Comparison of two estradiol transdermal systems (Oesclim 50 and Estraderm TTS 50). I. Tolerability, adhesion and efficacy

OBJECTIVES: The objectives were to compare the tolerability, adhesion and efficacy of a new matrix-type estradiol transdermal system, Oesclim 50, with those of Estraderm TTS 50, a reservoir-type system. METHODS: This was an open, randomised, parallel-group, multi-centre clinical trial, performed in six European countries. A total of 143 healthy menopausal women were allocated to treatment with Oesclim 50 and 140 to Estraderm TTS 50. The transdermal systems were applied twice weekly for 24 days out of each 28-day cycle, over a period of four cycles. Oral progestogen treatment was taken by non-hysterectomised patients for the last 12 days of estrogen therapy in each cycle. RESULTS: The local skin tolerability of the Oesclim 50 transdermal system was significantly better than that of Estraderm TTS 50. In the Oesclim 50 group, 4.2% of applications caused a reaction, compared with 9.5% in the Estraderm TTS 50 group (P < 0.001). Safety assessments showed both treatments to be well tolerated. Seven patients in the Oesclim 50 group, and 12 in the Estraderm TTS 50 group, discontinued due to adverse events. Of these discontinuations, one (0.7% of patients) in the Oesclim 50 group and seven (5.1% of patients) in the Estraderm TTS 50 group were due to application site reactions (P < 0.05). There was no statistically significant difference between the two groups in the percentage of patients with signs of hyperestrogenism (29 patients (20.3%) in the Oesclim group and 28 patients (20.0%) in the Estraderm TTS 50 group). Adhesion was significantly better for the Oesclim 50 transdermal system, with 6.0% of Oesclim 50 applications becoming detached compared with 11.3% of Estraderm TTS 50 applications (P < 0.001). The greater adhesion of Oesclim 50 was particularly apparent when the systems were exposed to water, with three times fewer Oesclim 50 systems becoming detached during a shower or bath (P < 0.001 in each case). Both treatments produced significant and comparable improvements in vasomotor symptoms, other menopausal symptoms and gynaecological assessments. A near-maximal effect on vasomotor symptoms was observed after approximately 1 month of treatment, and was maintained for the entire treatment period. CONCLUSION: Overall, Oesclim 50 provided statistically significantly better local skin tolerability and adhesion than Estraderm TTS 50, together with comparable efficacy and safety.     

How to stabilize the level of ionized calcium and citrate during plateletpheresis

Felodipine is a calcium antagonist, one of the dihydropyridines, with potential application in transdermal therapeutic systems (TTS). Earlier studies reported that the high lag time of this drug limited its potential development in a TTS. The present study analyzes the effect of d-limonene at concentrations of 0.5, 1, 5 and 10% on the transdermal penetration of this drug. The study was performed using a diffusion technique in vitro, with the skin of the hairless rat. d-Limonene significantly reduced the lag time (Tl) to 1.4 h at a concentration of 1% (compared with 9.8 h in its absence). Higher concentrations did not produce a significant decrease in the value of this parameter. The presence of d-limonene in the formulae produces an increase in the permeability constant (Kp) and the flux (J). The relation between this increase and the percentage of d-limonene was non-linear. An asymptotic value was obtained at a concentration of 5%, with increases of 993% and 1570% for Kp and J, respectively.     

Metastatic cutaneous melanoma promoted by ultraviolet radiation in mice with transgene-initiated low melanoma susceptibility

An inbred-strain (C57BL/6) transgenic (Tyr-SV40E) mouse model of ultraviolet radiation (UVR)-induced metastatic cutaneous melanoma was produced without the use of chemical carcinogens and without resulting in other skin malignancies. Expression of this transgene occurs specifically in melanocytic-lineage cells. In untreated hemizygous mice of transgenic line 12 there are no skin melanomas, and the oncogenic sequence, which is expressed at a very low level, functions solely as a weak initiating stimulus. UVR [including 65% ultraviolet B (280-320 nm wavelength)] supplied the necessary promoting stimulus leading to melanomas. Of various trial protocols, eight were successful and involved exposure of 112 mice for a limited time on each of 3-10 days starting at 2-3 days of age and totalling 1.1-3.7 J/cm2 UVR. Fourteen of these animals developed a total of 15 invasive skin melanomas on the head and body, arising between 37-115 weeks of age and, therefore, often after a relatively long latency. The tumors were melanotic and in five of the mice they yielded macrometastases in regional and distant sites. The single most favorable protocol (1.9 J/cm2 total UVR, at 0.38 J/cm2/day for 5 days starting at 3 days of age) led to the highest incidence of melanoma (5 of 19 mice) and one of the lowest mortality rates (2 of 19). No melanomas occurred in UVR-treated nontransgenic C57BL/6 controls. Benign skin keratoacanthomas arose and often regressed in treated transgenic as well as nontransgenic mice. This new transgenic mouse model introduces many novel possibilities for experimental analysis of the melanoma-promoting mechanisms of UVR and also of the ability of specific genetic changes to impede or facilitate the UVR effect.     

The tearing topography surface as the zone associated with hydrogen embrittlement processes in pearlitic steel

This article deals with a new nonconventional microscopic fracture mode with a characteristic feature: the tearing topography surface (TTS), associated with hydrogen embrittlement processes in pearlitic steel. The TTS mode appeared in fracture tests on precracked and notched specimens when tested under hydrogen charging. Experimental results showed phenomenological relations between the size of the TTS region and variables such as the electrochemical potential and the maximum stress intensity factor during fatigue precracking (for cracked samples) or the time to failure and the geometry (for notched samples). A hydrogen diffusion model is proposed which explains, from the theoretical point of view, the phenomenological relations between the TTS size and the test variables. According to this model, hydrogen diffuses not only toward the places of minimum concentration, but also to the sites of maximum hydrostatic stress. Formerly Associate Professor, Department of Materials Science, Polytechnical University of Madrid Formerly Associate Professor, Department of Materials Science, Polytechnical University of Madrid     

Organ-specific and Agamous-regulated expression and glycosylation of a pollen tube growth-promoting protein

Transmitting tissue-specific (TTS) protein is a pollen tube growth-promoting and attracting glycoprotein located in the stylar transmitting tissue extracellular matrix of the pistil of tobacco. The TTS protein backbones have a deduced molecular mass of about 28 kDa, whereas the glycosylated stylar TTS proteins have apparent molecular masses ranging between 50 and 100 kDa. TTS mRNAs and proteins are ectopically produced in transgenic tobacco plants that express either a cauliflower mosaic virus (CaMV) 35S promoter-TTS2 transgene or a CaMV 35S-promoter-NAG1 (NAG1 = Nicotiana tabacum Agamous gene) transgene. However, the patterns of TTS mRNA and protein accumulation and the quality of the TTS proteins produced are different in these two types of transgenic plants. In 35S-TTS transgenic plants, TTS mRNAs and proteins accumulate constitutively in vegetative and floral tissues. However, the ectopically expressed TTS proteins in these transgenic plants accumulate as underglycosylated protein species with apparent molecular masses between 30 and 50 kDa. This indicates that the capacity to produce highly glycosylated TTS proteins is restricted to the stylar transmitting tissue. In 35S-NAG transgenic plants, NAG1 mRNAs accumulate constitutively in vegetative and floral tissues, and TTS mRNAs are induced in the sepals of these plants. Moreover, highly glycosylated TTS proteins in the 50- to 100-kDa molecular mass range accumulate in the sepals of these transgenic, 35S-NAG plants. These results show that the tobacco NAGI gene, together with other yet unidentified regulatory factors, control the expression of TTS genes and the cellular capacity to glycosylate TTS proteins, which are normally expressed very late in the pistil developmental pathway and function in the final stage of floral development. The sepals in the transgenic 35S-NAG plants also support efficient pollen germination and tube growth, similar to what normally occurs in the pistil, and this ability correlates with the accumulation of the highest levels of the 50- to 100-kDa glycosylated TTS proteins.     

Urocanic acid isomers in patients with basal cell carcinoma and cutaneous malignant melanoma

Urocanic acid (UCA) is a major chromophore for ultraviolet (UV) radiation in the skin. On UV exposure, the naturally occurring trans-isomer converts to the cis-isomer in a dose-dependent manner. Accumulating evidence indicates that cis-UCA acts as an initiator of the UV-induced suppression of certain skin immune functions. This immunomodulation is recognized as an important factor in the development of skin cancer. In this study, pigmentation and UCA isomers were measured in 29 patients with previous basal cell carcinoma (BCC), 23 patients with previous cutaneous malignant melanoma (MM), and 32 healthy controls. Measurements were performed on UV-exposed (forehead, upper back) and UV non-exposed (buttock) skin. No significant differences in pigmentation percentage, total UCA concentration, relative (%) or absolute (nmol/cm2) cis-UCA concentration were observed between the groups in any of the body sites studied. The net production of cis-UCA after irradiation with a single test UV dose was evaluated. The relative production of cis-UCA following irradiation was significantly higher in both cancer groups when compared with the control group, while no significant difference was found between the BCC and the MM patients.     

Effects of impulse noise on cortical response threshold and inner ear activity of succinic dehydrogenase and acetylcholinesterase in guinea pigs

The effects of impulse noise (firecrackers at 170 dB SPL, 1, 10, 20 rounds) on auditory cortical response threshold (CRT) and activity of succinic dehydrogenase (SDH) and acetylcholinesterase (AchE) in the inner ear were studied in 37 guinea pigs. The results showed that extent of damage in the cochlea was related to amount of exposure to the noise. Exposure to 10 rounds resulted in temporal threshold shift (TTS); to 20 rounds the result was permanent threshold shift (PTS). For the period when TTS existed, inverse correlation was noticed between enzyme activity change and CRT shift. The correlation could not be established when PTS was induced. The results suggest that the pathomechanism of PTS was more complex than that of TTS. The significance of the results is discussed.     

Effect of transcutaneous electrostimulation on noise-induced temporary threshold shift

The effect of transcutaneous electrostimulation around the ear before and during noise exposure on noise-induced temporary threshold shift (TTS) was examined in 26 volunteers. Electrostimulation reduced TTS in the majority of cases and the reduction was statistically significant. Two possible mechanisms for this reduction are proposed: stimulation of the olivocochlear bundle and alteration of cochlear blood flow. Transcutaneous electrostimulation may be useful for prevention or treatment of noise induced hearing damage and for treatment of tinnitus.     

Acute cholecystitis from metastatic melanoma to the gall-bladder in a patient with a low-risk melanoma

OBJECTIVES: An investigation was conducted to determine whether ongoing transmission of Mycobacterium tuberculosis was occurring in a California state prison. METHOD: Prison pharmacy records were used to identify cases of active tuberculosis (TB). RESULTS: Ten of the 18 cases of active TB treated at the facility during 1991 were diagnosed at the prison that same year (an incidence of 184 per 100,000). Three inmates were infectious for a total of 7 months while imprisoned. The prevalence of TB skin test-positivity among inmates was 30%, and the incidence of new infection attributable to incarceration was 5.9 per 100 inmates per year. CONCLUSIONS: Transmission of M. tuberculosis may be occurring in the California prison system.     

Scintigraphic evaluation of malignant melanoma lesions with Tc-99m tetrofosmin

Two cases of malignant melanoma (primary and metastatic lesions) imaged with Tc-99m tetrofosmin are reported. One patient showed intense uptake in a primary skin lesion of the thorax, and the other patient had accumulation in skin, cerebellum, breast, and lymph node metastases. Like Tc-99m MIBI, Tc-99m tetrofosmin imaging may be of clinical relevance in the evaluation of suspicious skin lesions and in patients with known cutaneous malignant melanoma in the assessment of recurrent disease during follow-up evaluation.     

An animal model for human melanoma

Experimental animal models that are directly relevant to human melanoma are lacking. We propose the Angora goat as a potentially useful field model with experimental potential and to this end have examined the prevalence and site distribution of all skin cancers in 28 Angora goat herds in Queensland, Australia. The prevalence of benign melanocytic lesions (lentigines) and their experimental induction by sunlight were also investigated. Among 1731 goats over 2 years of age, 139 malignant skin tumors were excised from 95 affected animals. The prevalence of squamous cell carcinoma (SCC) was 3.8% and of melanoma, 2.2%. Main site of occurrence of melanoma (83%) was the dorsal surface of the ear; in contrast SCC occurred mostly (84%) on the perineum. Lentigines were darker and more prevalent on the exposed compared with the unexposed surface of the ear in Angoras, analogous to the higher prevalence of nevi on the exposed compared with the less exposed inner surface of the arm in humans. Lentigines, which were also found on the perineum though lighter in color than on the dorsal ear, were absent in young animals under 3 months but were numerous in 1-3 year olds. Furthermore in an experimental substudy eight goats, having one flank repeatedly shorn and the contralateral flank left unshorn, revealed consistently more solar lentigines on the shorn flank (P < 0.05) when both sides were examined after 9 months. Histopathological examination of paired skin biopsies from five of these goats also showed more abundant pigmentation in skin from the exposed, as compared with the unexposed flank. These findings indicate that sunlight induces tumors and lentigines in goats in a highly site-specific manner. The Angora goat model may suggest paradigms for explaining the site differences observed for human melanoma and may also be useful in the future clarification of molecular changes following carcinogenic levels of sun exposure.     

Clinical analysis of 15 patients with primary malignant melanoma in the genital tract

The penetrating wound of palm with the defect of tissues was usually caused by blunt crushing of gun-shot injury. It was difficult to treat clinically. In order to repair the skin defect of palm and dorsum in one operation, 2 kinds of dumbbell-shaped double-leaf flap were desigened. From February 1993 to March 1996, 5 cases with penetrating wound of palm were treated by this method in which the interosseous posterior artery flap in 4, and the superficial epigastric flap in 1. There were 4 males and 1 female with the ages ranging from 15 to 47 years old. The results were as follows: total survival of the flap in 4 cases and partial necrosis of skin margin of the distal leaf in 1 case. The appearance and function of the flap were satisfactory after a follow-up from 4 months to 3 years. It was concluded that the interosseous posterior artery flap had a long vascular pedicle with its constant anatomical distribution, and the 2nd stage of division of the pedicle of the flap was not necessary. It was a perfect flap in repairing the penetrating wound of the palm with small skin defect. The superficial epigastric flap was cumbersome in appearance and was necessary to divide the pedicle of the flap in 2nd staged operation. It was suitable in repairing the penetrating wound with large skin defect. Regarding the operative technique, a meticulous debridement and the appropriate flap area were required, and the blood vessel of the flap should not be compressed by the surrounding tissues. The advantages of this operation provided a simple method to handle, high rate of survival, and one-staged operation.     

Intratumoral oxygen tension in metastatic melanoma

Tumour hypoxia can lead to a decrease in the biological effectiveness of radiation and alkylating agents. Few data are available on oxygen tension (PO2) in melanoma. In 20 patients with past history of melanoma, PO2 was evaluated in normal tissues and suspected metastatic lesions (nodes and skin metastases). Oxygen tension was measured using a needle probe technique (KIMOC-6650 histograph, Eppendorf, Germany), the day before the surgical removal of the suspected metastatic lesion. Histological confirmation of the malignant origin of the removed lesion was obtained in 18 cases. In two cases invasion by the known melanoma was not seen histologically. The median PO2 for normal tissues was 40.5 mmHg. For tumours, the median PO2 was 11.6 mmHg, and it was 17.1 mmHg in nodes and 6.7 mmHg in skin metastases. Very low values (< 2 mmHg) accounted for 20% of the recorded values in nodes and 15% in skin metastases. When analysed according to the node size (< or > or = 3 cm in diameter), the median PO2 was 10.4 mmHg in large nodes (six patients) and 53.3 mmHg in small nodes (six patients). For the two non-tumoral lesions, the median PO2 values were 20.9 and 25.1 mmHg, with no values below 10 mmHg. Thus a decrease in PO2 values, probably corresponding to tumour hypoxia, was found in most of the metastatic tumours when compared with normal tissues. The prognostic value of these PO2 measurements in melanoma remains to be demonstrated in the tumour response to radiotherapy or alkylating agents. However, tumour hypoxia can already be investigated as a target for new treatment modalities in metastatic melanoma.     

Enhancing the early detection of melanoma within current guidelines

Queensland has the highest reported incidence of malignant melanoma in the world, and early detection offers the possibility of reducing the burden of this cancer in the short term. We report on a survey of 995 residents of the Gold Coast, Queensland, regarding behavioural aspects of the early detection of skin cancer. Survey results suggest that although many people report some form of skin examination behaviour, by either checking their own skin, having another nonmedical person check their skin, or by going to their general practitioner for a skin check, much of this activity may be inadequate. They indicate that current early detection could be enhanced by encouraging individuals and general practitioners to extend the coverage of the examinations they already conduct.     

Borrelia burgdorferi, taxonomy, pathogenicity and spread

In connection with the development of transdermal delivery systems (TTS) of the laminated adhesive patches type, HPLC was selected for analytical evaluation of active principles. It was employed for analysis of glycerol trinitrate (GTN) as one of the drugs administered in the form of medicinal adhesive patches. After isolation from the patch, GTN was analysed by reverse phase HPLC, employing methanol and water as the mobile phase, and detected at 206 nm. The total amount of GTN in the patch was evaluated and its concentrations in a lactose trituration and the reservoir layer were determined. In the patches manufactured in a test series, the elaborated HPLC method was used to investigate the release of GTN in a liberation study and its permeation through excised human skin in experiments performed in vitro. In connection with the stability study, the decomposition products of GTN were also determined.     

Managing cutaneous melanoma

Cutaneous melanoma represents the main cause of death among skin cancers. Early diagnosis gives, for the time being, the only possibility for high rate of curative treatment. Diagnosis is based on pathological findings, and at primary tumor stage. Breslow thickness of the lesion is the best prognostic index. At local stage of the disease, treatment is precisely codified by international recommendations and consensus conferences. Follow-up after surgical treatment is also well codified. Treatment of lymph node invasion or metastatic disease is, on the other hand, less codified. Despite recent advances, especially in immunotherapy, treatment of advanced stages of melanoma remains difficult.     

Are young adults checking their skin for melanoma?

This study examined the prevalence and predictors of self screening for melanoma in a large sample of young New Zealanders. A self-report questionnaire was administered to a sample of 909, 21-year-olds to investigate if young adults check their skin for changes in lesions which could be melanoma, and to identify the factors which influence this behaviour and any subsequent help seeking. Fifty-three per cent reported checking their skin in the past year, with 20% noticing a change in a mole or freckle. Forty-five per cent of those who noticed a change sought medical advice. The most common reason for not seeking advice was cost. Women were more likely that men to have checked their skin, to have noticed a change and to have sought medical advice. In addition to gender, tendency to self check was also associated with knowledge of melanoma and perceived risk of melanoma. These results are discussed in light of the current debate regarding skin cancer screening. This study fills a gap in the literature regarding self screening for melanoma in young adults and identifies ways in which future prevention campaigns might be modified to address the concerns of this age group.     

Survival analysis in patients with cutaneous malignant melanoma

INTRODUCTION: Cutaneous malignant melanoma (MM) takes only 3% of all malignant tumours of the skin, but for reason of its increased frequency and pronounced tendency to rapid growth and metastases, it causes 60% of total lethal outcomes due to malignant tumours of the skin [1]. Primary MM is a diagnostic problem because of the great variety of its clinical features. Asymmetric configuration, irregular border, speckled color(r)diameter of more than 6 mm, and elevation of the surface, suggest suspicion of malignant alteration, but even then misdiagnosis is possible. For the final diagnosis of MM histopathological confirmation is necessary. The method to use is the extensive excisional biopsy of the lesion and its borders [2]. Histopathological diagnosis is based on microscopic findings which include: histogenetic type of MM, tumour thickness according to Breslow, level of invasion according to Clark, presence of ulceration, grade of lymphocyte infiltration, mitote rate, type of cells, presence of melanin in cells [2, 3]. PATIENTS AND METHODS: A five-year survival of patients with cutaneous malignant melanoma (MM) was studied according to sex, age and distinct features of the tumour: site, type of initial therapy, stage of the disease, time from the first signs of the disease to diagnosis of MM, histological findings (histogenetic type, Breslow's tumour thickness, Clark's level of invasion, presence of ulceration, degree of lymphocyte infiltration, number of mitoses, type of cells, intensity of pigmentation) and presence of metastases. The retrospective study included 336 patients with cutaneous MM. There were 185 female (55.1%) and 151 male patients (44.9%), aged 14-83 years, mean age 48.8 years, who were treated at the institute of Oncology and Radiology in Belgrade from 1978 to 1990. The mean follow-up was 60 months (1-144 months). Melanoma in situ had 16 (4.1%) patients. Stage I had 45 patients (14.1%), stage II 163 (48.5%), stage III 83 (24.7%) and stage IV 29 (8.6%) patients. Acral location on hands and feet had 40 (11.9%) patients, on head and neck 36 (10.7%), on the trunk 146 (43.5%) and on the extremities (except hands and feet) 114 (33.9%) patients. Nodular melanoma (NM) was the most frequent histogenetic type revealed in 150 (44.6%) patients, superficial spreading melanoma (SSM) in 105 (31.1%) patients, acral melanoma (AM) in 39 (11.5%) and lentigo malignant melanoma (LMM) in 32 (9.4%) patients (Table 1). Five-year survival rate was calculated according to Kaplan-Meier's method and significance of the difference between some categories was tested by Long-Rank's test; the significance less than 0.05 was accepted. RESULTS: Statistically highly significant differences in a five-year survival (p < 0.01) were related to sex p = 0.0005, age p = 0.0017, tumour site p = 0.0025, initial therapy p = 0.0036, stage of MM p = 0.0000, histological features of the tumour p = 0.0000 and presence of metastases p = 0.0000. A better five-year survival prognosis was found in female patients (64.5%) compared to male patients 44.5%, aged 27-46 years (87.3%) compared to patients younger than 26 years (43.5%); patients with melanoma on the extremities (except hands and feet) had a better five-year survival (66.7%) compared to patients younger than 26 years (43.5%); patients with melanoma on the extremities (except hands and feet) had a better five-year survival (65.7%) compared to patients with melanoma on the trunk or acral melanoma (47.3%). Higher survival was recorded in the group of patients with the tumour 1.5-3 mm thick, in whom the tumours was excised and regional nodes dissected as the primary therapy (66.9%) compared to those who underwent excision of the tumor only (48.8%). A five-year survival of patients with MM in situ was 100% for those in stage I; 85% in stage II; 42% in stage III, 16% and 0% in stage IV. The patients in whom the diagnosis of MM was established within 10 months after the first signs of the disease had significa