Current status of endocrine therapy for metastatic breast cancer

Hormonal manipulation is currently the mainstay of palliative care for metastatic breast cancer because it is well tolerated and produces significant responses in approximately one-third of unselected patients. Tamoxifen, a nonsteroidal antiestrogen, is currently considered first-line therapy. Second-line agents include progestins and aromatase inhibitors. New agents, such as the "pure" antiestrogens and the gonadotropin-releasing hormone (GnRH) agonists, are being tested. Other approaches for affecting the hormonal milieu are also under investigation, including combinations of hormonal agents, hormonal agents plus biologics, and hormonal agents plus antiproliferative agents. This review will address the basis for endocrine therapy and possible mechanisms of hormonal resistance, currently available agents and newer ones on the horizon, and areas of future interest.     

Doxorubicin, vincristine, and cis-diamminedichloroplatinum (II) therapy in patients with advanced breast cancer

Thirty-six male albino rats were injected with either saline or 0.6 mg/kg scopolamine and placed on a metal grid. The grid was wired to a transistor-biased detector which determined, every second, whether the subject's resistance was above or below a preset threshold value. Over test sessions of five minutes, drug subject's resistances were above each of the three threshold values used (5, 10, 15 megohms) for significantly longer than those of control subjects. Scopolamine treated rats would therefore receive lower shock levels than control subjects in a shock experiment.     

Tamoxifen (antiestrogen) therapy in advanced breast cancer

Fifty-nine postmenopausal women with advanced breast cancer were treated with tamoxifen (antiestrogen), 20 mg orally twice a day for at least 2 months. They had been previously treated with other types of hormonal therapy or intensive chemotherapies, or both. Nineteen of the 59 patients (32%) had either a complete response (seven patients) or partial response (12 patients). The median duration of response was 9+ months. Tumors containing estrogen receptors and those that responded to previous hormonal manipulation tended to respond to tamoxifen (60% and 69%, respectively). Patients with receptor-negative tumor or with a history of failure of previous hormonal treatments did not respond to tamoxifen therapy. Tamoxifen is effective against advanced breast cancer. Side effects of the treatment were mild.     

Oestrogen-regulated genes in breast cancer: association of pLIV1 with response to endocrine therapy

Northern hybridization analyses of the oestrogen-inducible mRNAs pLIV1 and pS2 were compared with oestrogen receptor (ER) immunocytochemistry assessments in 40 untreated primary or early recurrent breast tumours. Significant associations were observed between pLIV1/ER (P < 0.03), pS2/ER (P < 0.001) and pLIV1/pS2 (P < 0.04) status. After disease recurrence, patients were treated with assessable courses of endocrine therapies. Positive pLIV1, pS2 and ER statuses in primary disease were consequently found to be predictive of endocrine responsiveness in the secondary lesions (P < 0.03, P < 0.02, P < 0.005 respectively). However, despite these associations, a number of pLIV1- and/or pS2-positive tumours failed to respond to therapy.     

Primary endocrine therapy for advanced breast cancer: to start with tamoxifen or with medroxyprogesterone acetate?

BACKGROUND: The availability of compounds effective against metastatic disease and at the same time excellently tolerated even in long-term administration has determined the choice of tamoxifen as primary treatment for palliation in metastatic breast cancer. Other drugs or other hormonal approaches were hardly tested against tamoxifen, especially as first-line treatment. PATIENTS AND METHODS: 119 patients with metastatic breast cancer and no prior endocrine therapy were randomized to receive either tamoxifen (TAM) 20 mg/day orally (64 patients), or medroxyprogesterone acetate (MAP) 1g/day i.m. 5 days/week for 4 weeks and then 500 mg twice a week (55 patients). The subsequent endocrine therapy was also prospectively defined at study entry. RESULTS: A total of 111 events, contributing to the endpoint 'time to progression' have so far been observed: a study of similar size would have a 90% power to detect a hazard ratio of 1.85. Initial MAP was associated with a significantly higher remission rate (50% versus 30% for tamoxifen; p = 0.023) and a marginally significantly longer median time to progression (8.8 versus 5.4 months; p = 0.051). Overall survival was also longer for the MAP group (28 versus 20 months; p = 0.384). The use of MAP was associated with a significantly higher toxicity, mainly hypertension, weight gain and tremor. CONCLUSIONS: The implications of these results are that initial endocrine therapy in postmenopausal patients with metastatic disease should be MAP if the patient is willing to accept the side effects of high-dose progestins. Progestins should be tested in the adjuvant setting for postmenopausal women, especially those with no tendency to hypertension or obesity.     

Fatty acid composition of breast adipose tissue in breast cancer patients and in patients with benign breast disease

In this study, we report on the cell adhesion properties of marrow stromal cells to extracellular matrix components such as collagen and noncollagenous proteins. The osteoblastic cells and their non-osteoblastic counter-parts (MBA series) from the marrow stroma differentially recognized a spectrum of extracellular matrix proteins. The osteoblastic cells, MBA-15, preferentially attached to bone matrix proteins, whereas fibroendothelial MBA-2.1 and adipocytic 14F1.1 cells did not. The MBA-15 cells demonstrated a preference in their attachment to fibronectin > mixture of collagens > bone matrix extracts > collagen type I > noncollagenous proteins. Clonal subpopulations derived from the MBA-15 cell line representing various stages along the osteogenic lineage expressed differential attachment preference. MBA-15.4, a less differentiated clonal line, was compared to MBA-15.6, a mature cell line.     

Short-term effects of telephone therapy for breast cancer patients.

The authors report the short-term effects of a clinical trial testing 2 telephone therapies for breast cancer patients. Women (N = 222) with breast cancer were recruited and randomly assigned to cancer education, emotional expression, or standard care. Oncology nurses conducted 6 individual 30-min-therapy phone sessions. Women in the cancer education condition reported greater perceived control than women in the standard care condition. No treatment effects were obtained for mood or quality of life. These are the 1st data from a large-scale study testing telephone therapy, and they suggest that such therapies may be ineffective. Explanations for the results include therapy type and delivery, participant characteristics, short- versus long-term results, therapy content, and whether therapy is necessary for breast cancer patients. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Determinants of global clinical change assessment in patients with early Alzheimer''s disease

L-pyroglutamyl-D-alanine amide significantly enhanced freezing response in the group of rats with massed training and reduced it in the group with spaced training. The control animals revealed a higher freezing response with the spaced training. No differences occurred between the groups in a cue test.     

Incidence of primary malignancies other than breast cancer among women treated with radiation therapy for benign breast disease

In addition to left ventricular pump failure and low cardiac output, structural and metabolic alterations of skeletal muscle are thought to contribute to exercise intolerance seen in patients with CHF. Studies using cardiac myocytes have implicated nitric oxide elaborated by inducible nitric oxide synthase (iNOS) as a potential agent associated with the genesis of dilated cardiomyopathy. The present study was designed to locate iNOS in the working skeletal muscle of patients with congestive heart failure. Specific antibodies were used to detect iNOS by immunohistochemistry in skeletal muscle biopsies (m. vastus lateralis) of 37 patients with left ventricular pump failure and 8 normal controls. The expression was restricted to skeletal muscle myocytes and was increased five- to ninefold in patients with chronic heart failure. There was no statistically significant difference in iNOS expression between patients with dilated cardiomyopathy and those with ischemic cardiomyopathy. The finding of a locally increased expression of iNOS and the experimental evidence that NO attenuates the contractile performance of the skeletal muscle suggest that the expression of iNOS may be responsible for the exercise intolerance seen in patients with chronic heart failure.     

Incidence and clinical relevance of the occurrence of bundle-branch block in patients treated with thrombolytic therapy

BACKGROUND: Whether thrombolytic therapy alters the incidence and clinical outcome of bundle-branch block is unclear. METHODS AND RESULTS: We examined the occurrence of new-onset bundle-branch block, both transient and persistent, in 681 patients with acute myocardial infarction enrolled in the Thrombolysis and Angioplasty in Myocardial Infarction 9 and Global Utilization of Streptokinase and t-PA for Occluded Arteries 1 protocols. Each patient underwent continuous 12-lead ECG monitoring for 36 to 72 hours with the Mortara ST monitoring system. Bundle-branch block was characterized as right, left, alternating, transient, or persistent. The overall incidence of bundle-branch block was 23.6% (n = 161), with transient block in 18.4% (n = 125) and persistent block in 5.3% (n = 36). Right bundle-branch block was found in 13% (n = 89) of the population; left bundle-branch block was found in 7% (n = 48). Alternating bundle-branch block was seen in 3.5% (n = 24) of patients. Left anterior descending artery infarcts accounted for most bundles (54%, n = 79). Patients with bundle-branch block had lower ejection fractions, higher peak creatine phosphokinase levels (P < .0001), and more diseased vessels (P < .019). Mortality rates in patients with and without bundle-branch block were 8.7% and 3.5%, respectively (P < .007). A higher mortality rate was observed in the presence of persistent (19.4%) versus transient (5.6%) or no (3.5%) bundle-branch block (P < .001). CONCLUSIONS: Thrombolytic therapy reduces the overall mortality rate associated with persistent bundle-branch block. However, persistent bundle-branch block remains predictive of a higher mortality rate than either transient or no bundle-branch block. Continuous 12-lead ECG monitoring provides an accurate characterization of the incidence and type of conduction disturbances after acute myocardial infarction.     

L-arginine--substrate for no synthesis--its beneficial effects in therapy of patients with peripheral arterial disease: comparison with placebo-preliminary results

Thoracoscopic enucleation of leiomyoma of the esophagus was successfully performed in three cases with a new technique called the "balloon push-out method." Instead of pulling the tumor, which is hard to grasp because of its delicate nature, we pushed it out of the esophageal wall with a balloon-mounted intraluminal endoscope in order to perform the operation faster and more safely. We found this technique to be very useful in this kind of operation.     

Photodynamic therapy using mono-L-aspartyl chlorin e6 (Npe6) for the treatment of cutaneous disease: a Phase I clinical study

The activity of a new photosensitizer, mono-L-aspartyl chlorin e6 (Npe6), was assessed in an ascending dose Phase I study for patients with superficial tumor. Eleven patients, with a total of 14 tumor sites, were treated with photodynamic therapy (PDT) using Npe6. Lesions included recurrent adenocarcinoma of the breast, basal cell carcinoma, and squamous cell carcinoma. The phototherapy protocol consisted of a single i.v. injection of 0.5-3.5 mg/kg Npe6, followed 4 h later by 25-100 j/cm2 at 664 nm of light. PDT using Npe6 caused no significant toxicity with the exception of temporary generalized skin photosensitivity. In all cases, light treatment caused immediate tissue blanching, followed by a marked necrosis of the tumor mass. Regression of tumor occurred over 24-48 h after the light treatment and was followed by the formation of a heavy eschar over the tumor site. Tumor regression was short-lived at Npe6 doses of 1.65 mg/kg and below. In two of three patients, tumor regression was either incomplete or tumors recurred within the 12-week observation period. Increasing the Npe6 dose to 2.5 or 3.5 mg/kg combined with 100 J/cm2 of light energy resulted in better control of tumor regrowth with 66% (6/9) of sites remaining tumor-free through 12 weeks observation. This increased tumor response came at the expense of the tissue selectivity observed at Npe6 doses of 1.65 mg/kg and below. There was no apparent selectivity for destruction of tumor compared with normal skin at Npe6 doses of 2.5 mg/kg and above. These data demonstrate that Npe6 is both an effective and safe photosensitizer for use in PDT and provide the impetus for continued study in Phase II clinical trials.     

Mitosin (a new proliferation marker) correlates with clinical outcome in node-negative breast cancer

Tumor proliferation rate is an important prognostic factor in breast cancer, and S-phase fraction (SPF), as measured by flow cytometry, is the most clinically validated of several methods for measuring it. However, flow cytometry is not well suited to evaluating the formalin-fixed, paraffin-embedded tumors that are routinely available or to the increasing number of small breast cancers. These and other limitations have motivated research into alternative methods for measuring proliferation, including immunohistochemistry (IHC) against cell cycle-related antigens, which are better suited for the evaluation of small archival tissue samples. Mitosin is a recently described 350 kD nuclear phosphoprotein that is expressed in the late G1, S, G2, and M phases of the cell cycle but not in G0. Using a new monoclonal antibody (14C10), this pilot study evaluated mitosin expression by IHC in a series of 386 node-negative, formalin-fixed, archival breast cancers and correlated the results with several prognostic factors and clinical outcome (median follow-up, 78 months; range 3-214 months). The median and range of mitosin positive cells were 7% and 1-47%, respectively. There was a strong positive correlation between mitosin and SPF (r = 0.57; P = 0.0001), and there were significant negative correlations with estrogen receptor, progesterone receptor, and patient age. Mitosin was not related to overall survival in this pilot study. However, in a univariate cutpoint analysis of disease-free survival (DFS), patients with high levels of mitosin (>9% positive cells) had significantly worse DFS than did patients with lower levels (68% versus 84% at 5 years, respectively). In a multivariate analysis of DFS, large tumor size (>2 cm) and high mitosin were the only independently significant predictors of recurrence (relative risks = 2.47 and 1.72, respectively) in a model containing the additional factors estrogen receptor, progesterone receptor, patient age, and SPF. These preliminary results suggest that mitosin as assessed by IHC may be superior to SPF as a prognostic factor in node-negative breast cancer, but additional studies are necessary to validate these promising findings.     

Prognostic factors for disease progression in advanced Hodgkin''s disease: an analysis of patients aged under 60 years showing no progression in the first 6 months after starting primary chemotherapy

Cell and tissue concentrations of NO2- and NO3- are important indicators of nitric oxide synthase activity and crucial in the regulation of many metabolic functions, as well as in nonenzymatic nitric oxide release. We adapted the capillary electrophoresis technique to quantify NO2- and NO3- levels in single identified buccal neurons and ganglia in the opisthobranch mollusc Pleurobranchaea californica, a model system for the study of the chemistry of neuron function. Neurons were injected into a 75-microm separation capillary and the NO2- and NO3- were separated electrophoretically from other anions and detected by direct ultraviolet absorbance. The limits of detection for NO2- and NO3- were <200 fmol (<4 microM in the neurons under study). The NO2- and NO3- levels in individual neurons varied from 2 mM (NO2-) and 12 mM (NO3-) in neurons histochemically positive for NADPH-diaphorase activity down to undetectable levels in many NADPH-diaphorase-negative cells. These results affirm the correspondence of histochemical NADPH-diaphorase activity and nitric oxide synthase in molluscan neurons. NO2- was not detected in whole ganglion homogenates or in hemolymph, whereas hemolymph NO3- averaged 1.8 +/- 0.2 x 10(-3) M. Hemolymph NO3- in Pleurobranchaea was appreciably higher than values measured for the freshwater pulmonate Lymnaea stagnalis (3.2 +/- 0.2 x 10(-5) M) and for another opisthobranch, Aplysia californica (3.6 +/- 0.7 x 10(-4) M). Capillary electrophoresis methods provide utility and convenience for monitoring NO2-/NO3- levels in single cells and small amounts of tissue.     

CEA and CA 15-3 in pleural effusion of advanced breast cancer patients: clinical relevance and diagnostic value

Serum and pleural effusion fluid were tested for CEA concentration in 83 advanced breast cancer patients, in 43 of whom CA 15-3 was also determined. All pleural effusions were clinically malignant. The sensitivity of the CEA test for the presence of pleural metastases was closer to that of the CA 15-3 test in effusion (0.59 and 0.79, respectively) than the sensitivity of CEA compared to CA 15-3 in serum (0.43 vs. 0.79). The use of two markers combined with cytology increased the diagnostic rate from 48% (cytologically positive) to 88% (cytologically positive and/or with one or both markers increased in effusion). A high diagnostic rate in cytologically negative effusions (65%), and in effusions presented as the sole metastatic involvement (100%), points to the clinical value of these two markers. Our results show that markers produced by pleural metastases may be secreted either into the effusion fluid or into serum, or both. This finding, as well as some other observations, are discussed in the present paper.     

The first clinical pilot study of roquinimex (Linomide) in cancer patients with special focus on immunological effects

Issues related to context effects in hypnosis research are briefly reviewed. The contributions of Canadian hypnosis researchers to current theory and research on context effects are acknowledged. Bowers and colleagues at the University of Waterloo emphasized the scope and subtlety of contextual influences on correlates of hypnotic suggestibility, and they promoted the development of a consistency motivation theory of context effects. Spanos and colleagues at Carleton University generalized context effects within the domain of hypnosis, prompting extension of this work to general personality measurement. Implications of findings on consistency motivation for hypnosis research are discussed in terms of person-by-situation interactions.     

Impact of menopausal hormone-replacement therapy on clinical and laboratory characteristics of breast cancer

In response to the General Medical Council's initiative to reform UK medical undergraduate education only a minority of medical schools have developed entirely novel curricula. Although the experiences gained by these schools in curriculum design and planning have not been recorded in the literature they are likely to be of interest to other medical schools still contemplating course revision. The medical school at the University of Liverpool recently launched an integrated problem-based course differing radically from its predecessor. The General Medical Council considered integration of contributing disciplines one of the most important aims of reform, yet courses that integrate independent component disciplines may be perceived by staff as threatening due to the loss of structure and disciplinary autonomy. Strategies for early course development must take account of these concerns as well as dealing with the identification of course content. A multidisciplinary consensus group process, designed to combat some of these problems, was employed to identify the learning objectives and core content for the new course. The purpose of this paper is to describe, first, the processes employed to identify the core palliative care component for a new PBL curriculum and secondly, how these objectives were integrated horizontally and vertically throughout all course elements.     

Results of combination therapy of UFT-E with low-dose CDDP for patients with advanced recurrent breast cancer]

CDDP, as a modulator for 5-FU, has already been described as a very effective treatment for gastrointestinal tract cancer. We administered a dose of 400 mg of UFT-E orally every day, and 10 mg of CDDP by drip infusion twice weekly, for more than 10 weeks to 12 outpatients with metastatic local, pulmonary, hepatic, osteal or multiple-organ cancer which showed a poor response to the pretreatment, and assessed its efficacy and drug toxicity. In terms of the clinical efficacy of this therapy, CR was noted in one patient and PR in 2 patients with a response rate of 25%. The incidence of drug toxicity was low. Complications included temporal transient nausea and anorexia in two patients and leukopenia grade 2 as bone marrow suppression in 3 patients. From the standpoint of QOL, as well as in terms of both antitumor effect and drug toxicity, the therapy mentioned above was believed to be effective for outpatients with advanced recurrent breast cancer.