TORSAFUF - Surgical exploration for torsion of spermatic cord suspicion and risk factors for unnecessary surgery: Results of a French nationwide retrospective study on 2940 patients.

BACKGROUNDS: Spermatic cord torsion is a frequent urological emergency that mostly concerns teenagers and young adults. This study aimed to determine the clinical and surgical characteristics of young adults who had scrotal exploration for suspected spermatic cord torsion and to identify clinical risk factors associated with needless scrotal exploration. METHODS: We retrospectively collected national data from patients aged 12years and older who underwent a surgical exploration for suspicion of torsion of the spermatic cord between 2005 and 2019 in 17 hospitals. We analyzed demographics, surgical and postoperative characteristics in our population. We compared the cohort according to the intraoperative diagnosis of torsion or not. RESULTS: In total, 2940 had surgical exploration: 1802 (61.3%) patients had torsion of the spermatic cord and 1138 (38.7%) had another diagnosis. In multivariate analysis, age (OR: 1.04; 95% CI: 1.01-1.06; P=0.005), medical history of cryptorchism (OR: 4.14; 95% CI: 1.05-16.31; P=0.042) and VAS pain score (OR: 0.91; 95% CI: 0.83-0.98; P=0.018) were risk factors significantly associated with unnecessary surgical exploration. The rate of complications in the 90days after surgery was 11% in the "torsion" group, and 9.7% in the "non-torsion" group (P=0.28). CONCLUSION: Scrotal exploration without intraoperative diagnosis of torsion was performed in 40% of our cohort. VAS pain score and cryptorchism history can help for the diagnosis but scrotal exploration remains the way to diagnose spermatic cord torsion and should be performed on the slightest suspicion, even after 24hours of symptoms, as the chances for testicular salvage remains around 50%.

[Impact of positive surgical margins on prostate cancer prognosis]. / Impact carcinologique des marges positives après prostatectomie totale.

OBJECTIVE: To examine the impact of positive surgical margins (PSM) after radical prostatectomy (RP) for prostate cancer on oncological results. PATIENTS AND METHODS: We performed a study where all patients who underwent radical prostatectomy between January 2004 and December 2018 for prostate cancer were included. The preoperative, postoperative data and the carcinological results collected were analyzed. Data were analysed using Kaplan-Meier survival analysis and proportional hazards models. RESULTS: A total of 319 patients with a median age of 65 years (IQR : 62-69) were included. The median follow-up was 43.6 months (IQR: 19.4-79.3). The overall rate of PSM was 33.5%. PSM was associated with biochemical recurrence (P<0.001). Overall mortality was not associated with positive margins. A clinical stage> T1c was an independent predictor of PSM on multivariate analysis (P=0.01). CONCLUSION: PSM would increase the risk of biochemical recurrence with no impact on survival. Clinical stage>T1c was an adverse predictor for PSM. LEVEL OF EVIDENCE: 3.

Urinary S-PMA related to indoor benzene and asthma in children.

INTRODUCTION: Benzene is a ubiquitous pollutant of both indoor and outdoor environments which impacts on respiratory health. Our aim was to relate urinary S-phenylmercapturic acid (S-PMA), a biomarker of benzene exposure, to benzene concentrations and related sources at home and asthma in a population-based sample of children. METHODS: Exposure to benzene was assessed in the dwellings of 63 children (32 asthmatics and 31 controls) through the identification of sources of benzene and in situ assessments with passive samplers. The determination of urinary S-PMA was obtained by liquid chromatography-mass spectrometry. RESULTS: At home, asthmatics were significantly more polluted by benzene levels from ambient sampling than controls (p ≤ 0.05). Benzene exposure significantly aggravated asthma symptoms overall in non-atopic children (OR = 10.10; 95% confidence interval: 10.10). Urinary S-PMA was significantly associated with benzene concentrations in the entire population (regression coefficient = 0.28, 95% CI: 0.07-0.49; p < 0.05) and asthma (OR = 7.69; 95% CI: 1.37-42.52 for an increase of 1 µg/g creatinine of urinary S-PMA). However, after adjustment for environmental tobacco smoking exposure, familial allergy, age and sex, the latter relationship was no more significant (OR = 4.95; 95% CI: 0.91-27.4, p < 0.10). Both benzene concentrations and urinary S-PMA concentrations were higher in dwelling built after 1948 and in flats. CONCLUSIONS: Our study suggests a relationship between childhood asthma and benzene concentrations at home, even at low levels of this pollutant. This was confirmed when considering urinary S-PMA, which was related to both benzene concentrations and asthma. Further epidemiological and toxicological studies are needed to confirm our results.

Identification of biological factors predictive of response to imatinib mesylate in aggressive fibromatosis.

BACKGROUND: Imatinib induces responses and disease stabilisations in non-resectable patients with aggressive fibromatosis (AF). The precise target of imatinib in AF and predictive factors for response to treatment are unknown. METHODS: We investigated factors potentially predictive of response to imatinib in a series of 40 patients with progressive AF included in a phase II trial of imatinib: we tested the presence of KIT exon 10 variant (M541L), the expression of imatinib-sensitive kinases and cell cycle proteins by immunohistochemistry (IHC), and other clinical and biological factors. RESULTS: Of 10 patients for whom DNA could be extracted, 3 had a KIT exon 10 variant (30%), with no correlation with response or progression-free survival (PFS). The expression of other imatinib targets (PDGFRA/B, macrophage colony-stimulating factor receptor (M-CSFR)) and of downstream components of the cell cycle, cell proliferation and proliferation pathway (cyclin D1, ERK, MEK 1-2) did not correlate with PFS. Pre-treatment lymphopenia (<1500/microl) and tumour size >120 mm correlated with shorter PFS in univariate and multivariate analyses. CONCLUSION: Our findings show that a baseline biological characteristic of the patient is the major parameter influencing response to imatinib in aggressive fibromatosis. Tumour characteristics, including the presence of a KIT exon 10 M541L variant, may influence tumour control but this needs to be confirmed and better explained.

Indoor air pollution and childhood asthma: variations between urban and rural areas.

UNLABELLED: Health effects of indoor pollution have been investigated overall in urban areas. To compare the potential effect of home air pollutants on asthma in urban and rural houses, two case-control populations, composed of children living in the city (32 asthmatics and 31 controls) and in the countryside (24 asthmatics and 27 controls) were included. During 1 week, nitrogen dioxide, fine particles, and volatile organic compounds (formaldehyde, acetaldehyde, benzene, toluene, ethylbenzene, and xylenes) were assessed at home. Urban dwellings were found to be more polluted than rural ones, with concentrations up to two times higher. In the whole population, exposure to acetaldehyde and toluene was significantly associated with a higher risk of asthma. In the urban population, the association with toluene was significant in children studied during winter, and with toluene, xylenes, and ethylbenzene when cases were restricted to current asthmatics. In rural settings, a relationship between asthma and formaldehyde exposure was observed (OR = 10.7; 95% CI 1.69-67.61). Our findings suggest that daily continuous exposures to pollutants may be implicated in asthma, even in the case of low exposure, as those found in rural areas. Our results could also indicate a specific effect of indoor pollution in the rural environment. PRACTICAL IMPLICATIONS: Everyday exposure to indoor pollution was associated with a higher risk of childhood asthma. These findings suggest that even at low concentrations, pollutants could be implicated in asthma and reinforce the importance of establishing guideline values to improve indoor air quality by limiting sources or by optimizing ventilation. Specific effects could occur in rural environments where pollution differs from urban area.

Neo/adjuvant chemotherapy does not improve outcome in resected primary synovial sarcoma: a study of the French Sarcoma Group.

BACKGROUND: There are only scarce data about the benefit of adjunctive chemotherapy in patients with localized synovial sarcoma (SS). PATIENTS AND METHODS: Data from 237 SS patients recorded in the database of the French Sarcoma Group were retrospectively analyzed. The respective impact of radiotherapy, neo-adjuvant chemotherapy and adjuvant chemotherapy on overall survival (OS), local recurrence-free survival (LRFS) and distant recurrence-free survival (DRFS) were assessed after adjustment to prognostic factors. RESULTS: The median follow-up was 58 months (range 1-321). Adjuvant, neo-adjuvant chemotherapy and postoperative radiotherapy were administered in 112, 45 and 181 cases, respectively. In all, 59% of patients treated with chemotherapy received an ifosfamide-containing regimen. The 5-year OS, LRFS and DRFS rates were 64.0%, 70% and 57%, respectively. On multivariate analysis, age >35 years old, grade 3 and not-R0 margins were highly significant independent predictors of worse OS. After adjustment to prognostic factors, radiotherapy significantly improved LRFS but not DRFS or OS. Neither neo-adjuvant nor adjuvant chemotherapy had significant impact on OS, LRFS or DRFS. CONCLUSION: As for other high-grade soft-tissue sarcomas, well-planned wide surgical excision with adjuvant radiotherapy remains the cornerstone of treatment for SS. Neo-adjuvant or adjuvant chemotherapy should not be delivered outside a clinical trial setting.

Phase II multicenter study of larotaxel (XRP9881), a novel taxoid, in patients with metastatic breast cancer who previously received taxane-based therapy.

BACKGROUND: Treatment options are limited for patients with refractory metastatic breast cancer (MBC). Larotaxel (XRP9881) is a novel taxoid with preclinical activity against taxane-resistant breast cancer. The current phase II trial of larotaxel was conducted in women with taxane-treated MBC. PATIENTS AND METHODS: Patients were stratified by response to prior taxane therapy (resistant or nonresistant). Larotaxel 90 mg/m(2) was administered as a 1-h infusion every 3 weeks. Patients were evaluated for tumor response every two cycles. A blinded external response review committee determined the overall response rate (ORR), duration of response (DOR), and time to progression (TtP) of the disease. Median survival time (MST) and safety were also evaluated. RESULTS: One hundred and thirty patients were treated. In the nonresistant group, the ORR was 42%; median DOR 5.3 months; median TtP 5.4 months; and MST 22.6 months. In the resistant group, the ORR was 19%; median DOR 5.0 months; median TtP 1.6 months; and MST 9.8 months. The most common grade 3/4 adverse events were neutropenia (82%), fatigue (15%), diarrhea (12%), febrile neutropenia (9%), neutropenic infection (8%), and sensory neuropathy (7%). CONCLUSIONS: Larotaxel has good activity, manageable toxicity, and a favorable therapeutic index in women with taxane-pretreated MBC.

Practical guidance for the management of aromatase inhibitor-associated bone loss.

BACKGROUND: Recent studies indicate that women with breast cancer are at increased risk of fracture compared with their age-matched peers. Current treatment guidelines are inadequate for averting fractures in osteopenic women, especially those receiving aromatase inhibitor (AI) therapy. Therefore, we sought to identify clinically relevant risk factors for fracture that can be used to assess overall fracture risk and to provide practical guidance for preventing and treating bone loss in women with breast cancer receiving AI therapy. METHODS: Systematic review of pertinent information from published literature and meeting abstracts through December 2007 was carried out to identify factors contributing to fracture risk in women with breast cancer. An evidence-based medicine approach was used to select risk factors that can be used to determine when to initiate bisphosphonate treatment of aromatase inhibitor-associated bone loss (AIBL). RESULTS: Fracture risk factors were chosen from large, well-designed, controlled, population-based trials in postmenopausal women. Evidence from multiple prospective clinical trials in women with breast cancer was used to validate AI therapy as a fracture risk factor. Overall, eight fracture risk factors were validated in women with breast cancer: AI therapy, T-score <-1.5, age >65 years, low body mass index (BMI <20 kg/m(2)), family history of hip fracture, personal history of fragility fracture after age 50, oral corticosteroid use >6 months, and smoking. Treatment recommendations were derived from randomized clinical trials. CONCLUSIONS: The authors recommend the following for preventing and treating AIBL in women with breast cancer. All patients initiating AI therapy should receive calcium and vitamin D supplements. Any patient initiating or receiving AI therapy with a T-score >/=-2.0 and no additional risk factors should be monitored every 1-2 years for change in risk status and bone mineral density (BMD). Any patient initiating or receiving AI therapy with a T-score <-2.0 should receive bisphosphonate therapy. Any patient initiating or receiving AI therapy with any two of the following risk factors-T-score <-1.5, age >65 years, low BMI (<20 kg/m(2)), family history of hip fracture, personal history of fragility fracture after age 50, oral corticosteroid use >6 months, and smoking-should receive bisphosphonate therapy. BMD should be monitored every 2 years, and treatment should continue for at least 2 years and possibly for as long as AI therapy is continued. To date, the overwhelming majority of clinical evidence supports zoledronic acid 4 mg every 6 months to prevent bone loss in women at high risk. Although there is a trend towards fewer fractures with zoledronic acid, studies completed to date have not been designed to capture significant differences in fracture rate, and longer follow-up is needed.

Characterization of the pathogenicity of strains of Pseudomonas syringae towards cherry and plum.

Bacterial canker is a major disease of Prunus avium (cherry), Prunus domestica (plum) and other stone fruits. It is caused by pathovars within the Pseudomonas syringae species complex including P. syringae pv. morsprunorum (Psm) race 1 (R1), Psm race 2 (R2) and P. syringae pv. syringae (Pss). Psm R1 and Psm R2 were originally designated as the same pathovar; however, phylogenetic analysis revealed them to be distantly related, falling into phylogroups 3 and 1, respectively. This study characterized the pathogenicity of 18 newly genome-sequenced P. syringae strains on cherry and plum, in the field and laboratory. The field experiment confirmed that the cherry cultivar Merton Glory exhibited a broad resistance to all clades. Psm R1 contained strains with differential specificity on cherry and plum. The ability of tractable laboratory-based assays to reproduce assessments on whole trees was examined. Good correlations were achieved with assays using cut shoots or leaves, although only the cut shoot assay was able to reliably discriminate cultivar differences seen in the field. Measuring bacterial multiplication in detached leaves differentiated pathogens from nonpathogens and was therefore suitable for routine testing. In cherry leaves, symptom appearance discriminated Psm races from nonpathogens, which triggered a hypersensitive reaction. Pathogenic strains of Pss rapidly induced disease lesions in all tissues and exhibited a more necrotrophic lifestyle than hemibiotrophic Psm. This in-depth study of pathogenic interactions, identification of host resistance and optimization of laboratory assays provides a framework for future genetic dissection of host-pathogen interactions in the canker disease.

To which mixtures are French pregnant women mainly exposed? A combination of the second French total diet study with the EDEN and ELFE cohort studies.

Pregnant women and their unborn child are exposed to a large number of substances during pregnancy. Some of these substances may cross the placenta, resulting in exposure of the foetus. There is growing evidence that certain substances could interact to produce a mixture effect. It is therefore essential to identify the main mixtures mothers are exposed to. This study aimed to identify the major mixtures French pregnant women included in EDEN and ELFE cohorts were exposed to, on the basis of the 441 substances analysed in the second French total diet study. Exposure systems and the composition of substances were identified from co-exposures using sparse non-negative matrix under-approximation to generate the main mixtures. Individuals were clustered to define clusters with similar co-exposure profiles. Six clusters associated with eight mixtures were identified. For example in ELFE, cluster 2 comprising 10% of the population was characterised by mixtures "Pest-1" mainly contains pesticides and "TE-F-PAH″ contains trace elements, furans and polycyclic aromatic hydrocarbons. Five other clusters were also described with their associated mixtures. Similar results were observed for EDEN. This study helps to prioritise mixtures for which it is crucial to investigate possible toxicological effects and to recommend epidemiological studies concerning health effects.

Multiparametric prognostic evaluation of biological factors in primary breast cancer.

BACKGROUND: An array of biological features related to tumor cell differentiation status, growth rate, and invasive potential have been identified as potential prognostic factors in breast cancer. We were interested in determining their relative importance in predicting patient survival. PURPOSE: We evaluated the relative weight of the following four biological factors in predicting survival of patients with breast cancer: tumor cell DNA content (determined by flow cytometry), tumor cell proliferation rate (determined by thymidine kinase activity), expression levels of cathepsin D and urokinase plasminogen activator, and several "classical" clinical and histological factors. METHODS: Selected from a prospectively updated database, the study population consisted of 319 primary breast cancer patients who received treatment and follow-up care (median, 6 years) in the Centre René Huguenin. To determine the profile of biological factors for each patient, we used frozen tumor specimens and (except for the flow cytometric DNA content assay) commercially available assay kits. We determined by Cox multivariate analysis the relationships of the biological factors to each other, to classical prognostic factors, and to disease-free and metastasis-free survival. RESULTS: In the overall population, disease-free survival was best predicted by node status (P = .004), clinical tumor size (P = .02), and cathepsin D expression (P = .01), whereas metastasis-free survival was best predicted by node status (P = .0004), clinical tumor size (P = .009), and urokinase plasminogen activator expression (P = .04). In node-negative patients, thymidine kinase activity was the only factor selected for disease-free (P = .04) and metastasis-free (P = .05) survival. In node-positive patients, the number of positive axillary lymph nodes was the only factor selected for disease-free (P = .0008) and metastasis-free (P = .00017) survival. CONCLUSIONS: Our retrospective analysis has identified protease expression and tumor cell proliferation rate as important biological prognostic factors in breast cancer. Prospective clinical trials should be undertaken to confirm these results.

Preoperative chemotherapy in primary operable breast cancer: results from the European Organization for Research and Treatment of Cancer trial 10902.

PURPOSE: To evaluate whether preoperative neoadjuvant chemotherapy in patients with primary operable breast cancer results in better overall survival (OS) and relapse-free survival rates and whether preoperative chemotherapy permits more breast-conserving surgery procedures than postoperative chemotherapy. PATIENTS AND METHODS: Six hundred ninety-eight breast cancer patients (T1c, T2, T3, T4b, N0 to 1, and M0) were enrolled onto a randomized phase III trial that compared four cycles of fluorouracil, epirubicin, and cyclophosphamide administered preoperatively versus the same regimen administered postoperatively (the first cycle administered within 36 hours after surgery). Patients were followed up for OS, progression-free survival (PFS), and locoregional recurrence (LRR). RESULTS: At a median follow-up of 56 months, there was no significant difference in terms of OS (hazards ratio, 1.16; P =.38), PFS (hazards ratio, 1.15; P =.27), and time to LRR (hazards ratio, 1.13; P =.61). Fifty-seven patients (23%) were downstaged by the preoperative chemotherapy, whereas 14 patients (18%) underwent mastectomy and not the planned breast-conserving therapy. CONCLUSION: The use of preoperative chemotherapy yields similar results in terms of PFS, OS, and locoregional control compared with conventional postoperative chemotherapy. In addition, preoperative chemotherapy enables more patients to be treated with breast-conserving surgery. Because preoperative chemotherapy does not improve disease outcome compared with postoperative chemotherapy, future trials should involve quality-of-life studies to investigate whether patients will benefit from this treatment modality.

Intensification of adjuvant chemotherapy: 5-year results of a randomized trial comparing conventional doxorubicin and cyclophosphamide with high-dose mitoxantrone and cyclophosphamide with filgrastim in operable breast cancer with 10 or more involved axillary nodes.

PURPOSE: To determine whether intensifying the dose of adjuvant chemotherapy improves the outcome of women with primary breast cancer and 10 or more involved axillary nodes. PATIENTS AND METHODS: Patients (n = 150) were randomized to receive either four cycles of standard doxorubicin 60 mg/m(2) plus cyclophosphamide 600 mg/m(2) every 3 weeks (arm A) or four courses of intensified mitoxantrone 23 mg/m(2) plus cyclophosphamide 600 mg/m(2), with filgrastim 5 g/kg/d from days 2 to 15, every 3 weeks (arm B). Disease-free survival (DFS), distant disease-free survival (DDFS), and overall survival (OS) were determined using life-table estimates. RESULTS: There were no significant differences in DFS (P =.44), DDFS (P =.67), or OS (P =.99) between the two groups at 5 years; DDFS was 45% (arm A) versus 50% (arm B), and DFS was 41% versus 49%, respectively. Five-year survival was similar in both arms (61% v 60%, respectively). Failure to note an intergroup difference in outcome was unrelated to relative dose-intensity. Analysis of patients with 15 or more positive nodes revealed a significant difference in 5-year DDFS (19% v 49% in arm B; P =.01). Toxicity was generally mild in both groups, with no toxic death. The incidence of febrile neutropenia was low (0.3% v 3%). Alopecia was less frequent in arm B (P <.001). CONCLUSION: This randomized trial confirms the feasibility of administering mitoxantrone 23 mg/m(2) with cyclophosphamide and filgrastim. Although there was no significant difference between conventional and intensified arms at 5 years, according to subgroup analysis, intensified treatment may decrease the risk of relapse in patients with 15 or more positive nodes compared with doxorubicin an cyclophosphamide.

A randomized double-blind comparison of ondansetron and metoclopramide in the prophylaxis of emesis induced by cyclophosphamide, fluorouracil, and doxorubicin or epirubicin chemotherapy.

Seventy-five breast cancer patients scheduled to receive a first course (in a new cycle) of cyclophosphamide, fluorouracil, and doxorubicin (FAC) or epirubicin (FEC) participated in a double-blind crossover study to compare the antiemetic efficacy and safety of ondansetron (GR38032), a 5-hydroxytryptamine3 (5-HT3) receptor antagonist, and metoclopramide. Ondansetron was given as an 8 mg loading dose (4 mg intravenously [IV] plus 4 mg orally) before chemotherapy followed by 8 mg every 8 hours orally for 3 to 5 days. Metoclopramide was given as an 80 mg loading dose (60 mg IV plus 20 mg orally) before chemotherapy followed by 20 mg every 8 hours orally for 3 to 5 days. A "period" interaction in the analysis of emetic response in the first 24 hours necessitated a parallel group analysis of first treatments only, 68 patients being assessable for this parameter. In the first 24 hours, complete or major control (zero to two emetic episodes) of emesis was achieved in 30 of 35 (86%) patients receiving ondansetron and in 14 of 33 (42%) patients receiving metoclopramide (P less than .001). Ondansetron was also more effective in reducing acute nausea. On days 2 to 3, the complete or major responses were significantly better with ondansetron (81% v 65%; P = .033), but there was no statistical difference in the control of nausea. There was a significant patient preference for ondansetron (63% v 26%; P = .001). Extrapyramidal reactions were observed in two metoclopramide treatments; both treatments were otherwise well tolerated. These results are consistent with serotonin (5-HT), being a significant neurotransmitter of cyclophosphamide/doxorubicin- or epirubicin/fluorouracil-induced emesis.

Dissemination risk index based on plasminogen activator system components in primary breast cancer.

PURPOSE: To study interactions between disease-free survival (DFS) and four components of the plasminogen activator system: urokinase-type plasminogen activator (uPA), its two inhibitors (PAI-1 and PAI-2), and its membrane receptor uPAR. PATIENTS AND METHODS: We conducted a retrospective study of 499 primary breast cancer patients (median follow-up, 6 years). uPA, PAI-1, and PAI-2 were determined on cytosols and uPAR on solubilized pellets, using enzyme-linked immunoadsorbent assay kits (American Diagnostica, Greenwich, CT). Classical univariate and multivariate statistical methods were used together with multiple correspondence analysis to graphically examine interactions between the variables and outcome. RESULTS: By univariate analysis, higher uPA and PAI-1 values were significantly related to shorter DFS (P =.002; P <.00002). PAI-2 was not significantly related to DFS, although patients with high and very low PAI-2 values had a longer DFS. Multiple correspondence analysis showed the parallel impact of uPA and PAI-1 on outcome, and the clearly different behavior of PAI-2 compared with PAI-1. The prognostic contribution of uPAR seemed weak by both methods. A dissemination risk index [uPA x PAI-1/(PAI-2 + 1)], taking into account the modulation of uPA proteolytic activity by the ratio of its two inhibitors, was then tested. Dissemination risk index was selected as an independent variable in the Cox model in the overall population (P <.000001) and in node-positive patients (P <.00001). It was the only variable selected in node-negative patients (P =. 003). CONCLUSION: A dissemination risk index determined on primary tumor and taking into account the different effects of PAI-1 and PAI-2 on uPA can be of major help in clinical management of breast cancer, particularly in node-negative patients.

Phase II study of oxaliplatin and fluorouracil in taxane- and anthracycline-pretreated breast cancer patients.

PURPOSE: Phase II study evaluating efficacy and safety of combined oxaliplatin/fluorouracil (5-FU) in taxane-pretreated advanced and metastatic breast cancer (ABC) patients. PATIENTS AND METHODS: Sixty-four taxane- and anthracycline-pretreated (within 6 months of study entry) women were treated with oxaliplatin 130 mg/m(2) (2-hour intravenous [IV] infusion), day 1, and 5-FU 1,000 mg/m(2)/d (continuous IV infusion) days 1 to 4, every 3 weeks. RESULTS: Median patient age was 51 years (range, 34 to 71 years), with a median of two involved organs (range, one to six organs), and metastases in the liver (70%), bone (47%), and lung (34%). Patients had a median of two prior chemotherapy regimens (range, one to six regimens), and 78% had previous hormonal therapy, with clinical taxane and anthracycline resistance in 53% and 34%, respectively. A total of 367 cycles were administered, with a median of six cycles/patient (range, one to 15 cycles). Sixty patients were assessable for response (World Health Organization criteria): 17 partial response, 26 stable disease, and 17 disease progression, giving an overall response rate of 27% (95% confidence interval, 16.3% to 39.1%), and 26% and 36% in taxane- and anthracycline-resistant populations, respectively, all responders having metastatic liver disease. Median time to progression was 4.8 months, and median overall survival was 11.9 months. Four treatment-related serious adverse events occurred, seven patients withdrew because of treatment-related toxicity. Hematotoxicity was prevalent but rarely severe, with grade 3-4 neutropenia, leukopenia, and thrombocytopenia in 34%, 19%, and 16% of patients, respectively, and a single episode of febrile neutropenia. One third of patients developed grade 2-3 peripheral neuropathy (oxaliplatin-specific scale), with grade 3 in only 8%. CONCLUSION: This oxaliplatin/5-FU combination is effective with an excellent safety profile in anthracycline/taxane-pretreated ABC patients, showing encouraging activity in patients with anthracycline/taxane-resistance or visceral disease.

Randomized phase II trial comparing different doses of the bisphosphonate ibandronate in the treatment of hypercalcemia of malignancy.

PURPOSE: To evaluate the hypocalcemic effect and safety of three different doses of the bisphosphonate ibandronate in tumor-associated hypercalcemia, and to identify factors predicting response. PATIENTS AND METHODS: One hundred seventy-four cancer patients with a serum calcium level greater than 2.7 mmol/L (10.8 mg/dL) were enrolled onto the trial. If hypercalcemia persisted after fluid repletion, patients were randomly assigned to treatment with 0.6 mg, 1.1 mg, and 2.0 mg of ibandronate. Response, defined as restoration of normocalcemia, was evaluated by an intent-to-treat analysis. RESULTS: One hundred seventy-three (99%) patients were assessable for toxicity and 151 (87%) for efficacy. The administration of 0.6 mg (group A), 1.1 mg (group B), or 2.0 mg (group C) of ibandronate led to response rates of 44%, 52%, and 67%, respectively. Significantly more patients in group C responded than in group A (P = .0276). Of the various parameters examined, only the initial serum calcium level (P < .0001; odds ratio, 0.083) and the dose of ibandronate (P = .0162; odds ratio, 2.094) correlated with response. One hundred ninety-five adverse events (AEs) were reported, 99 classified as serious and 96 as nonserious. Three serious and sixteen nonserious AEs were considered related to ibandronate treatment. The three serious AEs were one case with thrombocytopenia, one with nausea, and one with fever. CONCLUSION: Ibandronate therapy led to a dose-dependent reduction in serum calcium levels. The response to ibandronate treatment correlated negatively with the initial serum calcium level and positively with the dose administered. A dose of 2 mg was necessary to achieve a response rate comparable to that in previous studies with the bisphosphonates pamidronate and clodronate. Because the incidence of drug-associated AEs was low, a dose escalation of ibandronate can be recommended for further clinical trials.

Activity of exemestane in metastatic breast cancer after failure of nonsteroidal aromatase inhibitors: a phase II trial.

PURPOSE: To evaluate the antitumor activity and toxicity of a new steroidal aromatase inactivator, exemestane, in postmenopausal women with metastatic breast cancer who had progressive disease (PD) after treatment with a nonsteroidal aromatase inhibitor. PATIENTS AND METHODS: In this phase II trial, eligible patients were treated with exemestane 25 mg daily (n = 241) followed, at the time PD was determined, by exemestane 100 mg daily (n = 58). RESULTS: On the basis of the intent-to-treat analysis by independent review, exemestane 25 mg produced objective responses in 6.6% of patients (95% confidence interval [CI], 3.8% to 10.6%) and overall success (complete response + partial response + no change for 24 weeks or longer) in 24.3% (95% CI, 19.0% to 30.2%). The median durations of objective response and overall success were 58.4 weeks (95% CI, 49.7 to 71.1 weeks) and 37.0 weeks (95% CI, 35.0 to 39.4 weeks), respectively. Increasing the dose of exemestane to 100 mg upon the development of PD produced one partial response (1.7%; 95% CI, 0.0% to 9.2%). Both dosages were well tolerated and were discontinued because of adverse events in only 1.7% of patients. CONCLUSION: Exemestane 25 mg once daily seems to be an attractive alternative to chemotherapy for the treatment of patients with metastatic breast cancer after multiple hormonal therapies have failed.

How to maximize the efficacy of taxanes in breast cancer.

The life-expectancy of women with metastatic breast cancer (MBC) is closely linked to response to therapy. A significant increase in progression-free survival (PFS) and overall survival (OS) has been demonstrated in women who achieve a complete response. Anthracycline combinations have been proven as highly effective in MBC, and anthracycline regimens plus cyclophosphamide with or without fluorouracil were established as first-line chemotherapy for MBC in the 1990s. Clinical trials have shown that anthracycline-taxane combinations are more effective than anthracyclines or taxanes alone in terms of overall response rates (ORR), PFS and OS in women who have not received prior anthracycline chemotherapy. The use of anthracycline-based regimens is limited, however, by the widespread use of anthracycline adjuvant therapy and the development of anthracycline-resistance. Platinum-taxane combinations have similar efficacy to anthracycline-based regimens and are well-tolerated by patients. Carboplatin combined with paclitaxel or docetaxel is more effective than carboplatin or taxanes alone, with ORR of 53-62%. Taxane combinations with gemcitabine or capecitabine are also more effective than docetaxel, paclitaxel, capecitabine or gemcitabine administered alone. The efficacy of docetaxel and paclitaxel can be increased, and drug-related toxicity decreased, by adapting dose-dense schedules of drug administration. The addition of trastuzumab to taxane-based chemotherapy increases the efficacy of taxane-based regimens in women with HER2-positive MBC.

Relationship between c-erbB-2 and other tumor characteristics in breast cancer prognosis.

The aim of this study was to evaluate c-erbB-2 overexpression by means of a quantitative biochemical technique in 488 primary breast cancer patients with long-term follow-up (median, 10 years) and its relation to other biochemical prognostic factors (uPA, p53, and epidermal growth factor receptor) and adjuvant therapy. High levels of c-erbB-2 (>500 IU/mg protein) were associated with estrogen receptor (ER) and progesterone receptor negativity, high histoprognostic SBR grade and high levels of uPA and p53. Univariate analyses showed shorter metastasis-free survival (MFS) and overall survival (OS) in patients whose tumors overexpressed c-erbB-2 in the overall population, in subgroups defined by ER and uPA status, and in patients with positive pathological nodal status, SBR grade II, progesterone receptor, and p53-negative tumors. Patients with ER-positive, c-erbB-2-positive tumors had a shorter MFS and OS than those patients with c-erbB-2-negative tumors. No difference was observed between adjuvant-treated and untreated patients (chemotherapy and/or hormone therapy) in the c-erbB-2-negative subgroup. There was a trend toward a longer short-term MFS in c-erbB-2-positive patients treated with chemotherapy, whereas an opposite effect was observed with hormone therapy. Cox multivariate analyses showed that high levels of c-erbB-2 negatively influenced MFS in the overall population as well as in node-positive patients and in tamoxifen-treated patients, along with pN and uPA. Results for OS were comparable with those obtained for MFS. These results suggest that c-erbB-2 overexpression in breast cancer may be a better predictor of the response to tamoxifen than is ER status alone.