Etiology of hormone receptor positive breast cancer differs by levels of histologic grade and proliferation.

Limited epidemiological evidence suggests that the etiology of hormone receptor positive (HR+) breast cancer may differ by levels of histologic grade and proliferation. We pooled risk factor and pathology data on 5,905 HR+ breast cancer cases and 26,281 controls from 11 epidemiological studies. Proliferation was determined by centralized automated measures of KI67 in tissue microarrays. Odds ratios (OR), 95% confidence intervals (CI) and p-values for case-case and case-control comparisons for risk factors in relation to levels of grade and quartiles (Q1-Q4) of KI67 were estimated using polytomous logistic regression models. Case-case comparisons showed associations between nulliparity and high KI67 [OR (95% CI) for Q4 vs. Q1 = 1.54 (1.22, 1.95)]; obesity and high grade [grade 3 vs. 1 = 1.68 (1.31, 2.16)] and current use of combined hormone therapy (HT) and low grade [grade 3 vs. 1 = 0.27 (0.16, 0.44)] tumors. In case-control comparisons, nulliparity was associated with elevated risk of tumors with high but not low levels of proliferation [1.43 (1.14, 1.81) for KI67 Q4 vs. 0.83 (0.60, 1.14) for KI67 Q1]; obesity among women ≥50 years with high but not low grade tumors [1.55 (1.17, 2.06) for grade 3 vs. 0.88 (0.66, 1.16) for grade 1] and HT with low but not high grade tumors [3.07 (2.22, 4.23) for grade 1 vs. 0.85 (0.55, 1.30) for grade 3]. Menarcheal age and family history were similarly associated with HR+ tumors of different grade or KI67 levels. These findings provide insights into the etiologic heterogeneity of HR+ tumors

Tissue hyaluronan expression, as reflected in the sputum of lung cancer patients, is an indicator of malignancy

Hyaluronan (HA) shows promise for detecting cancerous change in pleural effusion and urine. However, there is uncertainty about the localization of HA in tumor tissue and its relationship with different histological types and other components of the extracellular matrix, such as angiogenesis. We evaluated the association between HA and degree of malignancy through expression in lung tumor tissue and sputum. Tumoral tissue had significantly increased HA compared to normal tissue. Strong HA staining intensity associated with cancer cells was significant in squamous cell carcinoma compared to adenocarcinoma and large cell carcinoma. A significant direct association was found between tumors with a high percentage of HA and MVD (microvessel density) in tumoral stroma. Similarly significant was the direct association between N1 tumors and high levels of HA in cancer cells. Cox multivariate analysis showed significant association between better survival and low HA. HA increased in sputum from lung cancer patients compared to cancer-free and healthy volunteers and a significant correlation was found between HA in sputum and HA in cancer tissue. Localization of HA in tumor tissue was related to malignancy and reflected in sputum, making this an emerging factor for an important diagnostic procedure in patients suspected to have lung cancer. Further study in additional patients in a randomized prospective trial is required to finalize these results and to validate our quantitative assessment of HA, as well as to couple it to gold standard sputum cytology.Research supported by FAPESP (2010/11005-5 and 2010/04462) and CNPq (#471939/2010-2 and 483005/2012-6

Prognostic model to predict postoperative acute kidney injury in patients undergoing major gastrointestinal surgery based on a national prospective observational cohort study.

Background: Acute illness, existing co-morbidities and surgical stress response can all contribute to postoperative acute kidney injury (AKI) in patients undergoing major gastrointestinal surgery. The aim of this study was prospectively to develop a pragmatic prognostic model to stratify patients according to risk of developing AKI after major gastrointestinal surgery. Methods: This prospective multicentre cohort study included consecutive adults undergoing elective or emergency gastrointestinal resection, liver resection or stoma reversal in 2-week blocks over a continuous 3-month period. The primary outcome was the rate of AKI within 7 days of surgery. Bootstrap stability was used to select clinically plausible risk factors into the model. Internal model validation was carried out by bootstrap validation. Results: A total of 4544 patients were included across 173 centres in the UK and Ireland. The overall rate of AKI was 14·2 per cent (646 of 4544) and the 30-day mortality rate was 1·8 per cent (84 of 4544). Stage 1 AKI was significantly associated with 30-day mortality (unadjusted odds ratio 7·61, 95 per cent c.i. 4·49 to 12·90; P < 0·001), with increasing odds of death with each AKI stage. Six variables were selected for inclusion in the prognostic model: age, sex, ASA grade, preoperative estimated glomerular filtration rate, planned open surgery and preoperative use of either an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker. Internal validation demonstrated good model discrimination (c-statistic 0·65). Discussion: Following major gastrointestinal surgery, AKI occurred in one in seven patients. This preoperative prognostic model identified patients at high risk of postoperative AKI. Validation in an independent data set is required to ensure generalizability

Association between age and survival in a cohort of Brazilian patients with operable breast cancer

Whether age is an independent prognostic factor in breast cancer is a matter of debate. This is a retrospective cohort study of 767 breast cancer patients, stages I-III, treated at the Hospital das Clínicas, Minas Gerais Federal University, Belo Horizonte, Minas Gerais State, Brazil, from 2001 to 2008, aiming to study the relationship between age and survival. We included variables related to patients, tumors, and types of treatment. Different sets of Cox models were used for survival analysis. Hazard ratios (HR) and 95%CI were calculated. The relationship between age and breast cancer survival did not change substantially in any of them. In the model that accounted for all variables, women aged 70 and older (HR = 1.51, 95%CI: 1.04-2.18), and 35 or younger (HR = 1.78, 95%CI: 1.05-3.01) had shorter cancer specific survival than patients aged between 36 and 69. In addition, older age, having at least one comorbidity, and being white were associated with a higher risk of dying from other causes. In conclusion, shorter breast cancer survival is expected among the youngest and oldest patients

Effectiveness of acupuncture, special dressings and simple, low-adherence dressings for healing venous leg ulcers in primary healthcare: study protocol for a cluster-randomized open-labeled trial

<p>Abstract</p> <p>Background</p> <p>Venous leg ulcers constitute a chronic recurring complaint that affects 1.0–1.3% of the adult population at some time in life, and which corresponds to approximately 75% of all chronic ulcers of the leg. Multilayer compression bandaging is, at present, the only treatment that has been proved to be effective in treating this type of ulcer. There is no consensus, however, about the dressings that may be applied, beneath the compression, to promote the healing of this type of ulcer, as there does not seem to be any added benefit from using special dressings rather than simple, low-adherence ones. As well as analgesia, acupuncture provokes peripheral vasodilation, in skin and muscles – which has been demonstrated both experimentally and in clinical practice – probably due to the axon reflex, among other mechanisms. The aim of the present study is to measure the effectiveness and cost of compression treatment for venous leg ulcers combined with special dressings, in comparison with low-adherence ones and acupuncture.</p> <p>Methods/design</p> <p>Cluster-randomized open-labeled trial, at 15 primary healthcare clinics in the Sevilla-Sur Healthcare District, with a control group treated with compression bandaging and low-adherence dressings; the experiment will consist, on the one hand, of the compression treatment applied in combination with special dressings (Treatment 1), and on the other, the compression treatment applied in association with low-adherence dressings, together with acupuncture (Treatment 2).</p> <p>Discussion</p> <p>The results will be measured and recorded in terms of the median time elapsed until complete healing of the ulcer, and the rate of complete healing at 3 months after beginning the treatment. An economic analysis will also be made.</p> <p>This study, carried out in the context of real clinical practice, will provide information for decision-taking concerning the effectiveness of special dressings. Moreover, for the first time a high-quality study will evaluate the effectiveness of acupuncture in the process of healing venous leg ulcers.</p> <p>Trial registration</p> <p>Current Controlled Trials ISRCTN26438275.</p

3,3′-Diindolylmethane Induces G1 Arrest and Apoptosis in Human Acute T-Cell Lymphoblastic Leukemia Cells

Certain bioactive food components, including indole-3-carbinol (I3C) and 3,3′-diindolylmethane (DIM) from cruciferous vegetables, have been shown to target cellular pathways regulating carcinogenesis. Previously, our laboratory showed that dietary I3C is an effective transplacental chemopreventive agent in a dibenzo[def,p]chrysene (DBC)-dependent model of murine T-cell lymphoblastic lymphoma. The primary objective of the present study was to extend our chemoprevention studies in mice to an analogous human neoplasm in cell culture. Therefore, we tested the hypothesis that I3C or DIM may be chemotherapeutic in human T-cell acute lymphoblastic leukemia (T-ALL) cells. Treatment of the T-ALL cell lines CCRF-CEM, CCRF-HSB2, SUP-T1 and Jurkat with DIM in vitro significantly reduced cell proliferation and viability at concentrations 8- to 25-fold lower than the parent compound I3C. DIM (7.5 µM) arrested CEM and HSB2 cells at the G1 phase of the cell cycle and 15 µM DIM significantly increased the percentage of apoptotic cells in all T-ALL lines. In CEM cells, DIM reduced protein expression of cyclin dependent kinases 4 and 6 (CDK4, CDK6) and D-type cyclin 3 (CCND3); DIM also significantly altered expression of eight transcripts related to human apoptosis (BCL2L10, CD40LG, HRK, TNF, TNFRSF1A, TNFRSF25, TNFSF8, TRAF4). Similar anticancer effects of DIM were observed in vivo. Dietary exposure to 100 ppm DIM significantly decreased the rate of growth of human CEM xenografts in immunodeficient SCID mice, reduced final tumor size by 44% and increased the apoptotic index compared to control-fed mice. Taken together, our results demonstrate a potential for therapeutic application of DIM in T-ALL

M6 Membrane Protein Plays an Essential Role in Drosophila Oogenesis

We had previously shown that the transmembrane glycoprotein M6a, a member of the proteolipid protein (PLP) family, regulates neurite/filopodium outgrowth, hence, M6a might be involved in neuronal remodeling and differentiation. In this work we focused on M6, the only PLP family member present in Drosophila, and ortholog to M6a. Unexpectedly, we found that decreased expression of M6 leads to female sterility. M6 is expressed in the membrane of the follicular epithelium in ovarioles throughout oogenesis. Phenotypes triggered by M6 downregulation in hypomorphic mutants included egg collapse and egg permeability, thus suggesting M6 involvement in eggshell biosynthesis. In addition, RNAi-mediated M6 knockdown targeted specifically to follicle cells induced an arrest of egg chamber development, revealing that M6 is essential in oogenesis. Interestingly, M6-associated phenotypes evidenced abnormal changes of the follicle cell shape and disrupted follicular epithelium in mid- and late-stage egg chambers. Therefore, we propose that M6 plays a role in follicular epithelium maintenance involving membrane cell remodeling during oogenesis in Drosophila