A phase I, randomized, double-blind study to assess the safety, tolerability and efficacy of the topical RORC2 inverse agonist PF-06763809 in participants with mild-to-moderate plaque psoriasis.

BACKGROUND: Transcription factor retinoic acid-related orphan receptor 2 (RORC2/RORγT) mediates interleukin (IL)-17A and IL-17F expression. IL-17A plays a central role in the pathogenesis of several inflammatory disorders, including psoriasis. The RORC2 inhibitor PF-06763809 has been hypothesized to inhibit IL-17A production in T-helper 17 (Th17) cells, thereby reducing psoriasis symptoms. AIM: To assess the safety, tolerability and effect on skin infiltrate thickness of PF-06763809 in participants with mild/moderate chronic plaque psoriasis. METHODS: This was a randomized, double-blind, first-in-human study (trial registration: ClinicalTrials.gov NCT03469336). Participants received each of the following six treatments once daily for 18 days: three topical doses (2.3%, 0.8%, 0.23%) of PF-06763809, a vehicle and two active comparators (betamethasone and calcipotriol). Primary endpoints included change from baseline in psoriatic skin infiltrate thickness [echo-poor band (EPB) on ultrasonography] at Day 19, and safety. Change in psoriasis-associated gene expression (Day 19), evaluated by real-time reverse transcription PCR of skin biopsies, was an exploratory endpoint. RESULTS: In total, 17 participants completed the study. Change from baseline in the EPB on Day 19 for all three doses of PF-06763809 was not significantly different from that of vehicle (P > 0.05). A significant reduction in EPB from baseline was observed with betamethasone on Day 19 relative to all other treatments (P < 0.0001). Treatment-related adverse events were mild/moderate. There were no significant differences in gene expression on Day 19 between vehicle and PF-06763809-treated skin lesions. CONCLUSION: Using a psoriasis plaque test design, PF-06763809 was found to be well tolerated with an acceptable safety profile in participants with psoriasis, but without reduction in skin infiltrate thickness or disease biomarkers.

Adapting epicutaneous patch testing protocols to assess immediate-type skin reactions.

OBJECTIVE: During the development of cosmetic formulations, in vitro and in vivo methods are essential tools used to reliably assess the skin irritation potential of a product or ingredient. Epicutaneous patch testing (single and/or multiple application protocols) has long been used as an initial in vivo method to screen for possible skin irritation properties of a substance or formulation. To confirm the mildness and dermatological and/or consumer acceptance of a product, use tests are often subsequently conducted. A study was therefore initiated to see how well patch test results correlate with use tests with respect to irritation elicited by skincare (leave-on) products. METHODS/RESULTS: A number of different cosmetic formulations were assessed in both tests. Although the patch test results did not indicate substantial irritation potentials, immediate-type reactions (stinging and redness) were observed in some volunteers which disappeared within approx. 1 h. Although transient, these reactions suggested that consumer acceptance would probably be low and the studies were discontinued. Immediate-type reactions are rare but have been described for some substances used in cosmetics. These unexpected results were nevertheless intriguing and prompted the start of a journey to see if patch test protocols could be modified to assess these reactions. An occlusive short-term patch test protocol with an application period of 20 min was developed. Successful identification of the spontaneous reactions became possible. Furthermore, there was a correlation between the intensity of reactions observed in the short-term patch test and those observed in the controlled in-use studies. Short-term patch testing using the developed protocol can therefore reliably be used as a screening method, for example in the development and optimization of cosmetic formulations containing ingredients that could cause spontaneous reactions, for instance of non-immunological contact urticaria type. CONCLUSION: The lessons learned from this studies indicate that simple modifications of existing test protocols can lead to important insights into skin reactions. These modifications can then be used to create further building blocks in the development and optimization of test strategies for cosmetic formulations which offer reliable study designs for possible reactions product developers may encounter.

OBJECTIF: Lors du développement de formulations cosmétiques, les méthodes in vitro et in vivo sont des outils essentiels utilisés pour évaluer de manière fiable le potentiel d'irritation cutanée d'un produit ou d'un ingrédient. Le test épicutané (protocoles d'application uniques et / ou multiples) est utilisé depuis longtemps comme méthode initiale in vivo pour dépister les éventuelles propriétés d'irritation cutanée d'une substance ou d'une formulation. Afin de confirmer la douceur et l'acceptation dermatologique et / ou consommateur d'un produit, des tests d'usage sont souvent effectués ultérieurement. Une étude a donc été initiée pour voir dans quelle mesure les résultats des tests épicutanés correspondent aux tests d'usage en ce qui concerne l'irritation provoquée par les produits de soin (sans rinçage). MÉTHODES/RÉSULTATS: Un certain nombre de formulations cosmétiques différentes ont été évaluées dans les deux tests. Bien que les résultats du test épicutané n'indiquent pas de potentiels d'irritation substantiels, des réactions de type immédiat (picotements et rougeurs) ont été observées chez certains volontaires. Celles-ci ont disparu en à peu près 1 heure. Bien que transitoires, ces réactions de type 5 suggéraient que l'acceptation du consommateur serait probablement faible et les études ont été interrompues. Les réactions de type immédiat 6 sont rares mais ont été évoquées en relation avec certaines substances utilisées en cosmétique. Ces résultats inattendus étaient néanmoins intrigants et ont incité le lancement d'un processus pour voir si les protocoles de test épicutané pouvaient être modifiés pour évaluer ces réactions. Un protocole de test épicutané à court terme occlusif avec une période d'application de 20 min a été développé, permettant l'identification réussie des réactions spontanées. Il a été de plus constate une corrélation entre l'intensité des réactions observées dans le test épicutané à court terme et celles observées dans les test d'usage contrôlés. Le test épicutané à court terme utilisant le protocole développé peut donc être utilisé de manière fiable comme méthode de dépistage, par exemple dans le développement et l'optimisation de formulations cosmétiques contenant des ingrédients qui pourraient provoquer des réactions spontanées, par exemple de type urticaire de contact non immunologique. CONCLUSION: Les leçons tirées de ces études indiquent que de simples modifications des protocoles de test existants peuvent révéler des informations importantes sur les réactions cutanées. Ces modifications peuvent ensuite être utilisées pour créer d'autres blocs de construction dans le développement et l'optimisation de stratégies de test pour des formulations cosmétiques qui offrent des conceptions d'études fiables pour les réactions possibles que les développeurs de produits peuvent rencontrer.

A phase I randomized trial to assess the effect on skin infiltrate thickness and tolerability of topical phosphodiesterase inhibitors in the treatment of psoriasis vulgaris using a modified psoriasis plaque test.

BACKGROUND: Oral phosphodiesterase (PDE)4 inhibitors have shown efficacy in chronic obstructive pulmonary disease and psoriasis. OBJECTIVES: To assess the effectiveness, local safety and tolerability, and systemic pharmacokinetics of two topical PDE4 inhibitors, roflumilast and TAK-084, in plaque psoriasis. METHODS: An intraindividual comparison of six topical products was made in 15 patients aged 18-65 years with stable chronic plaque psoriasis in an investigator-blinded, within-subject randomized study. The products evaluated were calcipotriol 0·005% cream; betamethasone valerate 0·1% (both in their marketed formulations); investigational cream formulations of roflumilast 0·5% and TAK-084 0·5% and 5%; and a vehicle cream formulation as a control. Each treatment was applied daily to different test sites located on psoriasis plaques for 3 weeks. RESULTS: The primary end point of (mean) change from baseline in skin infiltrate thickness after 3 weeks of treatment showed statistically significant improvements for all treatments: betamethasone valerate cream (-286·9 µm), the selective PDE4 inhibitors roflumilast 0·5% (-237·1 µm) and TAK-084 (0·5% cream, -153·6 µm; 5% cream, -216·7 µm) and calcipotriol 0·005% (-187·7 µm) when compared with vehicle cream control (all P < 0·001). Both the TAK-084 5% and roflumilast 0·5% formulations performed well overall compared with the potent corticosteroid, betamethasone, and were ranked better than the vitamin D analogue calcipotriol. All adverse events were mild or moderate and none was serious. CONCLUSIONS: Topical treatment with cream formulations of the PDE4 inhibitors roflumilast and TAK-084 reduced inflammation, measured as a change in skin infiltrate thickness, and reduced psoriasis severity. Corticosteroid treatments have known systemic and cutaneous side-effects; PDE4 inhibitors could offer an alternative to these and deserve further study.

Efficacy of a tyrothricin-containing wound gel in an abrasive wound model for superficial wounds.

BACKGROUND: Topical preparations are a common treatment for superficial acute wounds, which at the least do not interfere with healing and ideally result in enhanced wound healing irrespective of microbial colonization. OBJECTIVE: To examine the effects of a topical antimicrobial gel and its vehicle on the wound healing of standardized, superficial abrasions. METHODS: Thirty-three healthy volunteers were enrolled in a double-blinded, randomized, intraindividual comparison study. Three standardized, superficial abrasions were induced on their forearms. A tyrothricin 0.1% gel (Tyrosur® gel; Engelhard Arzneimittel GmbH & Co. KG, Niederdorfelden, Germany) and its vehicle were randomly applied to two of the test areas, and one lesion remained untreated. RESULTS: A significant improvement of wound healing was seen with both tyrothricin 0.1% gel and its corresponding vehicle in the clinical assessment. The mean area under the curve (AUC) of wound healing scores was the same for both preparations and the mean reepithelization scores were comparable at all test points over the entire 12 days. A lower mean AUC representing less reepithelization was found for the untreated test fields. CONCLUSION: The use of tyrothricin 0.1% gel and its corresponding vehicle resulted in statistically significant improved wound healing with an earlier onset of healing in particular. Based on these results obtained using an abrasive wound model, it can be concluded that the addition of tyrothricin 0.1% to the gel vehicle did not interfere with the improved wound healing seen with the vehicle alone.

Late complications after radiotherapy for prostate cancer.

BACKGROUND: The aim of the present study was to analyze in detail the time course of the incidence of radiation-induced late effects. For this purpose, unpublished data of patients treated by radiation therapy in Hamburg in the late 1980s were analyzed. Relatively large volumes were exposed to comparatively high doses, thus leading to a high rate of treatment-related side effects. PATIENTS AND METHODS: A total of 180 consecutive patients received radiotherapy for prostate cancer. The median age was 66 years (range 41-88 years). The median of the maximum dose was 77.5 Gy (range 56.3-95 Gy) and overall treatment time was 51 days (range 28-128 days). Endpoints analyzed were late complications of grade 3 or higher, overall and disease-free survival, local tumor control, and distant metastases. Data analysis was actuarial and the log-rank test was used to compare the various subgroups. RESULTS: After 2 years, 80.5 ± 3.2% of the patients were without any complications of grade 3 or higher, and after 5 years a constant level of 70.3 ± 4.0% was approached. When multiple lesions occurred per patient, the later events were disregarded. A total of 66 complications occurred in 42 patients. The percentage of patients being free from late complications, plotted as a function of time after start of radiation therapy, was adequately described by an exponential function and a constant fraction. Complications approached a constant level of 70.3% at a rate of 5.3% per month. This means that patients who will develop a complication do so at exponential kinetics and at a relatively high rate, whereas about 70% of the patients will never experience a late effect even over long observation periods. After subdividing the maximum dose into three equal dose groups of 55 patients each (< 73.3 Gy, 73.3-80 Gy, > 80 Gy), the constant fraction decreased from 85.7 to 72.8% and 52.2%, whereas the incidence rate was 4.3%, 7.7%, and 5.6% per month and, thus, almost independent of radiation dose. CONCLUSION: For a given group of patients, the rate of the incidence of late complications appears to be independent of radiation dose and (from analyzing data in the literature) independent of the grade of lesions, whereas the fraction of patients without late effects depends on both parameters.

Tandem repeated irritation in aged skin induces distinct barrier perturbation and cytokine profile in vivo.

BACKGROUND: The barrier perturbation pattern and molecular markers of inflammation upon tandem repeated irritation in chronologically aged skin have not been previously studied. OBJECTIVES: We aimed to investigate the barrier impairment kinetic and in vivo cytokine profile following sequential irritation with sodium lauryl sulfate (SLS) and undiluted toluene (Tol) in aged compared with young skin. METHODS: Four fields on the volar forearm of healthy aged and young volunteers (median age, respectively, 63.9 and 32.6 years) were sequentially exposed to 0.5% SLS and undiluted toluene in a controlled tandem repeated irritation test; an adjacent nontreated field served as control. The permeability barrier function was monitored by repeated measurements of transepidermal water loss (TEWL), capacitance and erythema every 24 h up to 96 h. The stratum corneum cytokines were harvested by sequential tape stripping and quantified by multiplex bead array and enzyme-linked immunosorbent assay. RESULTS: Compared with young skin, aged skin was characterized by delayed and/or less pronounced alterations in the visual irritation score, TEWL, chromametry a*-value and capacitance, assessed by the respective Δ-values for each parameter and monitoring time point. In both groups, exposure to SLS/SLS, SLS/Tol and Tol/SLS resulted in decreased interleukin (IL)-1α levels, whereas the application of Tol/Tol induced an increase in IL-1α. Furthermore, decreased IL-1 receptor antagonist (IL-1RA) levels and a lower IL-1RA/IL-1α ratio were found following repeated exposure to the irritants. CONCLUSIONS: Our results provide evidence for selective alterations in the cytokine profile and distinct barrier impairment kinetic following tandem repeated irritation with SLS and Tol in aged compared with young skin in vivo.

Bioavailability, antipsoriatic efficacy and tolerability of a new light cream with mometasone furoate 0.1%.

Mometasone furoate, a potent glucocorticoid (class III) with a favorable benefit/risk ratio, has emerged as a standard medication for the treatment of inflammatory skin disorders. The purpose of the investigation presented here was to determine the noninferiority of a topical mometasone formulation, a light cream (O/W 60/40 emulsion) with mometasone furoate 0.1% (water content of 33%) versus marketed comparators. Using the vasoconstrictor assay, a strong blanching effect of the new cream (called Mometasone cream) comparable to that of a mometasone comparator, a fatty cream with mometasone furoate 0.1%, could be demonstrated. Thus, the topical bioavailability of the active ingredient mometasone furoate (0.1%) was regarded to be similar for Mometasone cream and the mometasone comparator. Using the psoriasis plaque test, a strong antipsoriatic effect comparable to that of the mometasone comparator was found for Mometasone cream after 12 days of occlusive treatment. A nearly identical reduction in the mean infiltrate thickness and similar mean AUC values were noted with both formulations confirmed by clinical assessment data. The noninferiority of Mometasone cream to its active comparator with respect to the AUC of change to baseline in infiltrate thickness was demonstrated. Both medications were well tolerated. Overall, Mometasone cream and the mometasone comparator showed similar efficacy and tolerability. Mometasone cream, in addition to its high potency and good tolerability, provides the properties of a light cream, which might make this new medication particularly suitable for application on acutely inflamed and sensitive skin.

Using a novel wound model to investigate the healing properties of products for superficial wounds.

OBJECTIVE: To establish a new wound model that can induce uniform abrasions and use it to assess the healing properties of a range of products commonly applied to these wounds. METHOD: Ten healthy volunteers were enrolled into an open-label, randomised, intra-individual comparison pilot study. Five standardised, superficial abrasions were induced on their forearms by repeatedly scrubbing the skin with a surgical brush until the first signs of uniform glistening and punctuate bleeding were observed. Three products that promote a moist wound environment (polyurethane, hydrocolloid, hydrogel) and two standard plasters were randomly allocated to the test areas. RESULTS: Evaluation of wound healing on days 2, 5, 8 and 14 +/- 1 showed best results for the polyurethane and hydrocolloid plasters. Visible re-epithelialisation was recorded on days 5 and 8. More than 50% of the wound area had closed. Video microscope images support these findings. The investigator and volunteers assessed cosmetic outcomes on day 31 +/- 2. Best results were obtained for the polyurethane and hydrocolloid products, which had high mean scores close to the maximum of 10. Histological examination of biopsies taken from the abrasions of two volunteers showed the dermis remained intact, making the model highly suitable for the study of superficial wounds. CONCLUSION: Uniform and identical standardised wounds created using an abrasive brush technique can be used to reliably detect differences in the performance of plasters intended for superficial wounds. In general, products that promote a moist wound environment produced better results than those that promote a dry wound environment, with an earlier onset of healing and better healing outcomes. Superficial cutaneous wounds treated with polyurethane or hydrocolloid products demonstrated superior rates of re-epithelialisation and overall cosmetic outcomes. DECLARATION OF INTEREST: This study was funded by Beiersdorf AG. Neither author has any interest in the sponsor's commercial activities.

Prognostic value of haemoglobin levels during concurrent radio-chemotherapy in the treatment of oesophageal cancer.

AIMS: To evaluate the prognostic value of haemoglobin levels during radio-chemotherapy for overall survival, metastases-free survival (MFS) and locoregional control in patients with locally advanced oesophageal cancer. MATERIALS AND METHODS: Age, gender, performance status, tumour location, tumour length, histology, histologic grading, T-stage, N-stage, UICC-stage and weekly haemoglobin levels during concurrent radio-chemotherapy were retrospectively investigated and related to outcome in 108 patients, who received radio-chemotherapy for stage II/III oesophageal cancer. Radio-chemotherapy consisted of 59.4-60 Gy irradiation, two to four courses of cisplatin (75 mg/m2 on day 1) and 5-fluorouracil (1000 mg/m2 on days 1-5). Haemoglobin levels during radio-chemotherapy were compared among the following three groups: patients with over 60% of haemoglobin levels less than 12 g/dl; patients with over 60% of haemoglobin levels at 12-14 g/dl; and patients with over 60% of haemoglobin levels greater than 14 g/dl. RESULTS: On univariate analysis, haemoglobin levels of 12-14 g/dl and greater than 14 g/dl during concurrent radio-chemotherapy provided better outcomes than haemoglobin levels less than 12 g/dl. The 2-year overall survival rates were 34%, 35% and 16%, respectively (P = 0.002). The 2-year MFS survival rates were 23%, 46% and 21%, respectively (P = 0.06). The 2-year locoregional control rates were 44%, 58% and 19%, respectively (P < 0.001). ECOG performance status (1 better than 2-3) was significantly associated with overall survival (P = 0.013), tumour length (<7 cm better than > or = 7 cm) with overall survival (P = 0.002) and MFS (P = 0.002), N-stage (N0 better than N1) with overall survival (P = 0.004) and MFS (P < 0.001), and UICC-stage (stage II better than III) with overall survival (P = 0.025) and MFS (P = 0.010). On multivariate analysis, haemoglobin levels during radio-chemotherapy maintained significance for overall survival (P = 0.002) and locoregional control (P < 0.001), tumour length for overall survival (P = 0.002) and MFS (P = 0.008), and N-stage for MFS (P = 0.003). CONCLUSIONS: Haemoglobin during radiotherapy and concurrent radio-chemotherapy is an independent prognostic factor in oesophageal cancer treatment. To improve outcome, it seems important to maintain the haemoglobin at 12-14 g/dl.

Solid phantom material for the dosimetry of iodine-125 seed ophthalmic plaques.

PURPOSE: A tissue-equivalent solid phantom material, RE-1, closely simulating the radiological attenuation and scattering properties of the human eye for the iodine-125 photon spectrum and their Compton-scattered secondary photons, was fabricated on a polyethylene base with CaCO3 and MgO as inorganic additives. METHODS AND MATERIALS: A 24 mm diameter spherical phantom was made from 1.1 mm thick sheets of RE-1, and holes were drilled in which 1 mm3 TLD cubes were placed. RESULTS: The radial dose function g(r), which determines the dose profile on the transverse axis, was measured in a quasi-infinite phantom of RE-1. CONCLUSION: The values obtained deviate only slightly from those for a quasi-infinite phantom made from water-equivalent material.

Dosimetry and physical treatment planning for iodine eye plaque therapy.

The dosimetry of eye plaques loaded with iodine-125 seeds (type 6702) was performed by means of computer calculations and measurements with thermoluminescent dosimeters (TLD). Measurements of the depth dose distribution (2-25.5 mm) along the transverse axis of a single seed were performed in water equivalent phantom material. The transverse axis attenuation and geometry factor F(r) was obtained by applying a least squares fit to the measured data. Based on the resulting radial dose function, a computer program was developed which calculates dose distributions within the eye for arbitrary loading and placement of the eye plaque. The computational results were verified by TLD measurements in an eye phantom.

Autoradiography for iodine-125 seeds.

To study the interior design of model 6702 and 6711 iodine-125 seeds contact autoradiographs were performed using mammography film. Improved resolution was obtained using a pin-hole camera with a hole of 0.1 mm x 0.1 mm. With these techniques, qualitative determination of the relative activity distribution within each seed was possible. The number of the activated resin spheres and the positions of the centers of these spheres can be exactly determined. A model calculation shows, that variations in the arrangement of the activated spheres within a seed have a moderate influence on the dose distribution at source distances below 10 mm. Knowing the exact source configuration may be useful when comparing dose calculations with measured data for model 6702 125I seeds which are currently employed in ophthalmic plaque and implant therapy of other tumors.

Changes in S-phase fraction and micronucleus frequency as prognostic factors in radiotherapy of cervical carcinoma.

Twenty-five patients with cervical carcinoma were treated with combined external beam and high dose rate afterloading radiotherapy. Biopsies obtained at different time points in the course of therapy were analysed with respect to cell proliferation and cytogenetic damage. The fraction of cells with an S-phase DNA-content as well as the frequency of micronuclei were determined. These two parameters were then related to treatment outcome, in particular patient survival. Neither S-phase fraction nor the micronucleus frequency before radiotherapy were predictive of treatment outcome in this small group of patients. However, when changes in response to therapy were considered, patients whose S-phase fraction decreased and patients whose micronucleus frequency increased tended to have a better prognosis. Although statistical significance was not achieved with either criterion alone, when applied together the combination predicted patient survival quite reliably; the 5-year survival rate of those patients who showed a decrease in S-phase fraction as well as an increase in micronucleus frequency was about 90% in contrast to less than 30% for the non-responders (p < 0.03).

Quantification of late complications after radiation therapy.

BACKGROUND: An increasing number of patients survive cancer after having received radiation therapy. Therefore, the occurrence of late normal tissue complications among long-term survivors is of particular concern. METHODS: Sixty-three patients treated by radical surgery and irradiation for rectal carcinoma were subjected to an unconventional sandwich therapy. Preoperative irradiation was given in four fractions of 5 Gy each applied within 2 or 3 days; postoperative irradiation consisted mostly of 15 x 2 Gy (range, 20-40 Gy). A considerable proportion of these patients developed severe late complications (Radiother Oncol 53 (1999) 177). The data allowed a detailed analysis of complication kinetics, leading to a new model which was tested using data from the literature. RESULTS: Data on late complications were obtained for eight different organs with a follow-up of up to 10 years. For the various organs, the percentage of patients being free from late complications, plotted as a function of time after start of radiation therapy, was adequately described by exponential regression. From the fit, the parameter p(a) was obtained, which is the percentage of patients at risk in a given year of developing a complication in a given organ during that year. The rate p(a) remained about constant with time. Following sandwich therapy, the annual incidence of complications in the bladder, ileum, lymphatic and soft tissue, and ureters was about the same (p(a)=10-14%/year), whereas complications in bone or dermis occurred at lower rates (4.7 or 7.5%/year, respectively). DISCUSSION: Numerous data sets collected from published reports were analyzed in the same way. Many of the data sets studied were from patients in a series where there was a high incidence of late effects. Three types of kinetics for the occurrence of late effects after radiotherapy were identified: Type 1, purely exponential kinetics; Type 2, exponential kinetics, the slope of which decreased exponentially with time; Type 3, curves composed of two components, a fast initial decline followed by an exponential decrease. For each kind of kinetics, provided that the dose distribution is not too heterogeneous, the incidence of late effects appears to occur at exponential or approximately exponential kinetics, even many years after treatment. This implies that a random process might be involved in the occurrence of late radiation sequelae. CONCLUSIONS: There might be a lifelong risk of developing late complications, of which patients and clinicians should be aware. It appears worthwhile to try to identify, in follow-up examinations of patients after radiation therapy, what kind of processes might be involved in triggering subclinical residual injury to develop into a clinically manifest late effect.

Late complications after a combined pre and postoperative (sandwich) radiotherapy for rectal cancer.

BACKGROUND AND PURPOSE: The purpose of this study was to analyse the treatment related side effects, the outcome and the prognostic significance of clinical parameters in two groups of patients with rectal cancer receiving either preoperative or pre and postoperative radiotherapy after radical resection. The authors of this study were not involved in the radiation treatments. PATIENTS AND METHODS: From 1986 to 1990, 63 patients received a combined pre and postoperative (sandwich) radiotherapy. Preoperative irradiation was given in four fractions of 5 Gy each applied within 2 or 3 days. Postoperative irradiation consisted mostly of 15 x 2 Gy (31 patients) but the range was 20-40 Gy. The results were compared with those on 73 patients who only received preoperative radiotherapy in the same time period. The distribution of prognostic factors was not very different between treatment groups. Out of 63 patients in the sandwich group, 22 received concurrent chemotherapy and 18 also received radiotherapy to the liver. Radical surgery usually followed on the day after the last preoperative radiotherapy session. Median follow-up of survivors was 6 years. RESULTS: Local tumour control was 88% after 5 years and 84% after 8 years in the sandwich group, and 90 and 85%, respectively, in the preoperative radiotherapy group. Thus, tumour control was similar for the two radiotherapy regimens applied. However, the percentage of patients suffering from one or more complications after 5 years was 84% in the sandwich and 17% in the preoperative radiotherapy group. The incidence of severe late complications (grade > or = 3) was recorded as a function of time after start of treatment. In the sandwich group the actuarial rates of late complications at 5 years (and the median time to diagnosis) were 53% (27 months) for anorectum, 43% (37 months) for bladder, 28% (51 months) for bone, 19% (36 months) for dermis, 47% (48 months) for ileum, 41% (32 months) for lymphatic and soft tissue, and 44% (53 months) for ureters. CONCLUSIONS: Severe late reactions did not occur within a certain period of time, but continued to appear for at least 10 years after radiotherapy. Sandwich therapy, as given in this series, did not appear to give a greater tumour control than preoperative radiotherapy alone, whereas the rate of complications was drastically enhanced. Thus, the rationale of a sandwich therapy with a long time interval between surgery and postoperative irradiation appears questionable.

Influence of dose per fraction and overall treatment time on the response of pulmonary micrometastases of the R1H-tumour to fractionated irradiation.

BACKGROUND AND PURPOSE: Macroscopic subcutaneously growing R1H-tumours have been shown to respond almost independently of the dose per fraction when treated under ambient conditions. In addition decelerated repopulation during fractionated irradiation has been shown for this experimental tumour. The aim of the present study was to investigate whether this is also the case for pulmonary micrometastases which are assumed to be fully oxygenated or whether differences in the oxygenation status of the tumour possibly alters its response to fractionation. The influence of the dose per fraction and overall treatment time on the response of micrometastases to fractionated irradiation was studied. MATERIALS AND METHODS: Pulmonary metastases were induced by i.v. injection of viable tumour cells. Treatment was started 14 days later, when metastases reached an average size of four cells. Total doses of 16 to 28 Gy were administered within an overall treatment time of 11 or 25 days, using doses per fraction of 1, 2, or 4 Gy. Tumour response was quantified by metastatic control (MCD(37%)). RESULTS: Fractionation had a significant influence on local control (P=0.009). After application of 1, 2, or 4 Gy and an overall treatment time of 11 days the MCD(37%) was 25.4 (95% C.I.: 21.5-32.0) Gy, 20.7 (17. 0-24.0) Gy, and 18.5 (14.9-21.6) Gy, respectively. When overall treatment time was prolonged to 25 days the MCD(37%) increased to 25. 5 (21.3-33.5) Gy when fractions of 2 Gy where applied, but this difference was not significant (P=0.13). The doubling time of 12.8 days determined for the metastatic clonogenic tumour cells during fractionated irradiation was significantly longer than the 4.1 days observed for untreated metastases (P=0.006). CONCLUSIONS: The results show a strong influence of fractionation on treatment outcome and a decelerated repopulation during fractionated irradiation treatment for well oxygenated pulmonary metastases of the R1H-tumour.

Complications associated with brachytherapy alone or with laser in lung cancer.

Relatively little has been reported about destruction through brachytherapy of mucosa-perforating and extraluminary tumors with probable large vessel involvement causing major hemorrhagic or fistular complications. We report 12 patients subjected to laser and brachytherapy for centrally occluding lung cancer, whom we have periodically followed up from June 1986 until they died. Although all laser procedures were free from complications, necrotic cavitation in five cases, two of which were accompanied by large bronchoesophageal fistulas, and massive fatal hemoptysis occurred in six. Minor complications included radiation mucositis (two), noncritical mucosal scarring (two), and cough (four). Characteristics that will identify patients at risk of developing fatal hemoptysis and fistulas should be better defined by imaging and endoscopic techniques. In such cases, modifying the protocol or using alternative procedures should be considered. Minor complications, such as cough, can be avoided by using topical steroid therapy (eg, beclomethasone dipropionate).

Self-application of a protective cream. Pitfalls of occupational skin protection.

OBJECTIVES: To determine if a protective cream (PC) is adequately applied to the hands by workers in several occupations and to quantify what areas are covered or missed. DESIGN: Prospective diagnostic study. SETTINGS: Metalworking factory, construction sites, and university hospital. PARTICIPANTS: One hundred fifty healthy volunteers (50 from each setting) were recruited for a questionnaire interview and typical self-application of a PC. INTERVENTION: None. MAIN OUTCOME MEASURE: Percentage of sufficient cover with PC as assessed with fluorescence under Wood light. RESULTS: Many areas were skipped when viewed under Wood light. The application of PC was incomplete, especially on the dorsal aspects of the hands. CONCLUSION: Individuals should be made aware of the most commonly missed regions to ensure complete skin protection. This simple method is a useful adjunct to quantify self-application and in worker education.

Interstitial high dose rate brachytherapy in locally progressive or recurrent head and neck cancer.

In a retrospective study, 19 patients with progressive or recurrent head and neck cancer which had been treated with interstitial high dose rate brachytherapy were analysed. All of them had been previously treated with external radiation. Initial therapy further included surgery in 9 cases and chemotherapy in 3 patients. Staging according to the TNM system revealed advanced stage tumors in the majority of patients. Interstitial brachytherapy was carried out with the isotope Iridium-192. The applied total dose at the reference isodose varied between 10 and 30 Gy. Application was fractionated once a week. A complete tumor remission was achieved in 5 patients and partial remission in 10 patients. In 4 patients the tumor continued to grow despite brachytherapy. The mean follow-up in our collective was 21 months. The calculated local control rate was 34% at 24 months. The survival rate was 49% at 12 months and 35% at 24 months. Interstitial brachytherapy is recommended as a palliative treatment in preirradiated squamous cell carcinoma with local recurrence or progression.