A (Slightly Less Brutal) Method for Numerically Evaluating Structure Functions

A fast numerical algorithm for the evolution of parton distributions in x space is described. The method is close in spirit to `brute' force techniques. The necessary integrals are performed by summing the approximate contributions from small steps of the integration region. Because it is a numerical evaluation it shares the advantage with brute force numerical integration that there are no restrictions placed on the functional form of the distributions to be evolved. However, an improvement in the approximation technique results in a significant reduction in the number of integration steps and a savings in time on the order of three hundred fifty. The method has been implemented for the structure functions F_2 and g_1 at next-to-leading order.Comment: 21 pages, LaTeX, 11 epsf figures include

CF6 jet engine diagnostics program. High pressure turbine roundness/clearance investigation

The effects of high pressure turbine clearance changes on engine and module performance was evaluated in addition to the measurement of CF6-50C high pressure turbine Stage 1 tip clearance and stator out-of-roundness during steady-state and transient operation. The results indicated a good correlation of the analytical model of round engine clearance response with measured data. The stator out-of-roundness measurements verified that the analytical technique for predicting the distortion effects of mechanical loads is accurate, whereas the technique for calculating the effects of certain circumferential thermal gradients requires some modifications. A potential for improvement in roundness was established in the order of 0.38 mm (0.015 in.), equivalent to 0.86 percent turbine efficiency which translates to a cruise SFC improvement of 0.36 percent. The HP turbine Stage 1 tip clearance performance derivative was established as 0.44 mm (17 mils) per percent of turbine efficiency at take-off power, somewhat smaller, therefore, more sensitive than predicted from previous investigations

CF6 jet engine performance improvement: High pressure turbine roundness

An improved high pressure turbine stator reducing fuel consumption in current CF6-50 turbofan engines was developed. The feasibility of the roundness and clearance response improvements was demonstrated. Application of these improvements will result in a cruise SFC reduction of 0.22 percent for new engines. For high time engines, the improved roundness and response characteristics results in an 0.5 percent reduction in cruise SFC. A basic life capability of the improved HP turbine stator in over 800 simulated flight cycles without any sign of significant distress is shown

The CF6 Jet Engine Performance Improvement - Low Pressure Turbine Active Clearance Control

A low pressure turbine (LPT) active clearance control (ACC) cooling system was developed to reduce the fuel consumption of current CF6-50 turbofan engines for wide bodied commercial aircraft. The program performance improvement goal of 0.3% delta sfc was determined to be achievable with an improved impingement cooling system. The technology enables the design of an optimized manifold and piping system which is capable of a performance gain of 0.45% delta sfc

Gemcitabine and carboplatin in intensively pretreated patients with metastatic breast cancer

Background: Patients with metastatic breast cancer (MBC) are increasingly exposed to anthracyclines and taxanes either during treatment of primary breast cancer or during initial therapy of metastatic disease. The combination of gemcitabine and carboplatin was therefore investigated as an anthracycline- and taxane-free treatment option. Patients and Methods: MBC patients previously treated with chemotherapy were enrolled in a multicenter phase II study. Treatment consisted of gemcitabine (1,000 mg/m(2) i.v. on days 1 and 8) and carboplatin (AUC 4 i.v. on day 1) applied every 3 weeks. Results: Thirty-nine patients were recruited, and a total of 207 treatment cycles were applied with a median of 5 cycles per patient. One complete response and 11 partial responses were observed for an overall response rate of 31% (95% CI: 17-48%). Twelve patients (31%) had stable disease. Median time to progression was 5.3 months (95% CI: 2.6-6.7 months) and median overall survival from start of treatment was 13.2 months (95% CI: 8.7-16.7 months). Grade 3/4 hematological toxicity included leukopenia (59%/5%), thrombo-cytopenia (26%/23%) and anemia (10%/0%). Nonhematological toxicity was rarely severe. Conclusion: Combination chemotherapy with gemcitabine and carboplatin is an effective and generally well-tolerated treatment option for intensively pretreated patients with MBC. Due to a considerable incidence of severe thrombocytopenia it would be reasonable to consider starting gemcitabine at the lower dose level of 800 mg/m(2). Copyright (c) 2008 S. Karger AG, Basel

Follow-up for breast cancer - the patients' view

Background: International and national guidelines (S3 guideline) for the surveillance of post-treatment breast cancer patients recommend a clinical follow-up including routine history and physical examination and regular mammograms. The practice of a clinical follow-up has been often discussed, but has been proven not to be inferior when compared to an intensified follow-up in randomized trials. Patients and Methods: The present manuscript reports the patients' view on the basis of a survey including 2000 patients with a history of breast cancer. Results: A total of 452 patients (22.6%) answered the questionnaire. The median age was 62 years (range 23-85 years). More than 80% of the patients were disease-free at the time of the survey. The need for surveillance was affirmed by the majority of patients (>95%), and one third stated that there was a need for more technical efforts during follow-up. In contrast to the follow-up guidelines, the results of the present survey indicated that most of the regularly scheduled follow-up visits were expanded using extensive laboratory and imaging procedures. Conclusion: This survey shows that the majority of physicians obviously do not accept the present follow-up guidelines. A new surveillance study investigating the efficacy of an intensified surveillance based on the improved possibilities of modern diagnostics and endocrine, immunotherapeutic, chemotherapeutic and interventional treatment options is warranted

Ribociclib plus fulvestrant for postmenopausal women with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer in the phase III randomized MONALEESA-3 trial: updated overall survival

Background: Ribociclib plus fulvestrant demonstrated significant progression-free survival (PFS) and overall survival (OS) benefits in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+/HER2-) advanced breast cancer (ABC). Here we present a new landmark in survival follow-up for a phase III cyclin-dependent kinases 4 and 6 inhibitor clinical trial in patients with ABC (median, 56.3 months). Patients and methods: This phase III, randomized, double-blind, placebo-controlled trial was conducted at 174 sites (30 countries). Patients were men and postmenopausal women (age ≥18 years) with histologically/cytologically confirmed HR+/HER2- ABC. Patients could have received ≤1 line of endocrine therapy (ET) but no chemotherapy for ABC. Patients, assigned 2:1, were stratified by the presence/absence of liver/lung metastases and previous ET. Patients received intramuscular fulvestrant (500 mg, day 1 of each 28-day cycle plus day 15 of cycle 1) with oral ribociclib (600 mg/day, 3 weeks on, 1 week off) or placebo. Efficacy analyses were by intention to treat. Safety was assessed in patients receiving ≥1 dose study treatment. OS was a secondary endpoint. MONALEESA-3 is registered with ClinicalTrials.gov (NCT02422615; no longer enrolling). Results: Between 18 June 2015 and 10 June 2016, 726 patients were randomly assigned (484, ribociclib; 242, placebo). At data cut-off (30 October 2020), median OS (mOS) was 53.7 months (ribociclib) versus 41.5 months (placebo) [hazard ratio (HR), 0.73; 95% confidence interval (CI) 0.59-0.90]. Subgroup analyses were consistent with overall population. In the first-line setting, most patients in the ribociclib arm (∼60%) lived longer than median follow-up; mOS was 51.8 months in the placebo arm (HR, 0.64; 95% CI 0.46-0.88). In the second-line setting, mOS was 39.7 months (ribociclib) versus 33.7 months (placebo) (HR, 0.78; 95% CI 0.59-1.04). No apparent drug-drug interaction between ribociclib and fulvestrant or new safety signals were observed. Conclusions: This analysis reported extended OS follow-up in MONALEESA-3. mOS was ∼12 months longer in patients with HR+/HER2- ABC treated with ribociclib plus fulvestrant compared with fulvestrant monotherapy

HLA-J, a Non-Pseudogene as a New Prognostic Marker for Therapy Response and Survival in Breast Cancer

The human leukocyte antigen (HLA) genes are cell-surface proteins, essential for immune cell interaction. HLA-G is known for their high immunosuppressive effect and its potential as predictive marker in breast cancer. However, nothing is known about the HLA-J and its immunosuppressive, prognostic and predictive features, as it is assumed to be a pseudogene by in silico sequence interpretation. HLA-J, ESR1, ERBB2, KRT5 and KRT20 mRNA expression were analysed in 29 fresh frozen breast cancer biopsies and their corresponding resectates obtained from patients treated with neoadjuvant chemotherapy (NACT). mRNA was analysed with gene specific TaqMan-based Primer/Probe sets and normalized to Calmodulin 2. All breast cancer samples did express HLA-J and frequently increased HLA-J mRNA levels after NACT. HLA-J mRNA was significantly associated with overexpression of the ESR1 mRNA status (Spearman ρ 0,5679; p = 0.0090) and KRT5 mRNA (Spearman ρ 0,6121; p = 0.0041) in breast cancer core biopsies and dominated in luminal B subtype. Kaplan Meier analysis revealed that an increase of HLA-J mRNA expression after NACT had worse progression free survival (p = 0,0096), indicating a counterreaction of tumor tissues presumably to prevent elimination by enhanced immune infiltration induced by NACT. This counterreaction is associated with worse prognosis. To our knowledge this is the first study identifying HLA-J as a new predictive marker in breast cancer being involved in immune evasion mechanisms.Humane Leukozyten-Antigene (HLA) sind Proteine auf der Zelloberfläche, die essenziell für die Immunzellinteraktion sind. HLA-G ist für seine hohe immunosuppressive Wirkung sowie als potenzieller prädikativer Marker für Brustkrebs bekannt. Dagegen ist kaum etwas über HLA-J und seine immunosuppressiven, prognostischen und prädiktiven Eigenschaften bekannt, da es basierend auf In-silico-Sequenzanalysen als „Pseudogen“ interpretiert wurde. Die Expression von HLA-J, ESR1, ERBB2, KRT5 und KRT20 mRNA wurde in 29 frisch gefrorenen Brustkrebsbiopsien analysiert und mit den klinisch-pathologischen Daten von Patientinnen, welche mit neoadjuvanter Chemotherapie behandelt wurden, verglichen. Die mRNA-Expression wurde mit genspezifischen TaqMan-basierten Primer/Probe-Sets analysiert und auf Calmodulin 2 normalisiert. Alle Gewebeproben von Patientinnen mit Brustkrebs exprimierten HLA-J, und der HLA-J-mRNA-Spiegel war nach NACT oft erhöht. In den Brustkrebsstanzbiopsien war die HLA-J-mRNA-Expression signifikant mit der Überexpression von ESR1-mRNA (Spearmans ρ 0,5679; p = 0,0090) und KRT5-mRNA (Spearmans ρ 0,6121; p = 0,0041) assoziiert und dominierte im Luminal-B-Subtyp. Die Kaplan-Meier-Analyse zeigte, dass ein Anstieg der HLA-J-mRNA-Expression nach NACT mit einem schlechteren progressionsfreien Überleben einhergeht (p = 0,0096), womöglich als Gegenreaktion des Tumorgewebes, um eine Eliminierung durch tumorinfiltrierende Lymphozyten, welche durch eine NACT induziert wurden, zu verhindern. Diese Gegenreaktion ist mit einer schlechteren Prognose assoziiert. Soweit uns bekannt, handelt es sich hierbei um die erste Studie, die HLA-J als neuen prädiktiven Marker im Brustkrebs identifiziert hat und möglicherweise zur Immunevasion beiträgt