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PubMed2004

Microarray analysis to identify molecular mechanisms of radiation-induced microvascular damage in normal tissues.

PURPOSE: Radiation-induced vascular injury can be a serious problem for cancer survivors. In capillary vessels, this manifests as telangiectasia, causing cosmetic problems when occurring in the skin and more serious problems, e.g. excessive bleeding requiring surgery, when occurring in rectal or bladder mucosa. In addition, thrombotic, inflammatory, and fibrogenic events play an important role in the development of late radiation injury in many tissues. However, the sequence of these events and the relationship between various mechanistic pathways is unclear. The purpose of this project is to identify genes that are differentially expressed in tissues with manifest vascular damage, with the ultimate goal of intervening in this process to block the progressive development of tissue injury. METHODS AND MATERIALS: Microarray experiments were performed using amplified RNA isolated from irradiated mouse kidney and rectum, and from sham-irradiated controls, at 10 and 20 weeks after treatment. Tissue samples were also taken for histologic evaluation of vascular damage at 10, 20, and 30 weeks after irradiation. Expression profiles for irradiated and sham-irradiated samples were compared, and differentially expressed genes were identified after normalization procedures, using information from straight color, color reverse, and self-self experiments. The extent of overlap in expression profiles for kidney and rectum during the phase of vascular damage was also examined. RESULTS: The mouse kidney experiments showed upregulation of 31 genes at 10 weeks and 42 upregulated genes at 20 weeks. Only 20 genes showed significantly increased expression at both time points. Some of these genes were of particular interest in terms of their known involvement in vascular injury and signal transduction pathways. Irradiated mouse rectum had 278 upregulated genes at 10 weeks and 86 upregulated genes at 20 weeks. Only 19 of the genes upregulated during the period of identified telangiectasia (10-20 weeks) were common to both tissues. These included jagged 1 and Kruppel-like factor 5 (KLF5), which are reported to play a role in vascular development and remodeling. CONCLUSIONS: Microarray analysis of RNA from irradiated normal tissues is an effective tool for identifying new genes of potential interest in the development of late tissue injury. Such experiments should be regarded as generating testable hypotheses for mechanisms of radiation-induced injury.

Animals↗
PubMed2005

TLD skin dose measurements and acute and late effects after lumpectomy and high-dose-rate brachytherapy only for early breast cancer.

PURPOSE: This report examines the relationships between measured skin doses and the acute and late skin and soft tissue changes in a pilot study of lumpectomy and high-dose-rate brachytherapy only for breast cancer. METHODS AND MATERIALS: Thirty-seven of 39 women enrolled in this pilot study of high-dose-rate brachytherapy (37.2 Gy in 10 fractions b.i.d.) each had thermoluminescent dosimetry (TLD) at 5 points on the skin of the breast overlying the implant volume. Skin changes at TLD dose points and fibrosis at the lumpectomy site were documented every 6 to 12 months posttreatment using a standardized physician-rated cosmesis questionnaire. The relationships between TLD dose and acute skin reaction, pigmentation, or telangiectasia at 5 years were analyzed using the GEE algorithm and the GENMOD procedure in the SAS statistical package. Fisher's exact test was used to determine whether there were any significant associations between acute skin reaction and late pigmentation or telangiectasia or between the volumes encompassed by various isodoses and fibrosis or fat necrosis. RESULTS: The median TLD dose per fraction (185 dose points) multiplied by 10 was 9.2 Gy. In all 37 patients, acute skin reaction Grade 1 or higher was observed at 5.9% (6 of 102) of dose points receiving 10 Gy or less vs. 44.6% (37 of 83) of dose points receiving more than 10 Gy (p < 0.0001). In 25 patients at 60 months, 1.5% telangiectasia was seen at dose points receiving 10 Gy or less (1 of 69) vs. 18% (10 of 56) telangiectasia at dose points receiving more than 10 Gy (p = 0.004). Grade 1 or more pigmentation developed at 1.5% (1 of 69) of dose points receiving less than 10 Gy vs. 25% (14 of 56) of dose points receiving more than 10 Gy (p < 0.001). A Grade 1 or more acute skin reaction was also significantly associated with development of Grade 1 or more pigmentation or telangiectasia at 60 months. This association was most significant for acute reaction and telangiectasia directly over the lumpectomy site (p < 0.001). Grade 1 or more fibrosis, in 25 patients with a 60-month follow-up, occurred in 47.4% (9 of 19) of patients with a volume of 45 cm3 or less covered by the 100% isodose vs. 83.3% (5 of 6) of patients with a larger volume (p = 0.180). Asymptomatic and biopsy-proven fat necrosis occurred in 5 patients. No significant differences in fat necrosis rates according to volume were detected. CONCLUSIONS: For high-dose-rate brachytherapy to the lumpectomy site, TLD skin dose was significantly related to acute skin reaction and to pigmentation and telangiectasia at 60 months. An acute skin reaction was also significantly associated with the development of telangiectasia at 60 months. TLD skin dose measurement may allow modification of the brachytherapy implant geometry (dwell times and position) to minimize late skin toxicity.

Adult↗
PubMed2006

Accelerated partial-breast irradiation using proton beams: initial clinical experience.

PURPOSE: We present our initial clinical experience with proton, three-dimensional, conformal, external beam, partial-breast irradiation (3D-CPBI). METHODS AND MATERIALS: Twenty patients with Stage I breast cancer were treated with proton 3D-CPBI in a Phase I/II clinical trial. Patients were followed at 3 to 4 weeks, 6 to 8 weeks, 6 months, and every 6 months thereafter for recurrent disease, cosmetic outcome, toxicity, and patient satisfaction. RESULTS: With a median follow-up of 12 months (range, 8-22 months), no recurrent disease has been detected. Global breast cosmesis was judged by physicians to be good or excellent in 89% and 100% of cases at 6 months and 12 months, respectively. Patients rated global breast cosmesis as good or excellent in 100% of cases at both 6 and 12 months. Proton 3D-CPBI produced significant acute skin toxicity with moderate to severe skin color changes in 79% of patients at 3 to 4 weeks and moderate to severe moist desquamation in 22% of patients at 6 to 8 weeks. Telangiectasia was noted in 3 patients. Three patients reported rib tenderness in the treated area, and one rib fracture was documented. At last follow-up, 95% of patients reported total satisfaction with proton 3D-CPBI. CONCLUSIONS: Based on our study results, proton 3D-CPBI offers good-to-excellent cosmetic outcomes in 89% to 100% of patients at 6-month and 12-month follow-up and nearly universal patient satisfaction. However, proton 3D-CPBI, as used in this study, does result in significant acute skin toxicity and may potentially be associated with late skin (telangiectasia) and rib toxicity. Because of the dosimetric advantages of proton 3D-CPBI, technique modifications are being explored to improve acute skin tolerance.

Aged↗
PubMed2006

Reduced late rectal mucosal changes after prostate three-dimensional conformal radiotherapy with endorectal balloon as observed in repeated endoscopy.

PURPOSE: The aim of this study was to investigate prospectively the rectal wall (Rwall) spatial dose distribution, toxicity, and mucosal changes after prostate cancer radiotherapy with or without an endorectal balloon (ERB). METHODS AND MATERIALS: A total of 24 patients with ERB and 24 without ERB (No-ERB) were treated with three-dimensional conformal radiotherapy (3D-CRT) to a dose of 67.5 Gy. The Rwall was divided into 16 mucosal areas and Rwall dose surface maps were constructed. After 3 months, 6 months, 1 year, and 2 years a rectosigmoidoscopy was performed, and each mucosal area was scored on telangiectasia, congestion, ulceration, stricture, and necrosis. Late rectal toxicity was correlated with the endoscopic findings. RESULTS: The ERB significantly reduced the Rwall volume exposed to doses >40 Gy. Late rectal toxicity (grade >or=1, including excess of bowel movements and slight rectal discharge) was reduced significantly in the ERB group. A total of 146 endoscopies and 2,336 mucosal areas were analyzed. Telangiectases were most frequently seen and appeared after 6 months. At 1 and 2 years, significantly less high-grade telangiectasia (T 2-3) was observed in the ERB group at the lateral and posterior part of the Rwall. In mucosal areas exposed to doses >40 Gy, less high-grade telangiectases (T 2-3) were seen in the ERB group compared with the No-ERB group. CONCLUSIONS: An ERB reduced the Rwall volume exposed to doses >40 Gy, resulting in reduction of late rectal mucosal changes and reduced late rectal toxicity. Although further analysis is needed, these data suggest an ERB-induced increased tolerance for late Rwall damage.

Gastrointestinal Hemorrhage↗
PubMed2005

Videocapillaroscopic alterations in erythematotelangiectatic rosacea.

BACKGROUND: Rosacea is a common chronic dermatosis that involves the cutaneous microvasculature of the face. There are no objective measures for assessing the severity of erythematotelangiectatic rosacea. OBJECTIVE: Our purpose was to characterize and provide objective measures of vessel changes in erythematotelangiectatic rosacea by videocapillaroscopy. METHODS: We compared 30 patients with erythematotelangiectatic rosacea with 30 age- and sex-matched patients with facial seborrheic dermatitis and 30 healthy control subjects. Videocapillaroscopy was performed both on the cheeks and on the nailfold region. The analyzed parameters of the face were morphological (background color, vessel irregularities) and quantitative (polygonal net perimeter, telangiectasia, and vessel diameters). RESULTS: Characteristic alterations of skin vessels were observed in facial rosacea, with a pattern distinct from that of facial seborrheic dermatitis. In particular, rosacea showed neoangiogenesis and significantly larger polygons (13.21 +/- 3 vs 7.8 +/- 3 mm; mean +/- standard deviation, P < .001), more prominent telangiectases (267.8 +/- 108 vs 118.2 +/- 35 microm; P < .001) and larger mean vessel diameter (46.71 +/- 9 vs 24 +/- 10 microm; P < .001) compared with seborrheic dermatitis. Seborrheic dermatitis displayed more polygon irregularities and vessel tortuosity. In contrast, no differences were found in the nailfold region. LIMITATIONS: Vessel irregularities and overall erythema may be difficult to quantify. CONCLUSIONS: Videocapillaroscopy may represent a valid adjunctive method in the early diagnosis and measurement of erythematotelangiectatic rosacea.

Adult↗
PubMed2006

The effects of external subretinal fluid drainage on secondary glaucoma in Coats' disease.

PURPOSE: We sought to investigate the effect of external subretinal fluid drainage (SRFD) on secondary or impending secondary glaucoma caused by bullous exudative retinal detachment for saving eyes with Coats' disease. METHODS: By retrospective chart review, we collected the treatment results of 56 patients younger than 15 years of age with Coats' disease. External SRFD was performed when exudative retinal detachment became bullous enough to cause anterior displacement of the lens-iris diaphragm or when secondary angle-closure glaucoma occurred. Treatment results were regarded as successful when secondary angle-closure glaucoma was prevented or responded to treatment. RESULTS: The mean age of those who underwent external SRFD was 3.1+/-1.8 years. Exudative retinal detachment was found in 48 eyes (86%), and external SRFD was needed initially in 19 (28%). External SRFD initially was performed in 19 eyes (28%) and in 2 (3%) after initial cryotherapy. Of these 21 eyes, no definite neovascular glaucoma was detected, and it took on average 1.2 SRFDs to treat or prevent secondary angle-closure glaucoma. All treatments were successful, and no eye was enucleated. CONCLUSIONS: External SRFD should be considered early as a treatment for secondary angle-closure glaucoma associated with bullous exudative retinal detachment in Coats' disease.

Adolescent↗
PubMed2004

Endothelial cell differentiation in hepatocellular adenomas: implications for histopathological diagnosis.

BACKGROUND/AIMS: Little information is available about the patterns of endothelial cell differentiation observed in hepatocellular adenomas. We therefore aimed to analyze the endothelial cell immunophenotype in a large series of these tumors and evaluate its possible diagnostic relevance. METHODS: The expression of continuous and sinusoidal endothelial cell markers and of extracellular matrix proteins was analyzed by immunoperoxidase in 56 adenomas, as compared with 30 cases of focal nodular hyperplasia (FNH), 2 cases of telangiectatic FNH and 40 cases of hepatocellular carcinoma (HCC). RESULTS: Twenty-eight adenomas (50%) presented a sinusoidal pattern of endothelial cell differentiation, characterized by the expression of specific sinusoidal endothelial cell markers and the presence of a subendothelial matrix resembling the normal perisinusoidal matrix. Eleven tumors (19.5%) presented a continuous pattern of endothelial cell differentiation. Seventeen tumors (30.5%) showed a mixed pattern. Twenty-eight FNH presented a sinusoidal pattern of endothelial cell differentiation; all HCC presented a continuous pattern of endothelial cell differentiation. CONCLUSIONS: In hepatocellular adenomas, intra-tumoral vessels usually present a sinusoidal pattern of endothelial cell differentiation. However, the vascular phenotypic heterogeneity observed in our study questions the potential relevance of endothelial cell immunophenotyping for the differential diagnosis between hepatocellular adenomas and well differentiated HCC.

Adenoma, Liver Cell↗
PubMed2006

Duration of illness is an important variable for untreated children with juvenile dermatomyositis.

OBJECTIVE: To evaluate the impact of duration of untreated symptoms in children with juvenile dermatomyositis (JDM) on clinical and laboratory status at diagnosis. STUDY DESIGN: We examined physical and laboratory data from the first physician visit for 166 untreated children with JDM. Disease activity scores (DASs) assessed skin and muscle involvement. Height and weight were compared with the National Health and Nutrition Examination Survey III dataset. Duration of untreated illness was designated as the time from first sign of rash or weakness to diagnostic visit. RESULTS: Boys and girls with untreated JDM were shorter and lighter than national norms (P > .0005 for both), and nonwhite children were weaker than white children (P > .0005). Older children had more dysphagia (P = .017) and arthritis (P > .001). Duration of untreated JDM was negatively associated with DAS weakness (P > .0005), unrelated to DAS skin, and positively associated with pathological calcifications (P = .006). With untreated disease > or = 4.7 months, serum levels of 4 muscle enzymes (aldolase, lactic dehydrogenase, creatine kinase, serum glutamic-oxaloacetic transaminase/aspartate aminotransferase) tended toward normal (P > .01 for each). CONCLUSIONS: Duration of untreated symptoms is an important variable and should be included in decisions concerning both diagnostic criteria and intensity of therapy for children with JDM.

Abdominal Pain↗
PubMed2005

Iliac artery stenosis in a child with cutis marmorata telangiectatica congenita.

Cutis marmorata telangiectatica congenita (CMTC) is a rare congenital disorder. We describe an 8-year-old boy with CMTC who presented with symptomatic claudication and diminished distal pulses. Imaging showed severe stenosis of the right common iliac artery, and the child underwent uncomplicated ilio-iliac bypass using prosthetic graft. This is the first report of a patient with CMTC and major vessel stenosis, successfully treated with a prosthetic graft bypass.

Blood Vessel Prosthesis Implantation↗
PubMed2004

The use of the source-skin distance measuring bridge indeed reduces skin teleangiectasia after interstitial boost in breast conserving therapy.

BACKGROUND AND PURPOSE: In 1990 the skin source measuring bridge was proposed as a tool to measure (1) the distance between the interstitial implant and the overlying skin during brachytherapy boost treatment as well as (2) the distances between the lateral source end and the exit point of the guide needle. The present study reports on the clinical experience using the source skin measuring bridge with respect to incidence and grade of teleangiectasia, and their relation to source skin distances and doses. PATIENTS AND METHODS: Two hundred and twenty-two breast cancer patients (229 breasts) treated between 1983 and 1996 with breast conserving therapy including a brachytherapy boost were scored on the occurrence of teleangiectasia. The minimum distance between the sources (above implant and laterally) and the skin surface were measured. RESULTS: If no bridge was used the appearance of teleangiectasia in the epiderm above the implant is 77, 63 and 50% for boost doses of 25, 20 and 15 Gy, respectively. For brachytherapy boost doses of 25 and 20 Gy and distances smaller than 10mm between the implant and the overlying epiderm, as determined with the skin source measuring bridge, the appearance of teleangiectasia was 78 and 46%, respectively. When respecting provisional dosimetry to spare the skin for a boost dose of 15 Gy, resulting in distances between 10 and 15 mm for the implant overlying skin and distances between 5 and 10 mm for the lateral skin, teleangiectasia can be reduced to a minimum (6.3% above and 3.3% laterally). While in a univariate analysis several parameters (use of the bridge, boost dose, boost modality, external beam therapy modality) were predictive factors, the use of the bridge remained the only significant variable in a multivariate analysis. CONCLUSIONS: The skin source measuring bridge reduces teleangiectasia after interstitial brachytherapy boost treatment. A hypothesis made previously relating teleangiectasia and source skin distances was verified and extended. Even when 3D planning is used, the bridge allows for a provisional calculation of the security margins between source positions and the skin at the time of BT implantation to assure a correct needle positioning from the beginning, instead of correcting dwell times later on to avoid unnecessary high skin doses.

Adult↗
PubMed2006

Clinical experience with the MammoSite radiation therapy system for brachytherapy of breast cancer: results from an international phase II trial.

BACKGROUND AND PURPOSE: In a prospective multi-center phase II trial, we investigated the MammoSite Radiation Therapy System, a new device for delivering intracavitary brachytherapy following breast conserving surgery. The MammoSite is a dual lumen, closed ended catheter with a small, spherical inflatable balloon and a port for connecting a remote afterloader to the central lumen. We analyzed the surgical procedure and placement of the MammoSite, treatment planning and radiation delivery complications and cosmesis, as well the comfort for the patients. PATIENTS AND METHODS: Between 2002 and 2004 a total of 32 patients (pts) were implanted using the MammoSite. The reference isodose was defined 1cm from the balloon surface. We analyzed the post-implant anatomic position of the applicator and the geometric form of the balloon via ultrasound, CT and X-ray, related side effects, cosmetic outcome and patient quality of life. RESULTS: Twenty-three out of 32 patients (72%) were eligible for MammoSite intracavitary brachytherapy. Twenty-eight percentage had to be excluded because of different reasons. Eleven patients were treated with primary brachytherapy with a total dose of 34 Gy (2 x 3.4 Gy) and 12 had a boost with a mean dose of 13.3 Gy (range: 7.5-15 Gy; 2 x 2.5 Gy) combined with EBRT and doses ranged between 46 and 50 Gy. In three cases a balloon rupture occurred. We observed two abscesses within 3 months of implantation and serious seroma development in 10 patients (39%). Skin related side effects were erythema in 21 patients (91%), hyperpigmentation in 13 patients (56%) and teleangiectasia in six patients (26%) after mean follow-up 20 months. CONCLUSIONS: The MammoSite Radiation Therapy System is a feasible treatment modality for intracavitary brachytherapy of breast cancer after breast conserving surgery. The advantage of the system is only one applicator is necessary for the delivery of a fractionated radiotherapy. In addition, patient tolerance of the procedure is high. Critical issues concern possible overdosages at the skin reflected by a high rate of late skin damage after only 20 months of follow-up time. The method could serve as an alternative to conventional multi-catheter brachytherapy for a selected group of patients.

Aged↗