[Strategies to Overcome Acquired Resistance to EGFR-TKI Therapy Based on T790M Specific Substances using Osimertinib as an Example]. / Strategien zur Überwindung der erworbenen EGFR-TKI-Resistenz durch T790M spezifische Substanzen am Beispiel von Osimertinib.

Tyrosine kinase inhibitors (TKIs) of the epidermal growth factor receptor (EGFR) are widely used in non-small cell lung cancer patients harboring activating EGFR mutations. However, resistance mechanisms, particularly the T790 M mutation, hamper longer-term therapeutic success of first and second generation EGFR-TKIs. To address this unmet medical need, EGFR-TKIs of the third generation are under clinical development. Relevant clinical efficacy with mainly mild to moderate class-specific side effects has been shown for third-generation EGFR-TKIs. Molecular testing is of major importance in deciding for treatment with third generation EGFR-TKIs. This article elucidates the developmental state of third generation EGFR-TKIs with its focus on Osimertinib, the first and currently the only compound in this class which is approved in Germany. Additionally, the medical importance of molecular diagnosis using tumor tissue and circulating tumor DNA is discussed.

BAY 94-9027, a PEGylated recombinant factor VIII, exhibits a prolonged half-life and higher area under the curve in patients with severe haemophilia A: Comprehensive pharmacokinetic assessment from clinical studies.

INTRODUCTION: Recombinant factor VIII (rFVIII) products with extended half-lives, such as BAY 94-9027, can potentially maintain higher FVIII levels for longer periods of time, thus providing improved bleeding protection vs standard-acting FVIII products. AIM: To characterize the pharmacokinetic (PK) profile of BAY 94-9027 from phase 1, phase 2/3 (PROTECT VIII) and phase 3 (PROTECT VIII Kids) clinical trials in adults, adolescents and children with severe haemophilia A METHODS: Patients with severe haemophilia A (FVIII <1%) with >50 FVIII exposure days (EDs) and no history of inhibitors were included in the phase 1 (18-65 years, ≥150 EDs), PROTECT VIII (12-65 years, ≥150 EDs) and PROTECT VIII Kids (<12 years, >50 EDs) trials. PK parameters were assessed following a 25-IU/kg or 60-IU/kg BAY 94-9027 dose in the phase 1 study after the first and repeated infusion, in PROTECT VIII after the first and repeated 60-IU/kg infusion and in PROTECT VIII Kids after a single 60-IU/kg infusion. The chromogenic assay was used to assess FVIII activity. RESULTS: Compared with sucrose-formulated rFVIII, BAY 94-9027 had reduced clearance that resulted in a ~1.4-fold increase in half-life and dose-normalized area under the curve (AUC). The BAY 94-9027 PK profile was comparable after single- and repeated-dose administrations. Dose-proportional increases were observed between 25- and 60-IU/kg administrations. BAY 94-9027 PK characteristics were age dependent, consistent with other FVIII products. CONCLUSIONS: BAY 94-9027 shows an extended half-life and increased AUC vs standard-acting FVIII products. These PK characteristics will result in higher FVIII levels for longer duration.

Immediate and delayed neuroendocrine responses to social exclusion in males and females.

Social exclusion is a complex phenomenon, with wide-ranging immediate and delayed effects on well-being, hormone levels, brain activation and motivational behavior. Building upon previous work, the current fMRI study investigated affective, endocrine and neural responses to social exclusion in a more naturalistic Cyberball task in 40 males and 40 females. As expected, social exclusion elicited well-documented affective and neural responses, i.e., increased anger and distress, as well as increased exclusion-related activation of the anterior insula, the posterior-medial frontal cortex and the orbitofrontal cortex. Cortisol and testosterone decreased over the course of the experiment, whereas progesterone showed no changes. Hormone levels were not correlated with subjective affect, but they were related to exclusion-induced neural responses. Exclusion-related activation in frontal areas was associated with decreases in cortisol and increases in testosterone until recovery. Given that results were largely independent of sex, the current findings have important implications regarding between-sex vs. within-sex variations and the conceptualization of state vs. trait neuroendocrine functions in social neuroscience.

[Subgroup Analysis of the Non-interventional REASON Study: PFS and OS According to Age, Smoking History, Gender, and Histology in NSCLC Patients Treated with Gefitinib or Chemotherapy]. / Subgruppenanalyse aus der nicht-interventionellen Beobachtungsstudie REASON: PFS und OS gemäß Alter, Raucherstatus, Geschlecht und histologischem Subtyp unter Verwendung von Gefitinib bzw. chemotherapeutischer Behandlung bei NSCLC-Patienten.

PURPOSE: Assessment of several clinical factors on progression-free (PFS) and overall survival (OS) in NSCLC patients (pts.) (stage IV) with mutated epidermal growth factor receptor (EGFRm+) treated with gefitinib (gef) or with chemotherapy (CT) under real-world conditions. METHODS: 285 EGFRm+ pts. of the non-interventional REASON study treated with gef (n = 206) or CT (n = 79) as first-line therapy or with gef (n = 213) or CT (n = 61) in any line throughout the course of therapy were analyzed according to age, gender, smoking history and histology. RESULTS: Compared with CT, patients treated with gef showed prolongation of PFS and OS in all subgroups. PFS was significantly increased in women and non-smokers. OS was significantly increased in women, non-smokers, (ex)-smokers, patients with adenocarcinoma and elderly patients when treated with gef compared to CT. Female gender turned out to be an independent positive predictive factor for OS in patients treated with gef (HRmale: 1.74, p = 0.0009). CONCLUSION: A clinical benefit of gef was shown for all analyzed clinical subgroups of EGFRm+ pts. This was confirmed for the female gender in a multivariate analysis.

[Exon-dependent Subgroup-analysis of the Non-interventional REASON-Study: PFS and OS in EGFR-mutated NSCLC Patients Treated with Gefitinib or Chemotherapy]. / Exonabhängige Subgruppenanalyse der nicht-interventionellen REASON-Studie: PFS und OS beim EGFR-mutierten NSCLC mit Behandlung von Gefitinib versus Chemotherapie.

PURPOSE: To analyze the influence of the localization of mutations in the epidermal growth factor receptor (EGFR) gene on progression-free (PFS) and overall survival (OS) in patients (pts) with locally advanced or metastatic non-small cell lung cancer (NSCLC) treated with gefitinib (gef) or chemotherapy (CT) under real world conditions within the REASON study. METHODS: Subgroups of pts with mutations in exon 19 (n = 141), 18/20 (n = 43), and 21 (n = 104) were analyzed for PFS and OS according to gef or CT treatment and compared using the log-rank test. RESULTS: Pts with mutations in exon 19 and 18/20 treated with gef as first line therapy showed increased PFS and OS compared to CT. This increase was statistically significant in pts with exon 19 mutation (11.3 vs. 6.5 months), but was not found in pts with exon 21 mutation (9.1 vs. 9.3 months). Also, OS was significantly increased in patients with mutation in exon 19 treated with gef ever over all treatment lines compared to CT (21.8 vs. 10.6 months), whereas this was not found in pts with mutation in exon 21 (14.1 vs. 13.9 months). CONCLUSION: Localization and nature of EGFR mutations influences gefitinib treatment outcomes under routine conditions and should therefore be analyzed in detail.

Interim estimates of the effectiveness of seasonal trivalent inactivated influenza vaccine in preventing influenza hospitalisations and primary care visits in Auckland, New Zealand, in 2014.

We present preliminary results of influenza vaccine effectiveness (VE) in New Zealand using a case test-negative design for 28 April to 31 August 2014. VE adjusted for age and time of admission among all ages against severe acute respiratory illness hospital presentation due to laboratory-confirmed influenza was 54% (95% CI: 19 to 74) and specifically against A(H1N1)pdm09 was 65% (95% CI:33 to 81). For influenza-confirmed primary care visits, VE was 67% (95% CI: 48 to 79) overall and 73% (95% CI: 50 to 85) against A(H1N1)pdm09.

Effectiveness of seasonal trivalent inactivated influenza vaccine in preventing influenza hospitalisations and primary care visits in Auckland, New Zealand, in 2013.

This study reports the first vaccine effectiveness (VE) estimates for the prevention of general practice visits and hospitalisations for laboratory-confirmed influenza from an urban population in Auckland, New Zealand, in the same influenza season (2013). A case test-negative design was used to estimate propensity-adjusted VE in both hospital and community settings. Patients with a severe acute respiratory infection (SARI) or influenza-like illness (ILI) were defined as requiring hospitalisation (SARI) or attending a general practice (ILI) with a history of fever or measured temperature ≥38 °C, cough and onset within the past 10 days. Those who tested positive for influenza virus were cases while those who tested negative were controls. Results were analysed to 7 days post symptom onset and adjusted for the propensity to be vaccinated and the timing during the influenza season. Influenza vaccination provided 52% (95% CI: 32 to 66) protection against laboratory-confirmed influenza hospitalisation and 56% (95% CI: 34 to 70) against presenting to general practice with influenza. VE estimates were similar for all types and subtypes. This study found moderate effectiveness of influenza vaccine against medically attended and hospitalised influenza in New Zealand, a temperate, southern hemisphere country during the 2013 winter season.

Henoch-Schönlein purpura and meningococcal B vaccination.

The risk of Henoch-Schönlein purpura (HSP) following vaccination with a group B meningococcal vaccine was assessed through active hospital safety monitoring. There was no increase in the relative incidence of HSP within 30 days after vaccination nor recurrence in HSP cases who received one or more further vaccine doses (re-challenge).

Novel role of HDAC inhibitors in AML1/ETO AML cells: activation of apoptosis and phagocytosis through induction of annexin A1.

The chimeric fusion protein AML1-ETO, created by the t(8;21) translocation, recruits histone deacetylase (HDAC) to AML1-dependent promoters, resulting in transcriptional repression of the target genes. We analyzed the transcriptional changes in t(8;21) Kasumi-1 AML cells in response to the HDAC inhibitors, depsipeptide (FK228) and suberoylanilide hydroxamic acid (SAHA), which induced marked growth inhibition and apoptosis. Using cDNA array, annexin A1 (ANXA1) was identified as one of the FK228-induced genes. Induction of ANXA1 mRNA was associated with histone acetylation in ANXA1 promoter and reversal of the HDAC-dependent suppression of C/EBPalpha by AML1-ETO with direct recruitment of C/EBPalpha to ANXA1 promoter. This led to increase in the N-terminal cleaved isoform of ANXA1 protein and accumulation of ANXA1 on cell membrane. Neutralization with anti-ANXA1 antibody or gene silencing with ANXA1 siRNA inhibited FK228-induced apoptosis, suggesting that the upregulation of endogenous ANXA1 promotes cell death. FK228-induced ANXA1 expression was associated with massive increase in cell attachment and engulfment of Kasumi-1 cells by human THP-1-derived macrophages, which was completely abrogated with ANXA1 knockdown via siRNA transfection or ANXA1 neutralization. These findings identify a novel mechanism of action of HDAC inhibitors, which induce the expression and externalization of ANXA1 in leukemic cells, which in turn mediates the phagocytic clearance of apoptotic cells by macrophages.

Expression of the angiomatrix and angiogenic proteins CYR61, CTGF, and VEGF in osteonecrosis of the femoral head.

Angiogenesis and bone repair are closely linked processes. VEGF, CYR61, and CTGF have been identified as signaling factors that control angiogenesis and could be important in fracture healing. The purpose of this study was to investigate the expression of these signaling factors in osteonecrosis of the femoral head. Twenty-one bone cylinders were retrieved from hips of patients with osteonecrosis of the femoral head at different ARCO stages. Immunohistochemistry for CD34, CYR61, CTGF, and VEGF expression was done on each bone cylinder representing the different regions of osteonecrosis (necrosis, fibrosis, transition zone, and edematous area). VEGF, CYR61, and CTGF were expressed in samples with osteonecrosis. Particularly VEGF and CYR61 were highly expressed in the edematous area. CYR61 was also highly expressed in the transition zone. CTGF was expressed mainly in the area of marrow fibrosis and edema. CYR61, CTGF, and VEGF are expressed to different degrees in the different repair zones of osteonecrosis. Particularly, the high expression of VEGF and CYR61 in the edematous area may represent a consequence of hypoxia and indicate a role of these proteins in the repair processes ongoing in osteonecrosis.

Knee arthroplasty for spontaneous osteonecrosis of the knee: unicompartimental vs bicompartimental knee arthroplasty.

Spontaneous osteonecrosis of the knee (SON) is an osteonecrosis that mainly affects the medial femoral condyle. In endstage SON, knee arthroplasty is the therapy of choice. Because of the unicompartimental nature of the knee, unicondylar knee arthroplasty is considered an ideal implant for treatment of this condition. The purpose of this study was to prove that the long-term results of unicondylar implants are better than the results of bicondylar implants for the treatment of SON. All patients treated for SON between 1984 and 2000 have been recorded. Two groups were formed according to the implant used. In all patients the preoperative radiograph was analyzed according to stage and size of the osteonecrotic lesion and the osteoarthritic changes. Postoperatively, the Knee Society Score and the radiograph were recorded. Thirty-nine patients were included in this study, of which 23 patients were treated by a unicondylar implant and 16 by a bicondylar implant. On a short-term basis, unicondylar implants had better clinical results; however, on a long-term basis bicondylar implants were better. In comparison, only unicondylar implants had to be revised. Radiolucency lines were mainly observed in patients with unicondylar impants and large areas of osteonecrosis. Our long-term results suggest that patients with SON are better treated by bicondylar implants. The reasons for the higher failure rate for unicondylar implants are poor bone stock and secondary arthritic changes.

[Osteochondral lesions of the talus -- indications for MRI with a contrast agent]. / Osteochondrale Läsionen am Talus - Indikationen zur MRT mit Kontrastmittel.

AIM: This study aims to establish the indication for a pre- and postoperative MRI examination with an intravenous contrast agent in patients with an osteochondral lesion of the talus. METHODS: 20 patients with an osteochondral lesion of the talus in the different stages according to DiPaola were prospectively examined preoperatively and 6 months postoperatively by an MRI investigation with an i. v. contrast agent. The Weber ankle score was determined pre- and postoperatively. A correlation was calculated between MRI and arthroscopic findings of an osteochondral lesion (Spearman-rho). RESULTS: There was a significant correlation among the radiological, the MRI and the arthroscopically determined locations. With regard to staging only 12 out of 20 lesions were staged correctly by MRI using arthroscopy as a gold standard. Due to metal artifacts and morphological changes the postoperative MRI could not be used for staging. CONCLUSION: A preoperative MRI investigation is indicated in patients with ankle pain of unknown origin, a normal radiograph and a suspected osteochondral lesion of the talus. MRI is not indicated to determine the localization and the stage of an osteochondral lesion. A postoperative MRI is only necessary for the exclusion of a secondary pathology.

Magnetic resonance imaging criteria of successful core decompression in avascular necrosis of the hip.

To identify imaging criteria that determine the outcome of core decompression (CD) in femoral-head avascular necrosis (AVN). Radiographs and magnetic resonance imaging (MRI) of 65 hips with early stage AVN treated by core decompression between January 1990 and December 2000 for AVN were reviewed. All hips were categorized into two groups according to the result of CD using total hip arthroplasty (THA) as an end point. Hips that had no THA at follow-up were allocated to group I; those treated with a THA were allocated to group II. CD results were calculated for each group using THA as an end point. The parameters analyzed were the presence or absence of edema associated with the double-line sign on the preoperative MRI, the type of epiphyseal scar (ES) according to Jing, and the type of necrosis according to Mitchell. On follow-up, 45 hips had no THA (group I); 20 patients had a THA (group II). Patients with a radiographic crescent sign and those with edema associated with the double-line sign progressed to THA significantly more frequently. The extent of the necrosis had less discriminatory effect between the two groups. ES and necrotic tissue types had no prognostic value. In regard to the success of CD, it is important to differentiate on MRI between a double line sign plus bone marrow edema and a double-line sign only.

Transient bone marrow edema syndrome progressing to avascular necrosis of the hip - a case report and review of the literature.

Transient bone marrow edema syndrome (TMES) is a rare disease of unknown etiology. Diagnosis is made by exclusion. There is still controversy as to whether TMES is considered to be a reversible form of avascular necrosis (AVN), a disease entity of its own or a form of non-traumatic algodystrophy. We here describe the extremely rare occurrence of three cases of TMES that progressed to AVN.

Epidermoid cyst mimicking monoarticular arthritis of the great toe.

Local swellings of the foot are a common presentation in rheumatological practice. In the following case report, an epidermoid cyst presenting with the typical features of monoarticular arthritis is described in a 27-year-old woman. The differential diagnosis of forefoot swelling is discussed, with particular emphasis on epidermoid cysts and monoarticular arthritis.

Arthrodesis in the treatment of hallux rigidus.

We reviewed 34 patients (38 joints) with hallux rigidus treated from 1989 to 1999 with arthrodesis of the first metatarsophalangeal joint. Average patient age at time of surgery was 52 (24-71) years, and the mean follow-up was 54 (18-116) months. There were six superficial infections, and all arthrodeses united. There was a good functional result with a significant pain reduction. The mean postoperative American Orthopaedic Foot and Ankle Society (AOFAS) score was 53 (5-84) points.

[Randomised trial of acupuncture compared with conventional massage and "sham" laser acupuncture for treatment of chronic neck pain - range of motion analysis]. / Randomisierte Studie zur Akupunktur im Vergleich mit konventioneller Massage und Schein-Laserakupunktur in der Behandlung chronischer HWS-Beschwerden - Bewegungsanalyse.

AIM: The aim of this study was to compare the effects of acupuncture on active motion of the cervical spine in patients with chronic neck pain with those of "sham" laser acupuncture and massage. MATERIAL AND METHODS: 177 patients with chronic neck pain were included in this prospective, randomized, placebo-controlled study. The patients were allocated by external randomization to five treatments over three weeks with acupuncture, massage and "sham" laser acupuncture. The range of active motion was measured by means of a 3D ultrasound real time motion analyzer. RESULTS: The analysis of cervical motion in three directions showed the largest increase in range of motion 14 days after acupuncture. Compared to massage, a significant improvement in total range of motion was seen in those patients treated by acupuncture immediately (p = 0,03) and one week (p = 0,03) weeks after therapy. There was no significant difference in those patients treated by sham laser acupuncture. CONCLUSION: The results of the study indicate that acupuncture is superior to conventional massage for improving active range of motion in patients with chronic neck pain. Because of its positive effects, its acceptance among patients and the lack of severe side effects, acupuncture can be recommended for the treatment of chronic neck pain, although there was no significant difference in results between "sham" laser acupuncture and acupuncture.

Annexin A1 processing is associated with caspase-dependent apoptosis in BZR cells.

Annexins are widely distributed and have been described in lung as well as in other cells and tissues. Annexin I (ANX AI) is a member of the calcium-dependent phospholipid binding protein family. Besides its anti-inflammatory function, ANX AI has been involved in several mechanisms such as the Erk repression pathway or apoptosis. To investigate the role of ANX AI on apoptosis in broncho-alveolar cells, we have constructed a plasmid containing the ANX AI full length cDNA. Transfected BZR cells displayed a higher level of both forms of ANX AI (37 and 33 kDa) as well as a decrease in cell viability (two-fold versus cells transfected with an empty vector). In order to analyse the endogenous ANX AI processing during stimulus-induced apoptosis, BZR cells were treated with a commonly used inducer, i.e. C2 ceramides. In these conditions, microscopic analysis revealed chromatin condensation in dying cells and the Bcl-2, Bcl-x(L)/Bax mRNA balance was altered. Caspase-3 is one of the key executioners of apoptosis, being responsible for the cleavage of many proteins such as the nuclear enzyme poly(ADP-ribose) polymerase (PARP). We demonstrate that caspase-3 was activated after 4 h treatment in the presence of ceramide leading to the cleavage of PARP. Dose-response experiments revealed that cell morphology and viability modifications following ceramide treatment were accompanied by an increase in endogenous ANX AI processing. Interestingly, in both ceramide and transfection experiments, the ANX AI cleaved form was enhanced whereas pre-treatment with the caspase inhibitor Z-VAD-fmk abolished ANX AI cleavage. In conclusion, this study demonstrates a complex regulatory role of caspase-dependent apoptosis where ANX AI is processed at the N-terminal region which could give susceptibility to apoptosis upon ceramide treatment.

Treatment of transient bone marrow oedema of the hip--a comparative study.

Between 1990 and 2000, we treated 43 patients with transient bone marrow oedema of the hip. Five were treated with nonsteroidal antiinflammatory drugs (NSAIDs) and limited weight bearing, and 38 by core decompression followed by limited weight bearing. At follow-up 2-10 years later, all patients were assessed by a structured interview as well as the Harris hip score (HHS) and the Western Ontario and MacMaster Universities Osteoarthritis Index (WOMAC). Both groups reached the same clinical outcome (HHS and WOMAC). Core decompression enabled a significantly faster recovery. There were no complications, but progression to avascular necrosis was seen in both groups. Core decompression induced fast pain relief, making it the preferable treatment.