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.

[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.

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.

[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.

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.

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.

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.

[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.

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.

[Therapy of local prostate carcinoma. Questions answered by outcome research]. / Therapie des lokal begrenzten Prostatakarzinoms Fragen beantwortet die Versorgungsforschung.

More and more localized prostate cancers with only a low risk for progression are diagnosed. In most cases the treatment consists of invasive procedures which may be accompanied by certain side effects. Ongoing randomized studies which are comparing irradiation and surgery with defensive strategies like Active Surveillance will not give results in the foreseeable future. In this situation it could be helpful to take data from health care research studies like HAROW. Neither the physicians nor the patients participating are selected. As a non-interventional study HAROW provides a data collecting in invasive therapies and in defensive strategies. Under everyday conditions data on cancer history, quality of life, patients' satisfaction and economics are collected. Since Active Surveillance (AS) is still a largely uncommon strategy we present criteria for enrollment, ongoing and termination. In international guidelines AS is assessed to be on a par with invasive procedures or even as the preferred treatment option.

[Lymph node dissection in patients with renal cell carcinoma]. / Lymphknotendissektion beim Nierenzellkarzinom.

The role of lymph node dissection in renal cell carcinoma has been controversial for decades. However, the results of the only prospective randomised study concerning this issue (EORTC 30881) are preliminary. Retrospective analyses were not able to demonstrate a diagnostic or therapeutic benefit of an extended lymph node dissection. Suspicious lymph nodes (imaging, palpation) should be excised during nephrectomy.

Tic22 is targeted to the intermembrane space of chloroplasts by a novel pathway.

Tic22 previously was identified as a component of the general import machinery that functions in the import of nuclear-encoded proteins into the chloroplast. Tic22 is peripherally associated with the outer face of the inner chloroplast envelope membrane, making it the first known resident of the intermembrane space of the envelope. We have investigated the import of Tic22 into isolated chloroplasts to define the requirements for targeting of proteins to the intermembrane space. Tic22 is nuclear-endoded and synthesized as a preprotein with a 50-amino acid N-terminal presequence. The analysis of deletion mutants and chimerical proteins indicates that the precursor of Tic22 (preTic22) presequence is necessary and sufficient for targeting to the intermembrane space. Import of preTic22 was stimulated by ATP and required the presence of protease-sensitive components on the chloroplast surface. PreTic22 import was not competed by an excess of an authentic stromal preprotein, indicating that targeting to the intermembrane space does not involve the general import pathway utilized by stromal preproteins. On the basis of these observations, we conclude that preTic22 is targeted to the intermembrane space of chloroplasts by a novel import pathway that is distinct from known pathways that target proteins to other chloroplast subcompartments.

Identification of proteins associated with plastoglobules isolated from pea (Pisum sativum L.) chloroplasts.

Plastoglobules are conspicuous lipid-containing structures in the chloroplast stroma and are thought to serve as lipid reservoirs for thylakoid membranes. Plastoglobules also contain low levels of proteins. We have purified plastoglobules from a pea chloroplast membrane fraction. Sodium dodecyl sulfate-polyacrylamide gel electrophoretic analysis of the purified plastoglobules revealed more than a dozen distinct polypeptides that we propose to term plastoglobulins. For one of the proteins, termed plastoglobulin 1 (PG1), we have obtained partial N-terminal and internal protein sequences. The amino acid sequence, deduced from cDNA, encoded a precursor protein of a calculated mass of 38,491 Da which contained a 48-residue-long N-terminal signal sequence. Pre-PG1 obtained by coupled in-vitro transcription/translation was imported into pea chloroplasts, its signal sequence was cleaved and mature PG1 was assembled into plastoglobules. Homology searches of the data bases revealed similarity of PG1 to the plastoglobule-associated protein of Capsicum annuum, the carotenoid-associated protein of Cucumis sativus and to a protein of the cyanobacterium Synechocystis sp., indicating that PG1 is a novel member of an ancient protein family. Immunoelectron microscopy using PG1 specific antibodies indicated that PG1 is present in multiple copies on the surface of plastoglobules.

Two components of the chloroplast protein import apparatus, IAP86 and IAP75, interact with the transit sequence during the recognition and translocation of precursor proteins at the outer envelope.

The interactions of precursor proteins with components of the chloroplast envelope were investigated during the early stages of protein import using a chemical cross-linking strategy. In the absence of energy, two components of the outer envelope import machinery, IAP86 and IAP75, cross-linked to the transit sequence of the precursor to the small subunit of ribulose-1, 5-bisphosphate carboxylase (pS) in a precursor binding assay. In the presence of concentrations of ATP or GTP that support maximal precursor binding to the envelope, cross-linking to the transit sequence occurred predominantly with IAP75 and a previously unidentified 21-kD polypeptide of the inner membrane, indicating that the transit sequence had inserted across the outer membrane. Cross-linking of envelope components to sequences in the mature portion of a second precursor, preferredoxin, was detected in the presence of ATP or GTP, suggesting that sequences distant from the transit sequence were brought into the vicinity of the outer membrane under these conditions. IAP75 and a third import component, IAP34, were coimmunoprecipitated with IAP86 antibodies from solubilized envelope membranes, indicating that these three proteins form a stable complex in the outer membrane. On the basis of these observations, we propose that IAP86 and IAP75 act as components of a multisubunit complex to mediate energy-independent recognition of the transit sequence and subsequent nucleoside triphosphate-induced insertion of the transit sequence across the outer membrane.

Isolation of components of the chloroplast protein import machinery.

Components of the protein import machinery of the chloroplast were isolated by a procedure in which the import machinery was engaged in vitro with a tagged import substrate under conditions that yielded largely chloroplast envelope-bound import intermediates. Subsequent detergent solubilization of envelope membranes showed that six envelope polypeptides copurified specifically and, apparently, stoichiometrically with the import intermediates. Four of these polypeptides are components of the outer membrane import machinery and are associated with early import intermediates. Two of these polypeptides have been characterized. One is a homolog of the heat shock protein hsp70; the other one is a channel-protein candidate.