Cetuximab, fluorouracil and cisplatin with or without docetaxel for patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck (CeFCiD): an open-label phase II randomised trial (AIO/IAG-KHT trial 1108).

BACKGROUND: The combination of cisplatin, 5-fluorouracil (5-FU) and cetuximab (PFC) is the reference first-line treatment for recurrent/metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN). We analysed whether treatment intensification by the addition of docetaxel to PFC improved efficacy in R/M SCCHN. METHODS: A total of 180 patients with R/M SCCHN (1:1) were assigned to receive either cisplatin (40 mg/m2), docetaxel (40 mg/m2) and 5-FU (2000 mg/m2) at days 1 and 8 and cetuximab (400/250 mg/m2) at days 1, 8 and 15 (DPFC) or standard cisplatin (100 mg/m2) at day 1, 5-FU (1000 mg/m2) at days 1-4 and cetuximab (400/250 mg/m2) at days 1, 8 and 15 (PFC). Chemotherapy was repeated every 21 days and continued for a maximum of 6 cycles in absence of disease progression or limiting toxicity, followed by cetuximab maintenance (500 mg/m2 every 2 weeks). The primary end-point was progression-free survival (PFS). RESULTS: A preplanned interim analysis for toxicity after 20 patients/arm revealed excessive grade 3 and 4 gastrointestinal (65%) and infectious toxicities (35%) in arm A, which led to dose reduction of cisplatin to 30 mg/m2 and 5-FU to 1000 mg/m2 for subsequent patients. With a median follow-up of 2 years, grade 4 toxicities were 21.3% vs. 30.8% for DPFC and PFC, respectively. More treatment-related deaths occurred with DPFC vs. PFC, with 11.2% and 6.6%, respectively. For DPFC and PFC, the median PFS was 6.3 vs. 6.4 months (hazard ratio [HR] = 0.97, p = 0.87), the median overall survival was 8.9 vs. 10.6 months (HR = 1.29 p = 0.1) and response rates were 38.2% vs. 31.9% (p = 0.9), respectively. CONCLUSIONS: DPFC failed to improve efficacy in R/M SCCHN. On the contrary, a high toxicity and mortality rate was detected in both arms, which underscores the vulnerability of patients with R/M SCCHN, and research on the need for further optimisation of the front-line chemotherapy backbone is ongoing.

Cross-sectional increase of adherence to multidisciplinary tumor board decisions.

BACKGROUND: Cancer research has made great progress in the recent years. With the increasing number of options in diagnosis and therapy the implementation of tumorboards (TUBs) has become standard procedure in the treatment of cancer patients. Adherence tests on tumor board decisions are intended to enable quality assurance and enhancement for work in tumor boards in order to continuously optimize treatment options for cancer patients. METHODS: Subject of this study was the adherence of the recommendations made in three of 14 tumorboards, which take place weekly in the Center for Integrated Oncology (CIO) at the University Hospital Bonn. In total, therapy recommendations of 3815 patient cases were checked on their implementation. A classification into four groups has been made according to the degree of implementation. A second classification followed regarding the reasons for differences between the recommendation and the therapy which the patient actually received. RESULTS: The study showed that 80.1% of all recommendations in the three TUBs were implemented. 8.3% of all recommendations showed a deviance. Most important reasons for the deviances were patient wish (36.5%), patient death (26%) and doctoral decision, due to the patient's comorbidities or side effects of the treatment (24.1%).Interestingly, deviance in all three tumor boards in total significantly decreased over time. CONCLUSIONS: Aim of the study was to clarify the use of tumor boards and find approaches to make them more efficient. Based on the results efficiency might be optimized by increased consideration of patients` preferences, improved presentation of patient-related data, more detailed documentation and further structuring of the tumor board meetings.

[Functional Comparison of the Outcome after Midvastus and Medial Parapatellar Surgical Approach in Total Knee Arthroplasty]. / Vergleich funktioneller Ergebnisse zwischen medialem parapatellarem und Midvastus-Zugang in der Knieendoprothetik.

There are various approaches for total knee arthroplasty (TKA). On the basis of an analysis of the clinical results, it has been demonstrated that the midvastus approach (MV) is advantageous in the early postoperative period compared to the medial parapatellar surgical approach (MPP). The aim of this investigation was therefore to investigate whether the clinical advantage of MV is reflected in the functional outcome. This single blinded, prospective, randomised study was based on a power analysis. Selected randomised patients (MPP = 10, MV = 11) were examined using an instrumental gait analysis system (VICON) preoperatively, and 5 weeks (5 W) and 6 months (6 M) after implantation. The results were compared to a healthy control group (CG = 53). Besides clinical parameters, the primary objective of this study was to measure objective gait parameters; the secondary objective was to record self-assessment (Knee Society score, WOMAC). In both treatment groups, the measurements improved during the investigation period, although most parameters did not reach the CG levels. MV gave better values for the kinetic parameters sagittal knee moment (5 W) and knee power (5 W, 6 M), as well as self-assessment (WOMAC, 6 M). Other clinical parameters were similar in the two groups. In summary, in the early postoperative period, MV led to advantages in function and in subjective behaviour in daily life. From the biomechanical point of view, the MV approach is preferable.

[Soft tissue tumors of the head and neck region]. / Weichteiltumoren des Kopf-Hals-Bereichs.

BACKGROUND: The incidence of soft tissue tumors of the head and neck region is low: 300 and 3 in 100,000 for benign and malignant tumors, respectively. However, sarcomas particularly show a wide variety of different histological subtypes. This article provides an overview of the soft tissue tumors of the head and neck region treated in the authors' institution. MATERIAL AND METHODS: This is a retrospective study including 106 patients treated between 2002 and 2010 due to a soft tissue tumor. Tumor- and patient-specific data were collected (benign/malignant tumor, location, TNM classification, therapy, R classification, grade). RESULTS: In total, 77 benign tumors, 5 of intermediate benign/malignant nature and 24 sarcomas (with 7 different subtypes) were identified. Whereas the benign and intermediate tumors were treated by surgical removal, in 21 of the 24 sarcomas, treatment comprised a multimodal therapy regimen including radio- and/or chemotherapy. CONCLUSION: Whereas benign tumors can be successfully treated by surgical resection, there is no uniform therapy regimen for sarcomas due to the variety of different histological subtypes. Only case-specific interdisciplinary disease management can offer good perspectives for therapeutic success.

[Quality of life after treatment of head and neck tumors : longitudinal comparison after operation and adjuvant radio(chemo)therapy]. / Lebensqualität nach Therapie von Kopf-Hals-Tumoren : Longitudinaler Vergleich von Operation und adjuvanter Radio(chemo)therapie.

BACKGROUND: Quality of life is extraordinary affected by malignant tumors of the head and neck region as functions of social interaction are disturbed. MATERIALS AND METHODS: The influence of surgical treatment and postoperative radio(chemo)therapy (RCT) on the quality of life was studied in patients with head and neck cancer. Twenty patients treated with curative intention completed the questionnaires EORTC QLQ-C30 and EORTC QLQ-H&N35 at three time points. RESULTS: In most questions, patients reported poorer quality of life after RCT compared to postoperatively. Most of these differences were not significant. However, global quality of life and overall health was significantly worse after RCT as compared to postoperatively. CONCLUSION: Both operation and postoperative RCT, lead to decreased quality of life in patients with a head and neck cancer. In comparison, RCT seems to have a more pronounced effect on the quality of life than operative therapy.

Evaluation of transmyocardial laser revascularization by following objective parameters of perfusion and ventricular function.

BACKGROUND: Does transmyocardial laser revascularization (TMLR), a new surgical technique for treating patients with otherwise intractable angina pectoris, improve myocardial perfusion, metabolism, and, consequently, function? METHODS: Patients referred for TMLR, alone or with coronary artery bypass grafting (CABG), were preoperatively evaluated clinically and by treadmill stress testing, echocardiography, ventriculography, radionuclide assessment of perfusion and metabolism, and hemodynamic assessment. Intraoperatively it was decided that some patients only required CABG. Follow-up evaluations were repeated after 6 (n = 40) and 12 months (n = 23) and compared with preoperative values. RESULTS: CABG only was performed in 35 cases, TMLR + CABG in 17, TMLR only in 45. 1-year mortality was 11% in the TMLR, zero in the TMLR + CABG, and 11% in the CABG groups. In all groups a significantly improved CCS angina- and NYHA class was observed immediately after operation and after 6 and 12 months. In all study groups treadmill tolerance (p<0.05) improved, but regional and global function, perfusion at rest, and metabolism were not significantly changed at 6 and 12-months follow-ups. Perfusion studies under stress demonstrated an improvement only in the CABG group after 12 months (p<0.05), whereas in both TMLR groups the lasered ischemic segments remained unchanged. CONCLUSIONS: TMLR significantly improves long-term clinical status and treadmill stress tolerance, but appears to have little if any effect upon regional and global function, perfusion, and metabolism.

Evidence for the activation of myeloperoxidase by f-Meth-Leu-Phe prior to its release from neutrophil granulocytes.

Activity and release of myeloperoxidase (MPO) was measured in heparinized whole blood samples after activation of neutrophil granulocytes by the chemoattractant N-formyl-methionyl-leucyl-phenylalanine (fMLP) using two different methods: (i) by determination of the amount of MPO released into the blood plasma using a MPO enzyme-immunoassay, and (ii) simultaneously, by measuring the remaining activity within the neutrophils by flow cytometry using the Bayer Technicon H3. Although a part of MPO was released immediately after addition of fMLP, remaining MPO activity within the neutrophils surprisingly increased during the first minutes after incubation. Subsequently, MPO activity dropped due to a continuous release of MPO. In addition to fMLP, granulocyte-macrophage colony stimulating factor (GM-CSF) enhanced MPO activity in neutrophils. These results indicate that MPO is present in resting granulocytes in an inactive or only partially active form and is activated by fMLP and GM-CSF.

Phagocytic activity and oxidative burst of granulocytes in persons with myeloperoxidase deficiency.

In the present study, phagocytosis and the oxidative metabolism of neutrophil granulocytes from five clinically healthy persons with different degrees of myeloperoxidase deficiency were investigated and compared to those of normal persons. The identification of individuals with myeloperoxidase deficiency was performed with the Bayer/Technicon H3 blood cell counter, which differentiates the leukocytes by measuring the peroxidase activity. Neutrophils of three out of five investigated myeloperoxidase deficient persons showed extremely low peroxidase indices (-53 and lower), but only the neutrophils of one person totally lacked myeloperoxidase. This was demonstrated by comparing myeloperoxidase mass concentration measured with an enzyme immunoassay, lack of HOCl production, and was further confirmed by measuring luminol- and lucigenin-enhanced chemiluminescence. Characteristically, myeloperoxidase deficient granulocytes showed a strikingly decreased luminol-enhanced chemiluminescence while the lucigenin-enhanced chemiluminescence was significantly increased compared to normal granulocytes. Although there is a DNA sequence homology of about 70%, the activity of peroxidase in eosinophils was not affected in any myeloperoxidase deficient person investigated. Moreover, a person with a very rare defect of eosinophil peroxidase had completely normal myeloperoxidase activity. The lack of myeloperoxidase activity is compensated for by an increased phagocytic activity, an increased production of superoxide anion (lucigenin-chemiluminescence) and probably by an alternative metabolism of H2O2; since persons lacking myeloperoxidase activity do not normally suffer from severe infections, H2O2 is obviously metabolized to other reactive oxygen substrates than HOCl, e.g. to OH-radicals.

A series of annexins from human placenta and their characterization by use of an endogenous phospholipase A2.

Membranes from human placenta contain proteins which inhibit the activity of phospholipases A2 by binding to phospholipid thus impeding substrate availability. We used unilamellar mixed liposomes and a partially purified cytosolic phospholipase A2 from placenta for characterizing this substrate-depleting activity. A major portion of these inhibitory proteins was released by extracting washed membranes with a Ca+(+)-chelator. Biochemical fractionation and systematic analysis resulted in the unequivocal identification of a series of annexin proteins. We describe a straightforward procedure which allows to obtain 8 annexins from placenta either in pure form or as a mixture of two annexins. One of them was obtained in two forms which had the same molecular mass of 68 kDa but differed in charge. We also present suggestive evidence for a novel annexin I-related polypeptide of Mr 45,000 which is an excellent in vitro substrate for protein kinase C. We estimate that about 2% of the total placental membrane proteins are annexins. For achieving half inhibition of phospholipase A2 activity with pure annexins, up to a 6.5-fold difference in the amounts of protein was observed when calculated on a molar basis. This suggests specificity of individual annexin species.

Membranes exert indirect negative control on phospholipase A2 in human placenta.

Phospholipase A2 (PLA2) activity of human term placenta is distributed about equally between cytosol and membranes. The latter activity was detached by treating membranes with EGTA, but this extraction also released inhibitory protein, which complicated the assay and has probably often led to underestimation of such PLA2. Varying the substrate concentration, we found that large amounts of liposome substrate relieve PLA2 suppression in the extract. This suggests substrate depletion by the inhibitory protein as the mechanism by which PLA2 enzymes are negatively controlled in placenta. Membrane-bound PLA2 was purified about 700-fold and appeared to be one enzyme species (PLA2-M). By contrast, cytosolic PLA2 activity could be fractionated into four separate fractions, one of which was further purified (PLA2-S1). As judged on the basis of a variety of biochemical properties, PLA2-M and PLA2-S1 seem to be identical enzyme forms. They are distinct from the class of pancreas/venom-type phospholipases A2.