Abgeschlossene und derzeit laufende adjuvante Therapieprotokolle bei Patientinnen mit operablem Mammakarzinom (II)

Summary Background: Between 1984 and 1996 4336 patients with operated breast cancer were included in trials of the Austrian breast cancer study group. Methods: Based on prognostic factors patients were randomised with 2 different treatment groups. Results: The largest ever performed oncological trial (study VI) in postmenopausal breast cancer patients is already finished. 5 other trials are open for randomisation. Conclusions: It is the intention of the Austrian breast cancer study group to accrue patients for ongoing trials in whole Austria and to increase the number of randomised patients. K. Abbrederis, Ch. Armbruster, Gabriele Barbieri, Doris Bauer, Th. Bauernhofer, S. Beller, J. Berger, O. B?ckl, A. Brunhofer, F. Burger, Ursula Denison, Elke Derstvenscheg, Ch. Dittrich, Manuela Djavanmard, W. D?ller, Daniela Eckhoff, H. Eidtmann, R. Fegerl, J. Fellinger, F. Friedrich, Sabine Fuchs, Barbara Gebhart, Friederike Gieseking, Ch. Gr?ger, Karin Haider, D. Haidinger, E. Hanzal, E. Hell, C. Hinterbuchinger, W. Horvath, W. Jonat, Daniela Kandioler, Anna-Katrin Kasparek, M. Kern, R. Kocher, Veronika Kohlmayer, R. Kolb, Ch. Kopf, S. Kriwanek, Irene Kührer, Christine Kurz, Iris Kuss, W. Kwasny, Caroline Lackner, M. Lang, O. Langer, J. Lenz, S. Leodolter, A. Lepsinger, P. Lisborg, G. Lokker, H. Ludwig, G. Luschin-Ebengreuth, H. Maass, M. Markovic, P. Mayer, M. Medl, Elisabeth Melbinger, R. Menzel, Brigitte Mlineritsch, Elke Moosbrugger, E. Moritz, Renate Moser, W. Neunteufel, A. Obermair, J. Omann, P. Oppitz, M. Pecherstorfer, A. Pertl, Catharina Pietrzak, F. Ploner, M. Pober, R. P?hnl, R. Punzengruber, Friederike Püribauer, Ch. Rass, J. Ritschl, H. Rosen, Christine Sam, L. Schiller, W. Schippinger, J. Schüller, M. Seifert, M. Smola, P. Speiser, H. Spoula, G. Steger, Birgit Steiner, H. St?ger, G. Tatzer, Susanne Taucher, J. Tschmelitsch, P. Uher, A. Unger, M. Van Trotsenburg, N. Vavra, Sonja Vogl, B. Wenky, V. Wette, A. Wiegele, G. Winter, Monika Wirth, B. Zeh, G. Zimmermann.     

Neue Substanzen aus ätherischen Ölen verschiedener Artemisia-Species, 2. Mitt. Davanon,ein furanoides Sesquiterpenketon

New Substances from the Essential Oils of Artemisia Species, II: Davanone, a Furanoid C₁₅-Ketone The volatile oil of Artemisia maritima L. ssp. maritima L. has been separated chromatographically. One of the newly isolated compounds was the sesquiterpene ketone davanone, which till hitherto has not been described in essential oils of this species.     

The Kallikrein-Kinin system and muscle metabolism: Biochemical aspects

Infusion of bradykinin (BK) into the brachial artery in front of skeletal muscle of the human forearm yielding arterial concentrations of about 10^–12 mol/l caused not only acceleration of blood flow but also of glucose and branchedchain amino acid uptake into the muscle in healthy volunteers and maturity-onset diabetics. These effects were almost entirely abolished after inhibition of prostaglandin biosynthesis.Papaverine, although causing identical acceleration of capillary blood flow, induced no metabolic action. Apart from causing enlargement of the capillary bed, bradykinin has another metabolic effect which was underlined by results obtained in the isolated perfused rat heart, indicating increased glucose uptake at constant rates of coronary blood flow.In order to clarify whether kinins play a physiological role in muscle carbohydrate metabolism, the well-known work-induced acceleration of muscle glucose uptake was studied during the inhibition of kinin liberation from kininogen by application of a protease inhibitor (Trasylol^®) and during additional substitution with synthetic BK. The glucose uptake under a defined work load was almost completely abolished by the protease inhibitor; application of BK restored the normal effect. Almost identical responses have been observed concerning the well-known hypoxia-induced acceleration of muscle glucose uptake. Furthermore, insulin-induced acceleration of glucose uptake into the resting forearm was reduced by half when kinin liberation from kininogen was inhibited by Trasylol^®; additional application of synthetic BK restored the normal response.From the data presented, one may suggest that kinins are involved in carbohydrate and amino acid metabolism of skeletal muscle, most probably by improving the action of insulin.     

The predictive value of EGFR and HER-2/neu in tumor tissue and serum for response to anthracycline-based neoadjuvant chemotherapy of breast cancer

We investigated the predictive value of HER-2/neu and epidermal growth factor receptor (EGFR) in tumor tissue and prechemotherapy serum for histopathologic response in 108 patients with breast cancer undergoing neoadjuvant anthracycline-based chemotherapy.Response to chemotherapy, assessed by histopathologic classification of regression (grade 0 [no therapy effect] to 4 [no residual tumor]), correlated significantly with prechemotherapy serum HER-2/neu levels. Median prechemotherapy serum HER-2/neu levels were significantly higher in patients with regression grades 1 through 4 compared with those in patients with regression grade 0 (9.6 vs 8.55 ng/mL; P = .011; 95% confidence interval [CI], .009-.014). Median pretreatment serum HER-2/neu levels of patients with complete pathologic response (pCR) were significantly higher than in patients with moderate or no treatment response (10.95 vs 9.1 ng/mL; P = .041; 95% CI, .036-.046). Receiver operating characteristic curve analysis revealed a serum HER-2/neu value of more than 10.3 ng/mL to predict a pCR with 80% sensitivity and 69.4% specificity. There was no significant correlation of response with HER-2/neu and EGFR scores in tumor tissue or with serum EGFR levels.Results demonstrate prechemotherapy serum HER-2/neu to be a significant predictor of response to neoadjuvant anthracycline-based chemotherapy for breast cancer.     

Early human cytomegalovirus replication after transplantation is associated with a decreased relapse risk: evidence for a putative virus-versus-leukemia effect in acute myeloid leukemia patients

The impact of early human cytomegalovirus (HCMV) replication on leukemic recurrence was evaluated in 266 consecutive adult (median age, 47 years; range, 18-73 years) acute myeloid leukemia patients, who underwent allogeneic stem cell transplantation (alloSCT) from 10 of 10 high-resolution human leukocyte Ag-identical unrelated (n = 148) or sibling (n = 118) donors. A total of 63% of patients (n = 167) were at risk for HCMV reactivation by patient and donor pretransplantation HCMV serostatus. In 77 patients, first HCMV replication as detected by pp65-antigenemia assay developed at a median of 46 days (range, 25-108 days) after alloSCT. Taking all relevant competing risk factors into account, the cumulative incidence of hematologic relapse at 10 years after alloSCT was 42% (95% confidence interval [CI], 35%-51%) in patients without opposed to 9% (95% CI, 4%-19%) in patients with early pp65-antigenemia (P < .0001). A substantial and independent reduction of the relapse risk associated with early HCMV replication was confirmed by multivariate analysis using time-dependent covariate functions for grades II to IV acute and chronic graft-versus-host disease, and pp65-antigenemia (hazard ratio = 0.2; 95% CI, 0.1-0.4, P < .0001). This is the first report that demonstrates an independent and substantial reduction of the leukemic relapse risk after early replicative HCMV infection in a homogeneous population of adult acute myeloid leukemia patients.     

The preoperative lymphocyte to monocyte ratio predicts clinical outcome in patients with stage III colon cancer

Background:

Inflammation has a critical role in the pathogenesis and progression of cancer. The lymphocyte to monocyte ratio (LMR) could be shown to be prognostic in haematologic neoplasia. In this study, we analysed the LMR with clinical outcome in stage II and III colon cancer patients.

Methods:

Three hundred and seventy-two patients with stage II and III colon cancer were included in this retrospective study. Kaplan–Meier curves and multivariate Cox-regression analyses were calculated for time to recurrence (TTR) and overall survival (OS).

Results:

Including all patients, the elevated preoperative LMR was significantly associated with increased TTR and OS in multivariate analysis (HR: 0.47, 95%CI: 0.29–0.76, P=0.002; HR: 0.51, 95%CI: 0.31–0.83, P=0.007; respectively). In subanalyses, the association was limited to patients with stage III (HR: 0.40, 95%CI: 0.22–0.72, P=0.002), in contrast to patients with stage II (HR: 0.40, 95%CI: 0.28–1.66, P=0.397). When the subgroup of patients with ‘high-risk'' LMR⩽2.83 was analysed, no benefit of adjuvant 5-FU-based chemotherapy could be found (HR: 0.99; 95%CI: 0.60–1.63; P=0.953).

Conclusion:

The LMR might be an independent prognostic marker for TTR in stage III colon cancer patients. Our results further suggest that high-risk patients based on the LMR do not benefit from adjuvant chemotherapy. Independent validation of our findings is warranted.     

A common gene variant in PLS3 predicts colon cancer recurrence in women

Recent evidence suggests that PLS3 (T-Plastin), an important member of the actin filamentous network, significantly influences cell invasion and metastasis. Germline polymorphisms within the PLS3 gene may impact the gene’s function, resulting in inter-individual differences in tumor recurrence capacity. In the present study, we investigated the association of germline polymorphisms in PLS3 to predict time to recurrence (TTR) in patients with stage II and III colon cancer. A total of 264 patients with histologically confirmed colon cancer were included in this retrospective study. Germline DNA was genotyped for rs871773 C>T, rs757124 C>G, rs1557770 G>T, rs6643869 G>A, and rs2522188 C>T in the PLS3 gene by 5′-exonuclease (TaqMan?) technology. As the PLS3 gene is located on the X chromosome, a gender-specific statistical analysis was performed. In univariate analysis, the minor allele of PLS3 rs871773 C>T was significantly associated with decreased TTR in women (hazard ratio (HR)?=?5.02; 95 % confidence interval (CI)?=?1.251–20.114; p?=?0.023) and remained significantly associated in multivariate analysis (HR?=?6.165; 95 % CI?=?1.538–24.716; p?=?0.010). Female patients carrying the C/T genotype in PLS3 rs871773 showed a median TTR of 69 months. In contrast, female patients with homozygous C/C had a median TTR of 112 months. There were no significant associations between PLS3 rs871773 C>T and TTR in male and between the other polymorphisms and TTR in male or female colon cancer patients. In conclusion, we identified a common gene variant in PLS3 as an independent prognostic marker in female patients with stage II and III colon cancer. Larger prospective trials are warranted to confirm these findings.     

Single nucleotide polymorphisms in the hypoxia‐inducible factor‐1 gene and colorectal cancer risk

With an incidence of about 300 000 new cases colorectal cancer (CRC) is the second leading cause of cancer‐related death in Europe and the United States. Environmental and genetic factors influence CRC risk. Hypoxia‐inducible factor‐1 (HIF‐1), a heterodimeric protein composed of two subunits, HIF‐1 alpha and HIF‐1 beta, plays a critical role in oxygen homeostasis and is involved in angiogenesis and cell proliferation. The gene for the HIF‐1 alpha subunit (HIF1A) carries two common missense mutations—P582S (rs11549465) and A588T (rs11549467)—which both have been related to increased trans‐activation capacity of HIF1A. In our case–control study we investigated the association between these polymorphisms and CRC risk. We investigated 381 patients with histologically confirmed CRC and 2156 control subjects. HIF1A genotypes were determined by exonuclease (TaqMan) assays. For determination of microvessel density (MVD) tumor sections were stained using a mouse monoclonal antibody recognizing the pan‐endothelial marker CD31. In a multivariate logistic regression analysis including age and sex neither the HIF1A 582S allele (Odds ratio: 1.204; 95% confidence interval 0.911–1.592; P = 0.193) nor the 588T allele was significantly associated with CRC (Odds ratio: 0.851; 95% confidence interval 0.444–1.631; P = 0.626). However, in an exploratory analysis, the HIF1A 588T allele was associated with tumor localization (P = 0.016) and tumor size (P = 0.003). MVD was similar in tumors of patients carrying HIF1A 588T allele and patients without this rare allele. We conclude that functional polymorphisms in the HIF1A gene do not modify CRC risk but maybe associated with clinic‐pathological features of the disease. © 2010 Wiley‐Liss, Inc.