An unprecedented phosphinine with significant P(π)-donor properties

A hitherto unprecedented electronic situation has been observed for a substituted, pyridyl-functionalized phosphinine. In contrast to previous studies, this compound shows considerable π-donor properties as the result of the rather strong +M effect of the CH3S-substituent, changing the electronic properties of this low-coordinate and aromatic phosphorus heterocycle substantially

Development of a High Level Waste Tank Inspection System

The Westinghouse Savannah River Technology Center was requested by it`s sister site, West Valley Nuclear Service (WVNS), to develop a remote inspection system to gather wall thickness readings of their High Level Waste Tanks. WVNS management chose to take a proactive approach to gain current information on two tanks t hat had been in service since the early 70`s. The tanks contain high level waste, are buried underground, and have only two access ports to an annular space between the tank and the secondary concrete vault. A specialized remote system was proposed to provide both a visual surveillance and ultrasonic thickness measurements of the tank walls. A magnetic wheeled crawler was the basis for the remote delivery system integrated with an off-the-shelf Ultrasonic Data Acquisition System. A development program was initiated for Savannah River Technology Center (SRTC) to design, fabricate, and test a remote system based on the Crawler. The system was completed and involved three crawlers to perform the needed tasks, an Ultrasonic Crawler, a Camera Crawler, and a Surface Prep Crawler. The crawlers were computer controlled so that their operation could be done remotely and their position on the wall could be tracked. The Ultrasonic Crawler controls were interfaced with ABB Amdata`s I-PC, Ultrasonic Data Acquisition System so that thickness mapping of the wall could be obtained. A second system was requested by Westinghouse Savannah River Company (WSRC), to perform just ultrasonic mapping on their similar Waste Storage Tanks; however, the system needed to be interfaced with the P-scan Ultrasonic Data Acquisition System. Both remote inspection systems were completed 9/94. Qualifications tests were conducted by WVNS prior to implementation on the actual tank and tank development was achieved 10/94. The second inspection system was deployed at WSRC 11/94 with success, and the system is now in continuous service inspecting the remaining high level waste tanks at WSRC

Response rate by geographic region in patients with hormone receptor-positive, human epidermal growth factor receptor-2–negative advanced breast cancer from the SOLAR-1 trial

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Neoadjuvant bevacizumab and anthracycline-taxane-based chemotherapy in 678 triple-negative primary breast cancers; results from the geparquinto study (GBG 44)†

Background We evaluated the pathological complete response (pCR) rate after neoadjuvant epirubicin, (E) cyclophosphamide (C) and docetaxel containing chemotherapy with and without the addition of bevacizumab in patients with triple-negative breast cancer (TNBC). Patients and methods Patients with untreated cT1c-4d TNBC represented a stratified subset of the 1948 participants of the HER2-negative part of the GeparQuinto trial. Patients were randomized to receive four cycles EC (90/600 mg/m2; q3w) followed by four cycles docetaxel (100 mg/m2; q3w) each with or without bevacizumab (15 mg/kg; q3w) added to chemotherapy. Results TNBC patients were randomized to chemotherapy without (n = 340) or with bevacizumab (n = 323). pCR (ypT0 ypN0, primary end point) rates were 27.9% without and 39.3% with bevacizumab (P = 0.003). According to other pCR definitions, the addition of bevacizumab increased the pCR rate from 30.9% to 41.8% (ypT0 ypN0/+; P = 0.004), 36.2% to 46.4% (ypT0/is ypN0/+; P = 0.009) and 32.9% to 43.3% (ypT0/is ypN0; P = 0.007). Bevacizumab treatment [OR 1.73, 95% confidence interval (CI) 1.23-2.42; P = 0.002], lower tumor stage (OR 2.38, 95% CI 1.24-4.54; P = 0.009) and grade 3 tumors (OR 1.68, 95% CI 1.14-2.48; P = 0.009) were confirmed as independent predictors of higher pCR in multivariate logistic regression analysis. Conclusions The addition of bevacizumab to chemotherapy in TNBC significantly increases pCR rate

Pegfilgrastim ± ciprofloxacin for primary prophylaxis with TAC (docetaxel/doxorubicin/cyclophosphamide) chemotherapy for breast cancer. Results from the GEPARTRIO study

Background: TAC (docetaxel/doxorubicin/cyclophosphamide) is associated with high incidences of grade 4 neutropenia and febrile neutropenia (FN). This analysis compared the efficacies of four regimens for primary prophylaxis of FN and related toxic effects in breast cancer patients receiving neoadjuvant TAC. Patients and methods: Patients with stage T2-T4 primary breast cancer were scheduled to receive 6-8 cycles of TAC. Primary prophylaxis was: ciprofloxacin 500 mg orally twice daily on days 5-14 (n = 253 patients; 1478 cycles), daily granulocyte colony-stimulating factor (G-CSF) (filgrastim 5 μg/kg/day or lenograstim 150 μg/m2/day) on days 5-10 (n = 377; 2400 cycles), pegfilgrastim 6 mg on day 2 (n = 305; 1930 cycles), or pegfilgrastim plus ciprofloxacin (n = 321; 1890 cycles). Results: Pegfilgrastim with/without ciprofloxacin was significantly more effective than daily G-CSF or ciprofloxacin in preventing FN (5% and 7% versus 18% and 22% of patients; all P < 0.001), grade 4 neutropenia, and leukopenia. Pegfilgrastim plus ciprofloxacin completely prevented first cycle FN (P < 0.01 versus pegfilgrastim alone) and fatal neutropenic events. Conclusion: Ciprofloxacin alone, or daily G-CSF from day 5-10 (as in common practice), provided suboptimal protection against FN and related toxic effects in patients receiving TAC. Pegfilgrastim was significantly more effective in this setting, especially if given with ciprofloxaci

Cardiac safety of dual anti-HER2 blockade with pertuzumab plus trastuzumab in early HER2-positive breast cancer in the APHINITY trial.

BACKGROUND Trastuzumab increases the incidence of cardiac events (CEs) in patients with breast cancer (BC). Dual blockade with pertuzumab (P) and trastuzumab (T) improves BC outcomes and is the standard of care for high-risk human epidermal growth factor receptor 2 (HER2)-positive early BC patients. We analyzed the cardiac safety of P and T in the phase III APHINITY trial. PATIENTS AND METHODS Left ventricular ejection fraction (LVEF) ≥ 55% was required at study entry. LVEF assessment was carried out every 3 months during treatment, every 6 months up to month 36, and yearly up to 10 years. Primary CE was defined as heart failure class III/IV and a significant decrease in LVEF (defined as ≥10% from baseline and to <50%), or cardiac death. Secondary CE was defined as a confirmed significant decrease in LVEF, or CEs confirmed by the cardiac advisory board. RESULTS The safety analysis population consisted of 4769 patients. With 74 months of median follow-up, CEs were observed in 159 patients (3.3%): 83 (3.5%) in P + T and 76 (3.2%) in T arms, respectively. Most CEs occurred during anti-HER2 therapy (123; 77.4%) and were asymptomatic or mildly symptomatic decreases in LVEF (133; 83.6%). There were two cardiac deaths in each arm (0.1%). Cardiac risk factors indicated were age > 65 years, body mass index ≥ 25 kg/m2, baseline LVEF between 55% and <60%, and use of an anthracycline-containing chemotherapy regimen. Acute recovery from a CE based on subsequent LVEF values was observed in 127/155 patients (81.9%). CONCLUSIONS Dual blockade with P + T does not increase the risk of CEs compared with T alone. The use of anthracycline-based chemotherapy increases the risk of a CE; hence, non-anthracycline chemotherapy may be considered, particularly in patients with cardiovascular risk factors

Overall Survival with Palbociclib and Fulvestrant in Advanced Breast Cancer

BACKGROUND The cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor palbociclib, in combination with fulvestrant therapy, prolongs progression-free survival among patients with hormone-receptor–positive, human epidermal growth factor receptor 2 (HER2)–negative advanced breast cancer. We report the results of a prespecified analysis of overall survival. METHODS We randomly assigned patients with hormone-receptor–positive, HER2-negative advanced breast cancer who had progression or relapse during previous endocrine therapy to receive palbociclib plus fulvestrant or placebo plus fulvestrant. We analyzed overall survival; the effect of palbociclib according to the prespecified stratification factors of presence or absence of sensitivity to endocrine therapy, presence or absence of visceral metastatic disease, and menopausal status; the efficacy of subsequent therapies after disease progression; and safety. RESULTS Among 521 patients who underwent randomization, the median overall survival was 34.9 months (95% confidence interval [CI], 28.8 to 40.0) in the palbociclib– fulvestrant group and 28.0 months (95% CI, 23.6 to 34.6) in the placebo–fulvestrant group (hazard ratio for death, 0.81; 95% CI, 0.64 to 1.03; P=0.09; absolute difference, 6.9 months). CDK4/6 inhibitor treatment after the completion of the trial regimen occurred in 16% of the patients in the placebo–fulvestrant group. Among 410 patients with sensitivity to previous endocrine therapy, the median overall survival was 39.7 months (95% CI, 34.8 to 45.7) in the palbociclib–fulvestrant group and 29.7 months (95% CI, 23.8 to 37.9) in the placebo–fulvestrant group (hazard ratio, 0.72; 95% CI, 0.55 to 0.94; absolute difference, 10.0 months). The median duration of subsequent therapy was similar in the two groups, and the median time to the receipt of chemotherapy was 17.6 months in the palbociclib– fulvestrant group, as compared with 8.8 months in the placebo–fulvestrant group (hazard ratio, 0.58; 95% CI, 0.47 to 0.73; P<0.001). No new safety signals were observed with 44.8 months of follow-up. CONCLUSIONS Among patients with hormone-receptor–positive, HER2-negative advanced breast cancer who had sensitivity to previous endocrine therapy, treatment with palbociclib–fulvestrant resulted in longer overall survival than treatment with placebo– fulvestrant. The differences in overall survival in the entire trial group were not significant. (Funded by Pfizer; PALOMA-3 ClinicalTrials.gov number, NCT01942135.

Recommendations from an international expert panel on the use of neoadjuvant (primary) systemic treatment of operable breast cancer: new perspectives 2006

Neoadjuvant (primary systemic) treatment has become a standard option for primary operable disease for patients who are candidates for adjuvant systemic chemotherapy, irrespective of the size of the tumor. Because of new treatments and new understandings of breast cancer, however, recommendations published in 2006 regarding neoadjuvant treatment for operable disease required updating. Therefore, a third international panel of representatives of a number of breast cancer clinical research groups was convened in September 2006 to update these recommendations. As part of this effort, data published to date were critically reviewed and indications for neoadjuvant treatment were newly define