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AIM: Trastuzumab (T), a humanised monoclonal antibody against HER-2, is active in HER-2-positive MBC patients. However, nearly 60% of the patients do not benefit from T, stressing the need for additional predictive markers. The following markers could be implicated in response to T: (1) the magnitude of Her-2 gene amplification; (2) the co-expression of the other HER family receptors, possibly responsible for HER-2 trans-activation; (3) the activated status of HER-2; (4) the activated status of downstream effectors as mitogen-activated protein kinases (MAPKs), p38 and p27. METHODS: Medical files of patients with MBC treated with T either as a single agent or in combination with chemotherapy (CT) were reviewed. HER family members (EGFR, HER-2, HER-3, HER-4), the phosphorylated forms of EGFR (p-EGFR), HER-2 (p-HER-2) and of the downstream effectors were evaluated in the archival tumours. The correlation between clinical outcome and the expression of these markers was investigated. RESULTS: (1) Increasing values of Her-2 amplification were associated with a higher probability of achieving an objective response; (2) no statistical significant correlation between the expression of the HER family receptors was found; (3) p-HER-2 was predictive of response in patients treated with T+CT; (4) a statistically significant correlation between p-ERK 1/2, p-p38 and p-HER-2 emerged, pointing to the activated vertical pathway p-HER-2-->p-MAPKs. CONCLUSIONS: p-HER-2 and the magnitude of Her-2 amplification were predictive of response to T and their role deserves to be analysed in larger and more homogenous T-treated populations such as those from large phase III trials. [ABSTRACT FROM AUTHOR]

Validated biomarkers predictive of response/resistance to anthracyclines in breast cancer are currently lacking. The neoadjuvant Trial of Principle (TOP) study, in which patients with estrogen receptor (ER)-negative tumors were treated with anthracycline (epirubicin) monotherapy, was specifically designed to evaluate the predictive value of topoisomerase II-alpha (TOP2A) and develop a gene expression signature to identify those patients who do not benefit from anthracyclines. Here we describe in details the contents and quality controls for the gene expression and clinical data associated with the study published by Desmedt and colleagues in the Journal of Clinical Oncology in 2011 (Desmedt et al., 2011). We also provide R code to easily access the data and perform the quality controls and basic analyses relevant to this dataset.

Purpose: Genomic Grade Index (GGI) is a 97-gene signature that improves histologic grade (HG) classification in invasive breast carcinoma. In this prospective study we sought to evaluate the feasibility of performing GGI in routine clinical practice and its impact on treatment recommendations., Methods: Patients with pT1pT2 or operable pT3, N0-3 invasive breast carcinoma were recruited from 8 centers in Belgium. Fresh surgical samples were sent at room temperature in the MapQuant Dx™ PathKit for centralized genomic analysis. Genomic profiles were determined using Affymetrix U133 Plus 2.0 and GGI calculated using the MapQuant Dx® protocol, which defines tumors as low or high Genomic Grade (GG-1 and GG-3 respectively)., Results: 180 pts were recruited and 155 were eligible. The MapQuant test was performed in 142 cases and GGI was obtained in 78% of cases (n=111). Reasons for failures were 15 samples with <30% of invasive tumor cells (11%), 15 with insufficient RNA quality (10%), and 1 failed hybridization (<1%). For tumors with an available representative sample (≥ 30% inv. tumor cells) (n=127), the success rate was 87.5%. GGI reclassified 69% of the 54 HG2 tumors as GG-1 (54%) or GG-3 (46%). Changes in treatment recommendations occurred mainly in the subset of HG2 tumors reclassified into GG-3, with increased use of chemotherapy in this subset., Conclusion: The use of GGI is feasible in routine clinical practice and impacts treatment decisions in early-stage breast cancer., Trial Registration: ClinicalTrials.gov NCT01916837, http://clinicaltrials.gov/ct2/show/NCT01916837.

Purpose: Validated biomarkers predictive of response/resistance to anthracyclines in breast cancer are currently lacking. The neoadjuvant Trial of Principle (TOP) study, in which patients with estrogen receptor (ER) -negative tumors were treated with anthracycline (epirubicin) monotherapy, was specifically designed to evaluate the predictive value of topoisomerase II-α (TOP2A) and develop a gene expression signature to identify those patients who do not benefit from anthracyclines., Patients and Methods: The TOP trial included 149 patients, 139 of whom were evaluable for response prediction analyses. The primary end point was pathologic complete response (pCR). TOP2A and gene expression profiles were evaluated using pre-epirubicin biopsies. Gene expression data from ER-negative samples of the EORTC (European Organisation for Research and Treatment of Cancer) 10994/BIG (Breast International Group) 00-01 and MDACC (MD Anderson Cancer Center) 2003-0321 neoadjuvant trials were used for validation purposes., Results: A pCR was obtained in 14% of the evaluable patients in the TOP trial. TOP2A amplification, but not protein overexpression, was significantly associated with pCR (P ≤ .001 v P ≤ .33). We developed an anthracycline-based score (A-Score) combining three signatures: a TOP2A gene signature and two previously published signatures related to tumor invasion and immune response. The A-Score was characterized by a high negative predictive value ([NPV]; NPV, 0.98; 95% CI, 0.90 to 1.00) overall and in the human epidermal growth factor receptor 2 (HER2) -negative and HER2-positive subpopulations. Its performance was independently confirmed in the anthracycline-based arms of the two validation trials (BIG 00-01: NPV, 0.83; 95% CI, 0.64 to 0.94 and MDACC 2003-0321: NPV, 1.00; 95% CI, 0.80 to 1.00)., Conclusion: Given its high NPV, the A-Score could become, if further validated, a useful clinical tool to identify those patients who do not benefit from anthracyclines and could therefore be spared the non-negligible adverse effects.

This randomized phase-II trial investigated the efficacy and tolerability of weekly docetaxel or paclitaxel in metastatic breast cancer (MBC) patients considered unfit for a 3-weekly therapy. The primary study endpoint was antitumor activity, the second endpoint was tolerability, time to progression (TTP) and overall survival (OS). In intent-to-treat analysis, we observed for paclitaxel and docetaxel respectively partial response (PR) in 48% versus 38%, stable disease (SD) in 24% versus 16%, PD in 15% versus 30%. Median TTP was 21.1 weeks versus 12.7 weeks and median OS 55.7 weeks versus 32 weeks. Toxicity profiles were acceptable with more anemia and neurotoxicity for paclitaxel and more edema and fatigue for docetaxel. In patients with MBC unfit for 3-weekly docetaxel or paclitaxel, weekly administration of either compound may certainly be considered. They display different, but acceptable toxicity profiles, with levels of antitumoral efficacy comparable to those previously reported for 3-weekly regimens., (Copyright (c) 2009 Elsevier Ireland Ltd. All rights reserved.)

Single agent carboplatin has demonstrated antitumoral activity in patients with advanced breast cancer. Thirty patients with inoperable locally advanced and/or metastatic breast cancer were treated with carboplatin (300 mg/m2) in combination with cyclophosphamide (600 mg/m2) and 5-fluorouracil (500 mg/m2) given on day 1 in a 4-weekly schedule. Of 29 patients evaluable for response, 4 presented CR and 4 PR (28%). Seven out of 19 chemotherapy-naive patients achieved CR (4) or PR (3) (37%). In contrast, only one patient out of 10 achieved PR in the group with previous adjuvant chemotherapy (10%). Responses were observed in primary tumours as well as in metastatic sites, including lymph nodes, lung, liver and skin. Median duration of response was 7.5+ and 3.8 months in CR and PR patients respectively. Toxicity was generally mild. Only 2 patients presented with clinically relevant hematologic toxicity. No significant non-hematologic toxicity was observed. It appears that this regimen, at the dosage and schedule studied, possesses only modest activity in patients with breast cancer, while being relatively atoxic. Carboplatin merits further investigation in this disease, but dosing should be individualised using e.g. a pharmacokinetic formula.

The authors present three cases of retroperitoneal fibrosis. Two of which were induced by bromocriptine (PARLODEL). These three cases followed up for three years without recurrence were treated with corticoïds and internal derivations (double J catheters) in two of the three cases.

The concentrations of ciprofloxacin (1.5 mg/kg of body weight) in serum and in uninfected pleural exudates were studied after one and three intravenous injections had been given at 8-h intervals. The drug was assayed in serum and in pleural fluid by high-performance liquid chromatography. The peak concentrations in pleural fluid 1.5 h after one and three injections were (mean +/- standard error of the mean) 0.52 +/- 0.09 and 0.77 +/- 0.15 mg/liter, respectively; the corresponding 8-h concentrations were 0.19 +/- 0.05 and 0.39 +/- 0.10 mg/liter. At 1 and 8 h, the ratios of mean concentrations in pleural fluid to mean concentrations in serum were 112 and 158%, respectively, after one injection and 77 and 122% after three injections. This study suggested that there is a satisfactory pleural penetration of ciprofloxacin after intravenous injection.

We performed a phase I-II trial of escalating doses of cisplatin (CDDP: 50-100 mg/m2 per course) plus carboplatin (CBDCA: 300-400 mg/m2 per course) as a potential way in which to maximize platinum doses without causing excessive toxic effects in patients with advanced ovarian cancer. Thirty-three patients with nonoptimally debulked disease of FIGO (International Federation of Gynecology and Obstetrics) stages IIc-IV [median age: 60 yr; median WHO (World Health Organization) performance status: 2; no prior chemotherapy] received a median of six courses of therapy. CBDCA was infused on day 1 and CDDP on day 2 with an aggressive 48-hour hydration regimen. Myelosuppression was dose-limiting: at the highest dose levels, WHO grade 4 neutropenia and thrombocytopenia led to dose reduction and/or treatment delay in 45% of the patients. Nonhematologic toxic effects included acute nausea and vomiting (97% of the patients), mild alopecia (45%), ototoxic effects (39%), neurotoxic effects (21%), and renal toxic effects (serum creatinine greater than 1.5 mg/dL: 12.5%). The pathologic complete response rate was 22%. We conclude that CBDCA and CDDP can be given safely in combination at reasonably high doses (CBDCA at 300 mg/m2 per course and CDDP at 100 mg/m2 per course) over a 6-month period, provided a close hematologic follow-up is conducted. Randomized clinical trials are needed to define whether this regimen is any better than standard combination chemotherapy.

Retroperitoneal fibrosis has been observed in two patients with Parkinson's disease treated with bromocriptine. The patients complained of abdominal or lower back pain and presented with various degrees of renal insufficiency, with anuria in one. Laboratory evaluation furthermore showed an increased sedimentation rate and inflammatory anemia. Computerized tomography disclosed marked retroperitoneal thickening, and biopsy was performed in one patient. The symptoms appeared eighteen months and five years after treatment was started, at doses of 20 and 22.5 mg of bromocriptine daily. The medication was discontinued in both patients and steroid therapy was initiated, with resolution of all clinical, biological and radiological evidence of disease. This potential but rare complication of a widely prescribed drug warrants monitoring of renal function and sedimentation rate in patients undergoing bromocriptine treatment.

Mycotic aneurysms due to Salmonella are a classical but uncommon complication of Salmonella infections. We report two cases of such aneurysms, the first one having developed two successive aneurysms of the iliac arteries due to Salmonella typhimurium. The literature on Salmonella endarteritis is briefly reviewed. The importance of an aggressive surgical approach of the mycotic aneurysm, with removal of all infected material and extra-anatomic bypass through contaminated tissue is emphasized. The role of antibiotic treatment is also discussed.

In an open, comparative study, 225 patients with severe underlying diseases and suspected gram-negative bacillary septicemia were randomly assigned to receive aztreonam or ceftazidime empirically, 2 g intravenously three times daily. Twenty-five patients in the aztreonam group and 22 in the ceftazidime group had blood cultures that grew aerobic gram-negative bacilli and were evaluable for response to therapy. All pathogenic strains were sensitive to treatment. In the aztreonam group, 22 (88 percent) patients had cures, three (12 percent) had failures, and seven (28 percent) had development of superinfections (five were caused by gram-positive cocci and two by fungi). In the ceftazidime group, 18 (82 percent) patients had cures, one had improvement, three (14 percent) had failures, and three had superinfections. The median peak serum bactericidal activity was 1:2,048 after aztreonam administration and 1:512 after ceftazidime administration. Failures were not related to resistant strains or to low serum bactericidal activity.

Teicoplanin was evaluated in 47 patients with severe infections, including 14 patients with bone infections, 11 patients with soft-tissue infections, 7 patients with endocarditis, 5 patients with pneumonia, 3 patients with septic thrombophlebitis, 3 patients with septicemia of unknown origin, and 4 patients with miscellaneous infections. Overall, bacteremia was documented in 24 patients. The pathogens isolated were 35 strains of Staphylococcus aureus (including 8 methicillin-resistant strains), 4 strains of Staphylococcus epidermidis, 4 strains of Streptococcus faecalis, 2 strains of Streptococcus pneumoniae, 5 strains of other streptococci, and 1 Micrococcus luteus strain. A total of 22 patients (46.8%) were clinically cured, 8 patients (17.0%) improved, 2 patients (4.3%) had relapses after initial improvement, and 15 patients (31.9%) failed to respond. The results were better in nonbacteremic patients (19 of 23 patients [82.6%] were cured or improved) than in patients with bacteremia (12 of 24 patients [50%] were cured or improved). Bacteriological cure occurred in 25 patients (53.2%), and superinfections were documented in 6 patients (12.8%). No major adverse effects were observed. We conclude that teicoplanin is a potentially effective and well-tolerated antimicrobial agent for therapy of nonbacteremic infections caused by gram-positive bacteria.