used to overexpress Pgc-1ß in the tibialis cranialis (TC) and extensor digitorum longus (EDL) muscles. Downstream effects of Pgc-1ß on markers of mitochondrial oxidative capacity, oxidative stress and muscle lipid levels were characterised. Insulin action was examined ex vivo using intact muscle strips and in vivo via a hyperinsulinaemic-euglycaemic clamp. RESULTS: Pgc-1ß gene expression was increased >100% over basal levels. The levels of proteins involved in mitochondrial function, lipid metabolism and antioxidant defences, the activity of oxidative enzymes, and substrate oxidative capacity were all increased in muscles overexpressing Pgc-1ß. In rats fed a HFD, increasing the levels of Pgc-1ß partially ameliorated muscle insulin resistance, in association with decreased levels of long-chain acyl-CoAs (LCACoAs) and increased antioxidant defences. CONCLUSIONS: Our data show that an increase in Pgc-1ß expression in vivo activates a coordinated subset of genes that increase mitochondrial substrate oxidation, defend against oxidative stress and improve lipid-induced insulin resistance in skeletal muscle.

Prevention of tumour cell dissemination in diagnostic needle procedures.

BACKGROUND: A side effect of diagnostic needle biopsies is the possibility to disseminate tumour cells into the needle track, which may cause concern in certain malignant tumour types. METHODS: In order to prevent tumour cell dissemination we developed a technology that uses radiofrequency (RF) pulses to sterilise the needle track and denaturate tumour cells. To determine feasibility, we applied this technology to fine needle aspiration biopsy (FNAB) and used breast cancer as a model tumour. Routine FNAB was performed in 88 patients with adenocarcinoma and blood droplets passing the skin orifice were cytomorphologically analysed for the presence of tumour cells. RESULTS: The analysis showed the presence of tumour cells in 65/88 cases (74%). When using an experimental anti-seeding device in a subset of patients viable tumour cells were found in 0/31 cases (P<0.001). In all 31 patients blood passing the skin orifice was sparse. No degrading effect on the cytological sample inside the needle was detected and pain caused by the RF pulses was comparable to that of the biopsy procedure itself. CONCLUSION: The herein presented method has the potential to prevent the dissemination of viable tumour cells in the needle track and minimize bleeding without additional pain or degradation of the aspirate.

Expression of syndecan-1 in paired samples of normal and malignant breast tissue from postmenopausal women.

BACKGROUND: The mammary stroma is important for modulating epithelial breast cell response to sex steroid hormones. Proteoglycans, such as syndecan-1, promote the integration of cellular signals. MATERIALS AND METHODS: The immunohistochemical expression of syndecan-1 and of the androgen receptor (AR) was analyzed in paired samples of cancer and adjacent normal tissue from postmenopausal women. RESULTS: Normal and cancer tissue showed dramatic differences in the expression of syndecan-1. In malignant breast stroma, mean values were more than 10-fold higher than in normal tissue (p<0.001). There was also a marked redistribution from the epithelium to the stroma. The expression of AR was on average 2-fold higher in cancerous than in normal tissue (p<0.01). CONCLUSION: Breast cancer patients have very different prognoses. Syndecan-1 and the AR may be new molecular markers relevant to clinical outcome. The redistribution from the epithelium and the dramatic increase of syndecan-1 in cancerous stroma may be related to the natural history of the disease.

Hormone therapy and estrogen receptor expression in breast cancer.

Postmenopausal hormone therapy (HT) may increase breast cancer risk and influence tumor characteristics. We investigated 321 postmenopausal women aged 50-65 years, with breast cancer, diagnosed and treated at Radiumhemmet, Karolinska Hospital, during 1993-1997. In women using HT (n =90) estrogen receptor concentration (ER) at diagnosis were lower than in non-users (n =135) (1.17 vs 1.70 fmol/microg; p <0.05). HT users also had a tendency to less multifocal (5 vs 12%) (p <0.05) and metastatic disease (5% vs 2%) however this was not statistically significant. The estrogen receptor expression is always considered in the judgement on hormone dependency and the clinical decision on adjuvant endocrine therapy. A suppression of ER during HT could tentatively influence the treatment decisions in breast cancer patients and maybe disregard patients from endocrine treatment.

Are estrogen receptor content in breast cancer and effects of tamoxifen on sex hormone-binding globulin markers for individual estrogen sensitivity?

Individual women differ with respect to their sensitivity to estrogen and serum levels of sex hormone-binding globulin (SHBG) may reflect the individual response. We found a significant correlation between estrogen receptor (ER) concentrations in breast cancer tissue and SHBG levels during tamoxifen treatment. Estrogen sensitivity may be a general characteristic common to various organs and different between individual women.

Expression of sex steroid receptor subtypes in normal and malignant breast tissue - a pilot study in postmenopausal women.

Female sex steroids are implied in breast cancer development. The estrogen (ER) and progesterone (PR) receptor subtypes may have different roles to modulate the cellular response. Paired samples of cancer and adjacent normal tissue were collected from postmenopausal women at surgery for ductal breast cancer. The expression of ERa, ERss, PRA and PRB was quantified by immunostaining and digitized image analysis. We found ERss to be significantly reduced in breast cancer tissue (35% vs 50%; p?=?0.001) and there was also a decrease of the ERss/ERa ratio. Among women using hormones at the time of diagnosis tumor tissue showed higher values for both PRB and PRA, as compared to women without such treatment. The results extend previous animal data to be valid also in women. There is evidence that loss of ERss expression may relate to estrogen dependent tumor progression. Increased PR expression could possibly relate to breast cancer risk during combined estrogen/progestogen treatment.

Tamoxifen and megestrol acetate for postmenopausal breast cancer: diverging effects on liver proteins, androgens, and glucocorticoids.

AIM: To compare the effects of tamoxifen and megestrol acetate on liver proteins, androgens, and glucocorticoids during adjuvant treatment for postmenopausal breast cancer. METHODS: A subgroup of women within a large prospective multicenter trial were followed with blood sampling every 3 mo during 2 yr. Women were randomized to receive either continuous tamoxifen 40 mg/d or repeated sequential treatment with tamoxifen and megestrol acetate (MA) 160 mg/d. RESULTS: We found profound and distinct differences between the two regimens. Tamoxifen increased steroid-binding proteins (SHBG and CBG) and suppressed circulating androgens and IGF-I. In contrast, the metabolic effects of tamoxifen were clearly antagonized by MA. There was a rise in IGF-I and marked suppression of steroid-binding proteins. Levels of free testosterone were reduced by 70%. MA also caused apparent adrenal suppression. CONCLUSION: The different effects on anabolic/catabolic balance and adrenal function may relate to certain clinical effects during treatment.

Hormone receptor status in breast cancer--a comparison between surgical specimens and fine needle aspiration biopsies.

The present study was performed to evaluate the immunocytochemical analysis (ICA) of oestrogen (ER) and progesterone receptor (PR) in fine needle aspiration (FNA) biopsies from primary breast cancers as compared with the established enzyme immunoassays (ER-EIA and PR-EIA) based on cytosol homogenates from the corresponding resected tumour specimens. A total of 967 primary breast cancers were assessed for ER and PR content by both methods. Correlations between EIA and ICA expressed as percentage of tumour cells with a positive staining were highly significant (P < 0.001) for ER and PR. Staining intensity yielded only limited additional information. The concordance between the two techniques was about 80%. Evaluation of biological parameters by FNA may be useful to decide the optimal treatment for breast cancer patients.

Ontogenetic development and spatial distribution of the ileal apical sodium-dependent bile acid transporter and the ileal lipid-binding protein in apoE knockout and C57BL/6 mice.

BACKGROUND: Although apoE-/- mice are characterized by hypercholesterolemia, the bile acid enterohepatic circulation, which plays a crucial role in cholesterol homeostasis, has not been examined in these mice. The differences between apoE-/- and C57BL/6 mice in expression of the ileal ASBT and ILBP and in intestinal bile acid absorption were studied. METHODS: The intestinal tissues of the fetal, neonatal and post-weaning mice were processed for immunohistochemistry. Body retention and fecal excretion of 75SeHCAT were measured. The bile acid pool size and its composition were analysed by HPLC. RESULTS: In apoE-/- and C57BL/6 mice, the bile acid pool size was 75 +/- 13 and 78 +/- 13 micromol/ 100 g body weight, respectively, while the ratio of cholic acid/beta-muricholic acid was 1.8 +/- 0.3 and 1.4 +/- 0.3 (P < 0.05), respectively. The daily body retention of 75SeHCAT was 48% = 1.8% in C57 black mice and 58.4% +/- 2.7% in apoE-/- mice (P < 0.05). In both mouse strains, ASBT expression in the small intestine was found in the near-term fetal and post-weaning mice, while ILBP expression was found in all postnatal mice. In the post-weaning mice, ILBP expression was limited to the distal 25%-30% of the small intestine, while ASBT expression was limited to the distal 18%. CONCLUSIONS: The bile acid enterohepatic circulation in apoE-/- mice probably does not differ greatly from that in C57BL/6 mice.

The influence of UV exposure on 5-aminolevulinic acid-induced protoporphyrin IX production in skin.

The skin of nude mice was exposed to erythemogenic doses of UV radiation, which resulted in erythema with edema. An ointment containing 5-aminolevulinic acid (ALA) was topically applied on mouse and human skin. Differences in the kinetics of protoporphyrin accumulation were investigated in normal and UV-exposed skin. At 24 and 48 h after UV exposure, skin produced significantly less protoporphyrin IX (PpIX) than skin unexposed to UV. Human skin on body sites frequently exposed to solar radiation (the lower arm) also produced less PpIX than skin exposed more rarely to the sun (the upper arm). It is concluded that UV radiation introduces persisting changes in the skin, relevant to its capability of producing PpIX from ALA. The observed differences in ALA-induced PpIX fluorescence may be the result of altered penetration of ALA through the stratum corneum or altered metabolizing ability of normal and UV-exposed skin (or both).

Comparative biodistribution of meta-Tetra(Hydroxyphenyl) chlorin in multiple species: clinical implications for photodynamic therapy.

BACKGROUND AND OBJECTIVE: To optimize photodynamic therapy, it is necessary to know the distribution of photosensitizer in normal tissue as well as tumors and to know how well animal models match human. This study measured the biodistribution of meta-Tetra(Hydroxyphenyl) Chlorin (mTHPC) in three species of animals and in humans. STUDY DESIGN/MATERIALS AND METHODS: mTHPC was injected intravenously into dogs, rabbits, and humans, and drug levels in various tissues were determined 6 days later. One dog was perfused with 3 L of saline to remove blood trapped within organs. RESULTS: Absolute and relative concentrations of drug in specific tissues varied between species and between individuals. There was a general pattern of distribution. Highly vascularized tissues had the highest levels of mTHPC, not simply due to trapping of blood. mTHPC did not localize in bone and did not cross the blood-brain barrier. Humans had much higher levels of drug in their plasma and tissues than did animals. CONCLUSIONS: First, drug retention varies from one tissue to another. Second, there is significant variability from one individual to another, whether animal or human. Third, current models cannot accurately predict from animal studies the optimum dose for humans. Measurement of photosensitizer level in plasma at time of treatment would allow optimal photodynamic dosing.

Efficacy of intravenous delta-aminolaevulinic acid photodynamic therapy on rabbit papillomas.

Endogenously induced protoporphyrin IX (PPIX), a metabolite of delta-aminolaevulinic acid (ALA), has been evaluated as a photosensitising agent for destruction of papillomas in cottontail rabbit papillomavirus-infected Dutch belted and New Zealand rabbits. Three factors were evaluated: (1) relative retention ratio of drug in normal tissue, papilloma and plasma over time; (2) tissue tolerance to treatment factors; and (3) efficacy of treatment protocol. Three drug doses of ALA were examined: 50, 100 and 200 mg kg-1. Actual PPIX concentrations in tissue and plasma were determined spectrophotofluorometrically. The optimal treatment time occurred 3-6 h post ALA injection. The highest PPIX concentration ratio between papilloma and normal skin was 6:1. Different light doses were investigated, using an injection to exposure interval of 3 h and an irradiance of 100 mW cm-2 at a wavelength of 630 nm. Efficacy without risk of significant damage to normal skin was obtained using 100-200 mg kg-1 ALA and 40-60 J cm-2. A long-term (3 months) cure rate of 82% was obtained with a single treatment, provided that papilloma depth did not exceed 8 mm, volume was not more than 1000 mm3 and the plasma concentration of PPIX immediately before exposure was above 500 micrograms ml-1. The short time between injection and treatment and high efficacy, together with PPIX disappearance from plasma and tissue within 24 h, make injected ALA a highly attractive drug for photodynamic therapy.

Photodynamic therapy for recurrent nasopharyngeal cancer.

OBJECTIVE: A pilot study to determine if photodynamic therapy could be a safe and efficacious treatment for recurrent or persistent nasopharyngeal cancer. DESIGN: A consecutive sample intervention study with comparison with historic control subjects. SETTING: Tertiary referral hospital. PATIENTS: All patients with recurrent or persistent nasopharyngeal cancer following radiation therapy were considered for treatment. Patients with tumors with a depth of more than 10-mm invasion on computed tomographic scans were excluded, as were patients with recurrent metastasis to the neck. Five patients were thus acquired during a 3-year period. INTERVENTION: Four patients were injected intravenously with hematoporphyrin derivative (2.5 mg/kg) and one patient with porfimer sodium (2 mg/kg) (Photofrin, Quadra Logic Technologies, Vancouver, British Columbia) 48 hours before treatment. The drug was activated by a 630-nm laser light passed down a 1-mm core quartz fiber to a miniaturized convex mirror positioned in the nasopharynx via the contralateral nasal cavity. This procedure was carried out under topical anesthesia. MAIN OUTCOME MEASURE: Survival was determined after a minimum follow-up of 4 years. RESULTS: To date, three of five patients treated have no evidence of disease, with follow-up times of 51, 52, and 60 months, respectively. The patient with the longest survival time had been unsuccessfully treated with 136 Gy of ionizing radiation preceding photodynamic therapy. CONCLUSIONS: Long-term tumor control can be achieved by photodynamic therapy in cases where very high doses of ionizing radiation have failed. The entire treatment can be accomplished in 30 minutes under topical anesthesia. The technique carries no serious side effects.

Photodynamic therapy using m-tetra(hydroxyphenyl) chlorin. An animal model.

OBJECTIVE: To evaluate the potent photosensitizer m-tetra (hydroxyphenyl) chlorin (m-THPC) by using rabbits with cottontail rabbit papillomavirus-induced tumors and the canine larynx as model systems. DESIGN: Nonrandomized control trial. SETTING: Division of ear, nose, and throat research at a tertiary care teaching hospital. MATERIALS: Rabbits were used for relative retention ratio studies and tissue tolerance tests. Studies on the swelling of normal tissues in the larynx after photoactivation were done with canines. INTERVENTION: Animals were injected with 0.3 mg/kg of m-THPC. At varying intervals, tissues were exposed to 652 nm of light. OUTCOME MEASURES: Outcome measures consisted of four elements: (1) decay of plasma concentration over time, (2) interval to and duration of maximal ratio between drug concentration in normal tissue and tumor, (3) maximal permissible light exposure to normal tissue (skin and laryngeal mucosa) at an optimal interval, and (4) efficacy--number of tumors with partial and complete response. RESULTS: The largest papilloma to skin ratio (10:1) occurred 4 to 8 days after drug injection. The rabbit skin damage threshold was 40 to 60 J/cm2 at 6 days. The canine laryngeal edema and erythema thresholds were 50 to 70 J. A 75% cure rate of papillomas was achieved with tumors that were less than 100 mm2 in area at light doses that ranged from 25 to 75 J/cm2. CONCLUSIONS: m-THPC shows efficacy in treating papilloma virus-induced tumors. We present a protocol for rapid optimization of the factors required for tumor destruction with minimal normal tissue damage, thus permitting determination of an optimal therapeutic protocol for any photosensitizer.