Mortality after admission for acute myocardial infarction in Aboriginal and non-Aboriginal people in New South Wales, Australia: a multilevel data linkage study

Background - Heart disease is a leading cause of the gap in burden of disease between Aboriginal and non-Aboriginal Australians. Our study investigated short- and long-term mortality after admission for Aboriginal and non-Aboriginal people admitted with acute myocardial infarction (AMI) to public hospitals in New South Wales, Australia, and examined the impact of the hospital of admission on outcomes. Methods - Admission records were linked to mortality records for 60047 patients aged 25–84 years admitted with a diagnosis of AMI between July 2001 and December 2008. Multilevel logistic regression was used to estimate adjusted odds ratios (AOR) for 30- and 365-day all-cause mortality. Results - Aboriginal patients admitted with an AMI were younger than non-Aboriginal patients, and more likely to be admitted to lower volume, remote hospitals without on-site angiography. Adjusting for age, sex, year and hospital, Aboriginal patients had a similar 30-day mortality risk to non-Aboriginal patients (AOR: 1.07; 95% CI 0.83-1.37) but a higher risk of dying within 365 days (AOR: 1.34; 95% CI 1.10-1.63). The latter difference did not persist after adjustment for comorbid conditions (AOR: 1.12; 95% CI 0.91-1.38). Patients admitted to more remote hospitals, those with lower patient volume and those without on-site angiography had increased risk of short and long-term mortality regardless of Aboriginal status. Conclusions - Improving access to larger hospitals and those with specialist cardiac facilities could improve outcomes following AMI for all patients. However, major efforts to boost primary and secondary prevention of AMI are required to reduce the mortality gap between Aboriginal and non-Aboriginal people

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

Epidemiology and economic burden of herpes zoster and post-herpetic neuralgia in Italy: A retrospective, population-based study

<p>Abstract</p> <p>Background</p> <p>Data on the epidemiology and cost of herpes zoster (HZ) and post-herpetic neuralgia (PHN) in Italy are limited. This retrospective, population-based study was designed to determine the incidence of HZ and the proportion developing PHN in Italy and the associated medical resource utilisation and costs. It focused primarily on immunocompetent patients aged ≥50 years who would be eligible for preventive vaccination.</p> <p>Method</p> <p>Data were extracted from a primary-care database and national hospital-discharge records covering four major regions in Italy for 2003-2005. Cases of HZ and PHN (1 and 3 months' duration; PHN1 and PHN3) were identified by ICD9-CM codes and, additionally for PHN, prescription of neuropathic pain medication.</p> <p>Results</p> <p>Over 3 years, 5675 incident cases of HZ were documented in adults, of which 3620 occurred in immunocompetent patients aged ≥50 years (incidence of 6.31 per 1000 person-years [95% CI: 6.01-6.62]). Of the immunocompetent patients aged ≥50 years with HZ, 9.4% (95% CI: 8.2-10.7) and 7.2% (95% CI: 6.2-8.2) developed PHN1 and PHN3, respectively. Increasing age, female sex, and being immunologically compromised conferred increased risk for both HZ and PHN. Overall, about 1.3% of HZ and almost 2% of PHN cases required inpatient care, with 16.9% of all HZ-related hospitalisations due specifically to PHN. In patients aged ≥50 years, mean stay was 7.8 ± 5.4 days for HZ and 10.2 ± 8.6 days for PHN, and direct costs associated with inpatient care were more than 20 times outpatient costs per HZ case (mean ± SD: €2592 ± €1313 vs. €122.68 ± €97.51) and over 5 times more per episode of PHN (mean ± SD: €2806 ± €2641 vs. €446.10 ± €442.97). Total annual costs were €41.2 million, of which €28.2 million were direct costs and €13.0 million indirect costs.</p> <p>Conclusions</p> <p>This study, the largest to date on the epidemiology and economic impact of HZ and PHN in Italy, confirms the considerable disease and economic burden posed by HZ. As HZ and PHN disproportionately affect the elderly, without intervention this problem is likely to grow as the proportion of elderly in the Italian population continues to increase.</p

Comparative analysis of xanafide cytotoxicity in breast cancer cell lines

Xanafide, a DNA-intercalating agent and topoisomerase II inhibitor, has previously demonstrated comparable cytotoxicity to the parent drug amonafide (NSC 308847). The current study was conducted to investigate further the anti-proliferative effects of xanafide in human breast cancer cell lines, in vitro and in vivo. The in vitro activity of xanafide against MCF-7, MDA-MB-231, SKBR-3 and T47D cell lines was compared to that of paclitaxel, docetaxel, gemcitabine, vinorelbine and doxorubicin. In MCF-7, xanafide demonstrated comparable total growth inhibition (TGI) concentrations to the taxanes and lower TGI values than gemcitabine, vinorelbine and doxorubicin. MCF-7 (oestrogen receptor (ER)+/p53 wild-type) was the most sensitive cell line to xanafide. MDA-MB-231 and SKBR-3 exhibited similar sensitivity to xanafide. T47 D (ER+/p53 mutated), showed no response to this agent. The in vivo activity of xanafide was further compared to that of docetaxel in MCF-7 and MDA-MB-231 cell lines using the hollow fibre assay. Xanafide was slightly more potent than docetaxel, at its highest dose in MCF-7 cell line, whereas docetaxel was more effective than xanafide in MDA-MB-231 cell line. Our results show that there is no relationship between sensitivity of these cell lines to xanafide and cellular levels of both isoforms of topoisomerase II and suggest that ER and p53 status and their crosstalk may predict the responsiveness or resistance of breast cancer patients to xanafide

The distribution of the therapeutic monoclonal antibodies cetuximab and trastuzumab within solid tumors

<p><b>Abstract</b></p> <p>Background</p> <p>Poor distribution of some anticancer drugs in solid tumors may limit their anti-tumor activity.</p> <p>Methods</p> <p>Here we used immunohistochemistry to quantify the distribution of the therapeutic monoclonal antibodies cetuximab and trastuzumab in relation to blood vessels and to regions of hypoxia in human tumor xenografts. The antibodies were injected into mice implanted with human epidermoid carcinoma A431 or human breast carcinoma MDA-MB-231 transfected with <it>ERBB2 </it>(231-H2N) that express high levels of ErbB1 and ErbB2 respectively, or wild-type MDA-MB-231, which expresses intermediate levels of ErbB1 and low levels of ErbB2.</p> <p>Results</p> <p>The distribution of cetuximab in A431 xenografts and trastuzumab in 231-H2N xenografts was time and dose dependent. At early intervals after injection of 1 mg cetuximab into A431 xenografts, the concentration of cetuximab decreased with increasing distance from blood vessels, but became more uniformly distributed at later times; there remained however limited distribution and binding in hypoxic regions of tumors. Injection of lower doses of cetuximab led to heterogeneous distributions. Similar results were observed with trastuzumab in 231-H2N xenografts. In MDA-MB-231 xenografts, which express lower levels of ErbB1, homogeneity of distribution of cetuximab was achieved more rapidly.</p> <p>Conclusions</p> <p>Cetuximab and trastuzumab distribute slowly, but at higher doses achieve a relatively uniform distribution after about 24 hours, most likely due to their long half-lives in the circulation. There remains poor distribution within hypoxic regions of tumors.</p

Vinorelbine plus 3-weekly trastuzumab in metastatic breast cancer: a single-centre phase 2 trial

BACKGROUND: After two studies reporting response rates higher than 70% in HER2-positive metastatic breast cancer with weekly trastuzumab and vinorelbine, we planned a phase 2 study to test activity of the same combination, with trastuzumab given every 3 weeks. METHODS: Patients with HER2-positive metastatic breast cancer (3+ at immunohistochemistry or positive at fluorescence in situ hybridization), PS ≤2, normal left-ventricular ejection fraction (LVEF) and no more than one chemotherapy line for metastatic disease were eligible. Vinorelbine (30 mg/m(2)) was given on days 1&8 every 21 and trastuzumab (8 mg/kg day 1, then 6 mg/kg) every 21 days). A single-stage phase 2 design, with p(0 )= 0.45, p(1 )= 0.65, type I and II error = 0.10, was applied; 22 objective responses were required in 39 patients. RESULTS: From Nov 2002 to May 2005, 50 patients were enrolled, with a median age of 54 years (range 31–81). Among 40 patients eligible for response assessment, there were 7 complete and 13 partial responses (overall response rate 50%; 95% exact CI 33.8–66.2); 11 patients had disease stabilization, lasting more than 6 months in 10 cases. Response rate did not vary according to patients and tumor characteristics, type and amount of previous chemotherapy. Within the whole series, median progression-free survival was 9.6 months (95% CI 7.3–12.3), median overall survival 22.7 months (95% CI 19.5-NA). Fifteen patients (30%) developed brain metastases at a median time of 12 months (range 1–25). There was one toxic death due to renal failure in a patient receiving concomitant pamidronate. Twenty-three patients (46%) had grade 3–4 neutropenia, 2 (4%) grade 3 anemia, 4 (8%) febrile neutropenia. Two patients stopped treatment because of grade 2 decline of LVEF and one patient because of grade 2 liver toxicity concomitant with a grade 1 decline of LVEF. One patient stopped trastuzumab after 50 cycles because of grade 1 decline of LVEF. CONCLUSION: Although lower than in initial studies, activity of 3-weekly trastuzumab plus vinorelbine fell within the range of results reported with weekly schedules. Toxicity was prevalently manageable. This combination is safe and active for metastatic breast cancer patients who received adjuvant taxanes with anthracyclines

Multilineage hematopoietic recovery with concomitant antitumor effects using low dose Interleukin-12 in myelosuppressed tumor-bearing mice

<p>Abstract</p> <p>Background</p> <p>Interleukin-12 (IL-12) is a cytokine well known for its role in immunity. A lesser known function of IL-12 is its role in hematopoiesis. The promising data obtained in the preclinical models of antitumor immunotherapy raised hope that IL-12 could be a powerful therapeutic agent against cancer. However, excessive clinical toxicity, largely due to repeat dose regimens, and modest clinical response observed in the clinical trials have pointed to the necessity to design protocols that minimize toxicity without affecting the anti-tumor effect of IL-12. We have focused on the lesser known role of IL-12 in hematopoiesis and hypothesized that an important clinical role for IL-12 in cancer may be as an adjuvant hematological cancer therapy. In this putative clinical function, IL-12 is utilized for the prevention of cancer therapy-related cytopenias, while providing concomitant anti-tumor responses over and above responses observed with the primary therapy alone. This putative clinical function of IL-12 focuses on the dual role of IL-12 in hematopoiesis and immunity.</p> <p>Methods</p> <p>We assessed the ability of IL-12 to facilitate hematopoietic recovery from radiation (625 rad) and chemotherapy (cyclophosphamide) in two tumor-bearing murine models, namely the EL4 lymphoma and the Lewis lung cancer models. Antitumor effects and changes in bone marrow cellularity were also assessed.</p> <p>Results</p> <p>We show herein that carefully designed protocols, in mice, utilizing IL-12 as an adjuvant to radiation or chemotherapy yield facile and consistent, multilineage hematopoietic recovery from cancer therapy-induced cytopenias, as compared to vehicle and the clinically-utilized cytokine granulocyte colony-stimulating factor (G-CSF) (positive control), while still providing concomitant antitumor responses over and above the effects of the primary therapy alone. Moreover, our protocol design utilizes single, low doses of IL-12 that did not yield any apparent toxicity.</p> <p>Conclusion</p> <p>Our results portend that despite its past failure, IL-12 appears to have significant clinical potential as a hematological adjuvant cancer therapy.</p

Breast cancer biological subtypes and protein expression predict for the preferential distant metastasis sites: a nationwide cohort study

Introduction Some molecular subtypes of breast cancer have preferential sites of distant relapse. The protein expression pattern of the primary tumor may influence the first distant metastasis site. Methods We identified from the files of the Finnish Cancer Registry patients diagnosed with breast cancer in five geographical regions Finland in 1991-1992, reviewed the hospital case records, and collected primary tumor tissue. Out of the 2,032 cases identified, 234 developed distant metastases after a median follow-up time of 2.7 years and had the first metastatic site documented (a total of 321 sites). Primary tumor microarray (TMA) cores were analyzed for 17 proteins using immunohistochemistry and for erbB2 using chromogenic in situ hybridization, and their associations with the first metastasis site were examined. The cancers were classified into luminal A, luminal B, HER2+ enriched, basal-like or non-expressor subtypes. Results A total of 3,886 TMA cores were analyzed. Luminal A cancers had a propensity to give rise first to bone metastases, HER2-enriched cancers to liver and lung metastases, and basal type cancers to liver and brain metastases. Primary tumors that gave first rise to bone metastases expressed frequently estrogen receptor (ER) and SNAI1 (SNAIL) and rarely COX2 and HER2, tumors with first metastases in the liver expressed infrequently SNAI1, those with lung metastases expressed frequently the epidermal growth factor receptor (EGFR), cytokeratin-5 (CK5) and HER2, and infrequently progesterone receptor (PgR), tumors with early skin metastases expressed infrequently E-cadherin, and breast tumors with first metastases in the brain expressed nestin, prominin-1 and CK5 and infrequently ER and PgR. Conclusions Breast tumor biological subtypes have a tendency to give rise to first distant metastases at certain body sites. Several primary tumor proteins were associated with homing of breast cancer cells.BioMed Central Open acces