Catalyst-Free Hydroboration of CO2 With a Nucleophilic Diborane(4).

Hydroboration generally requires the presence of a catalyst to lower the barrier for hydride transfer. This work reports on the first catalyst-free CO2 hydroboration with a neutral boron compound, the nucleophilic diborane [HB(hpp)]2 , 1 (hpp=1,3,4,6,7,8-hexahydro-2H-pyrimido[1,2-a]pyrimidinate). Further hydroboration reactions to bis(boryl)acetals are possible. In acetonitrile, but not in dichloromethane solutions, hydroboration of a first CO2 is followed by hydroboration of a second CO2 molecule. Detailed kinetic measurements for both hydroboration steps were carried out and the influence of the solvent and the addition of a Lewis base on the rate constants analyzed. In contrast to catalyst-free hydroboration of CO2 , hydroboration of the less electrophilic acetone requires the presence of an activating Lewis acid.

Metal-Free Nitrile Diboration through Activation by an Electron-Rich Diborane.

Diboration of unsaturated organic compounds is an extremely useful reaction in synthetic chemistry. Herein, we report the first diboration of a nitrile by an electron-rich diborane, mediated by an electrophilic borane. The reaction is metal-free, and all of the reagents are readily available.

BRCA1-like profile predicts benefit of tandem high dose epirubicin-cyclophospamide-thiotepa in high risk breast cancer patients randomized in the WSG-AM01 trial.

BRCA1 is an important protein in the repair of DNA double strand breaks (DSBs), which are induced by alkylating chemotherapy. A BRCA1-like DNA copy number signature derived from tumors with a BRCA1 mutation is indicative for impaired BRCA1 function and associated with good outcome after high dose (HD) and tandem HD DSB inducing chemotherapy. We investigated whether BRCA1-like status was a predictive biomarker in the WSG AM 01 trial. WSG AM 01 randomized high-risk breast cancer patients to induction (2× epirubicin-cyclophosphamide) followed by tandem HD chemotherapy with epirubicin, cyclophosphamide and thiotepa versus dose dense chemotherapy (4× epirubicin-cyclophospamide followed by 3× cyclophosphamide-methotrexate-5-fluorouracil). We generated copy number profiles for 143 tumors and classified them as being BRCA1-like or non-BRCA1-like. Twenty-six out of 143 patients were BRCA1-like. BRCA1-like status was associated with high grade and triple negative tumors. With regard to event-free-survival, the primary endpoint of the trial, patients with a BRCA1-like tumor had a hazard rate of 0.2, 95% confidence interval (CI): 0.07-0.63, p = 0.006. In the interaction analysis, the combination of BRCA1-like status and HD chemotherapy had a hazard rate of 0.19, 95% CI: 0.067-0.54, p = 0.003. Similar results were observed for overall survival. These findings suggest that BRCA1-like status is a predictor for benefit of tandem HD chemotherapy with epirubicin-thiotepa-cyclophosphamide.

Nuclear karyopherin alpha2 expression predicts poor survival in patients with advanced breast cancer irrespective of treatment intensity.

Intensive lymph node involvement indicates poor prognosis in breast cancer patients. The significance of other molecular prognostic factors in this subgroup is unclear. Karyopherin alpha2 (KPNA2) has been reported as an important factor of tumorgenesis and progression of breast cancer. The aim of present study was to evaluate the impact of KPNA2 expression on prognosis of patients with high risk breast cancer (HRBC) and response intensive chemotherapy within the randomized WSG-AM-01 trial. KPNA2 nuclear expression (>10% vs. <10% of nuclei) was measured by immunohistochemistry on tissue arrays of 191 patients randomized to tandem high dose vs. conventional dose-dense chemotherapy in HRBC with >9 positive lymph nodes and correlated with clinical outcome (median follow-up of 63.3 months) by Kaplan-Meier and multivariate Cox hazard model analysis, including, molecular subtypes determined by k-clustering (k = 5). KPNA2 overexpression (n = 74, 39%) significantly correlated with shorter event-free and overall survival (OS) in both therapy arms by univariate analysis. Multivariate analysis showed that the overexpression of KPNA2 was an independent prognostic factor of decreased OS HR = 1.86 [95% CI: 1.07-3.23, p = 0.03]. This predictive value was independent of basal-like/Her-2/neu subtypes, significantly associated with KPNA2 and was addressed particularly to G2 tumors. Our data suggest the use of KPNA2 nuclear expression as novel prognostic marker in node-positive patients, especially in determination of G2 tumors in 2 subgroups of different prognosis. KPNA2 expression may be also considered as a marker for global chemoresistance, which can not be overcome by conventional dose-modification of chemotherapy in advanced breast cancer.

Randomized trial of single compared with tandem high-dose chemotherapy followed by autologous stem-cell transplantation in patients with chemotherapy-sensitive metastatic breast cancer.

PURPOSE: To compare progression-free survival between single and tandem high-dose chemotherapy (HDT) followed by autologous stem-cell transplantation in chemotherapy-sensitive metastatic breast cancer patients. PATIENTS AND METHODS: Between February 1997 and June 2001, 187 patients with complete and partial remission were randomly assigned to receive either one or two cycles of HDT, consisting of thiotepa (125 mg/m2/d for 4 days), cyclophosphamide (1,500 mg/m2/d for 4 days), and carboplatin (200 mg/m2/d for 4 days), followed by autologous stem-cell transplantation. RESULTS: One hundred seventy one of 187 randomly assigned patients completed first HDT, but only 52 of 85 completed the second HDT cycle in the tandem HDT arm. The rate of complete remission on an intent-to-treat-basis was 33% in the single-dose HDT arm and 37% in the tandem HDT arm (P = .48). The median progression-free survival times in single and tandem HDT arms were 9.4 and 11.2 months, respectively (one-sided P = .06; two one-sided P = .12), whereas median overall survival time tended to be greater after single versus tandem HDT (29 v 23.5 months, respectively; P = .4). In a multivariate analysis for progression-free survival, tandem HDT (hazard ratio [HR] = 0.71; 95% CI, 0.52 to 0.98; P = .03) and achievement of complete remission after induction chemotherapy (HR = 0.59; 95% CI, 0.37 to 0.96; P = .03) were factors for a better progression-free survival, whereas the factor of three or more sites of metastases (HR = 1.66; 95% CI, 1.12 to 2.47; P = .01) was associated with a worse progression-free survival. CONCLUSION: Despite a trend of improved progression-free survival, tandem HDT cannot be recommended for patients with chemotherapy-sensitive metastatic breast cancer because of a trend for shorter overall survival and higher toxicity compared with single HDT.

Comparison of rapidly cycled tandem high-dose chemotherapy plus peripheral-blood stem-cell support versus dose-dense conventional chemotherapy for adjuvant treatment of high-risk breast cancer: results of a multicentre phase III trial.

BACKGROUND: Breast cancer with extensive axillary-lymph-node involvement has a poor prognosis after conventional treatment. In trials with historical controls, high-dose chemotherapy produced improved outcomes. We compared an intensive double-cycle high-dose chemotherapy regimen with an accelerated conventionally dosed regimen in high-risk breast cancer in a multicentre trial. METHODS: Patients with at least nine positive nodes were randomly assigned either two courses of accelerated (2-week intervals, with filgrastim support), conventionally dosed epirubicin and cyclophosphamide followed by two courses of high-dose chemotherapy (epirubicin, cyclophosphamide, and thiotepa supported by peripheral-blood progenitors) or four identical cycles of epirubicin and cyclophosphamide followed by three cycles of accelerated cyclophosphamide, methotrexate, and fluorouracil. The primary endpoint was event-free survival. Analyses were done both by intention to treat and per protocol. FINDINGS: 403 patients were enrolled; 201 were assigned high-dose chemotherapy and 202 conventional treatment. The mean number of positive nodes was 17.6, and median follow-up was 48.6 months. 4-year event-free survival (intention-to-treat analysis) was 60% (95% CI 53-67) in the high-dose chemotherapy group and 44% (37-52) in the control group (p=0.00069). The corresponding overall survival was 75% (69-82) versus 70% (64-77; p=0.02). There were no treatment-related deaths. INTERPRETATION: Our finding of significant improvements in both event-free and overall survival for high-dose chemotherapy compared with a dose-dense conventional regimen contrasts with the results of other studies. The discrepancy might be due partly to design differences (tandem, brief induction) between our regimen and those studied in other trials. This approach merits further study.

Superior mobilisation of haematopoietic progenitor cells with glycosylated G-CSF in male but not female unrelated stem cell donors.

Granulocyte colony-stimulating factor (G-CSF) effectively mobilises haematopoietic stem cells to the peripheral blood. It is unclear whether the mobilisation of stem cells with lenograstim (glycosylated G-CSF) or filgrastim (non-glycosylated G-CSF) leads to a higher cell number of collected engraft able progenitor cells. Thus, we investigated harvesting efficiency of the licensed G-CSF preparations in mobilising peripheral stem cells in a randomised study. A total of 501 healthy unrelated donors, including 339 males and 162 females received either lenograstim (n = 261) or filgrastim (n = 240) at 10 microg/kg body weight (BW) per day. Aphaeresis was performed on day 5 and, if necessary, on day 6 of mobilisation. The number of CD34+ cells collected was 11.5% higher in the lenograstim group (7.19 x 10(6) vs. 6.44 x 10(6)/kg BW donor; P < 0.03). Univariate variance analysis revealed that this effect was caused by male donors: more progenitors cells per kg BW of the donor (7.73 x 10(6) vs. 6.88 x 10(6); P < 0.017) and of the recipient (10.1 x 10(6) vs. 8.88 x 10(6), P < 0.029) could be harvested. There was no significant difference in the percentage of donors in whom a second aphaeresis was required (9.6% vs. 11.6%). Lenograstim mobilises progenitor cells into the peripheral blood more effectively in males than filgrastim.