Final analysis of the prospective WSG-AGO EC-Doc versus FEC phase III trial in intermediate-risk (pN1) early breast cancer: efficacy and predictive value of Ki67 expression.

BACKGROUND: Taxane-based adjuvant chemotherapy is standard in node-positive (N+) early breast cancer (BC). The magnitude of benefit in intermediate-risk N+ early BC is still unclear. WSG-AGO epiribicine and cyclophosphamide (EC)-Doc is a large trial evaluating modern taxane-based chemotherapy in patients with 1-3 positive lymph nodes (LNs) only. PATIENTS AND METHODS: A total of 2011 BC patients (18-65 years, pN1) were entered into a randomized phase III trial comparing 4 × E90C600 q3w followed by 4 × docetaxel 100 q3w (n = 1008) with the current standard: 6 × F500E100C500 q3w (n = 828) or C600M40F600 d1, 8× q4w (n = 175). Primary end point was event-free survival (EFS); secondary end points were overall survival (OS), toxicity, translational research, and quality of life. Central tumor bank samples were evaluable in a representative collective (n = 772; 40%). Ki-67 was assessed centrally in hormone receptor-positive disease as a surrogate marker for the distinction of luminal A/B-like tumors. RESULTS: Baseline characteristics were well balanced between study arms in both main study and central tumor bank subset. At 59-month median follow-up, superior efficacy of EC-Doc [versus FEC (a combination of 5-fluorouracil, epirubicin, and cyclophosphamide)] was seen in EFS and OS: 5-year EFS: 89.8% versus 87.3% (P = 0.038); 5-year OS: 94.5% versus 92.8% (P = 0.034); both tests one-tailed. EC-Doc caused more toxicity. In hormone receptor-positive (HR)+ disease, only high-Ki-67 tumors (≥ 20%) derived significant benefit from taxane-based therapy: hazard ratio = 0.39 (95% CI 0.18-0.82) for EC-Doc versus FEC (test for interaction; P = 0.01). CONCLUSION: EC-Doc significantly improved EFS and OS versus FEC in intermediate-risk BC (1-3 LNs) within all subgroups as defined by local pathology. In HR+ disease, patients with luminal A-like tumors may be potentially over-treated by taxane-based chemotherapy. CLINICAL TRIAL NUMBER: ClinicalTrials.gov, NCT02115204.

Treatment of intraarticular middle phalanx fractures using the Ligamentotaxor®.

BACKGROUND: We evaluated the outcome of intraarticular middle phalanx fractures after dynamic treatment with the Ligamentotaxor® system. MATERIALS AND METHODS: Ten consecutive patients (seven male, three female; mean age 52 years) with intraarticular middle phalanx fractures were treated with the Ligamentotaxor® between 2009 and 2011. Proximal interphalangeal joint mobility, grip strength and 'Disabilities of the Arm, Shoulder and Hand' (DASH) score were evaluated in a 15-month follow-up. The reconstitution of the intraarticular space was measured immediately after trauma, at 6 weeks and at 15 months by radiograph control. The severity of the trauma was classified according to AO. RESULTS: We found B1 30 %, C1 (Seno I + II) 50 % and C3 (Seno III-V) 20 %. In 60 % of the cases, fractures were localized on the middle base of the fifth digit, in 20 % on the third digit and in 20 % on the index finger. The dynamic treatment lasted 7 weeks; patients were exposed to full workload after 9 weeks. The mean flexion mobility after 15 months reached 73° (range 60-100°), and the extension deficit was 13° (range 0-20°) on average. Grip strength attained 71.3 % (range 60-87 %) of the contralateral side. Initial x-ray after trauma compared to the x-ray after 15 months showed an intraarticular space reconstitution average of 0.5 mm (range 0.1-0.9 mm) anterior-posterior and 0.6 mm (range 0.1-1 mm) lateral. Patients evaluated their outcome with an average of 14.6 points (range 3.3-26.7) using the DASH score. CONCLUSION: Good results can be obtained with the Ligamentotaxor®. We recommend it for the dynamic treatment of intraarticular middle phalanx finger fractures. Larger series and long-term results are needed.

Endogenous CCK depresses contractile activity within the ascending myenteric reflex pathway of rat ileum.

The ascending excitatory reflex is an important part of the myenteric reflex. In order to study the ascending neural pathways, isolated segments of rat ileum were stimulated by electrical stimulation of the gut wall (20 V, 3 pulses per second, 1 ms) using platinum electrodes. The excitatory contractile response was recorded using perfused manometric side-hole tubing located 2 and 4 cm orally to the stimulation site. The contractile response to electrical stimulation was abolished by atropine (10(-6) M) or hexamethonium (10(-4) M). The excitatory response increased after administration of the cholecystokinin A (CCK(A)) receptor antagonists lorglumide (3x10(-6) M: +44.1%), devazepide (10(-8) M: +19.4%; 10(-7) M: +30.0%) and SR-27897 (10(-10) M: +21.8%, 10(-8) M: +47.0%, P<0.05, n=8). However, the CCK(B) receptor antagonist L-365,260 also caused a significant increase in the oral excitation (10(-6) M: +27.4%). sCCK-8 caused a significant reduction in the ascending response (10(-8) M: -11.5%) and induced spontaneously occurring contractions at doses ranging from 10(-10)-10(-6) M. CCK-9 significantly increased the ascending response (10(-7) M: +10.9%, P<0.05). However, caerulein (10(-10) M: -25.9%, 10(-8) M: -26.8%; P<0.01) and pentagastrin (10(-10) M: -20.2%, P<0.05; 10(-8) M: -23.7%, P<0.01; 10(-6) M: -28.3%, P<0.001) reduced the ascending contractile response significantly. These data, obtained with potent and highly specific CCK receptor antagonists, demonstrate an inhibitory role of endogenously released CCK within the ascending neural pathway. The data further suggest that exogenously applied CCK-related peptides have different effects on the myenteric reflex which might be due to excitation of the different involved neurons (short and long ascending inter- and motorneurons) in an unphysiological order. Thus in experiments investigating more complex neuronal circuits, experiments with antagonists should be regarded as more specific.

Positron emission tomography using [(18)F]Fluorodeoxyglucose for monitoring primary chemotherapy in breast cancer.

PURPOSE: To address the role of positron emission tomography (PET) using [(18)F]fluorodeoxyglucose (FDG) to monitor primary (neoadjuvant) chemotherapy in patients with locally advanced breast cancer. PATIENTS AND METHODS: Quantification of regional FDG uptake of the breast acquired after the first and second courses of chemotherapy was compared with the baseline scan in 22 patients with a total of 24 breast carcinomas. To evaluate the predictive value of PET imaging, histopathologic response after completion of chemotherapy classified as gross residual disease (GRD) or minimal residual disease (MRD) served as the gold standard. RESULTS: Significant differences in tracer uptake between nonresponding tumors (GRD) and responding lesions (MRD) were observed (P <.05) as early as after the first course of chemotherapy. Tracer uptake showed little change in tumors with GRD found later in pathologic analysis but decreased sharply to the background level in most tumors with MRD. After the first course, all responders were correctly identified (sensitivity 100%, specificity 85%) by a standardized uptake value decrease below 55% of the baseline scan. At this threshold, histopathologic response could be predicted with an accuracy of 88% and 91% after the first and second courses of therapy, respectively. CONCLUSION: This study demonstrates that in patients with advanced breast cancer undergoing primary chemotherapy, FDG-PET differentiates responders from nonresponders early in the course of therapy. This may help improve patient management by avoiding ineffective chemotherapy and supporting the decision to continue dose-intensive preoperative chemotherapy in responding patients.

Characterization of prejunctional and postjunctional muscarinic receptors of the ascending reflex contraction in rat ileum.

The ascending reflex contraction of the small intestine involves predominantly cholinergic neurotransmission. The orally projecting neural excitatory pathway of the myenteric reflex was studied in an in vitro model of rat ileal segments. The contractile response elicited by aboral field stimulation was significantly inhibited by a range of muscarinic receptor antagonists. Methoctramine and tripitramine (both M(2) selective, pIC(50) = 9.3 and 8.8, respectively), darifenacin and hexahydrosiladifenidol (both M(3) selective, pIC(50) = 7.3 and 7.7, respectively), and pirenzepine (M(1) selective, pIC(50) = 7.0). In radioligand binding experiments on synaptosomal and smooth muscle plasma membrane fractions, we examined whether prejunctional or postjunctional muscarinic receptors exist that could potentially contribute to the reflex contraction. In the synaptosomal fraction, the muscarinic ligand [(3)H]N-methylscopolamine labeled a homogeneous population of receptors (Hill coefficient = 1) with a K(d) value of 0.31 +/- 0.09 nM and a B(max) value of 185 +/- 16.6 fmol/mg protein. The ratio of potency of subtype-selective muscarinic receptor antagonists in competition studies was tripitramine (pK(i) = 8.7 +/- 0.3) > 1/6 x methoctramine (pK(i) = 7.9 +/- 0.02) > 1/25 x darifenacin (pK(i) = 7. 3 +/- 0.2) > 1/316 x hexahydrosiladifenidol (pK(i) = 6.2 +/- 0.1) > 1/2511 x pirenzepine (pK(i) = 5.3 +/- 0.1). In the smooth muscle plasma membrane fraction, the K(d) value was 0.29 +/- 0.05 nM and the B(max) value was 770 +/- 29 fmol/mg. The competition studies revealed a similar ratio of potency of the respective antagonists. These data suggest that muscarinic M(2) receptors, located at prejunctional and postjunctional sites, are predominantly involved in the ascending reflex contraction.

Ascending neural pathways in the rat ileum in vitro--effect of capsaicin and involvement of nitric oxide.

The aim of the present study was to develop and characterize an in vitro model of the rat ileum in which activation of the orally projecting neural excitatory pathway of the myenteric reflex is produced by electrical field stimulation anally to the recording site. The motility of a 10-cm segment of rat ileum was recorded using a perfused manometric assembly with side holes 2 and 4 cm orally to the stimulation site. Electrical field stimulation caused a contractile response in the oral but not in the aboral direction of the stimulation site. The contractile response, which was maximal using low stimulus frequencies (3 or 5 pulses per second (pps)) and decreased with higher frequencies (10 or 20 pps), was blocked by atropine (10(-6) M) at all frequencies tested after acute and after prolonged (greater than 30 min) treatment. The maximal contractile response at 3 pps was abolished by hexamethonium (10(-4) M), tetrodotoxin (5 x 10(-7) M) and by complete transection of the muscular wall between the stimulation and the recording site. Acute administration of capsaicin (8 x 10(-7) M) to the bath reduced the lag between the start of the electrical stimulation and the onset of the contractile response. Higher concentrations of capsaicin (10(-5) M) reduced the contractile response, but this was partly due to an unspecific effect of capsaicin. Blockade of nitric oxide (NO) synthesis by L-NG-nitro-arginine-methyl ester (L-NAME) (3 x 10(-4) M) augmented the contractile response to anal stimulation by 222.4% and reduced the lag period by 54.5%, whereas the stereoisomer D-NAME had no significant effect. The potentiating effects of L-NAME were reversed in the presence of L-arginine (3 x 10(-3) M) but not in the presence of the stereoisomer D-arginine (3 x 10(-3) M). This model can be used to study ascending neural pathways in the rat small intestine. The ascending excitatory response is abolished by atropine and hexamethonium and is modulated by capsicin-sensitive fibers. The ascending pathway is under tonic inhibition of metabolites of the L-arginine-NO pathway.