Effectiveness of aprepitant in addition to ondansetron in the prevention of nausea and vomiting caused by fractionated radiotherapy to the upper abdomen (AVERT).

PURPOSE: Despite a lower risk of nausea and vomiting in patients receiving radiotherapy to the upper abdomen (UA-RINV) with prophylactic 5-HT3 antagonist therapy, patients can still experience UA-RINV. The aim of this multicenter phase II study was to assess effectiveness, safety, and tolerability of protracted dual NK1-receptor and 5-HT3 antagonist prophylaxis against UA-RINV. METHODS: Patients receiving fractionated radiotherapy with radiosensitizing chemotherapy received oral ondansetron 8 mg po q12 h and aprepitant 125/80/80 mg on a Monday, Wednesday, Friday schedules throughout radiotherapy. The primary outcome was complete response (CR) defined as no vomiting or rescue therapy during the entire observation period of radiotherapy (OP). Nausea, vomiting, and use of rescue medication were recorded in a modified version of the MASCC antiemesis tool completed twice weekly. RESULTS: Fifty-five patients were enrolled at 5 sites, 52 of whom were evaluable. 57.7% of patients (30/52, 95% CI 43.2-71.3%) achieved CR on study, with 73.1% (38/52, 95% CI 59.0-84.4%) who did not vomit, and 71.2% (37/52, 95% CI 56.9-82.9%) who did not use rescue medication during the OP. Overall, participants vomited or experienced significant nausea (SN) for an average of 6.8% (95% CI 11.4-21.0) and 8.4% (95% CI 4.2-12.7%) of time on study, respectively. Nausea was common with 32 (61.5%) reporting SN at any time during the OP. CONCLUSIONS: UA-RINV remains an important morbidity despite the advent of modern radiotherapy. Aprepitant and ondansetron as dosed in this trial was not superior to standard ondansetron monotherapy.

Biomimetic formation of hydroxyapatite investigated by analytical techniques with high resolution.

Morphology, phase and chemical compositions of atmospheric plasma-sprayed (APS) hydroxyapatite (HAp) coatings were investigated by scanning electron microscopy (SEM), X-ray powder diffraction (XRD), proton-induced X-ray emission (PIXE) and Rutherford backscattering spectrometry (RBS). The study involved as-sprayed coatings and coatings incubated in simulated body fluid (rSBF) for up to 56 days. The results obtained using combined contributions from three complementary analytical techniques confirm that secondary Ca-deficient defect hydroxyapatite precipitated by a biomimetic process from the simulated body fluid onto the HAp coating surface after a prolonged induction time. Owing to its sensitivity proton-induced X-ray emission (PIXE) provides information on in vitro resorption of calcium phosphate ceramics and dynamic dissolution/precipitation events occurring during the incubation process.

Intensity-modulated radiation therapy in the treatment of gastric cancer: early clinical outcome and dosimetric comparison with conventional techniques.

The purpose of this study was to assess the efficacy and toxicity of intensity-modulated radiation therapy (IMRT) in the treatment of gastric cancer. Seven patients with gastric cancer were treated with IMRT. Six patients (all Stage III) received post-operative chemoradiotherapy with concurrent 5-fluorouracil and leucovorin. One received planned pre-operative radiation, though did not proceed to surgery. All patients were planned to receive 50.4 Gy in 1.8 Gy fractions. IMRT planning was compared with opposed anterior-posterior: posterior-anterior (AP/PA) and 3-field conventional three-dimensional plans. When compared with either AP/PA or 3-field plans, IMRT significantly reduced the volume exceeding the threshold dose of the liver and at least one kidney. Target coverage with IMRT was excellent, with 98+/-1% of the target receiving >or=100% of the dose. Compared with AP/PA and 3-field plans, IMRT plans had a greater percentage of target receiving the prescribed dose, but also a greater volume receiving >110% of the dose. IMRT was well tolerated; no patients developed acute gastrointestinal toxicity greater than grade 2. All seven experienced grade 2 nausea, three had grade 2 diarrhoea and two had grade 2 oesophagitis. Weight loss ranged from 0-12% (mean 6.1% and median 5.8%). IMRT in the treatment of gastric malignancies reduces the mean and above threshold doses to critical normal tissues. In an initial cohort of seven patients, 50.4 Gy delivered by IMRT is well tolerated and safe.

In vitro and in vivo performance of Ti6Al4V implants with plasma-sprayed osteoconductive hydroxylapatite-bioinert titania bond coat "duplex" systems: an experimental study in sheep.

To evaluate the in vivo performance of "duplex" hydroxylapatite top coat/TiO(2) bond coat systems, cylindrical Ti6Al4V rods of 130 mm in length and 11-13 mm in diameter were coated by atmospheric plasma spray (APS) technique with both a standard hydroxylapatite (HAp) layer and a HAp+TiO(2) bond coat "duplex" layer. In this pilot study coated and uncoated rods serving as controls were implanted into the femur of sheep so that their distal ends were freely suspended in the medulla of the femur. After an observation time of six months it was found that bone apposition and bone ingrowth were considerably increased in the presence of a osteoconductive coating. In particular, in vivo spalling and delamination frequently observed with HAp coatings was virtually absent in duplex coatings owing to the strong adhesion of the bond coat to the HAp top coat that anchored the latter solidly to the metallic surface of the implant. Some tentative mechanisms leading to this improved coating adhesion will be discussed.

Invariant p53 immunostaining in primary and recurrent breast cancer.

In animal models, acquired mutations of the p53 gene that result in increased p53 protein expression are associated with tumour recurrence following chemotherapy. The aim of this study was to test the hypothesis that breast cancer recurrences following adjuvant therapy exhibit aberrant p53 expression. We therefore evaluated p53 expression in paired primary and recurrent breast tumours: 48% of primary and 32% of recurrent tumours had abnormally increased p53 expression. Of the paired samples, 84% showed no change in p53 expression between the primary tumour and the metastasis. In fact, in no case was low (normal) p53 expression in the primary tumour followed by the development of high (aberrant) p53 expression in the recurrence. These results show that increased p53 expression is not selected for in the malignant cells emerging following adjuvant therapy, suggesting that p53 expression is unlikely to play a central role in breast cancer recurrences.

Compositional and microstructural changes of engineered plasma-sprayed hydroxyapatite coatings on Ti6Al4V substrates during incubation in protein-free simulated body fluid.

Hydroxyapatite (HAp) coatings engineered for maximum surface roughness (coating type I), porosity (coating type II), and tensile adhesion strength (coating type III) were deposited by atmospheric plasma spraying (APS) onto Ti6Al4V substrates and characterized for their microstructure, phase composition, and design properties. The composition of the as-sprayed coatings changed during treatment with protein-free simulated body fluid (Hank's Balanced Salt Solution, HBSS) for up to 12 weeks by preferential dissolution of thermal decomposition products, and amorphous calcium phosphate (ACP). From solutions supersaturated with respect to calcium and phosphorus ions, a thin, very porous layer precipitated onto the leached surfaces of coating type II samples after an incubation time of 8 weeks, consisting of spherical agglomerates of a poorly crystallized bone-like Ca-deficient defect hydroxyapatite that is thought to accelerate in vivo bone apposition rates and, hence, may induce favorable osseoconductive conditions.

Effect of radiotherapy after breast-conserving treatment in women with breast cancer and germline BRCA1/2 mutations.

PURPOSE: Recent laboratory data suggest a role for BRCA1/2 in the cellular response to DNA damage. There is a paucity of clinical data, however, examining the effect of radiotherapy (RT), which causes double-strand breaks, on breast tissue from BRCA1/2 mutation carriers. Thus the goals of this study were to compare rates of radiation-associated complications, in-breast tumor recurrence, and distant relapse in women with BRCA1/2 mutations treated with breast-conserving therapy (BCT) using RT with rates observed in sporadic disease. PATIENTS AND METHODS: Seventy-one women with a BRCA1/2 mutation and stage I or II breast cancer treated with BCT were matched 1:3 with 213 women with sporadic breast cancer. Conditional logistic regression models were used to compare matched cohorts for rates of complications and recurrence. RESULTS: Tumors from women in the genetic cohort were associated with high histologic (P =.0004) and nuclear (P =.009) grade and negative estrogen (P=.0001) and progesterone (P=.002) receptors compared with tumors from the sporadic cohort. Using Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer toxicity scoring, there were no significant differences in acute or chronic morbidity in skin, subcutaneous tissue, lung, or bone. The 5-year actuarial overall survival, relapse-free survival, and rates of tumor control in the treated breast for the patients in the genetic cohort were 86%, 78%, and 98%, respectively, compared with 91%, 80%, and 96%, respectively, for the sporadic cohort (P = not significant). CONCLUSION: There was no evidence of increased radiation sensitivity or sequelae in breast tissue heterozygous for a BRCA1/2 germline mutation compared with controls, and rates of tumor control in the breast and survival were comparable between BRCA1/2 carriers and controls at 5 years. Although additional follow-up is needed, these data may help in discussing treatment options in the management of early-stage hereditary breast cancer and should provide reassurance regarding the safety of administering RT to carriers of a germline BRCA1/2 mutation.

The impact of contralateral breast cancer on the outcome of breast cancer patients treated by mastectomy.

PURPOSE: To evaluate the clinical and pathological features of breast cancer patients who develop contralateral breast cancer (CBC) and assess the impact of the second breast cancer on their prognosis. PATIENTS AND METHODS: This retrospective study includes 2136 women with stage I-III breast cancer treated between 1927 and 1987 at the University of Chicago Hospitals. A total of 132 (6.2%) developed CBC during a median follow-up period of 14.2 years; all of them were treated with mastectomy for both breast cancers. We compare the prognostic characteristics, treatments, and outcomes of patients who developed bilateral breast cancer with those who had only unilateral breast cancer (UBC). We also compare the features of the first and the second tumors among patients with bilateral breast cancer (BBC). RESULTS: The annual incidence rate for CBC remained constant at an average rate of 0.23%, resulting in a cumulative incidence rate of 6.2%. Patients with BBC were significantly younger than those with UBC (median age, 51 years vs 54 years). No other significant differences were observed between BBC and UBC patients. Among BBC patients, the second cancer was smaller (2.0 cm vs 3.0 cm) and was associated with a lower incidence of axillary node involvement (29% vs 52%). The development of CBC was associated with worse survival (hazard ratio = 1.46 in comparison with patients who did not develop CBC, 95% CI of 1.09-1.95). On multivariate analysis, factors that decreased the disease-specific survival (DSS) in patients with BBC were a higher number of positive lymph nodes of the first and second cancers, a larger size of the second cancer, and a shorter interval between the two primaries. DISCUSSION: At the time of diagnosis of first breast cancer, BBC patients were significantly younger than UBC patients. The second cancer among the BBC patients was at an earlier stage than the first one; however, no difference was noticed in the pathological feature between the cancer in the UBC patients and the first cancer of BBC patients. There is an indication that the longer the interval between the two cancers, the better the survival of the BBC patients.

Individual characterisation of the metastatic capacity of human breast carcinoma.

The clinical implications of understanding the invasive and metastatic proclivities of an individual patient's tumour are substantial because the choice of systemic therapy needs to be guided by the likelihood of occult metastasis as well as by knowing when the metastases will become overt. Malignant potential is dynamic, progressing throughout the natural history of a tumour. Required of tumours is the development of critical phenotypic attributes: growth, angiogenesis, invasion and metastagenicity. Characterisation of the extent of tumour progression with regard to these major tumour phenotypes should allow the fashioning of individual therapy for each patient. To examine the clinical parameters and molecularly characterise the metastatic proclivity we have been studying a series of regionally treated breast cancer patients who received no systemic therapy and have long follow-up. Clinically we describe two parameters: metastagenicity - the metastatic proclivity of a tumour, and virulence--the rate at which these metastases appear. Both attributes increase with tumour size and nodal involvement. However, within each clinical group there is a cured population, even in those with extensive nodal involvement, underscoring the heterogeneity of breast cancers within each group and the need for further molecular characterisation. Using biomarkers that characterise the malignant phenotype we have determined that there is progression in the phenotypic changes. Angiogenesis and loss of nm23 are earlier events than the loss of E-cadherin, or abnormalities in TP53. The strongest biomarkers of poor prognosis are p53 and E-cadherin, but even when both are abnormal 42% of node-negative patients are cured indicating that other determinative steps need to occur before successful metastases are established. Identification of these critical later events will further increase the efficacy of determining the malignant capacities of individual tumours.

Should internal mammary nodes be sampled in the sentinel lymph node era?

BACKGROUND: Controversy exists regarding internal mammary lymph nodes (IMNs) in the staging and treatment of breast cancer. Sentinel lymph node identification with radiocolloid can map drainage to IMNs and directed biopsy can be performed with minimal morbidity. Furthermore, recent studies suggest that IMN drainage of breast tumors may be underestimated. To gain further insight into the prognostic value of IMNs, we reviewed the outcome of patients in whom the IMN status was routinely assessed. METHODS: A retrospective review of 286 patients with breast cancer who underwent IMN dissection between 1956 and 1987 was conducted. RESULTS: Median follow-up is 186 months, age was 52 years (range, 21-85 years), tumor size was 2.5 cm, and number of IMNs removed was 5 (range, 1-22); 44% received chemotherapy, 16% endocrine therapy, and 5% radiotherapy. Presence of IMN metastases correlated with primary tumor size (P < .0001) and number of positive axillary nodes (P < .0001) but did not correlate with primary tumor location or age. Overall, the 20-year disease-free survival is significantly worse for the 25% of patients with IMN metastases (P < .0001). In patients with positive axillary nodes and tumors smaller than 2 cm, there was a significantly worse survival (P < .0001) in the patients with IMN metastases. This difference in survival was not seen in women with tumors larger than 2 cm. CONCLUSIONS: Patients with IMN metastases, regardless of axillary node status, have a highly significant decrease in 20-year disease-free survival. Treatment strategies based on knowledge of sentinel IMN status may lead to improvement in survival, especially for patients with small tumors. At present, sentinel IMN biopsies should be performed in a clinical trial setting.

Separating favorable from unfavorable prognostic markers in breast cancer: the role of E-cadherin.

Distant metastases are the major cause of morbidity and mortality in women with breast cancer. The ability to predict the metastatic proclivity is essential in choosing the optimal treatment. Tumor size and grade, which are frequently used markers in node-negative breast cancer patients, are inadequate markers for prognosis and individualized treatment design. The steps in metastatic progression include angiogenesis, invasion, and changes in adhesion characteristics. We developed a strategy for choosing biomarkers representing these steps in malignant progression to identify patients with occult metastases who will need chemotherapy and spare those women whose tumors have not developed the capacity to spread. To evaluate the added significance of E-cadherin to that of nm23-H1 and angiogenesis in determining metastatic proclivity, we used archival material from 168 node-negative breast cancer patients who were treated with mastectomy without any adjuvant chemotherapy or hormone therapy. Immunohistochemistry was used to detect E-cadherin and nm23-H1 expression, whereas angiogenesis was determined by microvessel count (MVC) after immunohistochemical staining. The median follow-up is 14 years. We found that E-cadherin is better in identifying the poor prognosis patients. The 14-year disease-free survival (DFS) is 84%, 80%, and 56% in patients with high, intermediate, and low E-cadherin. The worst prognosis group using nm23-H1 and MVC as biomarkers has a 14-year DFS of 62%. In this group, if E-cadherin is low, the 14-year DFS is further decreased to 44%. Nm23-H1 and MVC are better in identifying the good prognosis patients. The long-term DFS is >90% if MVC is low or if nm23-H1 is high. Multivariate analysis shows that E-cadherin, nm23-H1, and MVC are more significant prognostic biomarkers than tumor size or grade. Loss of E-cadherin appears to be a latter step in the metastatic progression compared to angiogenesis and the loss of nm23-H1 expression.

Clinical progression of breast cancer malignant behavior: what to expect and when to expect it.

PURPOSE: Seemingly localized breast cancer is a heterogeneous mix of truly localized cancers and cancers with occult metastases. Our purpose is to determine the parameters of metastatic proclivity for the different clinical presentations of operable breast cancer and to present quantitative prognostic information useful to both doctors and patients. PATIENTS AND METHODS: A series of regionally treated breast cancer patients was analyzed to determine the likelihood and time of the appearance of clinical metastases for different clinical subgroups. Patients operated on at the University of Chicago from 1927 to 1987 for clinically regionally localized breast cancer, who received no systemic therapy as a part of their initial treatment, were included. Overall survival and distant disease-free survival in this mature series are analyzed. RESULTS: Metastagenicity, the metastatic proclivity of a tumor, increases with both tumor size and nodal involvement. This is also true for virulence, which is the rate at which these metastases appear. Each clinical group has a cured population, even those with extensive nodal involvement. A table provides a tool for determining the proportion of risk expended in each clinical group as a function of the distant disease-free survival. Whereas the likelihood of metastasis increases with tumor size and nodal involvement, the time to their appearance decreases. CONCLUSIONS: Breast cancer metastagenicity and virulence are heterogeneous even within clinically similar groups of operable breast cancer patients. Tumor progression is correlated with increasing tumor size and nodal involvement. Markers are needed to identify individual tumor virulence and metastagenicity.

Cathepsin B activity and protein levels in thyroid carcinoma, Graves' disease, and multinodular goiters.

Cathepsin B (CB) is involved in the hydrolysis of thyroglobulin (Tg) and thought to be regulated by thyroid stimulating hormone (TSH) in the normal thyroid. Our analyses of 91 thyroid tissues from 71 patients with Graves' disease (GD), multinodular goiter (MNG), papillary carcinoma (PC), or follicular carcinoma (FC), demonstrated a 2-fold increase in expression of CB in GD and an average increase of 1.5-fold in MNG (varying from 10-fold below normal to 6-fold above normal in MNG nodules), as might be predicted by the altered functional status of thyroid follicular cells in those diseases. However, CB activity was not downregulated in conjunction with the known "blocking effect" of malignancy on many thyroid functions, but rather increased on average 9-fold in papillary carcinomas (n = 33), and also showed a marked increase in 2 follicular carcinomas. Activity measurements were confirmed by CB protein detection on Western blot with moderately increased CB protein levels demonstrated in GD, variable expression in nodules of MNG, and markedly increased protein expression in carcinomas. In all diseased states, increased protein was detected primarily as overexpression of the 27 kd heavy chain of 2-chain mature CB and less frequently as overexpression of 31 kd single-chain mature CB. However, an additional 35 kd protein form was noted in 3 of 9 PCs, 1 of 2 FCs, and 1 of 4 GD cases but in none of 10 MNG cases. In conjunction with elevated CB activity plus additional protein bands on Western blots, altered patterns of CB immunohistochemical staining were observed, irrespective of the type of thyroid disease, suggesting certain common changes in CB expression, posttranslational processing, and vesicular trafficking. In summary, GD and MNG thyroid tissues demonstrated altered CB expression in keeping with predicted functional changes in thyroid follicular cells, while increased CB expression in carcinomas indicated a more pathological role for CB in thyroid cancers, possibly related to the processes of invasion or metastasis.

Microstructural and in vitro chemical investigations into plasma-sprayed bioceramic coatings.

Hydroxyapatite (HA) coatings plasma sprayed without and with bond coats (titania, zirconia) onto titanium alloy (Ti6A14V) substrates under both atmospheric and low pressure plasma spray conditions were investigated in terms of their microstructure and their resorption resistance during immersion in simulated body fluid (Hank's balanced salt solution). The microstructures of test samples were characterized using SEM on as-sprayed and leached surfaces and on the corresponding cross sections. Selected coating systems were studied by 2-dimensional secondary ion mass spectroscopy imaging to obtain information on plasma spray induced diffusional processes at the coating interfaces, as well as the spatial distribution of minor and trace elements. Coatings consisting of thin (10-15 microm) titania/zirconia (eutectic ratio) and titania bond coats, combined with a 150- to 180-microm thick HA top coat, yielded peel strengths in excess of 32 N/m, as well as sufficient resorption resistance.

Development of plasma-sprayed bioceramic coatings with bond coats based on titania and zirconia.

Bond coats for plasma-sprayed hydroxyapatite (HAp) coatings on Ti-6A1-4V hip endoprotheses are being developed for improved in vivo performance. Bond coat powders consisting of (i) CaO-stabilized zirconia, (ii) a eutectic composition of titania and non-stabilized zirconia, and (iii) titania were applied by atmospheric plasma spraying (APS) to Ti-6A1-4V-coupons and 100 microm-thick Ti-6A1-4V foils. Subsequently, a thick layer of HAp was sprayed onto the thin bond coats. Peel tests on Ti-6A1-4V foil/bond coat/HAp top coat assemblies revealed that titania and titania/ zirconia bond coats increased the peel adhesion strength in a statistically significant way from 22 N m(-1) (HAp without a bond coat) to >42 and 32 N m(-1), respectively. Microstructural investigations by SEM on cross-sections of coatings leached in simulated body fluid for up to 28 days led to the conclusion that the chemically very stable bond coats act as an improved chemical barrier against in vivo release of metal ions from the implant, as well as an improved adhesive bond by development of very thin well-adhering reaction layers, presumbly composed of perovskite, calcium dititanate, and/or calcium zirconate.

Aging, progression, and phenotype in breast cancer.

The malignant potential of cancer is dynamic, changing throughout the natural history of a tumor. For breast cancer, this is especially important because the clinical presentation has been altered by the increasing use of screening mammography. The varied outcomes of similarly staged patients is most consistent with breast cancer not being a homogeneous disease, but rather a spectrum of disease states that have varying capacities for growth and metastasis. Evolutionary pressures are at play in both tumor development and during the clinically apparent portion of the life of a tumor and are responsible for this spectrum of tumor heterogeneity. Required of tumors is the development of critical phenotypic attributes: growth, invasion, metastagenicity, and angiogenesis. The combination and permutation of genetic changes that result in the acquisition of these characteristics may vary, but they must result in some expression of each of these phenotypes. The expression of these attributes will differ as tumors evolve to become more adept at each of these characteristics. Recognizing tumor heterogeneity emphasizes the need to determine an individual tumor's place in the evolutionary spectrum. This may be accomplished using clinical features such as size, nuclear grade, and patient age, as well as by examining markers of angiogenesis, metastatic capacity, and proliferation. Identification of the extent of tumor progression with regard to these major tumor phenotypes should allow individual therapy to be fashioned for each patient.

Modulation of apoptotic response of a radiation-resistant human carcinoma by Pseudomonas exotoxin-chimeric protein.

Strategies to sensitize human tumors that are resistant to apoptosis have been clinically unsuccessful. We demonstrate that a structurally modified chimeric Pseudomonas exotoxin, PEdelta53L/TGF-alpha/KDEL, with binding specificity for the epidermal growth factor receptor, markedly enhances sensitivity of human xenografts to radiation killing. Exposure to PEdelta53L/TGF-alpha/KDEL decreases the apoptotic threshold through protein synthesis inhibition and simultaneous production of ceramide in tumor cells that lack functional p53 protein. In contrast, no increase in local or systemic toxicity was observed with the chimeric toxin and radiation. We conclude that biochemical targeting of the chimeric toxin and physical targeting of ionizing radiation may increase the therapeutic ratio in the treatment of human cancers with alterations of p53 expression. This strategy offers a high therapeutic potential for Pseudomonas exotoxin A chimeric proteins and irradiation.