The influence of inhibitors of apoptosis proteins (IAPs) on chronic rhinosinusitis with nasal polyps.

BACKGROUND: Inhibitors of apoptosis proteins (IAPs) modulate the inflammatory process, and may facilitate the formation of chronic rhinosinusitis with nasal polyps (CRSwNP). This study aimed to observe if IAPs were differently expressed between patients with CRSwNP and controls, and to correlate the expression of IAPs with some inflammatory markers, as with the response to nasal corticosteroids in patients with CRSwNP. METHODOLOGY: We obtained nasal biopsies from patients with CRSwNP (n=27) and controls (n=16). qRT-PCR measured the expression of IAPs and caspases, while Luminex assay measured the concentration of cytokines. Unpaired parametric tests and Principal Component Analysis (PCA) were used for statistical analysis. RESULTS: We observed lower expression of IAP genes (XIAP, BIRC2/IAP1, and BIRC3/IAP2) in CRSwNP patients compared to controls, and we identified that patients with bad response to corticosteroids presented lower levels of BIRC2/IAP1, XIAP, BCL2, CASP9, and IL-17, and higher levels of CASP7 and TGF-B. CONCLUSIONS: IAPs expression was downregulated in CRSwNP, and was associated with poorer response to nasal corticosteroids. The present findings suggest the importance of IAPs as a link between environment and the host inflammatory responses, and this pathway could be explored as a potential new target therapy for patients with CRSwNP.

El peso corporal y su efecto sobre indicadores bioproductivos en gallinas white leghorn l33 / The corporal weight and its effect on bioproductive indicators in white leghorn l33 hens

El objetivo del presente estudio fue evaluar el efecto del peso corporal sobre indicadores bioproductivos en gallinas White Leghorn L33. Se estudiaron 192 gallinas ponedoras con 39 semanas de edad durante un período de seis semanas y con tres observaciones semanales. Se diseñaron dos grupos según peso vivo, con 96 gallinas cada uno (tres réplicas de 32 aves), teniendo el grupo 1 entre 1500-1600 g y el grupo 2 entre 1735-1820 g; este último correspondió al rango establecido para este híbrido con esa edad. Además de la viabilidad y mortalidad se determinaron las variables bioproductivas (producción, peso, tamaño, forma y grosor de la cáscara de los huevos), así como la proporción de sucios, manchados y cascados. En la última semana del estudio, se analizó la calidad interna del huevo (dimensión y color de clara y yema) y se calcularon los índices de yema, clara y Unidades Haugh. Se realizó una estadística descriptiva y se utilizaron las pruebas T de Student y Fisher (P < 0,05) para comparar las medias entre grupos. Se evidenciaron diferencias estadísticas significativas entre producción, peso y tamaño de los huevos para el grupo de mayor peso corporal. Asimismo, se comprobó mayor calidad interna del huevo (altura de clara y yema) en este segundo grupo. Sin embargo, no se evidenciaron diferencias significativas en la calidad externa de los huevos (sucios, manchados, cascados), pero sí en el grosor de la cáscara. Se concluye que el peso corporal influye directa y positivamente sobre los indicadores bioproductivos en gallinas White Leghorn L33.

The objective of this study was to evaluate the effect of the corporal weight on bioproductive indicators in White Leghorn L33 hens. They were studied 192 egg-laying hens with 39 weeks of age during a period of six weeks and with a frequency of three weekly observations. Two groups according to the alive weight with 96 hens each one (three replies of 32 birds) were designed, having the group 1 (1500-1600 g) and group 2 (17351820 g), and being this last group the established range for this crossbreed with that age. Besides of viability and mortality bioproductive variables (production, weight, size, form and nutshell thickness of the eggs) were determined, as well as the proportion of dirty, stained and cracked eggs. In the last week of study the internal quality (dimension and color of egg white and yolk) was analyzed and the yolk and white index and Haugh Units were calculated. Descriptive statistics was realized and the Student's t and Fisher tests (P < 0.05) were used to compare means between groups. Significant statistical differences among production, weight, and size of eggs for group of bigger corporal weight were evidenced. Likewise, bigger internal quality of the egg (height of the egg white and yolk) in this second group was demonstrated. However, significant differences in the external quality of the eggs (dirty, stained and cracked) were not evidenced, unlike in the nutshell thickness. It is concluded that corporal weight influences direct and positively on bioproductive indicators in White Leghorn L33 hens.

Tooth bleaching increases dentinal protease activity.

Hydrogen peroxide is an oxidative agent commonly used for dental bleaching procedures. The structural and biochemical responses of enamel, dentin, and pulp tissues to the in vivo bleaching of human (n = 20) premolars were investigated in this study. Atomic force microscopy (AFM) was used to observe enamel nanostructure. The chemical composition of enamel and dentin was analyzed by infrared spectroscopy (FTIR). The enzymatic activities of dental cathepsin B and matrix metalloproteinases (MMPs) were monitored with fluorogenic substrates. The amount of collagen in dentin was measured by emission of collagen autofluorescence with confocal fluorescence microscopy. The presence of Reactive Oxygen Species (ROS) in the pulp was evaluated with a fluorogenic 2',7'-dichlorodihydrofluorescein diacetate (DCFDA) probe. Vital bleaching of teeth significantly altered all tested parameters: AFM images revealed a corrosion of surface enamel nanostructure; FTIR analysis showed a loss of carbonate and proteins from enamel and dentin, along with an increase in the proteolytic activity of cathepsin-B and MMPs; and there was a reduction in the autofluorescence of collagen and an increase in both cathepsin-B activity and ROS in pulp tissues. Together, these results indicate that 35% hydrogen peroxide used in clinical bleaching protocols dramatically alters the structural and biochemical properties of dental hard and soft pulp tissue.

Testicular testosterone: estradiol ratio in domestic cats and its relationship to spermatogenesis and epididymal sperm morphology.

The phenomenon of teratozoospermia in felids is not fully understood. In this study, we investigated the testicular androgen:estrogen balance in domestic cats and correlated these data with epididymal sperm morphology and the degree of spermatogenic activity. During spring and summer, testes and blood samples were obtained from 37 mixed-breed domestic cats (12 to 48 mo). The epididymal sperm were harvested and evaluated for sperm counts, motility, and morphology. Distal cytoplasmic droplets were not considered a defect, and samples were considered normozoospermic if they contained more than 60% normal sperm (N = 25) or teratozoospermic if they contained less than 45% normal sperm (N = 12). The testicular and serum concentrations of testosterone (T) and 17ß-estradiol (E2) were determined with an enzyme immunoassay. The gonadosomatic index and epididymal sperm numbers and motility did not differ between groups. The percentage of normal sperm was higher in normozoospermic (74.3 ± 2.0, mean ± SEM) than in teratozoospermic samples (43.1 ± 1.4). The most prevalent sperm defects in the teratozoospermic group were abnormal acrosomes (9.7 ± 2.0) and bent midpieces (12.2 ± 2.0) or tails (24.0 ± 2.7) with cytoplasmic droplets. Histomorphometric data were similar between groups, although there was a lower Leydig cell nuclear volume in teratozoospermic samples. Normozoospermic samples contained a higher percentage of haploid cells and had a higher index of total spermatogenic transformation than teratozoospermic samples. Serum concentrations of T (0.5 ± 0.1 vs. 0.8 ± 0.4 ng/mL) and E2 (9.5 ± 1.2 vs. 11.4 ± 2.3 pg/mL) and testicular T concentrations (471.6 ± 65.3 vs. 313.4 ± 57.6 ng/g) were similar between groups. However, compared with normozoospermic samples, teratozoospermic samples had higher testicular E2 concentrations (8.5 ± 3.6 vs. 5.4 ± 0.5 ng/g) and a lower T:E2 ratio (31.8 ± 4.1 vs. 87.2 ± 11.6). There were significant correlations between testicular E2 values and percentages of normal sperm (r = -0.55) as well as those with primary sperm defects (r = 0.58) or abnormal acrosomes (r = 0.64). The T:E2 ratio was also correlated with meiotic index (r = 0.45) and percentage of normal sperm (r = 0.58). In conclusion, a high testicular E2 concentration and a reduced T:E2 ratio were significantly associated with higher ratios of abnormal sperm types, suggesting that the balance between androgens and estrogens is an important endocrine component in the genesis of teratozoospermia in felids.

Association of glutathione S-transferase Ω 1-1 polymorphisms (A140D and E208K) with the expression of interleukin-8 (IL-8), transforming growth factor beta (TGF-ß), and apoptotic protease-activating factor 1 (Apaf-1) in humans chronically exposed to arsenic in drinking water.

Human exposure to arsenicals is associated with inflammatory-related diseases including different kinds of cancer as well as non-cancerous diseases like neuro-degenerative diseases, atherosclerosis, hypertension, and diabetes. Interindividual susceptibility has been mainly addressed by evaluating the role of genetic polymorphism in metabolic enzymes in inorganic arsenic (iAs) metabolism. Glutathione S-transferase omega 1-1 (GSTO1-1), which had been associated with iAs metabolism, is also known to participate in inflammatory and apoptotic cellular responses. The polymorphism A140D of GSTO1-1 has been not only associated with distinct urinary profile of arsenic metabolites in populations chronically exposed to iAs in drinking water, but also with higher risk of childhood leukemia and lung disease in non-exposed populations, suggesting that GSTO1-1 involvement in other physiologic processes different from toxics metabolism could be more relevant than is thought. We evaluated the association of the presence of A140D and E208K polymorphisms of GSTO1-1 gene with the expression of genes codifying for proteins involved in the inflammatory and apoptotic response in a human population chronically exposed to iAs through drinking water. A140D polymorphism was associated with higher expression of genes codifying for IL-8 and Apaf-1 mainly in heterozygous individuals, while E208K was associated with higher expression of IL-8 and TGF- gene, in both cases, the association was independently of iAs exposure level; however, the exposure to iAs increased slightly but significantly the influence of A140D and E208K polymorphisms on such genes expression. These results suggest an important role of GSTO1-1 in the inflammatory response and the apoptotic process and indicate that A140D and E208K polymorphisms could increase the risk of developing inflammatory and apoptosis-related diseases in As-exposed populations.

Effects of 174 G/C polymorphism in the promoter region of the interleukin-6 gene on plasma IL-6 levels and muscle strength in elderly women

We investigated the effect of -174 G/C single-nucleotide polymorphism in the promoter region of the IL6 gene on plasma IL-6 levels and muscle strength, and the relationship between IL-6 levels and muscle strength in elderly women. The sample consisted of 199 elderly residents (73.0 ± 7.8 years old) from rest homes and the community in Belo Horizonte, MG, Brazil. -174 G/C polymorphism was determined by direct sequencing of the product by PCR, and plasma IL-6 concentrations were measured by ELISA. Muscle strength in the knee joint was evaluated using a Biodex System 3 Pro® isokinetic dynamometer. ANCOVA was used to determine the effect of polymorphism on IL-6 levels and muscle strength, and the Pearson correlation coefficient to assess the relationship between IL-6 levels and muscle strength. -174 G/C polymorphism was associated with the plasma IL-6 levels of elderly women (P < 0.01) since homozygotes for the G allele showed high IL-6 levels (GG 3.85 pg/mL, GC + CC 2.13 pg/mL). There was no association of polymorphism on muscle strength (P > 0.05). No association was found between IL-6 levels and knee extensor muscle (r = 0.087, P = 0.306) or flexor (r = -0.011, P = 0.894) strength. An interaction between -174 G/C polymorphism and housing conditions of the sample of elderly women was identified, with the effect of genotype on IL-6 levels being higher in the institutionalized elderly. These results support the evidence that -174 G/C polymorphism of the IL6 gene associates with individual variability of plasma IL-6 levels in elderly women.

Effects of 174 G/C polymorphism in the promoter region of the interleukin-6 gene on plasma IL-6 levels and muscle strength in elderly women.

We investigated the effect of -174 G/C single-nucleotide polymorphism in the promoter region of the IL6 gene on plasma IL-6 levels and muscle strength, and the relationship between IL-6 levels and muscle strength in elderly women. The sample consisted of 199 elderly residents (73.0 ± 7.8 years old) from rest homes and the community in Belo Horizonte, MG, Brazil. -174 G/C polymorphism was determined by direct sequencing of the product by PCR, and plasma IL-6 concentrations were measured by ELISA. Muscle strength in the knee joint was evaluated using a Biodex System 3 Pro® isokinetic dynamometer. ANCOVA was used to determine the effect of polymorphism on IL-6 levels and muscle strength, and the Pearson correlation coefficient to assess the relationship between IL-6 levels and muscle strength. -174 G/C polymorphism was associated with the plasma IL-6 levels of elderly women (P < 0.01) since homozygotes for the G allele showed high IL-6 levels (GG 3.85 pg/mL, GC + CC 2.13 pg/mL). There was no association of polymorphism on muscle strength (P > 0.05). No association was found between IL-6 levels and knee extensor muscle (r = 0.087, P = 0.306) or flexor (r = -0.011, P = 0.894) strength. An interaction between -174 G/C polymorphism and housing conditions of the sample of elderly women was identified, with the effect of genotype on IL-6 levels being higher in the institutionalized elderly. These results support the evidence that -174 G/C polymorphism of the IL6 gene associates with individual variability of plasma IL-6 levels in elderly women.

Conservation genetics of the giant otter (Pteronura brasiliensis (Zimmerman, 1780)) (Carnivora, Mustelidae)

The giant otter (Pteronura brasiliensis) is an aquatic mammal of the Mustelidae family, endemic to South America. Its original distribution corresponds to the region from the Guyanas to Central-North Argentina, but it is extinct or on the verge of extinction in most of its historical range. Currently, the species is considered endangered by the World Conservation Union (IUCN). Based on its geographic distribution in the South American continent and on some morphological characters, two subspecies were suggested: P. brasiliensis brasiliensis, occurring in the Amazon and Orinoco River Basins, and P. brasiliensis paranensis, in the Paraná and Paraguai River Basins. However, there is no consensus on assuming this subspecies division and no detailed studies have been carried out to elucidate this question. This study aims to evaluate the genetic diversity and population structure of Pteronura brasiliensis along its range in Brazil to check the possibility of the existence of two distinct subspecies using also a reciprocal monophyly criterion. We analyzed the control region, and the Cytochrome b and Cytochrome c Oxidase subunit I genes of the mitochondrial DNA in several giant otter populations from the Amazon and Paraguai River Basins. Analyses have indicated some degree of geographic correlation and a high level of inter-population divergence, although the subspecies division is not highly supported. As we observed strong population structure, we cannot rule out the existence of further divisions shaping the species distribution. The results suggest that a more complex population structure occurs in P. brasiliensis, and the conservation practice should concentrate on preserving all remaining local populations.

A ariranha (Pteronura brasiliensis) é um mamífero aquático da família Mustelidae, endêmico da América do Sul. Sua distribuição original se estendia desde as Guianas até o centro-norte da Argentina, mas está extinta ou à beira da extinção na maior parte de sua distribuição histórica. Atualmente a espécie é considerada como ameaçada de extinção pela World Conservation Union (IUCN). Em função de sua distribuição no continente sul-americano e de algumas características morfológicas, duas subespécies foram sugeridas: P. brasiliensis brasiliensis, com ocorrência nas bacias do Amazonas e Orinoco, e P. brasiliensis paranensis, ocorrendo nas bacias dos Rios Paraná e Paraguai. Inexiste, contudo, um consenso sobre a validade da divisão em subespécies e nenhum estudo detalhado foi realizado para elucidar esta questão. Este trabalho tem o objetivo de avaliar a diversidade genética e a estrutura populacional de P. brasiliensis ao longo de sua distribuição no Brasil para verificar a existência de duas subespécies baseando-se também em um critério de monofilia recíproca. A região controle e os genes do Citocromo b e da Subunidade I da Citocromo c Oxidase do DNA mitocondrial foram analisados em diversas populações de ariranha que ocorrem nas bacias dos rios Amazonas e Paraguai. As análises indicaram um grau moderado de correlação geográfica e um alto nível de divergência inter-populacional, embora a divisão em subespécies não seja bem sustentada. Como uma forte estruturação populacional foi observada, não é possível descartar a existência de outras subdivisões nesta espécie. Os resultados indicam a presença de uma estrutura populacional mais complexa em P. brasiliensis, o que implica que medidas de conservação deveriam concentrar seus esforços preservando todas as populações locais remanescentes.

Inhibitory effect of trehalose dimycolate (TDM) and its stereoisometric derivatives, trehalose dicorynomycolates (TDCMs), with low toxicity on lung metastasis of tumour cells in mice.

We examined the effect of semisynthetic trehalose-6,6 '-dimycolate (TDM) and its synthetic stereoisomeric derivatives (trehalose 6,6'-dicorynomycolates; TDCMs) prepared in oil-in-water (o/w) emulsion on inhibition of lung metastasis produced by highly metastatic murine tumour cells, colon 26-M3.1 carcinoma and B16-BL6 melanoma cells, using experimental and spontaneous metastasis models. Intravenous (i.v.) administration of TDM (100 microg/mouse) 1, 3 or 8 days before tumour inoculation significantly inhibited lung metastasis of colon 26-M3.1 cells, in a dose-dependent manner. Single administration of TDM 1 day after tumour inoculation also showed the therapeutic effect on experimental lung metastasis of colon 26-M3.1 cells. Similarly, multiple administrations of TDM after tumour inoculation resulted in a significant inhibition of spontaneous lung metastasis of B16-BL6 cells (on day 35), although it showed no effect on suppression of tumour growth (on day 21). In comparison of toxicity in vivo among TDM and four TDCMs such as TDCM(2R,3R), TDCM(2S,3R), TDCM(2R,3S) and TDCM(2S,3S), all of the TDCMs appeared to be less toxic than TDM itself. Furthermore, all of the TDCMs were prophylactically as well as therapeutically active for inhibition of lung metastasis of both colon 26-M3.1 and B16-BL6 tumour cells, showing higher inhibitory activity than that of TDM. In particular, TDCMs induced a marked suppression of the growth of B16-BL6 tumour cells in vivo. These results suggest that systemic administration of TDM as well as TDCMs led to inhibition of tumour metastasis and TDCMs are more potential to suppress tumour growth and inhibit tumour metastasis than TDM.

Factors influencing cosmetic results after conservation therapy for breast cancer.

PURPOSE: Host, tumor, and treatment-related factors influencing cosmetic outcome are analyzed for patients receiving breast conservation treatment. METHODS AND MATERIALS: Four-hundred and fifty-eight patients with evaluable records for cosmesis evaluation, a subset of 701 patients treated for invasive breast cancer with conservation technique between 1969 and 1990, were prospectively analyzed. In 243 patients, cosmetic evaluation was not adequately recorded. Cosmesis evaluation was carried out from 3.7 months to 22.3 years, median of 4.4 years. By pathologic stage, tumors were 62% T1N0, 14% T1N1, 15%, T2N0, and 9% T2N1. The majority of patients were treated with 4-6 MV photons. Cosmetic evaluation was rated by both patient and physician every 4-6 months. A logistic regression analysis was completed using a stepwise logistic regression. P-values of 0.05 or less were considered significant. Excellent cosmetic scores were used in all statistical analyses unless otherwise specified. RESULTS: At most recent follow-up, 87% of patients and 81% of physicians scored their cosmetic outcome as excellent or good. Eighty-two percent of physician and patient evaluations agreed with excellent-good vs. fair-poor rating categories. Analysis demonstrated a lower proportion of excellent cosmetic scores when related to patient age > 60 years (p = 0.001), postmenopausal status (p = 0.02), black race (p = 0.0034), and T2 tumor size (p = 0.05). Surgical factors of importance were: volume of resection > 100 cm3 (p = 0.0001), scar orientation compliance with the National Surgical Adjuvant Breast Project (NSABP) guidelines (p = 0.0034), and > 20 cm2 skin resected (p = 0.0452). Extent of axillary surgery did not significantly affect breast cosmesis. Radiation factors affecting cosmesis included treatment volume (tangential breast fields only vs. three or more fields) (p = 0.034), whole breast dose in excess of 50 Gy (p = 0.0243), and total dose to tumor site > 65 Gy (p = 0.06), as well as optimum dose distribution with compensating filters (p = 0.002). Daily fraction size of 1.8 Gy vs. 2.0 Gy, boost vs. no boost, type of boost (brachytherapy vs. electrons), total radiation dose, and use of bolus were not significant factors. Use of concomitant chemotherapy with irradiation impaired excellent cosmetic outcome (p = 0.02). Use of sequential chemotherapy or adjuvant tamoxifen did not appear to diminish excellent cosmetic outcomes (p = 0.31). Logistic regression for excellent cosmetic outcome analysis was completed for age, tumor size, menopausal status, race, type of surgery, volume of breast tissue resected, scar orientations, whole breast radiation dose, total radiation dose, number of radiation fields treated, and use of adjuvant chemotherapy. Significant independent factors for excellent cosmetic outcome were: volume of tissue resected (p = 0.0001), type of surgery (p = 0.0001), breast radiation dose (p = 0.005), race (p = 0.002), and age (p = 0.007). CONCLUSIONS: Satisfactory cosmesis was recorded in 81% of patients. Impaired cosmetic results are more likely with improper orientation of tylectomy and axillary incisions, larger volume of breast resection, radiation dose to the entire breast in excess of 50.0 Gy, and concurrent administration of chemotherapy. Careful selection of treatment procedures for specific patients/tumors and refinement in surgical/irradiation techniques will enhance the cosmetic results in breast conservation therapy.

Management of the axilla in patients with breast cancers one centimeter or smaller.

Very small breast cancers are being diagnosed with increased frequency, and, until recently, little information regarding the incidence of axillary lymph node metastases in these most favorable tumors was available. Moreover, scarce data exist regarding axillary failure in this cohort as a function of initial treatment, be it surgery, radiation, or simply observation. In the present study, limited to women with invasive cancers measuring no more than 10 mm, the incidence of pathologically positive axillary nodes was 12.3%. The incidence of nodal metastases was influenced by tumor size (albeit not quite significantly, p = .08); not one patient with a tumor < or = 5 mm had axillary node metastases, compared to 14.7% in those with cancers 6 to 10 mm. The histologic grade and tumor location were also important in predicting nodal positivity. The incidence of positive nodes was 38% in those with poorly differentiated cancers, compared to 8% and 7% in women with well and moderately differentiated cancers, respectively, p = .03. Axillary nodal positivity was seen in 17% of outer quadrant vs 3% of central and inner quadrant primaries, p < .01. The axilla was managed with surgery alone (76%), radiation alone (6%), surgery and radiation (6%), or simply observation (10%). With a median follow-up of 55 months, not one patient has suffered a nodal recurrence, and in our experience, survival free of distant relapse was not adversely affected by the omission of axillary surgery.

Suppression of cAMP-induced pigment granule aggregation in RPE by organic anion transport inhibitors.

PURPOSE: To investigate the mechanism(s) by which intracellular cAMP levels are elevated to induce pigment granule aggregation in teleost retinal pigment epithelium (RPE). METHODS: Pigment granule migration was studied in vitro using RPE sheets isolated from dark-adapted green sunfish, Lepomis cyanellus. After preculture to allow pigment granule dispersion, RPE sheets were incubated with various agents to test their ability to induce pigment granule aggregation. RPE sheets were then fixed, and pigment granule position was assessed microscopically. RESULTS: Pigment granule aggregation was induced by nonderivatized cAMP. At maximally effective concentration (1 mM), cAMP was as effective as its more membrane-permeant analogs dbcAMP and 8-Br-cAMP. Forskolin (1 or 10 microM), a stimulator of adenylyl cyclase, was also effective at inducing pigment aggregation. Two inhibitors of organic anion transport, probenecid and sulfinpyrazone, inhibited cAMP-induced aggregation by approximately 80% but had no effect on forskolin-induced aggregation. Several agents shown to stimulate RPE adenylyl cyclase in other species failed to induce pigment aggregation in isolated RPE sheets. CONCLUSIONS: Our observations strongly suggest that exogenously applied, nonderivatized cAMP can gain access to the cytoplasm of isolated RPE cells via organic anion transporters. Thus, if cAMP were secreted by retinal cells into the subretinal space, it could be taken up by RPE cells and subsequently act as an intracellular messenger to activate dark-adaptive physiological processes such as pigment granule aggregation.

Regional nodal management and patterns of failure following conservative surgery and radiation therapy for stage I and II breast cancer.

PURPOSE: To determine the incidence, pattern of regional nodal failure, and treatment sequelae as determined by the extent of lymphatic irradiation. METHODS AND MATERIALS: The records of 511 patients with 519 Stage I and II breast cancers treated with breast conserving surgery with or without axillary dissection and irradiation were reviewed. The extent of nodal irradiation was at the discretion of the attending radiation oncologist and varied considerably over the years. Management of the axilla consisted of axillary dissection alone in 351, axillary dissection and supplemental irradiation in 74, irradiation alone in 75, and simply observation in 21 patients. RESULTS: Overall, axillary recurrence was uncommon (1.2%), but was slightly more frequent after irradiation alone (2.7%) than after surgery alone (0.3%), p = 0.14. There was no benefit for supplemental axillary irradiation after an axillary dissection yielding negative or 1 to 3 positive nodes. In the 21 patients in whom the axilla was observed, axillary recurrence was not observed. Supraclavicular failures were rare in women with negative or 1 to 3 positive axillary lymph nodes (0.5%), and not significantly affected by elective irradiation. Internal mammary node recurrence was seen in only one patient, and was not significantly influenced by elective internal mammary irradiation. Both arm and breast edema were significantly more common in women having breast and nodal irradiation than after breast irradiation alone. These sequelae were not influenced significantly by the number of lymph nodes obtained in the axillary dissection specimen. Radiation pneumonitis was seen with increased frequency with more extensive nodal radiotherapy. Pneumonitis was not found to be affected by the administration or sequencing of chemotherapy. CONCLUSION: There is little justification for axillary or supraclavicular irradiation following an axillary dissection which yields negative or minimally involved (1 to 3 positive) lymph nodes. There were too few patients with extensive axillary node metastases (> or = 4 positive) in our series to draw conclusions about the optimal extent of nodal irradiation in this subset. Elective internal mammary lymph node irradiation increases technical complexity, does not appear to be advantageous, and when combined with supraclavicular irradiation places the patient at highest risk for pneumonitis.

Breast conservation therapy for intraductal carcinoma of the breast.

PURPOSE: Between 1979 and 1987, 76 women with 77 ductal carcinomas in-situ of the breast were evaluated by The Radiation Oncology Center after breast conservation surgery. METHODS AND MATERIALS: Seventy breasts (91%) had tylectomy and irradiation and seven breasts (9%) had tylectomy alone. Median follow-up was 4.0 years, with a range of 2-10 years. Fifty patients (65%) had occult lesions discovered by mammography with a median mammographic size of 0.9 cm. The twenty-six patients with presenting symptoms had a median clinical tumor size of 1.95 cm. All patients had local excision of the primary tumor. Of 15 patients who had axillary dissections, one had nodal metastasis. Seventy breasts were irradiated. Seven patients refused radiotherapy. RESULTS: Overall 5-year actuarial survival was 99%; 5-year actuarial disease-free survival was 89%; the 5-year actuarial intramammary tumor control rate for irradiated patients was 93% vs. 57% for patients not irradiated (p < 0.001). Comedocarcinoma had a 5-year actuarial tumor control rate of 75%, 88% in the irradiated group as compared to 98% for all other histologic subtypes of ductal carcinoma in situ (p < 0.03). All six patients with local failure were successfully salvaged by further surgery. Multivariate analysis revealed significant factors in local control to be (a) radiotherapy, (b) comedocarcinoma histology, and (c) menopausal status. CONCLUSIONS: Although the number of patients treated is small, and follow-up time is limited, these early results support the contention that the treatment of ductal carcinoma in situ by excision and irradiation is an acceptable alternative to mastectomy. We urge caution in treating patients with the comedocarcinoma subtype and counsel these patients to have more treatment than excision alone.

Irradiation in relapsing carcinoma of the prostate.

BACKGROUND: Radiation therapy plays a major role in the management of patients with either locally recurrent or metastatic carcinoma of the prostate. RESULTS: In 23 patients with isolated postprostatectomy local recurrences treated with doses of 60-65 Gy, 17 (74%) had tumor control, and 45% survived relapse-free for 5 years after treatment of the recurrence. Pelvic irradiation has been used to treat patients with elevated prostate-specific antigen (PSA) levels after radical prostatectomy. This was tried, and 17 of 24 patients (70%) showed a significant decrease in PSA levels after irradiation, in five without subsequent elevation. Two of the seven patients with elevated PSA levels later had distant metastases. Local irradiation has been reported to yield excellent relief of symptoms in 100% of patients with hematuria, 80% with urinary outflow obstruction, and 50-70% with ureteral obstruction or pelvic pain secondary to locally advanced prostatic carcinoma. Reirradiation, particularly with brachytherapy (in preliminary studies combined with hyperthermia) has been used in the management of postirradiation prostatic recurrences with satisfactory tumor regression in approximately 75% of patients. The Radiation Therapy Oncology Group (RTOG) reported on the palliative effects of external irradiation on patients with bony metastasis. Approximately 54% of such patients had complete relief, and 29% had partial relief of bone pain. However, the retreatment rate of the bony metastasis was lower in the patients receiving higher doses. In a RTOG protocol in which all patients received local irradiation for osseous metastases, 77 were randomized to receive elective hemibody irradiation and 69, local treatment only. The frequency of additional treatment at 1 year was lower in the hemibody irradiation group (54% versus 78%). Occasionally, brain, mediastinal, or liver metastasis can be treated with irradiation. Radioactive phosphorus-32 or strontium-89 has been administered for disseminated bony metastasis with improvement of bone pain in approximately 70-80% of treated patients. CONCLUSION: The role of irradiation in the treatment of spinal cord compression is discussed. Significant improvement of neurologic function has been reported in 36-60% of the patients, depending on severity of deficit and promptness in instituting emergency treatment.

Locoregional recurrence of breast cancer: a retrospective comparison of irradiation alone versus irradiation and systemic therapy.

The role of systemic therapy in addition to irradiation for locoregional recurrence of breast cancer is controversial. In the absence of prospective randomized trials, treatment decisions must be based on retrospective studies. We retrospectively analyzed 230 patients treated for locoregionally recurrent breast cancer between 1964 and 1986. Forty-seven were premenopausal, 173 were postmenopausal, and the menopausal status was unknown in 10 patients. Each patient treated with radiotherapy (RT) and chemotherapy or with RT and hormonal therapy was matched with a control patient treated with RT alone. The addition of hormonal therapy to radiation therapy significantly improved the 5-year overall survival (50 versus 28%), disease-free survival (37 versus 26%), and distant metastases-free survival (45 versus 29%). No improvement in locoregional control was observed. In contrast, chemotherapy did not confer such survival benefits, but there was a trend towards improvement in 5-year locoregional control (68 versus 50%), p = 0.08. Our data support the use of hormonal therapy along with RT at the time of locoregional recurrence of breast cancer. Although our data suggest that chemotherapy is not routinely indicated, controlled clinical trials are needed to define which subsets of patients, if any, benefit from systemic therapy.

Breast conservation therapy. The St. Luke's Hospital experience.

Between 1979 and 1987, 170 patient with stages 0, I and II breast cancer were treated with breast conservation therapy. Twenty-eight women (16%) had intraductal carcinomas, 110 (65%) stage I disease and 32 (19%) had stage II breast cancers. Seventy-five percent of the patients received no adjuvant systemic treatment, whereas 20% received adjuvant chemotherapy and 5% were given Tamoxifen. All patients received radiation therapy to the breast after lumpectomy and, when appropriate, axillary dissection. Twelve patients (7%) recurred within the treated breast, whereas two patients (1%) recurred in regional lymph nodes. Fourteen women (8%) developed distant metastases and seven women (4%) developed contralateral breast cancer. The actuarial 5 year disease-free survival was 92% for the patients with intraductal carcinoma, 90% for T1 and 65% for T2 patients. Overall actuarial survival was 100%, 96% and 87%, respectively. The St. Luke's Hospital results are comparable to those reported in the literature. We conclude that breast conservation therapy, including irradiation, is an alternative to modified radical mastectomy and that this option should be thoroughly discussed with the patient.

Survival following locoregional recurrence of breast cancer: univariate and multivariate analysis.

Although prognostic variables for locoregional recurrence of breast cancer have been evaluated by univariate analysis, multifactorial analysis has not been previously performed. In the present study, survival following chest wall and/or regional lymphatic recurrence was determined in 230 patients with locoregionally recurrent breast cancer without evidence of distant metastases treated at the Radiation Oncology Center, Mallinckrodt Institute of Radiology and affiliated hospitals. Multifactorial analysis demonstrated that the site of recurrences correlated most strongly with overall survival (p = 0.001). The 5-year actuarial overall survival was 44-49% for patients with isolated chest wall, axillary, and internal mammary lymph node recurrence. Patients with either supraclavicular, multiple lymphatic, or concomitant chest wall and lymphatic recurrence had an 21-24% 5-year overall survival. The 5-year disease-free survival was 28-37% for patients with chest wall, axillary, or internal mammary recurrences compared to 4-13% for those with supraclavicular, chest wall and lymphatic, or those with multiple sites of lymphatic recurrence. Disease-free interval from mastectomy to recurrence was also found to be a significant prognostic factor for overall survival (p = 0.005). Fifty percent of patients with a disease-free interval of at least 2 years survived 5 years following locoregional relapse, compared to 35% for those with disease-free interval of less than 2 years. In the subset of patients with small chest wall recurrences (excised or less than 3 cm) and a disease-free interval of at least 2 years, the 5-year overall and disease-free survivals were 67% and 54%, respectively. These results suggest that subsets of patients with locoregional recurrence of breast cancer can survive for long periods of time. The conventional wisdom that chest wall and/or regional nodal recurrence following mastectomy uniformly confers a dismal prognosis is not necessarily true.