Weekly paclitaxel and concurrent pazopanib following doxorubicin and cyclophosphamide as neoadjuvant therapy for HER-negative locally advanced breast cancer: NSABP Foundation FB-6, a phase II study.

This multicenter single-arm phase II study evaluated the addition of pazopanib to concurrent weekly paclitaxel following doxorubicin and cyclophosphamide as neoadjuvant therapy in human epidermal growth factor receptor (HER2)-negative locally advanced breast cancer (LABC). Patients with HER2-negative stage III breast cancer were treated with doxorubicin 60 mg/m(2) and cyclophosphamide 600 mg/m(2) for four cycles every 3 weeks followed by weekly paclitaxel 80 mg/m(2) on days 1, 8, and 15 every 28 days for four cycles concurrently with pazopanib 800 mg orally daily prior to surgery. Post-operatively, pazopanib was given daily for 6 months. The primary endpoint was pathologic complete response (pCR) in the breast and lymph nodes. Between July 2009 and March 2011, 101 patients with stage IIIA-C HER2-negative breast cancer were enrolled. The pCR rate in evaluable patients who initiated paclitaxel and pazopanib was 17 % (16/93). The pCR rate was 9 % (6/67) in hormone receptor-positive tumors and 38 % (10/26) in triple-negative tumors. Pre-operative pazopanib was completed in only 39 % of patients. The most frequent grade 3 and 4 adverse events during paclitaxel and pazopanib were neutropenia (27 %), diarrhea (5 %), ALT and AST elevations (each 5 %), and hypertension (5 %). Although the pCR rate of paclitaxel and pazopanib following AC chemotherapy given as neoadjuvant therapy in women with LABC met the pre-specified criteria for activity, there was substantial toxicity, which led to a high discontinuation rate of pazopanib. The combination does not appear to warrant further evaluation in the neoadjuvant setting for breast cancer.

The use of anti-asthmatic inhalation therapy and the risk of dental caries in a group of Polish children: a prospective study.

AIM: Assessment of the effect of inhaled therapy with anti-asthmatic medications on the development of caries in children between 3 and 17 years old. METHODS: Study design: The study involved 208 patients, 114 in the study group and 94 in the control group. Data on general health condition of patients, use of medications, dietary habits and oral hygiene were obtained. Information on the onset of asthma, its severity and type, doses and method of administration of asthma medications were obtained from the available medical records by the paediatrician. Dental examination was performed using the DMFT/dmft and DMFS/dmfs index, ICDAS II classification and Nyvad's criteria for noncavitated white spot lesion differentiation. Additionally, an assessment of salivary S. mutans (SM) and Lactobacillus spp. (LA) was carried out using the CRT Bacteria (Ivoclar Vivadent) test. CONCLUSION: There is still no clear consensus among the authors as to whether asthma and medications used in its treatment increase the risk of caries. Nowadays, despite better access to various sources of information, there is still a need for increased awareness in patients and medical doctors on the dental care and caries prevention in patients with asthma.

Expression of an activation antigen, Mo3e, associated with the cellular response to migration inhibitory factor by HL-60 promyelocytes undergoing monocyte-macrophage differentiation.

HL-60 promyelocytic cells acquire the surface expression of the Mo3e antigenic determinant after exposure to PMA or compounds that raise intracellular concentrations of cyclic AMP (dibutyryl cyclic AMP or a combination of cholera toxin and IBMX). The expression of Mo3e by these stimulated HL-60 cells coincides with the development of features of monocyte-macrophage differentiation (characteristic morphology, nonspecific esterase activity, and respiratory burst activity). During in vitro monocyte-macrophage differentiation, HL-60 cells become responsive to migration inhibitory factor (MIF); the MIF responsiveness of differentiated HL-60 cells is blocked by anti-Mo3e monoclonal antibody. These findings further support the relationship between the expression of Mo3e and the cellular response to MIF.

Lovastatin and simvastatin are modulators of the proteasome.

Lovastatin and simvastatin are HMG-CoA reductase inhibitors widely used as antihyperlipidemic drugs, which also display antiproliferative properties. In the present paper, we provide evidence that both lovastatin and simvastatin are modulators of the purified bovine pituitary 20 S proteasome, since they mildly stimulate the chymotrypsin-like activity and inhibit the peptidylglutamylpeptide hydrolyzing activity without interfering with the trypsin-like activity. However, those effects are only observed when the closed ring forms of the drugs are used, while the opened ring form of lovastatin acts as a mild inhibitor of the chymotrypsin like activity. The closed ring form of lovastatin is much more potent as a cytotoxic agent on the Colon-26 (C-26) colon carcinoma cell line than the opened ring form, which is only mildly cytostatic. Moreover, neither the cytotoxic effects nor the effects on 20 S proteasome activities are prevented by mevalonate, which by itself inhibits the trypsin-like activity of the proteasome. Neither the opened ring nor the closed ring form of lovastatin induces an accumulation of ubiquitin-protein conjugates, which is observed after treatment with lactacystin, a selective proteasome inhibitor. In contrast with the opened ring form of lovastatin, the closed ring form induces the disappearance of detectable p27(kip1) from C-26 cells. Altogether, our results indicate that the closed ring form of lovastatin induces cytotoxic effects independent of its HMG-CoA inhibiting activity, however, those effects are mediated by a complex modulation of proteasome activity rather than by inhibition of the 20 S proteasome.

Comparative pharmacodynamics of Ro 41-3696, a new hypnotic, and zolpidem after night-time administration to healthy subjects.

In a double-blind, six-way crossover study the effects on psychomotor performance and memory of single doses of Ro 41-3696 (1, 3, 5 and 10 mg), a novel non-benzodiazepine partial agonist at the benzodiazepine receptor, zolpidem (10 mg) and placebo were compared after night-time administration to 12 healthy young male subjects. Psychomotor performance tests (tracking and attention as part of a standardized task battery) were conducted just before and at 1.5 and 8 h after drug intake. The memory test consisted of the recall of a list of 15 words at 8 h after drug intake which had been learned at 1.5 h after intake. At 1.5 h after drug intake 10 mg zolpidem induced markedly larger psychomotor effects than any dose of Ro 41-3696. The effects of 5 and 10 mg Ro 41-3696 and zolpidem were significantly greater than those of placebo (P < 0.05). The following morning, 8 h after drug intake, the slight residual effects of 5 and 10 mg Ro 41-3696 were statistically significantly greater than placebo, whereas zolpidem effects did not differ from placebo. The results of the memory test showed that learning as well as recall were most clearly impaired by zolpidem. An influence of Ro 41-3696 on these variables was not observed for doses up to 5 mg. In conclusion, Ro 41-3696 at all doses tested induced less effects on psychomotor performance and memory than 10 mg zolpidem at 1.5 h after intake. However, the effects of Ro 41-3696 appeared to be of longer duration.

Pharmacokinetics and pharmacodynamics of Ro 41-3696, a novel nonbenzodiazepine hypnotic.

This report describes the first evaluation in humans of Ro 41-3696. Based on its preclinical profile, Ro 41-3696, a nonbenzodiazepine partial agonist at the benzodiazepine receptor, offers promising perspectives as an innovative hypnotic drug in that it does not exhibit most of the disadvantages associated with full agonists. Single oral doses of 0.1, 0.3, 1.0, 3.0, 10, and 30 mg were administered sequentially to six groups of six healthy male volunteers in a placebo-controlled, double-blind design. Tolerability was assessed and pharmacokinetic and pharmacodynamic measurements were conducted during a period of 28 hours after drug intake. Ro 41-3696 was well tolerated at all doses, causing no clinically relevant changes in vital signs or laboratory parameters. At doses of 10 and 30 mg there were signs of unsteady gait, indicating a central nervous system depressant effect. Pharmacokinetic analyses revealed that Ro 41-3696 was absorbed and eliminated rapidly (tmax = approximately 1 hour; t1/2 = approximately 4 hours). At all times plasma levels of Ro 41-3290, the desethylated derivative of Ro 41-3696, were higher than those of the parent drug (tmax and t1/2 values = approximately 2 and 8 hours, respectively). Area under the curve (AUC) data indicated dose-proportional pharmacokinetics for both Ro 41-3696 and Ro 41-3290. Performance in both a tracking and a memory search test was significantly affected by doses of 10 and 30 mg, and long-term memory, as assessed by a word learning and recall test, was slightly impaired at these doses. The results of this study support the initiation of therapeutic efficacy studies with Ro 41-3696 in doses up to approximately 5 mg and further exploration of the characteristics of Ro 41-3290.

Tranquillisers and health care in crisis.

This paper addresses the issue of the crisis of therapeutic efficacy in Britain through a case study of benzodiazepine tranquilliser dependence. The paper traces the rise of tranquillisers and the crisis of legitimacy in prescribing behaviour in the 1980s. It documents growing concern with dependence and the claims made about it by experts and consumer groups. The paper goes on to analyse the importance of the television in these claims-making activity and its influence in shaping perceptions. Finally, we consider the implications of these events for the future of benzodiazepine tranquillisers as a form of treatment.

Impairment, disability and handicap in chronic respiratory illness.

Chronic obstructive airways disease (COAD) is a major, though neglected, medical and social problem in the United Kingdom today. Dyspnoea is one of the most distressing and disabling symptoms of COAD, which is itself the largest single cause of absence from work in the United Kingdom. 92 patients suffering from COAD were interviewed in order to assess impairment, disability and handicap. Measures included spirometric tests of lung function; the Fletcher breathlessness grading scale, the oxygen cost diagram and a visual analogue scale of dyspnoea; the Functional Limitations Profile (FLP); and the shortened 12 item General Health Questionnaire (GHQ-12), supplemented by the 7-item GHQ sub-scales of anxiety and severe depression. Low correlations were found between lung function and disability (-0.38, P less than 0.001), accounting for only 14% of the variance, and high correlations were found to exist between measures of dyspnoea and disability (-0.90, P less than 0.001). Major areas of disability and handicap included; household management, ambulation, sleep and rest, recreation and pastimes and work. Financial problems and difficulties, housing problems and problems of social isolation were also frequently reported. The paper goes on to discuss both the need for a more integrated approach to the care and rehabilitation of COAD patients and their families and for a complementary social perspective and approach to COAD and its treatment.

Hybrid high-dose bolus/continuous infusion interleukin-2 in patients with metastatic renal cell carcinoma: a phase II trial of the National Biotherapy Study Group.

BACKGROUND: Interleukin-2 (IL-2) is an active agent for the treatment of renal cell carcinoma. In animal studies, polyethylene glycol conjugated (PEG) IL-2 was found to be effective in certain IL-2-resistant models. When bolus/infusion IL-2 was administered to approximate the pharmacokinetics of PEG-IL-2, resistance was also overcome in these models. Based on these observations, the National Bio-therapy Study Group (NBSG) previously had conducted a pilot study (NBSG 90-01) and then a phase I trial of a hybrid regimen of bolus IL-2 followed by continuous IL-2 (NBSG 91-04). METHODS: In the current study, NBSG 92-09, a phase II trial was conducted in patients with metastatic renal cell carcinoma using IL-2 at a dose of 36 MIU/m2 followed by a 72-hour continuous infusion of IL-2 at 18 MIU/m2 per day, so that over 3 days a total of 90 MIU/m2 of IL-2 were delivered; the same amount as previously given during 5 days of continuous intravenous (i.v.) IL-2 at 18 MIU/m2 per day. This was repeated every 2 weeks for 2 months, and then monthly for up to 4 months. RESULTS: Thirty-one patients with a median age of 62 years were enrolled in this trial. During the first 4 biweekly treatments, the percentages of planned IL-2 administered were 98% for 31 patients, 99% for 27, 98% for 23, and 99% for 20 patients. Toxicities were qualitatively the same as those seen with other IL-2 regimens. During the first 2 months, 4 patients ceased treatment because of rapidly progressive disease while 7 patients stopped because of toxicity; 5 of the 7 were > 65 years of age. At the time of formal reassessment after 2 months of treatment, 7 additional patients had progressive disease for a treatment failure rate of 55% prior to monthly maintenance therapy. There were two partial responses among 22 patients who had measurable disease for a response rate of 9% (1 to 29%, 95% CI). Median survival was 10.2 months and failure-free survival (FFS) 3.4 months for the entire group. CONCLUSION: The response rate seen with this regimen is similar to those of other schedules of IL-2 requiring more prolonged hospitalization. This hybrid bolus/continuous infusion IL-2 schedule appears to be an equally effective and less expensive schedule of IL-2 administration than previously reported inpatient regimens. However, it is not likely that this regimen is superior to outpatient combination biotherapy regimens which are currently under investigation.

Hybrid high-dose bolus/continuous infusion interleukin-2 in patients with metastatic melanoma: a phase II trial of the Cancer Biotherapy Research Group (formerly the National Biotherapy Study Group).

PURPOSE: Interleukin-2 (IL-2) is an active agent for the treatment of melanoma. In animal studies, polyethylene glycol conjugated (PEG) IL-2 was found to be effective in certain IL-2-resistant models. Bolus/infusional IL-2 administered to approximate the pharmacokinetics of PEG-IL-2 also overcame resistance in these models. Based on these observations, the Cancer Biotherapy Research Group (CBRG) [formerly the National Biotherapy Study Group (NBSG)] previously had conducted a pilot study and then a phase I trial of bolus IL-2 followed by continuous IL-2 (NBSG 90-01). METHODS: In the current study, NBSG 92-09, a phase II trial was conducted using IL-2 at a dose of 36 MIU/m2 followed by a 72-hour continuous infusion of IL-2 at 18 MIU/m2/day, so that over 3 days a total of 90 MIU/m2 of IL-2 were delivered; the same amount as previously given during 5 days of continuous i.v. IL-2 at 18 MIU/m2/day. This schedule was repeated every 2 weeks for 2 months, and then monthly for up to 6 months. RESULTS: Twenty-two patients with metastatic melanoma were enrolled in this trial. Toxicities were qualitatively similar to those seen with other IL-2 regimens, but grade 3 and 4 toxicities were observed only in patients who received at least four cycles of treatment; only one patient went off study because of toxicity. For 18 patients with measurable disease, there were two complete and two partial responses in patients ages 32, 66, 72 and 83 years, for a response rate of 22% (6% to 48%; 95% confidence interval [Ci]). The median survival for all 21 evaluable patients enrolled in the trial was 8.5 months. CONCLUSION: The hybrid schedule of drug delivery in NBSG 92-09 allowed the same dose and intensity of IL-2 to be delivered over 3 days instead of 5 days, which resulted in fewer days of hospitalization and therefore decreased cost; but with no increase in toxicity and no decrease in efficacy in patients with metastatic melanoma.

Chemo-biotherapy with 5-fluorouracil, leucovorin, and alpha interferon in metastatic carcinoma of the colon--a Cancer Biotherapy Research Group [CBRG] phase II study.

BACKGROUND: Biochemical modulation of 5-Fluorouracil activity with Leucovorin has been well documented in colorectal cancer. Several studies have shown increased efficacy of 5-fluorouracil in combination with alpha interferon. We therefore initiated a phase II trial of dual modulation of 5-fluorouracil with leucovorin and alpha interferon to evaluate outcomes in patients with metastatic carcinoma of the colon. METHODS: Patients with metastatic colon carcinoma with expected survival > 4 months and performance status of ECOG < or = 2 were treated weekly with Leucovorin 400 mg i.v. followed by 5-FU 600 mg/m2 i.v. bolus. Alpha interferon 3-9 million units was administered subcutaneously every Monday, Wednesday and Friday. Patients were analyzed for toxicity, tumor response and survival. RESULTS: Sixteen patients with a median age of 66 years were treated. Three patients were not evaluable for response but were evaluable for toxicity. Grades 3 and 4 toxicities were neutropenia, diarrhea, mucositis, nausea and vomiting, fatigue, fever, asthenia and elevated hepatic enzymes. One patient died from complications associated with diverticulitis and neutropenia. Objective response rate was 23% (95% confidence interval 4-46%) and median survival was 11.5 months (95% confidence interval 6.3-19 months). Thirty-eight percent of the patients were alive at one year and 19% at two years. CONCLUSION: The combination of 5-fluorouracil, leucovorin and alpha interferon as administered in this phase II study did not result in enhanced response rate or survival. However this regimen was associated with considerable toxicity.

Effects of proteasome inhibitor PSI on neoplastic and non-transformed cell lines.

In this study we compared the sensitivity of different human and murine cell lines varying in the stage of transformation to dose- and time-dependent cytostatic and/or cytotoxic effects of PSI (a selective proteasome inhibitor), measured by a standard MTT assay. It was found that intensively proliferating cell lines were more sensitive to very small doses of PSI after 24 h incubation than the slow proliferating ones. Non-transformed cell lines showed no sensitivity to PSI, as there was no difference in cell viability in comparison with the control group even after 72 h incubation.

Localization of a proteasomal antigen in human spermatozoa: immunohistochemical electron microscopic study.

The ultrastructural localization of a proteasomal antigen in human spermatozoa was studied by means of immunolabeling with the MPC21 monoclonal antibody and secondary gold labeled antibody with 1.4 nm gold particles in combination with silver enhancement reaction using pre-embedding technique. The labeling was found in the acrosomal and postacrosomal regions, in the connecting-piece (neck) and, in some cases, in the middle-piece and also in the residual bodies. There was no significant reaction in condensed chromatin. In some abnormal forms of spermatozoa, in which the chromatin was not well condensed, the labeling in nuclei was present. The nuclear vacuoles with looser chromatin were usually strongly labeled. The nuclei of cells representing different stages of spermatogenesis, that were present in semen samples, were also labeled.

Effects of an inhibitor of tripeptidyl peptidase II (Ala-Ala-Phe-chloromethylketone) and its combination with an inhibitor of the chymotrypsin-like activity of the proteasome (PSI) on apoptosis, cell cycle and proteasome activity in U937 cells.

AAF-AMC is not a specific TPP II substrate, since it is also hydrolyzed by purified proteasomes. Moreover, AAF-cmk, claimed to be a specific TPP II inhibitor, also inhibits the chymotrypsin-like activity of the proteasome. While AAF-cmk itself is mildly cytostatic to U-937 cells and induces cell cycle block in G1, its combination with PSI does not induce an increase in the cytostatic/cytotoxic effects. This suggests that TPP II is possibly less important for cell metabolism than it was previously believed and it is less probable that it can be able to fully compensate for the loss of the proteasome function.

Views of survivors of stroke on benefits of physiotherapy.

OBJECTIVE: To describe the components of physiotherapy valued by survivors of a stroke. DESIGN: Qualitative study using in-depth interviews. SETTING: Two adjacent districts in North East Thames Regional Health Authority. PATIENTS: 82 survivors of stroke taken consecutively from a stroke register when they reached the tenth month after their stroke, 40 of whom agreed to be interviewed. MAIN MEASURES: Content analysis of interviews. RESULTS: Patients who agreed to the interview were significantly less likely to be disabled 12 months after stroke than those who did not. Twenty four patients had received physiotherapy, and these were more disabled than those who had not. Patients appreciated physiotherapy. It was believed to bring about functional improvement; the exercise component was valued because it was perceived to keep them active and busy and exercise programmes to follow at home were also valued for the structure they gave to each day; and therapists were considered a source of advice and information and a source of faith and hope. CONCLUSIONS: Many of the positive aspects of caring which patients described in the context of physiotherapy could be incorporated into the mainstream of rehabilitation care and training. However, health professionals need to be careful not to promote false expectations about recovery. IMPLICATIONS: The outcome of treatment is of critical importance to patients and should become a central dimension of patient satisfaction questionnaires. The impact of physiotherapy is not confined to reducing physical disability but may also affect wellbeing. The choice of outcome measures in rehabilitation research should reflect this situation.

Disablement in society: towards an integrated perspective.

Demographic and morbidity changes have undermined traditional responses to disease and disability. An expanded model of disablement is required, integrating consequences as well as causes. Three main concepts involved are impairment, disability, and handicap. These constitute a continuum ranging from bio-medical phenomena (impairment) through functional limitation and activity restriction (disability) to social disadvantage (handicap). Though complete sequences can occur, analytical and practical problems arise from the fact that their interrelationship is not always straightforward or predictable. From an analysis of available data it is calculated that 34% of the adult population in Great Britain are impaired. A tenth of these are severely disabled. The age structure and underlying causes of disablement challenge prevailing stereotypes: disablement becomes more frequent with age and it is caused in large part by chronic diseases. An attempt to assess handicap direct, rather than as a derivative of disability, displays severe disadvantages among the disabled. The model allows the possibility of gathering information relevant to different aspects of disablement and warns against reductionist or naive responses in health care and social policy.

Stroke patients' views on their admission to hospital.

OBJECTIVE: To explore which components of care were valued by patients admitted to hospital following a stroke. DESIGN: Qualitative study using in depth interviews 10 months after the stroke. SETTING: Two adjacent districts in North Thames Regional Health Authority. SUBJECTS: 82 survivors of stroke taken consecutively from a stroke register, 40 of whom agreed to be interviewed. RESULTS: Patients reported that during the acute stage of the stroke they wanted to put their faith in experienced and trusted experts who would help them make sense of the event, take all the actions necessary to ensure survival, and provide comfort and human warmth during the crisis. In addition to being reassured by the clinical tests and practical nursing help they received, patients valued feeling cared about by the staff. In most cases patients reported that their needs were met; however, the institutional nature of the hospital sometimes obstructed the fulfillment of their needs. CONCLUSION: Patients have important psychosocial needs during the acute stage of the stroke, which are often met by hospital admission. Patients gained benefits from their admission over and above those measurable in terms of morbidity or function. They used a combination of criteria to evaluate their care, focusing on the process as well as the outcome of care. Researchers and clinicians should do likewise.

Ophiobolin A induces paraptosis-like cell death in human glioblastoma cells by decreasing BKCa channel activity.

Glioblastoma multiforme (GBM) is the most lethal and common malignant human brain tumor. The intrinsic resistance of highly invasive GBM cells to radiation- and chemotherapy-induced apoptosis accounts for the generally dismal treatment outcomes. This study investigated ophiobolin A (OP-A), a fungal metabolite from Bipolaris species, for its promising anticancer activity against human GBM cells exhibiting varying degrees of resistance to proapoptotic stimuli. We found that OP-A induced marked changes in the dynamic organization of the F-actin cytoskeleton, and inhibited the proliferation and migration of GBM cells, likely by inhibiting big conductance Ca(2+)-activated K(+) channel (BKCa) channel activity. Moreover, our results indicated that OP-A induced paraptosis-like cell death in GBM cells, which correlated with the vacuolization, possibly brought about by the swelling and fusion of mitochondria and/or the endoplasmic reticulum (ER). In addition, the OP-A-induced cell death did not involve the activation of caspases. We also showed that the expression of BKCa channels colocalized with these two organelles (mitochondria and ER) was affected in this programmed cell death pathway. Thus, this study reveals a novel mechanism of action associated with the anticancer effects of OP-A, which involves the induction of paraptosis through the disruption of internal potassium ion homeostasis. Our findings offer a promising therapeutic strategy to overcome the intrinsic resistance of GBM cells to proapoptotic stimuli.

Chronic illness as biographical disruption.

The paper is based on semi-structured interviews with a series of rheumatoid arthritis patients. Chronic illness is conceptualised as a particular type of disruptive event. This disruption highlights the resources (cognitive and material) available to individuals, modes of explanation for pain and suffering, continuities and discontinuities between professional and lay thought, and sources of variation in experience.