A multicentre, open-label, phase-I/randomised phase-II study to evaluate safety, pharmacokinetics, and efficacy of nintedanib vs. sorafenib in European patients with advanced hepatocellular carcinoma.

BACKGROUND: This multicentre, open-label, phase-I/randomised phase-II trial evaluated safety, pharmacokinetics, maximum-tolerated-dose (MTD) per dose-limiting toxicities (DLTs), and efficacy of nintedanib vs. sorafenib in European patients with unresectable advanced hepatocellular carcinoma (aHCC). METHODS: Phase I: Patients were stratified into two groups per baseline aminotransferase/alanine aminotransferase and Child-Pugh score; MTD was determined. Phase II: Patients were randomised 2:1 to nintedanib (MTD) or sorafenib (400-mg bid) in 28-day cycles until intolerance or disease progression. Time-to-progression (TTP, primary endpoint), overall survival (OS) and progression-free survival (PFS) were determined. RESULTS: Phase-I: no DLTs observed; nintedanib MTD in both groups was 200 mg bid. Phase-II: patients (N = 93) were randomised to nintedanib (n = 62) or sorafenib (n = 31); TTP was 5.5 vs. 4.6 months (HR = 1.44 [95% CI, 0.81-2.57]), OS was 11.9 vs. 11.4 months (HR = 0.88 [95% CI, 0.52-1.47]), PFS was 5.3 vs. 3.9 months (HR = 1.35 [95% CI, 0.78-2.34]), respectively (all medians). Dose intensity and tolerability favoured nintedanib. Fewer patients on nintedanib (87.1%) vs. sorafenib (96.8%) had drug-related adverse events (AEs) or grade ≥ 3 AEs (67.7% vs. 90.3%), but more patients on nintedanib (28 [45.2%]) had AEs leading to drug discontinuation than did those on sorafenib (7 [22.6%]). CONCLUSIONS: Nintedanib may have similar efficacy to sorafenib in aHCC.

Manganese superoxide dismutase deficiency triggers mitochondrial uncoupling and the Warburg effect.

This corrects the article DOI: 10.1038/onc.2014.355.

A phase I study of daily afatinib, an irreversible ErbB family blocker, in combination with weekly paclitaxel in patients with advanced solid tumours.

BACKGROUND: This phase I study evaluated afatinib, an irreversible ErbB family blocker, plus paclitaxel in patients with advanced solid tumours likely to express human epidermal growth factor receptor (HER1/EGFR) or HER2. METHODS: Oral afatinib was combined with intravenous paclitaxel (80mg/m(2); days 1, 8 and 15 every four weeks) starting at 20mg once daily and escalated to 40 and 50mg in successive cohorts of ⩾3 patients. The primary objective was to determine the maximum tolerated dose (MTD) of afatinib combined with paclitaxel. Secondary objectives included safety, pharmacokinetics and antitumour activity. RESULTS: Sixteen patients were treated. Dose-limiting toxicities with afatinib 50mg were fatigue and mucositis. The MTD was determined as afatinib 40mg with paclitaxel 80mg/m(2), which proved tolerable with repeated dosing. Frequent adverse events (AEs) included diarrhoea (94%), fatigue (81%), rash/acne (81%), decreased appetite (69%) and inflammation of mucosal membranes (69%); no grade 4 treatment-related AEs were observed. Five (31%) confirmed partial responses were observed in patients with non-small cell lung cancer (n=3), oesophageal cancer and cholangiocarcinoma; eight (50%) patients remained on study for ⩾6months. Pharmacokinetic parameters of afatinib and paclitaxel were similar for single administration or in combination. CONCLUSIONS: The MTD and recommended phase II dose of once-daily afatinib combined with paclitaxel 80mg/m(2) (days 1, 8 and 15 every four weeks) was 40mg. AEs at or below this dose were generally manageable with repeated dosing. No pharmacokinetic interactions were observed. This combination demonstrated promising antitumour activity. TRIAL REGISTRATION: ClinicalTrials.gov, NCT00809133.

Life-threatening complications and outcomes in patients with malignancies and severe pulmonary embolism.

BACKGROUND: Data are scarce about ICU patients with malignancy and severe pulmonary embolism. Here, our main objective was to identify risk factors for life-threatening complications, organ failures, and death in ICU patients with severe pulmonary embolism, with special attention to the impact of malignancy. We also described the clinical features of PE in patients with and without malignancies. METHODS: Data from consecutive adults admitted to our ICU in 2002-2011 with severe pulmonary embolism were collected retrospectively. Multivariate analysis was performed to look for factors associated with death, organ failures, or life-threatening complications (major bleeding, recurrent PE, and cardiac arrest). RESULTS: Of 119 included patients (42 [35%] with bilateral pulmonary embolism), 41 had solid malignancies, 27 hematological malignancies, and 51 no malignancies. The most common symptoms were syncope (40%) and hemoptysis (18%) in patients with solid and hematological malignancies, respectively. Life-threatening complications occurred in 23 (19%) patients; risk factors were obesity (OR, 13.22; 1.93-90.70), disseminated intravascular coagulation/ischemic hepatitis (OR, 27.06; 5.14-142.46), fluid load ≥1000 mL/24 h (OR, 6.42; 1.60-25.76), and solid malignancy (OR, 5.45; 1.15-25.89). Inhospital mortality was 27/119 (23%) and respiratory or circulatory failure developed in 36 (30%) patients. Risk factors for these adverse outcomes were older age (OR, 1.04/year; 1.01-1.07), higher oxygen flow rate (OR, 1.28/L; 1.13-1.45); and renal failure (OR, 8.08; 2.50-26.11); whereas chest pain was protective (OR, 0.13; 0.04-0.48). CONCLUSION: In this study, solid malignancy was a risk factor for life-threatening complications but not for death.

Manganese superoxide dismutase deficiency triggers mitochondrial uncoupling and the Warburg effect.

Manganese superoxide dismutase (MnSOD) is a mitochondrially localized primary antioxidant enzyme, known to be essential for the survival of aerobic life and to have important roles in tumorigenesis. Here, we show that MnSOD deficiency in skin tissues of MnSOD-heterozygous knockout (Sod2(+/-)) mice leads to increased expresson of uncoupling proteins (UCPs). When MnSOD is deficient, superoxide radical and its resulting reactive oxygen species (ROS) activate ligand binding to peroxisome proliferator-activated receptor alpha (PPARα), suggesting that the activation of PPARα signaling is a major mechanism underlying MnSOD-dependent UCPs expression that consequently triggers the PI3K/Akt/mTOR pathway, leading to increased aerobic glycolysis. Knockdown of UCPs and mTOR suppresses lactate production and increases ATP levels, suggesting that UCPs contribute to increased glycolysis. These results highlight the existence of a free radical-mediated mechanism that activates mitochondria uncoupling to reduce ROS production, which precedes the glycolytic adaptation described as the Warburg Effect.

[Patterns of care of patients with localized prostate cancer in Germany: a health care study with focus on active surveillance]. / Die Versorgung von Patienten mit lokal begrenztem Prostatakarzinom in Deutschland : Active-Surveillance-Ergebnisse einer nicht-interventionellen Versorgungsstudie.

BACKGROUND: To date, evidence on active surveillance (AS) is restricted to protocol-based studies and the current practice pattern outside medical centers is unknown. OBJECTIVES: The goal of this work was to capture the current treatment pattern of AS for localized prostate cancer (PCa) in patients managed by office-based urologists in Germany. MATERIALS AND METHODS: Our cohort consisted of 361 patients included in the AS arm of the HAROW (Hormonal Treatment, Active Surveillance, Radiation Therapy, OP, Watchful Waiting) study, an observational health service study in Germany. Descriptive characteristics and active-treatment-free survival (ATFS), surgical outcomes, and triggers for active treatment were assessed. RESULTS: Currently, only 15% of all patients with localized PCa were treated with AS. At baseline, 83% and 58% of all AS patients met the Chism and PRIAS low-risk criteria, respectively. After a median follow-up of 24 months, no systemic progression was observed, 5 patients died of non-disease-specific causes and active treatment was delivered in 20.5% of all patients. Triggers for active therapy were progression at biopsy (42%), rise in prostate-specific antigen level (27%), medical advice (16%) and patient's preference (10%), respectively. CONCLUSION: Our short-term results indicate that - in the hands of office-based urologists - active surveillance might represent a feasible treatment option for patients with localized PCa. The majority of patients were free of active treatment 2 years after AS initiation. Generally accepted inclusion and progression criteria are lacking and should be developed in order to facilitate and standardize AS in patients with low-risk PCa.

[The HAROW study: an example of outcomes research: a prospective, non-interventional study comparing treatment options in localized prostate cancer]. / Die HAROW-Studie: ein Beispiel für Versorgungsforschung : Prospektive, nicht-interventionelle Studie zur Behandlung des Niedrig-Risiko-Prostatakarzinoms.

BACKGROUND: The HAROW study was initiated to investigate the provision of ongoing medical care for patients with localized prostate cancer in a prospective, noninterventional setting and to investigate treatment options (Hormonal treatment, Active surveillance, Radiotherapy, Operation, Watchful waiting) under real-life conditions. MATERIALS AND METHODS: A total of 3169 patients were enrolled by 259 participating physicians in private practice in Germany. The median follow-up was 28.4 months. At 6-month intervals, the treating physicians reported data on clinical parameters, clinical course of disease, and quality of patient-physician interaction. RESULTS: The highest proportion of patients with low risk tumor was found in the defensive treatment groups (AS and WW). As expected, the AS group showed the highest progression rate. In all, 112 AS patients (23.9%) changed therapeutic strategy, 21 of them upon medical advice in the absence of any signs of progression. Metastases were seen most frequently in the WW group (1.5%). No metastases occurred in AS patients. Medical support in managing the disease reached high scores in all groups, the highest in AS. CONCLUSION: The data enable a differentiated comparative analysis of patient and tumor characteristics of each treatment group. Indication of AS was predominantly consistent with the guideline. The high rate of AS termination based on the physician's recommendation rather than on clinical progression is remarkable, and may be interpreted as a kind of insecurity in dealing with AS. Results regarding communication indicate that patients appreciated being involved in treatment decisions.

[Implementation of clinical ethics consultation in German hospitals]. / Wird Klinische Ethikberatung in Krankenhäusern in Deutschland implementiert?

BACKGROUND: There have been different initiatives for the implementation of clinical ethics consultation during the past years. The present study surveys current data. METHODS: A structured questionnaire was used. Of the 1,858 contacted hospitals throughout Germany 550 answered to that questionnaire (return rate 29,6 %). The survey took place between September 2013 and January 2014. RESULTS: The clinical ethics committee is the mostly implemented structure of clinical ethics consultation. Recommendations to implement those structures (ZEKO 2006, AEM 2010) show less influence than the legally binding standard (HKHG 2011). Structures of clinical ethics consultation are respected as instrument to solving ethical conflicts in clinical routines. CONCLUSIONS: Establishing ethics consultation should be promoted. Preferably appropriate legal rules for the implementation of clinical ethics consultation should be developed further as well as their structural framing.

Redox proteomic identification of HNE-bound mitochondrial proteins in cardiac tissues reveals a systemic effect on energy metabolism after doxorubicin treatment.

Doxorubicin (DOX), one of the most effective anticancer drugs, is known to generate progressive cardiac damage, which is due, in part, to DOX-induced reactive oxygen species (ROS). The elevated ROS often induce oxidative protein modifications that result in alteration of protein functions. This study demonstrates that the level of proteins adducted by 4-hydroxy-2-nonenal (HNE), a lipid peroxidation product, is significantly increased in mouse heart mitochondria after DOX treatment. A redox proteomics method involving two-dimensional electrophoresis followed by mass spectrometry and investigation of protein databases identified several HNE-modified mitochondrial proteins, which were verified by HNE-specific immunoprecipitation in cardiac mitochondria from the DOX-treated mice. The majority of the identified proteins are related to mitochondrial energy metabolism. These include proteins in the citric acid cycle and electron transport chain. The enzymatic activities of the HNE-adducted proteins were significantly reduced in DOX-treated mice. Consistent with the decline in the function of the HNE-adducted proteins, the respiratory function of cardiac mitochondria as determined by oxygen consumption rate was also significantly reduced after DOX treatment. Treatment with Mn(III) meso-tetrakis(N-n-butoxyethylpyridinium-2-yl)porphyrin, an SOD mimic, averted the doxorubicin-induced mitochondrial dysfunctions as well as the HNE-protein adductions. Together, the results demonstrate that free radical-mediated alteration of energy metabolism is an important mechanism mediating DOX-induced cardiac injury, suggesting that metabolic intervention may represent a novel approach to preventing cardiac injury after chemotherapy.

Resistive Index or color-Doppler semi-quantitative evaluation of renal perfusion by inexperienced physicians: results of a pilot study.

BACKGROUND: Doppler-based renal resistive index (RI) calculation may help in the early detection of acute kidney injury (AKI). Its feasibility and reproducibility by inexperienced operators remain unknown. The main objective of this study was to compare performances of junior and senior operators in assessing renal perfusion using both the semiquantitative color-Doppler scale and RI calculation. METHODS: Prospective cohort study performed in 3 ICUs. Inexperienced juniors physicians attended a half-day course on renal perfusion assessment using RI calculation and color-Doppler (from 0, absence of renal perfusion; to 3, renal vessels identifiable in the entire field of view). Junior and senior operators used both methods in 69 mechanically ventilated patients, in blind fashion. RESULTS: Failure to obtain RI occurred for a junior operator in a single patient. RI and color-Doppler semi-quantitative values obtained by operators were correlated (r²=0.64 and r²=0.61, respectively). Systematic bias across operators as assessed using Bland-Altman plots was negligible (-0.001 and -0.29, respectively), although precision was limited (95% confidence intervals, +0.105 to -0.107 and +0.98 to -1.04, respectively). RI calculation and semi-quantitative assessment performed well for diagnosing persistent AKI (area under the receiver-operating characteristic curve, 0.84 [95% confidence interval, 0.73-0.97] and 0.87 [0.77-0.97], respectively). CONCLUSION: A brief course on renal Doppler allowed inexperienced operators to assess effectively renal perfusion with a good reliability when compared to senior operators. In addition, our results suggest the good diagnostic performance of both Doppler-based RI and semi-quantitative renal perfusion assessment in predicting short-term renal dysfunction reversibility.

Acute respiratory failure in neutropenic patients is associated with a high post-ICU mortality.

BACKGROUND: Few studies have evaluated outcomes of neutropenic patients admitted to the ICU at the onset of acute respiratory failure (ARF). The main objective of this study was to describe outcomes and to identify early predictors of hospital mortality in critically ill cancer patients with ARF during chemotherapy-induced neutropenia. METHODS: Retrospective analysis of prospectively collected data extracted from two recent prospective multicentre studies. We included neutropenic adults admitted to the ICU for ARF. RESULTS: Of the 123 study patients, 107 patients (87%) had haematological malignancies; 78 (64%) were male, median age was 57 years (44-62), and median LOD score at ICU admission was 6 (4-9). ICU and hospital mortality rates were 42% and 77%, respectively. Endotracheal mechanical ventilation was an independent risk factor for hospital mortality (odds ratio [OR], 7.73; 95% confidence interval [95%CI], 2.52-23.69); two factors independently protected from hospital mortality, namely, ICU admission for ARF during neutropenia recovery (OR, 0.23; 95%CI, 0.07-0.73) and steroid therapy before ICU admission (OR, 0.35; 95%CI, 0.11-0.95). CONCLUSION: Our study demonstrates a meaningful ICU survival in the studied population and identified factors associated with ICU and hospital mortality. Further work is needed to address the reasons for the high post-ICU mortality rate after ARF.

[Corneal metabolism with contact lenses in competitive sports]. / Hornhautstoffwechsel unter Kontaktlinsen im Sport.

The corneal metabolism during the use of contact lenses plays an important role for permanent corneal health, especially in competitive sports. Thus, it is important to understand the steps of corneal metabolism in general and during highly competitive sports activity in particular. The aim of this review is to summarize the current knowledge on physiological and biochemical effects of contact lens wear. Of the energy requirements of the cornea 75 % is supplied by aerobic processes; therefore, the eye needs the highest possible amount of oxygen and sufficient glucose which can be obtained from external air and to a lesser degree from within the anterior chamber. If the oxygen supply is too low this results in hypoxic edema. Fitting athletes with contact lenses must still be viewed with caution as the visual needs of athletes are usually much more demanding than those of the general public. An indiscriminate choice of lens design can adversely affect athletic performance and may even create a hazardous situation. An intelligent choice of contact lens can provide some subtle advantages that may improve athletic performance and provide the decisive margin for victory.

Diagnostic contribution from pulmonary biopsies in hematology patients with acute respiratory failure from undetermined etiology.

BACKGROUND: In about 20% of patients with malignancies with acute respiratory failure (ARF), no etiology can be determined, whatever the diagnostic strategy used. Lung biopsy could then be a precious diagnostic tool leading to therapeutic adaptations and increasing chances for cure. The aim of this study was to assess the diagnostic contribution of lung biopsy in patients for whom a complete diagnosis strategy failed to identify ARF etiology. METHODS: All hematology patients admitted for ARF to our ICU between 1995 and 2011, and for whom lung biopsy was performed were included in the study. Lung biopsies were surgical, CT guided, or post-mortem. Histological findings were compared to prebiopsy diagnosis and classified into specific or non-specific diagnosis. Therapeutic impact (or Goldman-class in post-mortem biopsies) was also recorded. RESULTS: Among the 1440 hematology patients with ARF managed during the study period, 21 (1%) biopsies were performed, including 10 post-mortem biopsies. Histological diagnoses were specific in 10 biopsies, non specific in 8 biopsies and lung parenchyma was normal in three patients. In 8/11 (72.7%) alive patients, lung biopsy had lead to therapeutic modifications, including treatment implementation in 5 patients and treatment withdrawal in 3 patients. One out of 10 (10%) patients had minor complications. For the 10 dead patients, only one Goldman-type 1 error was found. CONCLUSION: Diagnostic lung biopsy is rarely needed in hematology patients with ARF. But, it has a 73% therapeutic impact and has overall no major complications. Contribution from post-mortem biopsies seems less relevant.

[Is the staining grid usable? Investigation of the updated table in internet for cleaning solutions of the optometrist Gary Andrasko for usability]. / Ist die "Staining-grid-Tabelle" nutzbar? Untersuchung der im Internet fortgeschriebenen Tabelle für Reinigungslösungen des Optometristen Gary Andrasko auf ihre Anwendbarkeit.

The author presents the standards for testing the biocidal effectiveness of combined cleaning disinfection solutions (RDK solutions). By means of literature searches it was investigated whether the updated table of the optometrist Gary Andrasko in the internet is usable with respect to compatibility of combinations of commercially available contact lenses and commonly used RDK solutions by assessment of surface dye affinity. The methods used by Andrasko and the scientific basis of his approach are questioned based on various criteria and the value of the table is negated. The instructions for care given by the manufacturers of contact lenses are recommended.

[Diagnosis prostate cancer: who makes the treatment decision and which treatment is selected? Opinion survey in a prostate cancer patient support group]. / Diagnose Prostatakarzinom: Wer trifft welche Therapieentscheidung? : Befragung in den Selbsthilfegruppen des Bundesverbandes Prostatakrebs Selbsthilfe (BPS) bei neu diagnostiziertem Prostatakarzinom.

BACKGROUND: It is challenging to decide in which way we should care for localized prostate cancer. The current guideline can be accepted as an appropriate foundation. However, there are doubts if guideline recommendations are implemented. RESULTS: The presented opinion survey of prostate cancer support groups shows that we have too many prostatectomies in senior patients. It reveals deficiencies in the guidance of the patients. They are not sufficiently embedded in the process of decision-making. More attention should be paid to initiatives of patient support groups.

Histamine H1, H3 and H4 receptors are involved in pruritus.

Histamine has long been recognised as a classical inducer of pruritus. However, the specific mechanism of histamine-induced itch has still not been fully understood. The H1 and H4 receptor appear to be key components in the induction of itch. The specific role of the H3 receptor in histamine-induced itch remains unclear. The aim of our study was to investigate the role of the four known histamine receptors (H1-4) in acute itch in mice. Intradermal injection of the selective H3R inverse agonist pitolisant induced strong itch in mice. Pitolisant (50 nmol/injection)-induced pruritus could be completely blocked by a combined treatment with the H1R antagonist cetirizine (15 mg/kg) and the H4R antagonist JNJ 7777120 (15 mg/kg), whereas the H2R antagonist ranitidine (15 mg/kg) failed to inhibit the scratch response. Next, expression and function of histamine receptors on sensory neurons isolated from dorsal root ganglia of mice were investigated. As the itch sensation results from the excitation of sensory nerves in the skin, we further focused on skin specific sensory neurons. Therefore, neurons were retrograde labelled from the skin by means of a fluorescent tracer. Expression of H1R, H3R and H4R on skin innervating sensory neurons was detected. By single-cell calcium imaging, it was demonstrated that histamine induces a calcium increase in a subset of (skin-specific) sensory neurons via activation of the H1R and H4R as well as inhibition of the H3R. It is assumed that the decreased threshold in response to H3R antagonism activates H1R and H4R on sensory neurons, which in turn results in the excitation of histamine-sensitive afferents and therefore elicits the sensation of itch.

Significance of herpesvirus 6 in BAL fluid of hematology patients with acute respiratory failure.

PURPOSE: Human herpesvirus 6 (HHV6) is an emerging cause of interstitial pneumonia in immunocompromised hosts. However, the clinical significance of a positive PCR test for HHV6 in respiratory samples from patients with hematological malignancies remains unclear. METHODS: We retrospectively studied the features and outcomes of 29 critically ill hematology patients with acute respiratory failure and lung pulmonary infiltrates visible on a chest radiograph, who tested positive for a qualitative PCR for HHV6 in bronchoalveolar lavage fluid. RESULTS: Of the 29 patients, 18 (62%) were stem cell transplant recipients and 11 (38%) had received chemotherapy. All patients had a fever. Clinical manifestations consistent with extra-pulmonary HHV6 disease were noted in 17 (59%) patients. One or more co-pathogens were found in 25 (86%) patients. The four remaining patients diagnosed with HHV6 pneumonia and subsequently recovered with foscarnet therapy. Antiviral therapy was also given to seven patients with co-infections, of whom two ultimately died. CONCLUSIONS: In most cases, HHV6 recovered from BAL fluid is a co-pathogen whose clinical relevance remains undetermined. However, in some cases, HHV6 is the only pathogen, along with disseminated systemic viral disease, and the patient is likely to benefit from foscarnet therapy.