Tumor markers in breast cancer - European Group on Tumor Markers recommendations

Recommendations are presented for the routine clinical use of serum and tissue-based markers in the diagnosis and management of patients with breast cancer. Their low sensitivity and specificity preclude the use of serum markers such as the MUC-1 mucin glycoproteins ( CA 15.3, BR 27.29) and carcinoembryonic antigen in the diagnosis of early breast cancer. However, serial measurement of these markers can result in the early detection of recurrent disease as well as indicate the efficacy of therapy. Of the tissue-based markers, measurement of estrogen and progesterone receptors is mandatory in the selection of patients for treatment with hormone therapy, while HER-2 is essential in selecting patients with advanced breast cancer for treatment with Herceptin ( trastuzumab). Urokinase plasminogen activator and plasminogen activator inhibitor 1 are recently validated prognostic markers for lymph node-negative breast cancer patients and thus may be of value in selecting node-negative patients that do not require adjuvant chemotherapy. Copyright (C) 2005 S. Karger AG, Basel

Modulation of MicroRNA-194 and cell migration by HER2-targeting trastuzumab in breast cancer

Conceived and designed the experiments: XFL GAC RCB. Performed the experiments: XFL MIA WM RS MSN SZ. Analyzed the data: XFL SR. Contributed reagents/materials/analysis tools: YW GAC. Wrote the paper: XFL RCB.Trastuzumab, a humanized monoclonal antibody directed against the extracellular domain of the HER2 oncoprotein, can effectively target HER2-positive breast cancer through several mechanisms. Although the effects of trastuzumab on cancer cell proliferation, angiogenesis and apoptosis have been investigated in depth, the effect of trastuzumab on microRNA (miRNA) has not been extensively studied. We have performed miRNA microarray profiling before and after trastuzumab treatment in SKBr3 and BT474 human breast cancer cells that overexpress HER2. We found that trastuzumab treatment of SKBr3 cells significantly decreased five miRNAs and increased three others, whereas treatment of BT474 cells significantly decreased two miRNAs and increased nine. The only change in miRNA expression observed in both cell lines following trastuzumab treatment was upregulation of miRNA-194 (miR-194) that was further validated in vitro and in vivo. Forced expression of miR-194 in breast cancer cells that overexpress HER2 produced no effect on apoptosis, modest inhibition of proliferation, significant inhibition of cell migration/invasion in vitro and significant inhibition of xenograft growth in vivo. Conversely, knockdown of miR-194 promoted cell migration. Increased miR-194 expression markedly reduced levels of the cytoskeletal protein talin2 and specifically inhibited luciferase reporter activity of a talin2 wild-type 39-untranslated region, but not that of a mutant reporter, indicating that talin2 is a direct downstream target of miR-194. Trastuzumab treatment inhibited breast cancer cell migration and reduced talin2 expression in vitro and in vivo. Knockdown of talin2 inhibited cell migration/invasion. Knockdown of trastuzumab-induced miR-194 expression with a miR-194 inhibitor compromised trastuzumab-inhibited cell migration in HER2-overexpressing breast cancer cells. Consequently, trastuzumab treatment upregulates miR-194 expression and may exert its cell migration-inhibitory effect through miR-194-mediated downregulation of cytoskeleton protein talin2 in HER2-overexpressing human breast cancer cells.This work was supported by the Anne and Henry Zarrow Foundation, kind gifts from Stuart and Gaye Lynn Zarrow and from Mrs. Delores Wilkenfeld, the Laura and John Arnold Foundation, the RGK Foundation, and the MD Anderson NCI CCSG P30 CA16672. G.A.C. is supported as a Fellow at the University of Texas MD Anderson Research Trust, as a University of Texas System Regents Research Scholar and by the CLL Global Research Foundation

Pre-notification letter type and response rate to a postal survey among women who have recently given birth

Background: Surveys are commonly used in health research to assess patient satisfaction with hospital care. Achieving an adequate response rate, in the face of declining trends over time, threatens the quality and reliability of survey results. This paper reports on a postal satisfaction survey conducted with women who had recently given birth, and explores the effect of two strategies on response rates. Methods: A sample of 2048 Australian women who had recently given birth were invited to participate in a postal survey about their recent experiences with maternity care. The study design included two different strategies intended to increase response rates: a randomised controlled trial testing two types of pre-notification letter (with or without the option of opting out of the survey), and a request for consent to link survey data with existing routinely collected health data (omitting the latter data items from the survey reduced survey length and participant burden). Results: The survey had an overall response rate of 46%. Women receiving the pre-notification letter with the option of opting out of the survey were more likely to actively decline to participate than women receiving the letter without this option, although the overall numbers of women were small (27 versus 12). Letter type was not significantly associated with the return of a completed survey. Among women who completed the survey, 97% gave consent to link their survey data with existing health data. Conclusions: Seeking consent for record linkage was highly acceptable to women who completed the survey, and represents an important strategy to add to the arsenal for designing and implementing effective surveys. In addition to aspects of survey design, future research should explore how to more effectively influence personal constructs that contribute to the decision to participate in surveys.NHMR

Morphological and histochemical characterization of the digestive tract of the puffer fish Sphoeroides testudineus (Linnaeus 1758) (Tetraodontiformes: Tetraodontidae)

ABSTRACT Morphological analysis of the digestive tract of Sphoeroides testudineus showed an esophagus with an anterior and a posterior portion, the abdominal pouch. No stomach was observed between the abdominal pouch and the intestine. The intestine was arranged in three segments and two loops, and the distal portion had the rectum opening into the anus. Histochemical analyses showed that the esophagus secreted acid mucosecretions, and that there was a qualitative increase in goblet cells from the proximal to distal area of the intestine. The rectum showed cells secreting acid and neutral mucus. Given these features, this species presents a morphology which creates a link between its ecology and behavior

Different mechanisms for resistance to trastuzumab versus lapatinib in HER2- positive breast cancers -- role of estrogen receptor and HER2 reactivation

Introduction: The human epidermal growth factor receptor 2 (HER2)-targeted therapies trastuzumab (T) and lapatinib (L) show high efficacy in patients with HER2-positive breast cancer, but resistance is prevalent. Here we investigate resistance mechanisms to each drug alone, or to their combination using a large panel of HER2-positive cell lines made resistant to these drugs. Methods: Response to L + T treatment was characterized in a panel of 13 HER2-positive cell lines to identify lines that were de novo resistant. Acquired resistant lines were then established by long-term exposure to increasing drug concentrations. Levels and activity of HER2 and estrogen receptor (ER) pathways were determined by qRT-PCR, immunohistochemistry, and immunoblotting assays. Cell growth, proliferation, and apoptosis in parental cells and resistant derivatives were assessed in response to inhibition of HER or ER pathways, either pharmacologically (L, T, L + T, or fulvestrant) or by using siRNAs. Efficacy of combined endocrine and anti-HER2 therapies was studied in vivo using UACC-812 xenografts. Results: ER or its downstream products increased in four out of the five ER+/HER2+ lines, and was evident in one of the two intrinsically resistant lines. In UACC-812 and BT474 parental and resistant derivatives, HER2 inhibition by T reactivated HER network activity to promote resistance. T-resistant lines remained sensitive to HER2 inhibition by either L or HER2 siRNA. With more complete HER2 blockade, resistance to L-containing regimens required the activation of a redundant survival pathway, ER, which was up-regulated and promoted survival via various Bcl2 family members. These L-and L + T-resistant lines were responsive to fulvestrant and to ER siRNA. However, after prolonged treatment with L, but not L + T, BT474 cells switched from depending on ER as a survival pathway, to relying again on the HER network (increased HER2, HER3, and receptor ligands) to overcome L's effects. The combination of endocrine and L + T HER2-targeted therapies achieved complete tumor regression and prevented development of resistance in UACC-812 xenografts. Conclusions: Combined L + T treatment provides a more complete and stable inhibition of the HER network. With sustained HER2 inhibition, ER functions as a key escape/survival pathway in ER-positive/HER2-positive cells. Complete blockade of the HER network, together with ER inhibition, may provide optimal therapy in selected patients

The associated expression of Maspin and Bax proteins as a potential prognostic factor in intrahepatic cholangiocarcinoma

BACKGROUND: Maspin, a member of the serpin family, is a suppressor of tumor growth, an inhibitor of angiogenesis and an inducer of apoptosis. Maspin induces apoptosis by increasing Bax, a member of the Bcl-2 family of apoptosis-regulating proteins. In this exploratory study, we investigated the associated expression of Maspin and Bax proteins as a potential prognostic factor in intrahepatic cholangiocarcinoma (IHCCA). METHODS: Twenty-two paraffin-embedded samples were analyzed by immunohistochemical methods using Maspin, Bax and CD34 antibodies. Maspin was scored semiquantitatively (HSCORE). Apoptosis was assessed using an antibody against cleaved caspase-3. RESULTS: The strong relationship observed between the expression of Maspin and Bax, indicates that Bax is likely to be the key effector of Maspin-mediated induction of apoptosis as indicated by the activation of cleaved caspase-3. We categorized Maspin HSCORE by calculating the optimal cutpoint. A Maspin HSCORE above the cutpoint was inversely related with tumor dimension, depth of tumor and vascular invasion. Uni/multivariate analysis suggests that a Maspin HSCORE below the cutpoint significantly worsens the patients' prognosis. Tumors with Maspin HSCORE below the cutpoint had a shorter survival (11+/-5 months) than did patients with Maspin HSCORE above the cutpoint (27+/-4 months), whereas Kaplan-Meier analysis and logrank test showed no significant difference in overall survival between the patients. CONCLUSION: The associated expression of Maspin and Bax might delay tumor progression in IHCCA. Maspin above the cutpoint might counteract tumor development by increasing cell apoptosis, and by decreasing tumor mass and cell invasion. The combined expression of Maspin and Bax appears to influence the susceptibility of tumor cholangiocytes to apoptosis and thus may be involved in delaying IHCCA progression

Barriers to antiretroviral therapy adherence in rural Mozambique

<p>Abstract</p> <p>Background</p> <p>HIV is treated as a chronic disease, but high lost-to-follow-up rates and poor adherence to medication result in higher mortality, morbidity, and viral mutation. Within 18 clinical sites in rural Zambézia Province, Mozambique, patient adherence to antiretroviral therapy has been sub-optimal.</p> <p>Methods</p> <p>To better understand barriers to adherence, we conducted 18 community and clinic focus groups in six rural districts. We interviewed 76 women and 88 men, of whom 124 were community participants (CP; 60 women, 64 men) and 40 were health care workers (HCW; 16 women, 24 men) who provide care for those living with HIV.</p> <p>Results</p> <p>While there was some consensus, both CP and HCW provided complementary insights. CP focus groups noted a lack of confidentiality and poor treatment by hospital staff (42% CP vs. 0% HCW), doubt as to the benefits of antiretroviral therapy (75% CP vs. 0% HCW), and sharing medications with family members (66% CP vs. 0%HCW). Men expressed a greater concern about poor treatment by HCW than women (83% men vs. 0% women). Health care workers blamed patient preference for traditional medicine (42% CP vs. 100% HCW) and the side effects of medication for poor adherence (8% CP vs. 83% CHW).</p> <p>Conclusions</p> <p>Perspectives of CP and HCW likely reflect differing sociocultural and educational backgrounds. Health care workers must understand community perspectives on causes of suboptimal adherence as a first step toward effective intervention.</p

Are we doing enough? Evaluation of the Polio Eradication Initiative in a district of Pakistan's Punjab province: a LQAS study

<p>Abstract</p> <p>Background</p> <p>The success of the Global Polio Eradication Initiative was remarkable, but four countries - Afghanistan, Pakistan, India and Nigeria - never interrupted polio transmission. Pakistan reportedly achieved all milestones except interrupting virus transmission. The aim of the study was to establish valid and reliable estimate for: routine oral polio vaccine (OPV) coverage, logistics management and the quality of monitoring systems in health facilities, NIDs OPV coverage, the quality of NIDs service delivery in static centers and mobile teams, and to ultimately provide scientific evidence for tailoring future interventions.</p> <p>Methods</p> <p>A cross-sectional study using lot quality assessment sampling was conducted in the District Nankana Sahib of Pakistan's Punjab province. Twenty primary health centers and their catchment areas were selected randomly as <it>'lots'</it>. The study involved the evaluation of 1080 children aged 12-23 months for routine OPV coverage, 20 health centers for logistics management and quality of monitoring systems, 420 households for NIDs OPV coverage, 20 static centers and 20 mobile teams for quality of NIDs service delivery. Study instruments were designed according to WHO guidelines.</p> <p>Results</p> <p>Five out of twenty lots were rejected for unacceptably low routine immunization coverage. The validity of coverage was questionable to extent that all lots were rejected. Among the 54.1% who were able to present immunization cards, only 74.0% had valid immunization. Routine coverage was significantly associated with card availability and socioeconomic factors. The main reasons for routine immunization failure were absence of a vaccinator and unawareness of need for immunization. Health workers (96.9%) were a major source of information. All of the 20 lots were rejected for poor compliance in logistics management and quality of monitoring systems. Mean compliance score and compliance percentage for logistics management were 5.4 ± 2.0 (scale 0-9) and 59.4% while those for quality of monitoring systems were 3.3 ± 1.2 (scale 0-6) and 54.2%. The 15 out of 20 lots were rejected for unacceptably low NIDs coverage by finger-mark. All of the 20 lots were rejected for poor NIDs service delivery (mean compliance score = 11.7 ± 2.1 [scale 0-16]; compliance percentage = 72.8%).</p> <p>Conclusion</p> <p>Low coverage, both routine and during NIDs, and poor quality of logistics management, monitoring systems and NIDs service delivery were highlighted as major constraints in polio eradication and these should be considered in prioritizing future strategies.</p