Primary endocrine therapy in locally advanced breast cancers--the Nottingham experience.

INTRODUCTION: There are trials comparing different neoadjuvant chemotherapy regimens for locally advanced primary breast cancer (LAPC). Few studies have evaluated alternative therapeutic approaches towards LAPC. A previous trial from our institute in LAPC patients unselected for oestrogen receptor (ER) status, comparing primary endocrine therapy versus multimodal treatment, showed no difference in breast cancer related deaths or overall survival. We report our experience of primary endocrine therapy in ER+ LAPC. METHODS: Between 1988 and 2007, 195 ER+, non-inflammatory LAPC patients were treated with primary endocrine agents in our institute, due to patient choice, being unfit for chemotherapy, or recruitment into the above mentioned trial. All patients had disease assessable by UICC criteria. RESULTS: Median age was 69 years. The median follow-up was 61 months. 154 patients (79%) received endocrine treatment alone. 185 patients (95%) derived clinical benefit (complete response/ partial response/ stable disease) for > or =6 months from primary endocrine therapy. Overall 5-year survival was 76% and 5-year breast cancer specific survival was 86%. CONCLUSION: In selected group of ER+ LAPC patients, primary endocrine treatment achieves excellent survival outcome and is a viable alternative to other modalities of treatment.

Pacemaker programming in patients with first-degree AV-block: Programming pattern and possible consequences.

BACKGROUND: The optimal way of pacing in patients with an indication for pacing and concomitant first-degree atrioventricular (AV)-block is not known, and consequently, firm guidelines on this topic are lacking. This study explored the current pacemaker programming pattern in patients with first-degree AV-block who have a dual chamber pacemaker without cardiac resynchronization. METHODS: The study was a retrospective chart review conducted at Duke University Hospital. Patients receiving a pacemaker due to sinus node dysfunction with coexistent first-degree AV-block were studied. Baseline demographics and characteristics, as well as pacemaker programming parameters and follow-up data, were collected through chart review. Preimplantation and postimplantation electrocardiograms were analyzed. RESULTS: A total of 74 patients were included (mean age, 75 ± 11 y; 53% men). The mean ± SD preimplant PR interval and QRS duration was 243 ± 46 and 110 ± 30 milliseconds, respectively. A history of atrial fibrillation was present in 49% of the patients, and 77% had a normal left ventricular ejection fraction. The majority of patients (65%) had their pacemakers programmed to atrial pacing (AAI/DDD +/-R), whereas 32% and 2.7% of the pacemakers were programmed to AV-sequential pacing (DDD) and ventricular pacing (VVI), respectively. There were no significant differences in baseline characteristics or electrocardiogram measures between patients programmed to the 3 pacing modes. Patients with pacemakers programmed to AAI had a lower ventricular pacing percentage at follow-up (8 vs 55, and 46% [DDD and VVI, respectively]; P < .001). CONCLUSIONS: There was no evident association between baseline characteristics and programmed pacing mode in patients with first-degree AV-block. The choice of pacing mode affects long-term pacing burden, which in turn has been shown to influence outcome.

Evaluation of hollow fiber bioreactors as an alternative to murine ascites production for small scale monoclonal antibody production.

The objective of this study was to compare monoclonal antibody production in hollow fiber bioreactor systems and murine ascites to determine the feasibility of the bioreactor system as a potential alternative to the use of mice. Three hybridoma cell lines were grown in each of three different hollow fiber bioreactor systems and in groups of 20 mice. Mice were primed with 0.5 ml pristane intraperitoneally 14 days prior to inoculation of 1X10(6) hybridoma cells. Each mouse was tapped a maximum of three times for collection of ascites. Ascites volumes and daily clinical observations were recorded. Bioreactors were harvested three times weekly for 65 day and were monitored by cell counts, cell viability and media glucose consumption. Time and materials logs were maintained. The total quantity of monoclonal antibody produced in 20 mice versus the mean production for the three different bioreactors in 65 days was as follows: cell line 2B11, 455 mg vs. 168 mg; cell line 3C9, 446 mg vs. 565 mg; and cell line RMK, 997 mg vs. 1023 mg. Mean monoclonal antibody concentration ranged from 4.07 to 8.37 mg/ml in murine ascites, and from 0.71 to 11.10 mg/ml in hollow fiber bioreactor system. Although time and material costs were generally greater for the bioreactors, these results suggest that hollow fiber bioreactor system merit further investigations as potentially viable in vitro alternatives to the use of mice for small scale (< 1 g) monoclonal antibody production.

Low-dose postoperative aprotinin reduces mediastinal drainage and blood product use in patients undergoing primary coronary artery bypass grafting who are taking aspirin: a prospective, randomized, double-blind, placebo-controlled trial.

BACKGROUND: Although low-dose aprotinin administered after cardiopulmonary bypass has been reported to reduce mediastinal blood loss and blood product requirements in patients not taking aspirin, it is unknown whether low-dose postoperative aprotinin has any beneficial effects in patients undergoing coronary artery bypass operations who are at high risk of excessive postoperative bleeding and increased transfusion requirements because of aspirin use until just before the operation. METHODS: Fifty-five patients undergoing primary coronary artery operations with cardiopulmonary bypass who continued taking aspirin (150 mg/d) until the day before the operation were enrolled in a prospective, randomized, double-blind trial to receive a single dose of either placebo (n = 29) or 2 x 10(6) kallikrein inhibiting units of aprotinin (n = 26) at the time of sternal skin closure. RESULTS: Patients in the aprotinin group had a lower rate (28 +/- 18 vs 43 +/- 21 mL/h [mean +/- standard deviation], P <.005) and total volume of mediastinal drainage (955 +/- 615 vs 1570 +/- 955 mL, P <.007), as well as a shorter duration of mediastinal drain tube insertion (24.4 +/- 13.8 vs 31.3 +/- 16.5 hours, P <.05). In addition, a smaller proportion of patients receiving aprotinin required a blood product (31% vs 62%, P =.03), resulting in a reduction in the use of packed cells by 47% (P =.05), platelets by 77% (P =.01), fresh frozen plasma by 88% (P =.03), and total blood products by 68% (P =.01) in this group. CONCLUSIONS: These results suggest that postoperative administration of low-dose aprotinin in patients taking aspirin until just before primary coronary artery operations with cardiopulmonary bypass not only reduces the rate and total amount of postoperative mediastinal blood loss but also lowers postoperative blood product use.

In vitro hydrolysis of monofluorophosphate by dental plaque microorganisms.

Enzymic hydrolysis of sodium monofluorophosphate by suspensions of dental microorganisms has been demonstrated at pH 5.1, pH 7.0, and pH 8.4, using a fluoride-selective electrode. The extracellular medium from viable Streptococcus mutans K1R cells contained low MFPase and paranitrophenyl phosphatase activity. It is hypothesized that the enzymes responsible for MFP hydrolysis by S. mutans K1R are intracellular, and that cell disruption is necessary for hydrolysis to be manifested; this question requires further study. In vitro MFPase activity was of a magnitude consistent with the hypothesis that it may significantly raise the fluoride ion concentration of plaque within the several minutes MFP would be in the mouth during toothbrushing.

An analysis of resources for indigenous women in NSW about cervical screening.

OBJECTIVE: To examine resources about cervical screening made available to Indigenous women in NSW. METHOD: An Aboriginal woman, on behalf of another Aboriginal woman, telephoned 47 NSW based organisations in May 1998 for information about cervical screening. Received materials were analysed for format, content and readability and then submitted to a panel of Indigenous women for their feedback. RESULTS: Of those 34 organisations agreeing to send resources, only 20 (59%) did so. After removing duplicates, 12 cervical screening resources were available for review of which six were designed and printed in NSW and the other six originated outside NSW. Of the six resources developed in NSW, two (33%) were for Aboriginal women. Of the six resources originating from outside of NSW, another two (33%) also were for Aboriginal women. The Flesch readability scores for resources ranged from 58.6 to 87.27. Those developed in NSW had a significantly lower readability score than those from outside of NSW (p = 0.025). Despite lower education levels among the target group, there was no difference in the readability scores of resources designed for Indigenous women (p = 1). CONCLUSIONS: Most resources obtained by us were not tailored for Indigenous women. IMPLICATIONS: This study has set a base line for resources available for Indigenous women. Our method could be replicated in the future to evaluate and monitor improvement.

Effect of isoflurane on hematologic variables in ferrets.

Effects of isoflurane on the CBC in ferrets were studied. There was rapid decrease in all hematologic variables after induction of anesthesia. Percentage reductions in indices of the erythron (hematocrit, RBC count, hemoglobin concentration) exceeded those of plasma protein concentration and WBC count at the first postinduction time point. There was little additional decrease in these variables for the duration of anesthesia. The values had partially recovered to preanesthetic baseline at 45 minutes after anesthesia. Although these alterations appear to be well tolerated in healthy ferrets, care should be exercised when subjecting anemic, geriatric, or debilitated ferrets to isoflurane-induced anesthesia.

Distribution of technetium 99m-labeled red blood cells during isoflurane anesthesia in ferrets.

OBJECTIVE: To address the physiologic mechanism of isoflurane-associated reduction in hematologic variables in ferrets. ANIMALS: 6 young adult female ferrets. PROCEDURE: Distribution of 99mTc-labeled autologous erythrocytes was measured by serial in vivo imaging. Data were recorded in 4 ferrets, using a gamma camera, immediately prior to anesthesia, 15 minutes after 2% isoflurane anesthesia in O2 via endotracheal tube, 1 minute prior to and throughout a 10-minute phenylephrine infusion, 20 and 40 minutes after termination of the phenylephrine infusion, and 45 minutes after termination of anesthesia. Blood indices were also measured at times that paralleled those for imaging. One ferret served as a conscious control (no anesthetic administration), and another as an isoflurane control (no phenylephrine administration). RESULTS: In ferrets under anesthesia, splenic radioactivity increased from baseline of 10.2 +/- 2.0% to 38.4 +/- 3.2% (mean +/- SEM; P < 0.05) of the injected dose. Splenic radioactivity decreased to 13.4 +/- 3.8% of the injected dose during phenylephrine infusion and to near baseline for the recovery image. Splenic radioactivity in the conscious control remained constant throughout the study, whereas that of the anesthetized control was persistently increased throughout administration of isoflurane. Percentage reduction of the 15-minute sample values, compared with baseline values for all hematologic indices, was: RBC count, 33% (P < 0.05); hemoglobin concentration, 34% (P < 0.05); hematocrit, 35% (P < 0.05); and plasma protein concentration, 20% (P < 0.05). All RBC variables returned to within 7 to 14% of baseline by 45 minutes after termination of anesthesia. CONCLUSION: Isoflurane anesthesia causes splenic sequestration of RBC in ferrets that is partially reversed by phenylephrine infusion or termination of anesthesia. Thus, investigators and clinicians should be cautious when interpreting hematologic findings in isoflurane-anesthetized ferrets, and accordingly, fluid treatment and transfusion should be planned.

Neoadjuvant endocrine treatment in primary breast cancer - review of literature.

Chemotherapeutic agents have dominated neoadjuvant treatment compared to endocrine agents in the past and have demonstrated their ability to produce tumour shrinkage to allow breast conservation. However, in the more recent setting, studies have been emerging with the use of aromatase inhibitors, especially comparing its use with tamoxifen in selected group of patients. The role of tamoxifen in its ability to achieve tumour shrinkage has been evaluated in the past, and has shown to produce slow but sustained response. Aromatase inhibitors have shown superiority over tamoxifen in adjuvant and metastatic setting, and the aim of our study was to compare their outcome with regard to response and breast conservation in the neoadjuvant setting. We also looked into optimum duration of neoadjuvant treatment and also the role of pathological complete response as a surrogate marker for clinical outcome. Our review highlights the superiority of aromatase inhibitors over tamoxifen in the neoadjuvant setting and even challenges chemotherapy with regard to response in selected group of patients.

Aboriginal health: why is reconciliation necessary?

Many health professionals are deeply troubled by the persistent health inequities between Aboriginal and non-Aboriginal Australians. From a social and political perspective it is clear that, for there to be appreciable improvement in Aboriginal health, a process of reconciliation which acknowledges the past in the light of the present needs to be adopted across all sectors of society. We give some practical advice for promoting reconciliation.

Monoclonal antibody production in murine ascites. I. Clinical and pathologic features.

BACKGROUND AND PURPOSE: Murine ascites production has been associated with appreciable morbidity and mortality, thus raising animal-welfare concerns. To address these concerns, the clinicopathologic changes associated with in vivo production of monoclonal antibodies in mice were characterized, and results were compared among cell lines. METHODS: Five hybridoma cell lines were grown in groups of 20 mice. Fourteen days prior to inoculation with 10(6) hybridoma cells, mice were primed with 0.5 ml of pristane given intraperitoneally; 12 mice were sham treated (controls). Ascites fluid was collected a maximum of three times by abdominal paracentesis. Clinical observations and pre- and postabdominal tap body weights were recorded. Necropsies were performed on all mice. RESULTS: For all groups combined, overall survival to tap 1 was 98%, to tap 2 was 96%, and to tap 3 was 79%; survival among groups ranged from 90 to 100% for tap 1, 85 to 100% for tap 2, and 35 to 100% for tap 3. Disseminated intra-abdominal seeding with irregular soft tissue and/or solid tumor masses was observed at necropsy. CONCLUSIONS: Significant clinicopathologic changes were associated with monoclonal antibody production in mice, and differences between various hybridoma cell lines were apparent.

Monoclonal antibody production in murine ascites. II. Production characteristics.

OBJECTIVE: To characterize monoclonal antibody production parameters of five hybridoma cell lines in murine ascites for correlation with clinicopathologic changes in mice. METHODS: Five hybridoma cell lines were grown in groups of 20 mice. Fourteen days prior to inoculation with 10(6) hybridoma cells, mice were primed with 0.5 ml of pristane given intraperitoneally. Ascites fluid was collected a maximum of three times by abdominal paracentesis; volume was measured and antibody concentration was determined by ELISA for each sample. RESULTS: Trends differed among cell lines when comparing ascites volumes and antibody concentrations over time from the first to the third tap. Antibody production was greatest at tap 1 for Groups 2B11 and 2C6D9; tap 2 for Group 3C9; and tap 3 for Groups RMK and 3D6. Total antibody production ranged from 422.90 to 996.64 mg; total ascites fluid volume ranged from 74.2 to 115.7 ml; and mean antibody concentration for taps 1, 2, and 3 ranged from 2.50 to 15.03 mg/ml among cell lines. CONCLUSION: Production characteristics were significantly different among hybridoma cell lines. Determination of production characteristics of hybridomas and correlation with clinicopathologic changes in mice may be valuable in making recommendations for managing mice with ascites.

Diarrhea in U.S. troops deployed to Thailand.

Ninety-five (28%) of 333 U.S. military personnel deployed to Ubonratchathani, Thailand, for 1 month in February 1993 developed diarrhea. Campylobacter jejuni was identified in 6 (25%), attaching and effacing Escherichia coli was identified in 3 (13%), nontyphoidal Salmonella spp. were identified in 2 (8%), and rotavirus was identified in 1 (4%) of 24 persons who had diarrhea and submitted specimens.

Fetal DNA in maternal plasma is elevated in pregnancies with aneuploid fetuses.

Current non-invasive screening methods for the prenatal diagnosis of fetal aneuploidies are hampered by low sensitivities and high false positive rates. Attempts to redress this situation include the enrichment of fetal cells from maternal blood, or the use of fetal DNA in the plasma of pregnant women. By the use of real-time quantitative polymerase chain reaction (PCR) it has recently been shown that circulatory male fetal DNA in maternal plasma is elevated in pregnancies with trisomy 21 fetuses. In this independent study we confirm and extend upon these results by showing that the levels of fetal DNA are also elevated in pregnancies with other chromosomal aneuploidies (mean=185.8 genome equivalents/ml; range=62.2-471.7) when compared to pregnancies with normal male fetuses (mean=81.9 genome equivalents/ml; range=28.8-328.9), p=0.005. This elevation was greatest for fetuses with trisomy 21, whereas it was not significant for fetuses with trisomy 18, p=0.356. These data suggest that a quantitative analysis of such fetal DNA levels may serve as an additional marker for certain fetal chromosomal abnormalities, in particular for trisomy 21.

T10B9 (MEDI-500) mediated immunosuppression: studies on the mechanism of action.

The murine IgM anti-human CD3/TCR mAb T10B9 is an effective agent for the reversal of acute cellular renal allograft rejection which offers several advantages over conventional OKT3 therapy. These include reduced morbidity and a more rapid decrease in serum creatinine levels. In the studies presented here comparing T10B9 and OKT3, soluble T10B9 is shown to be a nonactivating anti-T cell mAb. Evidence for its lack of activating potential includes in vitro failure to stimulate PBMC proliferation either alone or in the presence of nonmitogenic doses of phorbol ester, failure to induce the expression of early and late activation antigens and failure to induce IFN-gamma, TNF-alpha, IL-6 or IL-2 release. Analysis of acute renal allograft rejection patient plasma cytokine levels 2 h after the first dose support the hypothesis that T10B9 has reduced immunoactivation activity in vivo. Both TNF alpha and IFN gamma patient plasma levels are significantly reduced in T10B9 as compared to OKT3 therapy. However, T10B9 is capable of cellular signaling as demonstrated by its ability to induce apoptosis and IL-2 release in the human T cell line Sup-T13. Thus T10B9 retains the potent immunosuppressive activity of OKT3 with reduced immunoactivation.

Acute fulminant sarcocystosis in a captive-born rhesus macaque.

A captive-born juvenile female rhesus macaque (Macaca mulatta) was acquired from a commercial breeder and placed in quarantine. Within 8 days of arrival, the animal became anorexic, inactive, and dehydrated. Subsequently, generalized edema and facial ecchymoses developed, and despite supportive therapy, the animal became moribund and was euthanatized. Macroscopic examination showed diffuse stippling and streaking of the myocardium. Histopathologic examination revealed multifocal to coalescing myocardial edema, necrosis, lymphohistiocytic inflammation, and generalized endothelial infection with Sarcocystis sp. Immature and mature schizonts within endothelial cells were most prevalent in the heart. Fewer schizonts were present in the vasculature of other tissues, including skeletal muscle, smooth muscle, adipose tissue, brain, and retina. Mature tissue cysts within muscle fibers were not found in the myocardium but were occasionally seen in skeletal muscle. Analysis of polymerase-chain-reaction-amplified 18s ribosomal RNA gene sequences revealed 96% identity to published sequences of S. hirsuta, S. hominis, and S. fusiformis and 95% identity to S. cruzi and S. tenella. However, sequences did not show complete identity with any organism in the GenBank database. Sequence homology suggests that this is a newly described Sarcocystis sp. Results of antibody tests for simian retrovirus, simian T-lymphotropic virus 1, and simian immunodeficiency virus were negative, suggesting that viral immunosuppression was unlikely to have augmented the pathogenicity of sarcosporidial infection. Clinical and histopathologic findings in this case of fulminant sarcosporidiosis are similar to those described in Dalmeny disease in cattle, which is associated with ingestion of massive numbers of infective Sarcocystis oocysts.

Mechanisms by which intracellular calcium induces susceptibility to secretory phospholipase A2 in human erythrocytes.

Exposure of human erythrocytes to the calcium ionophore ionomycin rendered them susceptible to the action of secretory phospholipase A(2) (sPLA(2)). Analysis of erythrocyte phospholipid metabolism by thin-layer chromatography revealed significant hydrolysis of both phosphatidylcholine and phosphatidylethanolamine during incubation with ionomycin and sPLA(2). Several possible mechanisms for the effect of ionomycin were considered. Involvement of intracellular phospholipases A(2) was excluded since inhibitors of these enzymes had no effect. Assessment of membrane oxidation by cis-parinaric acid fluorescence and comparison to the oxidants diamide and phenylhydrazine revealed that oxidation does not participate in the effect of ionomycin. Incubation with ionomycin caused classical physical changes to the erythrocyte membrane such as morphological alterations (spherocytosis), translocation of aminophospholipids to the outer leaflet of the membrane, and release of microvesicles. Experiments with phenylhydrazine, KCl, quinine, merocyanine 540, the calpain inhibitor E-64d, and the scramblase inhibitor R5421 revealed that neither phospholipid translocation nor vesicle release was required to induce susceptibility. Results from fluorescence spectroscopy and two-photon excitation scanning microscopy using the membrane probe laurdan argued that susceptibility to sPLA(2) is a consequence of increased order of membrane lipids.