Treatment of anthracycline extravasation with Savene (dexrazoxane): results from two prospective clinical multicentre studies.

BACKGROUND: The purpose of this study was to assess the efficacy and tolerability of i.v. dexrazoxane [Savene (EU), Totect (US)] as acute antidote in biopsy-verified anthracycline extravasation. PATIENTS AND METHODS: Two prospective, open-label, single-arm, multicentre studies in patients with anthracycline extravasation were carried out. Patients with fluorescence-positive tissue biopsies were treated with a 3-day schedule of i.v. dexrazoxane (1000, 1000, and 500 mg/m(2)) starting no later than 6 h after the incident. Patients were assessed for efficacy (the possible need for surgical resection) and toxicity during the treatment period and regularly for the next 3 months. RESULTS: In 53 of 54 (98.2%) patients assessable for efficacy, the treatment prevented surgery-requiring necrosis. One patient (1.8%) required surgical debridement. Thirty-eight patients (71%) were able to continue their scheduled chemotherapy without postponement. Twenty-two patients (41%) experienced hospitalisation due to the extravasation. Mild pain (10 patients; 19%) and mild sensory disturbances (nine patients; 17%) were the most frequent sequelae. Haematologic toxicity was common as expected from the fact that the extravasation occurred during a chemotherapy course. Other toxic effects were transient elevation of alanine aminotransferases, nausea, and local pain at the dexrazoxane injection site. CONCLUSION: Dexrazoxane proved to be an effective and well-tolerated acute treatment with only one out of 54 assessable patients requiring surgical resection (1.8%).

[Rheumatic fever behind acute chorea in a young girl. A case report]. / Reumatisk feber bakom hastigt påkommen korea hos ung flicka. En fallbeskrivning.

This article presents the case of a 13-year old girl who was admitted to the emergency department because of rapidly evolving, seriously disabling impairments in movement and speech. Investigation led to the conclusion that her problems were caused by Sydenham's chorea as a manifestation of rheumatic fever. A neuropsychiatric examination performed one year after the onset of disease revealed a hitherto unknown mild mental retardation. The case description is followed by a clinical update on rheumatic fever focusing on cerebral manifestations. The theories concerning the existence of PANDAS--an autoimmune neuropsychiatric disorder following streptococcal infections, distinct from rheumatic fever--are presented.

Alcohol dehydrogenase 3 genotype is not associated with risk of squamous cell carcinoma of the oral cavity and pharynx.

Alcohol is one of the major risk factors for oral and pharyngeal cancer. The rate-limiting step in alcohol metabolism is the oxidation (activation) of ethanol to acetaldehyde by the alcohol dehydrogenases (ADHs). It has been hypothesized that individuals who are homozygous for the fast allele (ADH(1-1)(3)) are at greater risk for alcohol-related cancers. To test this hypothesis, we investigated the association between the ADH3 genotype and oral and pharyngeal cancer risk in a large racially homogeneous case-control study of 229 patients and 575 matched control subjects with frequency matching on age, sex, and smoking status. Although the smoking status was matched between cases and controls, current and former alcohol use remained a significant risk factor, compared with never use (odds ratio, 2.08; 95% confidence interval, 1.37-3.17; odds ratio, 1.97; 95% confidence interval, 1.25-3.09; and odds ratio, 1.00, respectively). The ADH1(3) allele frequency of controls was 57.4%, consistent with reports of similar racial groups (50-60%). The genotype distribution in controls was also consistent with the Hardy-Weinberg equilibrium (P = 0.51). However, the ADH1(3) allele frequency and ADH(1-1)(3) genotype frequency were not significantly different between cases and controls [55.5% versus 57.4% (P = 0.52), and 30.6% versus 31.3% (P = 0.91), respectively]. There was no association between ADH3 genotypes (ADH(1-1)(3), ADH(1-2)(3), and ADH(2-2)(3)) and risk of oral and pharyngeal cancer (odds ratios, 1.00; 0.96; 95% confidence interval, 0.68-1.37; and odds ratio, 1.23; confidence interval, 0.78-1.93, respectively). Therefore, we found no evidence that supports a main effect of ADH3 genotype or a combined effect of alcohol and ADH3 genotype on risk of cancer of the oral cavity or pharynx.

The role of growth hormone in adaptation to massive small intestinal resection in rats.

The residual small bowel undergoes profound adaptive alterations after surgical resection. GH is considered to have a role in regulation of these adaptive changes, but its precise role is unknown. We investigated the role of GH by studying the response to intestinal resection in rats with isolated GH deficiency. Spontaneous dwarf rats, a strain of rats with congenital isolated GH deficiency, underwent 60% resection of the small intestine and parameters of the response of the intestinal remnant were compared with age-matched GH-deficient rats undergoing transection, GH-normal rats undergoing 60% resection, and nonmanipulated GH-normal rats. Deficiency of GH did not inhibit hyperplasia of the mucosal mass of the intestinal remnant, indicating that GH is not required for regulation of this aspect of the adaptive response. However, GH deficiency resulted in lack of accumulation of mucosal protein, including lack of accumulation of digestive hydrolases. In addition, GH deficiency resulted in alterations in processing of digestive hydrolases of the distal intestine, indicating that GH may have region-specific effects on small intestinal function. We conclude that GH is required for the normal expression of specific components of the adaptive response to massive small intestinal resection, but not for all aspects. The aspects that require GH appear to involve protein synthesis and processing.

Tumor infiltrating lymphocytes in melanoma comprise high numbers of T-cell clonotypes that are lost during in vitro culture.

Melanoma is generally accepted as being an antigenic tumor capable of eliciting T-cell responses that, however, in most cases are inadequate to control tumor growth. Tumor-infiltrating lymphocytes (TIL) in melanoma lesions comprise clonotypic T cells, indicating the in situ recognition of melanoma-associated peptide epitopes. Cultured TIL have been studied in order to unveil characteristics of TIL and the interactions of TIL and melanoma cells. Whether in vitro cultured TIL mirrors the in situ situation has, however, been questioned. In the present study we have taken advantage of T-cell receptor clonotype mapping methodology to conduct a full and detailed analysis of the T-cell clonotypes in melanoma lesions and in corresponding lines of TIL established in vitro. All melanoma lesions and the corresponding TIL cultures comprised high numbers of T-cell clonotypes, typically in the range of 40 to more than 60. The subsequent comparison of T-cell clonotypes present in the original lesions and in the corresponding T-cell lines established in vitro demonstrated that a very limited number of the T-cell clonotypes established in vitro are identical to the T-cell clonotypes expanded in situ. These results demonstrate that in situ T-cell clonotypes in melanoma are not readily expanded in vitro and that the majority of T-cell clonotypes present in cultured TIL are not present in situ.

[Primary breast reconstruction in connection with mastectomy for breast cancer. Indication, procedure and immediate surgical results]. / Primaer brystrekonstruktion i forbindelse med mastektomi ved mammacancer. Indikation, procedure og umiddelbare operative resultater.

Mastectomy and immediate reconstruction of 122 breasts were performed in 109 patients in close collaboration between plastic surgeons and general surgeons. In 56 patients reconstruction was performed using tissue expanders including 13 bilateral operations, 29 patients had a latissimus dorsi myocutaneous flap and 24 a free transverse rectus abdominis myocutaneous flap. There were 27 postoperative local complications in 122 reconstructions (22%), in five the reconstruction was lost. Only patients clinically in stage I were considered for reconstruction. After histopathological staging 27 patients received systemic treatment and 10 local radiotherapy as well. There was no complication during systemic therapy related to reconstruction. In 10 cases local radiotherapy was performed in full, with a delay of four weeks in one patient and a need for correction of the radiation field during treatment in one patient.

[Help to children and adolescents with malnutrition or eating disorders. Percutaneous endoscopic gastrostomy with button: simple, safe and cost-effective]. / Hjälp för barn och ungdomar med malnutrition eller ätstörning. Perkutan endoskopisk gastrostomi och knapp enkelt, säkert och billigt.

Percutaneous endoscopic gastrostomy (PEG) has gained great popularity for children with malnutrition and eating disorders secondary to chronic illness. However, the procedure is not without risks. We report on 62 infants and children, median age 4 years (1 month-20 years), who underwent PEG placement. Cerebral palsy with or without mental retardation was the most common diagnosis (50%). No complications related to the PEG procedure itself occurred, but postoperative pneumonia was seen in 10%. Late complications were few: intraperitoneal migration of the button in one child and prolapse of the stoma in another. At the time of button placement, after median 14 weeks, mean weight had increased from a standard deviation score of -2.7 to -2.2 (P < 0.001). We consider PEG to be a safe procedure for children with malnutrition requiring enteral feeding. Due to potential risks and complications related to this method, a multidisciplinary approach, as found in a "nutritional support team", is recommended.

Use of fluorine-18 fluorodeoxyglucose positron emission tomography in the detection of silent metastases from malignant melanoma.

Correct staging is crucial for the management and prognosis of patients with malignant melanoma. The aim of this prospective study was to compare staging by whole-body positron emission tomography using fluorine-18 fluorodeoxyglucose (18F-FDG) with staging by conventional methods. Thirty-eight patients with malignant melanoma of clinical stage II (local recurrence, in-transit and regional lymph node metastases) or III (metastases to other sites than in stage II) were included in the study. The results of the PET scans were compared with those obtained by clinical examination, computed tomography, ultrasound, radiography, and liver function tests and histology or clinical follow-up. With 18F-FDG PET we found for all foci a sensitivity of 97% and a specificity of 56%, compared with 62% and 22%, respectively, when using routine methods. For intra-abdominal foci, the sensitivity and specificity were 100% for both 18F-FDG PET and routine methods. Corresponding figures for pulmonary/intrathoracic foci were 100% and 33%, respectively. Of the patients included in this study, 34% would not have been staged correctly by conventional methods alone. We conclude from this study that 18F-FDG PET is a sensitive method superior to conventional methods for detecting widespread metastases from malignant melanoma. Mutilating surgery of no benefit can thereby be avoided. 18F-FDG PET is useful as a supplement to clinical examination in melanoma staging.

[Sentinel node biopsy in cutaneous malignant melanoma of the lower extremities]. / "Sentinel node"-biopsi ved kutant malignt melanom på underekstremiteterne.

Although a substantial number of patients with intermediate thickness cutaneous malignant melanoma (> 1.5-4 mm) have non-detectable regional node metastases, elective regional node dissection still remains controversial. One-three specific lymph node(s)--sentinel node(s)--in the first drained regional lymphatic basin can be visualised peroperatively by applying Patent V Blue intradermally at the site of the previous melanoma. Histological examination of the sentinel node can reveal metastases and therefore presumably give a more accurate oncological staging, thus enabling selection of patients who may benefit from elective regional node dissection. The aim of the present study was to describe our experience with this technique in 23 patients treated for cutaneous malignant melanoma of the lower extremity with a thickness > 1.5 mm. We found that sentinel node dissection, through a minimal surgical procedure, was efficient in detecting micrometastases in the regional lymph node(s).

[Sentinel node diagnostics in malignant melanoma]. / "Sentinel node"-diagnostik ved malignt melanom.

New trial have shown that immediate regional lymph node dissection offers increased survival in patients with regional lymph node metastases only. Introduction of isotope technique to identify the first node, the sentinel node (SN), receiving lymph from a tumour area has made it possible to avoid node dissection in SN metastasis negative patients. The feasibility of the technique is illustrated by to examples.

One-week treatment with omeprazole, clarithromycin, and metronidazole in children with Helicobacter pylori infection.

BACKGROUND: The efficacy of a 1-week "triple therapy" in children with Helicobacter pylori gastritis and recurrent abdominal pain was studied. The effect of treatment was also studied in correlation to recurrent abdominal pain. METHODS: Thirty-two children with recurrent abdominal pain were investigated with H. pylori serology, 13C-urea breath test, and endoscopy. Gastric biopsy specimens were analyzed with a rapid urease test and histopathology. H. pylori-positive children were treated with omeprazole, clarithromycin, and metronidazole for 7 days. The same treatment was repeated for 2 weeks if a urea breath test produced positive results 1 month after the treatment period. If the test results were still positive after treatment, a second endoscopy was performed with culture. RESULTS: Twenty-eight (87.5%) children were urea breath test-negative at follow-up 4 weeks (range, 4-15) after treatment. Another child became H. pylori-negative after a second treatment course. Two of the three children who were still positive after the two treatment periods, showed resistance to metronidazole and clarithromycin. CONCLUSIONS: One-week therapy with omeprazole, clarithromycin and metronidazole is an effective treatment in children with H. pylori infection. Bacterial resistance to clarithromycin and metronidazole must be monitored if treatment fails.

Effect of grapefruit juice on urinary 6 beta-hydroxycortisol/cortisol excretion.

1. The aim of the present study was to evaluate the effect of grapefruit juice on urinary 6 beta-hydroxycortisol and cortisol excretion in healthy subjects. 2. The ratio of 6 beta-hydroxycortisol/cortisol was significantly decreased (P = 0.036) in the 0-4 h fraction of urine after ingestion of grapefruit juice, but not in the 4-24 h fraction (P = 0.218) or for the compiled data, fraction 0-24 h (P = 0.114). 3. These results indicate that endogenous cortisol metabolism may not only be of hepatic origin, but may also be dependent on the metabolic capacity of cytochrome P450 IIIA (CYP3A) in the gut mucosa. 4. This finding may cast further doubts of the usefulness of the 6 beta-hydroxycortisol/cortisol ratio as an indicator of hepatic CYP3A activity.

Skin temperature of UV-induced erythema correlated to laser Doppler flowmetry and skin reflectance measured redness.

BACKGROUND/AIMS: The sensitivity of human skin to UV radiation is investigated by visual grading of the resulting erythema reactions 24 h after exposure to a series of increasing UV doses. Visual erythema assessment is, however, subjective and depends on pigmentation and redness of the adjacent un-irradiated skin and can be aided by skin reflectance spectroscopy and laser Doppler blood flow measurements. Erythema is accompanied by a raised skin temperature, and this reaction might be utilised as a simple objective measurement of UV sensitivity. METHODS: Sixteen patients with cutaneous malignant melanoma, 16 patients with basal cell carcinoma, and 36 healthy people were phototested with simulated sunlight on previously UV un-exposed buttock skin. The resulting erythema reactions were graded visually 20-24 h post-exposure and measured by skin reflectance spectroscopy and laser Doppler flowmetry, and the surface skin temperature was determined in the erythema reactions and in adjacent un-irradiated skin by a contact thermometer. RESULTS: Skin surface temperature in UV-induced erythema reactions was dose dependent, was statistically identical in skin cancer patients and in healthy people, and was age independent. The average temperature increase in barely perceptible erythema was 0.7°C (SD=1.1°C), and in bright red erythema it was 3.5°C (SD=2.0°C). Skin surface temperature increases were correlated to measurements by skin reflectance spectroscopy and by laser Doppler flowmetry. CONCLUSIONS: Skin surface temperature changes can be used as a simple objective measurement of UV sensitivity in healthy people and in skin cancer patients and may be particularly useful in heavily pigmented people where visual assessment of erythema is difficult or impossible.

Epidermal thickness, skin pigmentation and constitutive photosensitivity.

The important factors for UV sensitivity in humans are considered to be the skin pigmentation and the epidermal thickness. In this study on 73 Caucasians (age 20-85 years), we investigated in UV unexposed buttock skin the relationship between the UV sensitivity and constitutive skin pigmentation and thickness of the stratum corneum and the cellular part of the epidermis, in 34 normal people and in 39 skin cancer patients (20) patients with cutaneous malignant melanoma and 19 patients with basal cell carcinoma of the skin). Skin pigmentation was measured by skin reflectance spectroscopy, and UV sensitivity by phototest with a solar simulator. Thicknesses of the stratum corneum and the cellular part of the epidermis were determined by light microscopic evaluation of skin biopsies from the phototest areas. We found that epidermal thickness was independent of skin type and was not correlated to constitutive skin pigmentation. Thickness of the stratum corneum was statistically not different in normal persons and in skin cancer patients (P = 0.41) and was independent of gender (P = 0.61) and age (P = 0.56), while thickness of the cellular epidermis decreased with age (P < 0.01). Stratum corneum thickness was found to be of minor importance for the constitutive UV sensitivity (accounting for on average 11% of the total photoprotection), which was mainly determined by the constitutive skin pigmentation (goodness-of-fit for correlation r = 0.83). A theoretical model for the relationship of UV dose to induction of clinical erythema grade and skin pigmentation and thickness of the stratum corneum was developed. Objective measurements of skin pigmentation in UV unexposed skin by skin reflectance spectroscopy in Caucasians, normal people and people with cutaneous malignant melanoma and basal cell carcinoma of the skin predicts the constitutive UV sensitivity with a high degree of precision.

Pharmacokinetics and systemic effects of inhaled fluticasone propionate in healthy subjects.

AIMS: The present study was undertaken to see whether the difference in plasma cortisol suppression between single and repeated dosing of fluticasone propionate (FP) can be explained by systemic accumulation. METHODS: Twelve healthy subjects (six women) were given, in a crossover fashion, a single dose inhalation (1000 micrograms) of FP via Diskhaler and repeated inhalations (1000 micrograms twice daily) every 12 h during 7 days. There was a washout period of 2 weeks between the treatments. An intravenous dose of 20 micrograms FP was given as a reference. Plasma concentrations of FP for each treatment were determined by liquid chromatography plus tandem mass spectrometry. Plasma cortisol after the inhaled doses was determined using an immunoassay and was compared with baseline values. RESULTS: The average plasma concentration of FP was about 1.7 times higher after multiple inhalations than after a single dose. Systemic availability, mainly attributable to pulmonary deposition, was 15.6 [13.6-18.0]% of the nominal dose. Daytime plasma cortisol suppression vs baseline was 47 [20-65]% and 95 [93-97]% for the single and repeated doses, respectivley. CONCLUSIONS: To conclude, a slow elimination of FP leads to accumulation during repeated dosing. This accumulation may explain the marked decrease in plasma cortisol seen during treatment with fluticasone propionate within the clinical dose range.

The yeast site-specific recombinase Flp mediates alcoholysis and hydrolysis of the strand cleavage product: mimicking the strand-joining reaction with non-DNA nucleophiles.

The yeast site-specific recombinase Flp is covalently linked to DNA via a 3'-phosphotyrosyl bond during the strand-breakage step of recombination. We show that this phosphotyrosyl diester bond formed between Flp and DNA can serve as the target for alcoholysis or hydrolysis in an Flp-assisted reaction. Flp does not mediate alcoholysis of the labile phosphodiester bond within the DNA chain under our assay conditions. The body of available evidence supports the notion that the alcoholysis/hydrolysis reaction is mechanistically analogous to the strand-joining step of the recombination pathway. The only difference is that the DNA 5'-hydroxyl group that acts as the nucleophile during recombination is substituted by a non-DNA nucleophile. We find that the alcoholysis reaction occurs only within the normal cleavage complex produced by the "shared active site" assembled at the interface of two Flp monomers. Unlike the strand-joining reaction, alcoholysis does not occur on an activated DNA substrate linked at its 3'-phosphate end to a short tyrosyl peptide (not to the full-length Flp), and bound non-covalently by a Flp monomer. However, even in this substrate that mimics the strand-cleaved state, the joining reaction is competitively inhibited by a polyhydric alcohol such as glycerol.