Comparison of prognostic and predictive impact of genomic or central grade and immunohistochemical subtypes or IHC4 in HR+/HER2- early breast cancer: WSG-AGO EC-Doc Trial.

INTRODUCTION: Potential prognostic and predictive markers in early, intermediate-risk breast cancer (BC) include histological grade, Ki-67, genomic signatures, e.g. genomic grade index (GGI), and intrinsic subtypes. Their prognostic/predictive impact in hormone receptor (HR: ER and/or PR) positive/HER2- BC is controversial. WSG-AGO EC-Doc demonstrated superior event-free survival (EFS) in patients with 1-3 positive lymph node receiving epirubicin/cyclophosphamide-docetaxel (EC-Doc) versus 5-fluoruracil/epirubicin/cyclophosphamide (FEC). METHODS: In a representative trial subset, we quantify concordance among factors used for clinical chemotherapy indication. We investigate the impact of central histology (n = 772), immunohistochemistry for intrinsic subtyping and IHC4, and dichotomous (GG) or continuous (GGI) genomic grade (n = 472) on patient outcome and benefit from taxane chemotherapy, focusing on HR+/HER2- patients (n = 459). RESULTS: Concordance of local grade (LG) with central (CG) or genomic grade was modest. In HR+/HER2- patients, low (GG-1: 16%), equivocal (GG-EQ: 17%), and high (GG-3: 67%) GG were associated with respective 5-year EFS of 100%, 93%, and 85%. GGI was prognostic for EFS within all LG subgroups and within CG3, whereas IHC4 was prognostic only in CG3 tumors.In unselected and HR+/HER2- patients, CG3 and luminal-A-like subtype entered the multivariate EFS model, but not IHC4 or GG. In the whole population, continuous GGI entered the model [hazard ratio (H.R.) of 75th versus 25th = 2.79; P = 0.01], displacing luminal-A-like subtype; within HR+/HER2- (H.R. = 5.36; P < 0.001), GGI was the only remaining prognostic factor.In multivariate interaction analysis (including central and genomic grade), luminal-B-like subtype [HR+ and (Ki-67 ≥20% or HER2+)] was predictive for benefit of EC-Doc versus FEC in unselected but not in HR+/HER2- patients. CONCLUSION: In the WSG-AGO EC-Doc trial for intermediate-risk BC, CG, intrinsic subtype (by IHC), and GG provide prognostic information. Continuous GGI (but not IHC4) adds prognostic information even when IHC subtype and CG are available. Finally, the high interobserver variability for histological grade and the still missing validation of Ki-67 preclude indicating or omitting adjuvant chemotherapy based on these single factors alone. TRIAL REGISTRATION: The WSG-AGO/EC-Doc is registered at ClinicalTrials.gov, NCT02115204.

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.

MTHFR C677T polymorphism, folic acid and hyperhomocysteinemia in levodopa treated patients with Parkinson's disease.

Certain mutations (TT homozygous; CT heterozygous; CC wild-type) of the methylenetetrahydrofolate (MTHFR) gene and long-term levodopa application in patients with Parkinson's disease (PD) support onset of hyperhomocysteinemia. Total plasma homocysteine (t-hcys) depends on B6, B12, folic acid, all of which support remyelination from t-hcys to methionine. Objective of this trial were to compare B6, B12, folic acid and t-hcys levels in plasma of 83 levodopa treated PD patients and 44 controls. PD patients with the CT or TT genotype had significant higher t-hcys levels than controls or PD patients with the CC allele. Concentrations of B6 or B12 did not differ, but folic acid was significant higher in PD patients with the CT mutation. We recommend MTHFR genotyping, t-hcys monitoring and early vitamin supplementation in PD patients. The folic acid increase in PD patients with the CT allele is hypothetically due to an endogenous upregulation of folic acid absorption to decrease t-hcys.

Coenzyme Q10 serum levels in Huntington's disease.

Mitochondrial dysfunction contributes to the neurodegenerative process in Huntington's disease (HD). Coenzyme Q10 (CoQ10) enhances mitochondrial complex I activity and may therefore provide a therapeutic benefit in HD. We compared serum CoQ10 levels of previously untreated-and treated HD patients with those of healthy controls. CoQ10 did not significantly (ANCOVA F(dF 2, dF 55) = 2.57; p=0.086) differ between all three groups. However, the post hoc analysis showed no significant (p = 0.4) difference between treated HD patients ([CoQ10]: 88.12 [mean]+/-24.44 [SD], [range] 48.75-146.32 [pg/million platelets]) and controls (93.71+/-20.72, 65.31-157.94), however previously untreated HD patients (70.10+/-21.12, 38.67-106.14) had marked (p = 0.051) lower CoQ10 results than treated HD patients and controls (p = 0.017). Our results support that CoQ10 supplementation in HD patients may reduce impaired mitochondrial function in HD.

[Current therapy of idiopathic Parkinson disease. 2: Recent and alternative therapies]. / Aktuelle Therapie der idiopathischen Parkinson-Erkrankung. Teil 2: Neuere und alternative Therapieverfahren.

New possibilities in the medical treatment of Parkinson's disease are offered by the MAO-B inhibitor, selegiline, and L-dopa preparations with strongly accelerated or retarded kinetics. Possible new approaches to drug treatment might be, firstly, inhibition of the enzyme catechol-o-methyl-transferase, which influences the breakdown of dopamine, and secondly, administration of NADH with the aim of stimulating the body's own synthesis of dopamine. A third approach might be the reintroduction of stereotactic surgery with coagulation or stimulation of certain areas of the brain, that has now been made possible by the development of new and more subtle techniques. Neuroprotective and/or neuro-regenerative approaches, such as, for example, the administration or stimulation of growth factors and/or transplantation of neuronal dopaminergic cells might lead the treatment of Parkinson's disease from the palliative symptomatic approach it is today, to a future curative approach.

[Blood transfusion in surgical gynecology. Strategies for preventing homologous blood transfusion]. / Blutbedarf in der operativen Gynäkologie. Strategien zur Vermeidung von Fremdblut.

A statistical evaluation of homologous blood transfusions is imperative in any gynecological surgical department, to be able to define the transfusion-associated risk of the individual interventions. On the basis of our own statistical data and reports in the literature, strategies for limiting the use of homologous blood are discussed. So far, experience with autologous blood transfusion in surgical gynecology is limited, and clinical studies are needed to better define its role. In special cases, the use of erythropoietin and gonadotropin-releasing hormone (GnRH) analogues extends the possibilities for reducing homologous blood transfusion.

[Rehabilitation of paraplegic patients]. / Rehabilitation bei Querschnittgelähmten.

Comprehensive management and care of spinal-cord-lesioned patients start at the site of injury or at the moment of the onset of paralysis, depend with its consequences on the treatment in the acute phase, pass to the reactivation and rehabilitation phase and continue throughout all life of such patients. Considering that even a complete transverse lesion is only an instable, temporarily balanced situation, every small complication can destroy this balance and may lead from total independence to total dependence. Orthopedic, neurological, neurosurgical, urological, physio- or ergotherapeutic, socio-professional or other aspects in the field of comprehensive care and rehabilitation can never be analyzed or managed singularly, but have to be seen always in the context of the whole final outcome. The coordinating role of the paraplegiologist and the importance of adequate spinal cord injury units is stressed. The changing pattern of aetiopathogenesis or epidemiology of spinal cord lesions (increase of medical causes such as vascular lesions, tumors, infection disease) and the definition for rehabilitability due to the higher amount of elderly people will bring a new challenge for all careers in the field of rehabilitation.

Oral immunotherapy with grass pollen in enterosoluble capsules. A prospective study of the clinical and immunological response.

In a prospective study spanning 2 years, 60 patients with grass pollen allergy were treated with either a low dose oral, a high dose oral or a subcutaneous hyposensitization regime. No significant improvement was seen in the orally treated patients whereas those on the subcutaneous hyposensitization regime demonstrated a decreased specific cutaneous reactivity, a rise in specific IgG antibodies and a reduction in symptoms. This study suggests that oral hyposensitization, even with enterosoluble grass pollen capsules, is ineffective.

Observation of Mg2+.ATP and uncomplexed ATP in slow exchange by 31P-NMR at high magnetic fields.

The 31P-NMR lines of the beta-phosphate groups in Mg2+.ATP and in metalfree ATP can be observed separately up to 280 K at 8.5 T and up to 285 K at 11.7 T. At 274 K and 8.5 T the beta-phosphorous resonances are in slow exchange at pH values above pH 5, the gamma-phosphorous resonances are in slow exchange only near pH 6, but in fast exchange at low and high pH-values. The fast exchange condition holds for the alpha-phosphorous resonances over the entire pH-range. For Ca2+.ATP and metalfree ATP always fast exchange prevails down to the freezing point of water even at 11.7 T. Based on the separate observation of the 31P-NMR signals of Mg2+.ATP and uncomplexed ATP new experiments are proposed and possible sources of error in 'in vivo' NMR studies are discussed.

Discontinuation of bee venom immunotherapy in children and adolescents.

Sixty-six patients with a history of systemic allergy reactions to bee stings, positive skin prick test to less than or equal to 100 micrograms/ml bee venom, and positive radioallergosorbent test (RAST) results were given venom immunotherapy. IgE and IgG antibodies to bee venom were measured by RAST and enzyme-linked immunosorbent test (ELISA), respectively. IgE and IgG anti-bee venom levels rose initially, but subsequently fell during immunotherapy. In 31 patients in whom specific IgE fell to low (less than 6% counts bound) or unmeasurable levels, immunotherapy was discontinued, and sting challenge was carried out 1 to 3 years later. All patients tolerated sting challenge well. The specific IgE and IgG antibody levels did not change significantly after treatment was stopped. Our data suggest that hyposensitization treatment can be stopped when specific IgE serum concentrations have fallen to low or unmeasurable levels and specific IgG antibody values are maintained, and that in a considerable number of patients venom immunotherapy has a lasting therapeutic and immunologic effect.

[Efficacy of oral and parenteral hyposensitization with pollen extracts]. / Untersuchungen zur Wirksamkeit oraler und parenteraler Hyposensibilisierung mit Pollen-Extrakten.

Hyposensitization was undertaken in 26 children, aged 4-15 years, with proven sensitivity to grass and wheat pollen, in some orally (ten), in others parenterally (16), for two years before the start of the season. The administered cumulative dose with oral hyposensitization was 1,750,000 PNU (protein nitrogen units), corresponding to 3,500,000 NU (Noon units), and on parenteral sensitization 1,550 PNU, corresponding to 3,100 NU. A symptoms score was registered daily during the pollen season. It showed fewer symptoms in those with parenteral hyposensitization, although subjective assessment of the success of treatment did not indicate any difference between the two groups. Oral hyposensitization produced a higher IgE and a lower IgG immune response. Systemic side-effects were noted in half of those after oral but none after parenteral hyposensitization. Measured by side-effects, the cumulative dose and expense, the effectiveness of oral hyposensitization is inferior to parenteral administration.