Acute haematogenous prosthetic joint infection: prospective evaluation of medical and surgical management

The optimum treatment for prosthetic joint infections has not been clearly defined. We report our experience of the management of acute haematogenous prosthetic joint infection (AHPJI) in patients during a 3-year prospective study in nine Spanish hospitals. Fifty patients, of whom 30 (60%) were female, with a median age of 76 years, were diagnosed with AHPJI. The median infection-free period following joint replacement was 4.9 years. Symptoms were acute in all cases. A distant previous infection and/or bacteraemia were identified in 48%. The aetiology was as follows: Staphylococcus aureus, 19; Streptococcus spp., 14; Gram-negative bacilli, 12; anaerobes, two; and mixed infections, three. Thirty-four (68%) patients were treated with a conservative surgical approach (CSA) with implant retention, and 16 had prosthesis removal. At 2-year follow-up, 24 (48%) were cured, seven (14%) had relapsed, seven (14%) had died, five (10%) had persistent infection, five had re-infection, and two had an unknown evolution. Overall, the treatment failure rates were 57.8% in staphylococcal infections and 14.3% in streptococcal infections. There were no failures in patients with Gram-negative bacillary. By multivariate analysis, CSA was the only factor independently associated with treatment failure (OR 11.6; 95% CI 1.29-104.8). We were unable to identify any factors predicting treatment failure in CSA patients, although a Gram-negative bacillary aetiology was a protective factor. These data suggest that although conservative surgery was the only factor independently associated with treatment failure, it could be the first therapeutic choice for the management of Gram-negative bacillary and streptococcal AHPJI, and for some cases with acute S. aureus infections.

EMT and EGFR in CTCs cytokeratin negative non-metastatic breast cancer.

Circulating tumor cells (CTCs) are frequently associated with epithelial-mesenchymal transition (EMT).The objective of this study was to detect EMT phenotype through Vimentin (VIM) and Slug expression in cytokeratin (CK)-negative CTCs in non-metastatic breast cancer patients and to determine the importance of EGFR in the EMT phenomenon. In CK-negative CTCs samples, both VIM and Slug markers were co-expressed in the most of patients. Among patients EGFR+, half of them were positive for these EMT markers. Furthermore, after a systemic treatment 68% of patients switched from CK- to CK+ CTCs. In our experimental model we found that activation of EGFR signaling by its ligand on MCF-7 cells is sufficient to increase EMT phenotypes, to inhibit apoptotic events and to induce the loss of CK expression. The simultaneous detection of both EGFR and EMT markers in CTCs may improve prognostic or predictive information in patients with operable breast cancer.

Circulating prolactin and in situ breast cancer risk in the European EPIC cohort: a case-control study.

INTRODUCTION The relationship between circulating prolactin and invasive breast cancer has been investigated previously, but the association between prolactin levels and in situ breast cancer risk has received less attention. METHODS We analysed the relationship between pre-diagnostic prolactin levels and the risk of in situ breast cancer overall, and by menopausal status and use of postmenopausal hormone therapy (HT) at blood donation. Conditional logistic regression was used to assess this association in a case-control study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort, including 307 in situ breast cancer cases and their matched control subjects. RESULTS We found a significant positive association between higher circulating prolactin levels and risk of in situ breast cancer among all women [pre-and postmenopausal combined, ORlog2 = 1.35 (95%CI 1.04-1.76), Ptrend = 0.03]. No statistically significant heterogeneity was found between prolactin levels and in situ cancer risk by menopausal status (Phet = 0.98) or baseline HT use (Phet = 0.20), although the observed association was more pronounced among postmenopausal women using HT compared to non-users (Ptrend = 0.06 vs Ptrend = 0.35). In subgroup analyses, the observed positive association was strongest in women diagnosed with in situ breast tumors <4 years compared to ≥4 years after blood donation (Ptrend = 0.01 vs Ptrend = 0.63; Phet = 0.04) and among nulliparous women compared to parous women (Ptrend = 0.03 vs Ptrend = 0.15; Phet = 0.07). CONCLUSIONS Our data extends prior research linking prolactin and invasive breast cancer to the outcome of in situ breast tumours and shows that higher circulating prolactin is associated with increased risk of in situ breast cancer.

A comparative study of two methods of surgical treatment for painful neuroma.

Painful neuromas may follow traumatic nerve injury. We carried out a double-blind controlled trial in which patients with a painful neuroma of the lower limb (n = 20) were randomly assigned to treatment by resection of the neuroma and translocation of the proximal nerve stump into either muscle tissue or an adjacent subcutaneous vein. Translocation into a vein led to reduced intensity of pain as assessed by visual analogue scale (5.8 (SD 2.7) vs 3.8 (SD 2.4); p < 0.01), and improved sensory, affective and evaluative dimensions of pain as assessed by the McGill pain score (33 (SD 18) vs 14 (SD 12); p < 0.01). This was associated with an increased level of activity (p < 0.01) and improved function (p < 0.01). Transposition of the nerve stump into an adjacent vein should be preferred to relocation into muscle.

Assessment of Epstein-Barr virus nucleic acids in gastric but not in breast cancer by next-generation sequencing of pooled Mexican samples

Gastric (GC) and breast (BrC) cancer are two of the most common and deadly tumours. Different lines of evidence suggest a possible causative role of viral infections for both GC and BrC. Wide genome sequencing (WGS) technologies allow searching for viral agents in tissues of patients with cancer. These technologies have already contributed to establish virus-cancer associations as well as to discovery new tumour viruses. The objective of this study was to document possible associations of viral infection with GC and BrC in Mexican patients. In order to gain idea about cost effective conditions of experimental sequencing, we first carried out an in silico simulation of WGS. The next-generation-platform IlluminaGallx was then used to sequence GC and BrC tumour samples. While we did not find viral sequences in tissues from BrC patients, multiple reads matching Epstein-Barr virus (EBV) sequences were found in GC tissues. An end-point polymerase chain reaction confirmed an enrichment of EBV sequences in one of the GC samples sequenced, validating the next-generation sequencing-bioinformatics pipeline.

Enhanced antitumor activity of doxorubicin in breast cancer through the use of poly(butylcyanoacrylate) nanoparticles.

The use of doxorubicin (DOX), one of the most effective antitumor molecules in the treatment of metastatic breast cancer, is limited by its low tumor selectivity and its severe side effects. Colloidal carriers based on biodegradable poly(butylcyanoacrylate) nanoparticles (PBCA NPs) may enhance DOX antitumor activity against breast cancer cells, thus allowing a reduction of the effective dose required for antitumor activity and consequently the level of associated toxicity. DOX loading onto PBCA NPs was investigated in this work via both drug entrapment and surface adsorption. Cytotoxicity assays with DOX-loaded NPs were performed in vitro using breast tumor cell lines (MCF-7 human and E0771 mouse cancer cells), and in vivo evaluating antitumor activity in immunocompetent C57BL/6 mice. The entrapment method yielded greater drug loading values and a controlled drug release profile. Neither in vitro nor in vivo cytotoxicity was observed for blank NPs. The 50% inhibitory concentration (IC50) of DOX-loaded PBCA NPs was significantly lower for MCF-7 and E0771 cancer cells (4 and 15 times, respectively) compared with free DOX. Furthermore, DOX-loaded PBCA NPs produced a tumor growth inhibition that was 40% greater than that observed with free DOX, thus reducing DOX toxicity during treatment. These results suggest that DOX-loaded PBCA NPs have great potential for improving the efficacy of DOX therapy against advanced breast cancers.

Automatic landmarks detection in breast reconstruction aesthetic assessment.

This paper addresses a fully automatic landmarks detection method for breast reconstruction aesthetic assessment. The set of landmarks detected are the supraesternal notch (SSN), armpits, nipples, and inframammary fold (IMF). These landmarks are commonly used in order to perform anthropometric measurements for aesthetic assessment. The methodological approach is based on both illumination and morphological analysis. The proposed method has been tested with 21 images. A good overall performance is observed, although several improvements must be achieved in order to refine the detection of nipples and SSNs.

Predicting response and survival in chemotherapy-treated triple-negative breast cancer.

BACKGROUND In this study, we evaluated the ability of gene expression profiles to predict chemotherapy response and survival in triple-negative breast cancer (TNBC). METHODS Gene expression and clinical-pathological data were evaluated in five independent cohorts, including three randomised clinical trials for a total of 1055 patients with TNBC, basal-like disease (BLBC) or both. Previously defined intrinsic molecular subtype and a proliferation signature were determined and tested. Each signature was tested using multivariable logistic regression models (for pCR (pathological complete response)) and Cox models (for survival). Within TNBC, interactions between each signature and the basal-like subtype (vs other subtypes) for predicting either pCR or survival were investigated. RESULTS Within TNBC, all intrinsic subtypes were identified but BLBC predominated (55-81%). Significant associations between genomic signatures and response and survival after chemotherapy were only identified within BLBC and not within TNBC as a whole. In particular, high expression of a previously identified proliferation signature, or low expression of the luminal A signature, was found independently associated with pCR and improved survival following chemotherapy across different cohorts. Significant interaction tests were only obtained between each signature and the BLBC subtype for prediction of chemotherapy response or survival. CONCLUSIONS The proliferation signature predicts response and improved survival after chemotherapy, but only within BLBC. This highlights the clinical implications of TNBC heterogeneity, and suggests that future clinical trials focused on this phenotypic subtype should consider stratifying patients as having BLBC or not.

Dépistage du cancer du sein par l'examen physique: qui en bénéficie? [Physical examination in screening for breast cancer: who benefits?].

A survey was undertaken among a representative sample of the female population, aged 20 to 74, of the Canton of Vaud, Switzerland (total population 550,000) to assess the knowledge, attitudes and practices of women in respect to breast cancer and its prevention. The present study focuses on access by women to medical preventive measures (breast examination by physician and information on breast self-examination). The data are analyzed in relation to the individual risk factors affecting women, in particular age. While with age the risk of breast cancer grows in a linear fashion, the proportion of women having their breast examined by a physician declines. Women over 50 who had no children before the age of 30 constitute an especially high risk category, with the lowest access to information and prevention. This is explained in large part by the fact that they consult gynecologists less often. In this regard it should be noted that a visit to a gynecologist's office is associated much more often with breast examination than a visit to a family physician. It is important to take such findings into account in providing more appropriate and complete care for those groups. This involves sensitization of the physician and improved information for the women themselves.

An electronic portfolio for quantitative assessment of surgical skills in undergraduate medical education.

BACKGROUND We evaluated a newly designed electronic portfolio (e-Portfolio) that provided quantitative evaluation of surgical skills. Medical students at the University of Seville used the e-Portfolio on a voluntary basis for evaluation of their performance in undergraduate surgical subjects. METHODS Our new web-based e-Portfolio was designed to evaluate surgical practical knowledge and skills targets. Students recorded each activity on a form, attached evidence, and added their reflections. Students self-assessed their practical knowledge using qualitative criteria (yes/no), and graded their skills according to complexity (basic/advanced) and participation (observer/assistant/independent). A numerical value was assigned to each activity, and the values of all activities were summated to obtain the total score. The application automatically displayed quantitative feedback. We performed qualitative evaluation of the perceived usefulness of the e-Portfolio and quantitative evaluation of the targets achieved. RESULTS Thirty-seven of 112 students (33%) used the e-Portfolio, of which 87% reported that they understood the methodology of the portfolio. All students reported an improved understanding of their learning objectives resulting from the numerical visualization of progress, all students reported that the quantitative feedback encouraged their learning, and 79% of students felt that their teachers were more available because they were using the e-Portfolio. Only 51.3% of students reported that the reflective aspects of learning were useful. Individual students achieved a maximum of 65% of the total targets and 87% of the skills targets. The mean total score was 345 ± 38 points. For basic skills, 92% of students achieved the maximum score for participation as an independent operator, and all achieved the maximum scores for participation as an observer and assistant. For complex skills, 62% of students achieved the maximum score for participation as an independent operator, and 98% achieved the maximum scores for participation as an observer or assistant. CONCLUSIONS Medical students reported that use of an electronic portfolio that provided quantitative feedback on their progress was useful when the number and complexity of targets were appropriate, but not when the portfolio offered only formative evaluations based on reflection. Students felt that use of the e-Portfolio guided their learning process by indicating knowledge gaps to themselves and teachers.

Impact of tamoxifen dose on tamoxifen and its active metabolites exposure in breast cancer patients: preliminary results from a prospective, open-label trial

Background: CYP2D6 is the key enzyme responsible for tamoxifen bioactivation mainly into endoxifen. This gene is highly polymorphic and breast cancer patients classified as CYP2D6 poor metabolizers (PM) or intermediate metabolizers (IM) appear to show low concentrations of endoxifen and to achieve less benefit from tamoxifen treatment. Purpose: This prospective, open-label trial aimed to assess how the increase of tamoxifen dose influences the level of endoxifen in the different genotype groups (poor-, intermediate-, and extensive-metabolizers (EM)). We examined the impact of doubling tamoxifen dose to 20mg twice daily on endoxifen plasma concentrations across these genotype groups. Patients and methods: Patients were assayed for CYP2D6 genotype and phenotype using dextromethorphan test. Tamoxifen, N-desmethyltamoxifen, 4-hydroxytamoxifen and endoxifen plasma levels were determined on 2 occasions at baseline (20mg/day of tamoxifen) and at day 30, 90 and 120 after dose increase (20 mg twice daily) using liquid chromatography-tandem-mass spectrometry. Endoxifen plasma levels were measured 6 to 24 hours after last drug intake to evaluate its accumulation before and after doubling tamoxifen dosage. ANOVA was used to evaluate endoxifen levels increase and difference between genotype groups. Results: 63 patients are available for analysis to date. Tamoxifen, N-desmethyltamoxifen, 4-hydroxytamoxifen and endoxifen plasma reached steady state at 30 day after tamoxifen dose escalation, with a significant increase compared to baseline by 1.6 to 1.8 fold : geometric mean plasma concentrations (CV %) were 140 ng/mL (45%) at baseline vs 255 (47%) at day 30 for tamoxifen (P < 0.0001); 256 (49%) vs 408 (64%) for N-desmethyltamoxifen (P < 0.0001); 2.4 (46%) vs 3.9 (51%) for 4-OH-tamoxifen (P < 0.0001); and 20 (91%) vs 33 (91%) for endoxifen (P < 0.02). On baseline, endoxifen levels tended to be lower in PM: 7 ng/mL (36%), than IM: 16 ng/mL (70%), P=0.08, and EM: 24 ng/mL (71%), P<0.001. After doubling tamoxifen dosage, endoxifen concentrations rose similarly in PM, IM and EM with respectively, 1.5 (18%), 1.5 (28%) and 1.7 (30%) fold increase from baseline, P=0.18. Conclusion: Endoxifen exposure varies widely under standard tamoxifen dosage, with CYP2D6 genotype explaining only a minor part of this variability. It increases consistently on doubling tamoxifen dose, similarly across genotypes. This would enable exposure optimization based on concentration monitoring.

New insights into the role of the immune microenvironment in breast carcinoma.

Recently, immune edition has been recognized as a new hallmark of cancer. In this respect, some clinical trials in breast cancer have reported imppressive outcomes related to laboratory immune findings, especially in the neoadjuvant and metastatic setting. Infiltration by tumor infiltrating lymphocytes (TIL) and their subtypes, tumor-associated macrophages (TAM) and myeloid-derived suppressive cells (MDSC) seem bona fide prognostic and even predictive biomarkers, that will eventually be incorporated into diagnostic and therapeutic algorithms of breast cancer. In addition, the complex interaction of costimulatory and coinhibitory molecules on the immune synapse and the different signals that they may exert represent another exciting field to explore. In this review we try to summarize and elucidate these new concepts and knowledge from a translational perspective focusing on breast cancer, paying special attention to those aspects that might have more significance in clinical practice and could be useful to design successful therapeutic strategies in the future.

Extracapsular tumor spread and the risk of local, axillary and supraclavicular recurrence in node-positive, premenopausal patients with breast cancer.

BACKGROUND: Extracapsular tumor spread (ECS) has been identified as a possible risk factor for breast cancer recurrence, but controversy exists regarding its role in decision making for regional radiotherapy. This study evaluates ECS as a predictor of local, axillary, and supraclavicular recurrence. PATIENTS AND METHODS: International Breast Cancer Study Group Trial VI accrued 1475 eligible pre- and perimenopausal women with node-positive breast cancer who were randomly assigned to receive three to nine courses of classical combination chemotherapy with cyclophosphamide, methotrexate, and fluorouracil. ECS status was determined retrospectively in 933 patients based on review of pathology reports. Cumulative incidence and hazard ratios (HRs) were estimated using methods for competing risks analysis. Adjustment factors included treatment group and baseline patient and tumor characteristics. The median follow-up was 14 years. RESULTS: In univariable analysis, ECS was significantly associated with supraclavicular recurrence (HR = 1.96; 95% confidence interval 1.23-3.13; P = 0.005). HRs for local and axillary recurrence were 1.38 (P = 0.06) and 1.81 (P = 0.11), respectively. Following adjustment for number of lymph node metastases and other baseline prognostic factors, ECS was not significantly associated with any of the three recurrence types studied. CONCLUSIONS: Our results indicate that the decision for additional regional radiotherapy should not be based solely on the presence of ECS.

Vaccination of melanoma patients with Melan-A/Mart-1 peptide and Klebsiella outer membrane protein p40 as an adjuvant.

Toll-like receptor ligands are potentially useful adjuvants for the development of clinical T cell vaccination. Here we investigated the novel Toll-like receptor2 ligand P40, the outer membrane protein A derived from Klebsiella pneumoniae. Seventeen human leukocyte antigen-A*0201 positive stage III/IV melanoma patients were vaccinated with P40 and Melan-A/Mart-1 peptide subcutaneously in monthly intervals. Adverse reactions were mild-to-moderate. Fourteen patients received at least 8 vaccinations and were thus evaluable for clinical tumor and immune responses. Seven patients experienced progressive disease, whereas 2 patients had stable disease throughout the trial period, 1 of them with regression of multiple skin metastases. The remaining 5 patients had no measurable disease. Melan-A/Mart-1 specific CD8 T cells were analyzed ex vivo, with positive results in 6 of 14 evaluable patients. Increased percentages of T cells were found in three patients, memory/effector T cell differentiation in 4 patients, and a positive interferon-gamma Elispot assay in 1 patient. Antibody responses to P40 were observed in all patients. We conclude that vaccination with peptide and P40 was feasible and induced ex vivo detectable tumor antigen specific T cell responses in 6 of 14 patients with advanced melanoma.