Circulating innate immune markers and outcomes in treatment-naïve advanced non-small cell lung cancer patients.

INTRODUCTION: Innate immunity represents the first step of activation of the immune system and dictates the quality of adaptive immune responses. Studies have reported links between systemic inflammatory or innate immune markers and prognosis in patients with lung cancer. To our knowledge, the prospective and concomitant study of these systemic markers has never been performed. METHODS: Advanced treatment-naive non-small cell lung cancer (NSCLC) patients eligible for first-line platinum-based chemotherapy were prospectively included from December 2012 to July 2015 (N = 148). Blood samples of patients were collected before the first cycle for fresh NK cell phenotyping. Peripheral blood mononuclear cells were cryopreserved for natural cytotoxicity receptor (NCR) genotyping as well as sera for NCR's ligand quantification. Data on leukocytes, neutrophils and monocyte counts and lactate dehydrogenase (LDH) levels were extracted from electronic medical records. RESULTS: Among all studied markers, monocytosis, neutrophilia, leucocytosis, high LDH and sBAG6 levels and reduced levels of NCR3 transcripts were associated with poor overall survival (OS) in univariate analysis. The levels of NCR3 transcripts was linked to age, number of metastatic sites, monocyte counts, LDH and sBAG6 levels. Neutrophilia was associated to high sBAG6 levels. NCR3 was the unique innate immune parameter that remained as an independent factor associated with both OS (P = 0.003) and progression-free survival (P = 0.009) in the multivariate analysis. CONCLUSION: This study brought evidence that these biomarkers are entangled; parameters associated with an inflammatory process were related to reduced levels of NCR3 transcripts. Finally, the level of NCR3 transcripts was independently associated with outcomes in treatment-naive patients with advanced NSCLC.

CBP/p300 acetyltransferases regulate the expression of NKG2D ligands on tumor cells.

Tumor surveillance of natural killer (NK) cells is mediated by the cytotoxicity receptor natural-killer group 2 member D (NKG2D). Ligands for NKG2D are generally not expressed on healthy cells, but induced on the surface of malignant cells. To date, NKG2D ligand (NKG2D-L) induction was mainly described to depend on the activation of the DNA damage response, although the molecular mechanisms that regulate NKG2D-L expression remain largely unknown. Here, we show that the acetyltransferases CBP (CREB-binding protein) and p300 play a crucial role in the regulation of NKG2D-L on tumor cells. Loss of CBP/p300 decreased the basal cell surface expression of human ligands and reduced the upregulation of MICA/B and ULBP2 in response to histone deacetylase inhibitors or DNA damage. Furthermore, CBP/P300 deficiency abrogated the sensitivity of stressed cells to NK cell-mediated killing. CBP/p300 were also identified as major regulators of mouse NKG2D ligand RAE-1 in vitro and in vivo using the Eµ-Myc lymphoma model. Mechanistically, we observed an enhanced activation of the CBP/p300 binding transcription factor CREB (cAMP response element-binding protein) correlating to the NKG2D-L upregulation. Moreover, increased binding of CREB and CBP/p300 to NKG2D-L promoters and elevated histone acetylation were detectable. This study provides strong evidence for a major role of CBP and p300 in orchestrating NKG2D-L induction and consequently immunosurveillance of tumors in mice and humans. These findings might help to develop novel immunotherapeutic approaches against cancer.

[Immune-mediated neuropathies]. / Immunneuropathien.

The Guillain-Barré syndrome (GBS) and chronic inflammatory demyelinating polyneuropathy (CIDP) are the most common immune-mediated polyneuropathies, which can show variable clinical and electrophysiological manifestations. Rarer immune-mediated neuropathies encompass paraproteinemic neuropathies (PPN), multifocal motor neuropathy (MMN) and vasculitic neuropathies. The diagnosis usually relies on the history of symptom evolution, distribution of nerve dysfunction and particularly on characteristic features in nerve conduction studies, aided by cerebrospinal fluid (CSF) examination and nerve biopsy findings. The therapeutic toolbox encompasses corticosteroids, immunoglobulins and plasmapheresis often accompanied by long-term immunosuppression. It is important to note that immune-mediated neuropathies selectively respond to treatment and contraindications need to be considered. Despite treatment a considerable number of patients suffer from permanent neurological deficits.

[Diabetic neuropathy: do not only consider distal symmetrical neuropathy]. / Diabetische Neuropathie : Nicht nur an die distal-symmetrische Neuropathie denken.

BACKGROUND: Diabetic neuropathy is a common complication of diabetes mellitus. The length-dependent symmetrical sensorimotor type of neuropathy is the most prevalent form of diabetic neuropathy but other forms of diabetic neuropathy also need to be kept in mind. Their differential diagnosis is often more challenging but implicates specific forms of treatment other than improvement of metabolic control. AIM OF THE STUDY: This article gives an overview of the less frequent forms of diabetic neuropathy and discusses their impact, diagnostic and therapeutic implications. RESULTS: Autonomic diabetic neuropathy, diabetic small fiber neuropathy and less frequent forms of diabetic neuropathy, such as diabetic radiculoplexopathy, diabetic neuropathy of cranial nerves, therapy-induced neuropathy and alternative causes of peripheral neuropathy in patients with diabetes are described. DISCUSSION: Diagnosis of less frequent subtypes of diabetic neuropathy and differentiation towards alternative causes of peripheral neuropathy are often difficult in daily medical routine. Diagnostic clues are helpful in identifying rarer forms of diabetic neuropathy, thus enabling more specific treatment.

[Lesions of the peripheral nerves: MR neurography as an innovative supplement to electrodiagnostics]. / Läsionen peripherer Nerven: MR-Neurografie als innovative Ergänzung zur Elektrodiagnostik.

The diagnostic work-up of peripheral neuropathies largely depends on neurophysiological investigations. Recently, progress in magnetic resonance imaging (MRI) has lead to new perspectives in the diagnostics of disorders of the peripheral nervous system (PNS). Experimental data show how MR neurography visualises axonal and demyelinating lesions of the PNS. In clinical use, difficult cases of focal nerve compression, traumatic or inflammatory lesions can be solved by the combination of MR neurography and neurophysiology. In particular, the localisation of nerve lesions can be improved by MR techniques. Furthermore, MR neurography enables new insights in the pathophysiology of neuropathies which will be shown for diabetic polyneuropathy.

[Nerve lesions after minimally invasive total hip arthroplasty]. / Nervenläsionen nach minimal-invasiver Hüftendoprothetik.

Although there is no clear evidence, minimally invasive hip arthroplasty seems to be associated with slightly higher complication rates compared to standard procedures. Major nerve palsy is one of the least common but most distressing complications. The key for minimizing the incidence of nerve lesions is to analyze preoperative risk factors, accurate knowledge of the anatomy and minimally invasive techniques. Once clinical signs of nerve injury are evident, the first diagnostic steps are localization of the lesion and quantification of the damage pattern. Therefore, clinical assessment of the neurological deficits should be performed as soon as possible. Apart from rare cases of isolated transient conduction blockade or complete transection, the damage pattern is mostly combined. Thus, there can be evidence for dysfunction of nerve conduction (neuropraxia) and structural nerve damage (axonotmesis or neurotmesis) simultaneously. Because the earliest signs of denervation are detectable via electromyography after 1 week, it is not possible to make any reliable prognosis within the first days after nerve injury using electrophysiological methods. This review article should serve as a guideline for prevention, diagnostics and therapy of neural lesions in minimally invasive hip arthroplasty.

Estimation of variance components for postpartum dysgalactia syndrome in sows.

The postpartum dysgalactia syndrome (PDS) represents one of the most important diseases after parturition in sows. The genetic background of the disease has been investigated some time ago and heritability estimates around 0.10 have been obtained. To compute current estimates, a dataset of 1680 sampled sows and their 2001 clinically examined litters was used for variance components estimation with a threshold liability model. Affected sows were defined through clinical examination 12-48 h after parturition. Posterior mean of additive genetic variance was 0.10 and estimated heritability for PDS averaged 0.0879 with a 95% confidence interval of 0.0876 and 0.0881. The results are in agreement with those of other studies and emphasize the importance of considering the genetic predisposition for susceptibility to PDS as well as of additional factors including hygiene and management conditions.

Fertility and gonadal function in female survivors after treatment of early unfavorable Hodgkin lymphoma (HL) within the German Hodgkin Study Group HD14 trial.

BACKGROUND: In the HD14 trial, 2×BEACOPPescalated+2×ABVD (2+2) has improved the primary outcome. Compared with 4×ABVD, this benefit might be compromised by more infertility in women. Therefore, we analyzed gonadal function and fertility. PATIENTS AND METHODS: Women≤45 years in ongoing remission at least 1 year after therapy were included. Hormone parameters, menopausal symptoms, measures to preserve fertility, menstrual cycle, pregnancies, and offspring were evaluated. RESULTS: Three hundred and thirty one of 579 women addressed participated (57.2%) and 263 per-protocol treated patients qualified (A=ABVD: 137, B=2+2: 126, mean time after therapy 42 and 43 months, respectively). Regular menstrual cycle after treatment (A: 87%, B: 83%) and time to recovery (≤12 months) were not different. Follicle-stimulating hormone and anti-Muellerian hormone were significantly better in arm A. However, pregnancies after therapy favored arm B (A: 15%, B: 26%, P=0.043) and motherhood rates were equivalent to the German normal population. Multivariate analysis revealed prophylactic use of gonadotropin-releasing hormone (GnRH) analogues as highly significant prognostic factor for preservation of fertility (odds ratio=12.87, P=0.001). Severe menopausal symptoms were frequent in women≥30 years (A: 21%, B: 25%). CONCLUSIONS: Hormonal levels after 2+2 indicate a reduced ovarian reserve. However, 2+2 in combination with GnRH analogues does not compromise fertility within the evaluated observation time.

[Clinical application of pain-related evoked potentials]. / Klinische Anwendung schmerzevozierter Potenziale.

Pain-related evoked potentials (PREPs) represent a novel method for the evaluation of peripheral and central nociceptive pathways, e.g. in the diagnosis of small fiber neuropathy (SFN) or after therapeutic interventions for headache. Compared to contact heat-evoked and laser-evoked potentials, recording of PREPs is less stressful for the subjects and technically less demanding. The clinical usefulness of PREPs has been described for SFN associated with diabetes, HIV and hepatitis C infections as well as in headache and facial pain disorders. They have also been evaluated after interventional methods, such as direct current stimulation (tDCS). The article reviews and discusses the advantages and pitfalls of this technique in the context of recent clinical studies as compared to other paradigms of peripheral electrical stimulation and delineates perspectives and possible indications.

[Amyotrophic lateral sclerosis: management of bulbar symptoms]. / Amyotrophe Lateralsklerose: Symptomatische Therapie bulbärer Symptome.

Symptomatic treatment of amyotrophic lateral sclerosis (ALS) is relevant in preventing complications and improving quality of life as long as curative therapies are still out of sight. About one third of ALS patients show disabling problems associated with dysarthria, dysphagia, sialorrhea, and a pseudobulbar affective disorder already in the early stages of ALS. A multidisciplinary approach is the cornerstone of symptomatic treatment of bulbar and pseudobulbar ALS features. Except for riluzole randomized controlled trials are lacking. Here, we review the current views with regard to epidemiology, pathophysiology, diagnosis, and practical aspects of treating bulbar and pseudobulbar symptoms.

TNF-alpha-converting enzyme (TACE/ADAM17)-dependent loss of CD30 induced by proteasome inhibition through reactive oxygen species.

Combinations with proteasome inhibitors are currently being investigated to improve the therapy of hematological malignancies. We previously found that proteasome inhibition by bortezomib failed to sensitize anti-CD30 antibody (Ab)-based lymphoma cell killing. In this study, we demonstrate in L540 Hodgkin's lymphoma cells that proteasome inhibition not only communicates apoptosis but also more rapidly causes a loss of CD30 antigen from cell membrane and a simultaneous release of soluble CD30, a targeting competitor. This shedding was catalyzed by the tumor necrosis factor (TNF)-alpha-converting enzyme (TACE, ADAM17) and blocked by the ADAM17-selective inhibitor, Ro32-7315. In parallel with CD30 shedding, bortezomib caused the generation of reactive oxygen species (ROS). As apoptosis and shedding were inhibited by the radical scavenger, N-acetyl-L-cysteine, ROS might have a pivotal function in both effects. In contrast, the pan-caspase inhibitor, zVAD-fmk, blocked bortezomib-induced apoptosis but not CD30 shedding, and Ro32-7315 blocked shedding but allowed apoptosis. This suggests independent terminal signaling pathways that are conflicting in Ab-based immunotherapy. Consequently, shedding inhibition substantially improved the synergistic antitumor efficacy of the human anti-CD30 Ab, MDX-060, and bortezomib. As proteasome inhibition also stimulated loss of TNF receptors, interleukin-6 receptor and syndecan-1 in different leukemia and lymphoma cell lines, we concluded that proteasome inhibition might impede targeted therapy against antigens susceptible to shedding.

Enzyme replacement therapy with alglucosidase alfa in 44 patients with late-onset glycogen storage disease type 2: 12-month results of an observational clinical trial.

Late-onset glycogen storage disease type 2 (GSD2)/Pompe disease is a progressive multi-system disease evoked by a deficiency of lysosomal acid alpha-glucosidase (GAA) activity. GSD2 is characterized by respiratory and skeletal muscle weakness and atrophy, resulting in functional disability and reduced life span. Since 2006 alglucosidase alfa has been licensed as a treatment in all types of GSD2/Pompe disease. We here present an open-label, investigator-initiated observational study of alglucosidase alfa enzyme replacement therapy (ERT) in 44 late-onset GSD2 patients with various stages of disease severity. Alglucosidase alfa was given i.v. at the standard dose of 20 mg/kg every other week. Assessments included serial arm function tests (AFT), Walton Gardner Medwin scale (WGMS), timed 10-m walk tests, four-stair climb tests, modified Gowers' maneuvers, 6-min walk tests, MRC sum score, forced vital capacities (FVC), creatine kinase (CK) levels and SF-36 self-reporting questionnaires. All tests were performed at baseline and every 3 months for 12 months of ERT. We found significant changes from baseline in the modified Gowers' test, the CK levels and the 6-min walk test (341 +/- 149.49 m, median 342.25 m at baseline; 393 +/- 156.98 m; median 411.50 m at endpoint; p = 0.026), while all other tests were unchanged. ERT over 12 months revealed minor allergic reactions in 10% of the patients. No serious adverse events occurred. None of the patients died or required de novo ventilation. Our clinical outcome data imply stabilization of neuromuscular deficits over 1 year with mild functional improvement.

The effect of heated mash on performance and feeding behavior of newly weaned piglets.

The influence of heated mash on growth and feeding behavior of newly weaned piglets was investigated. An automatically ventilated nursery with 4 identical pens was used. Twenty piglets weaned at 21 d were housed in each pen. The experiment was repeated 3 times. In total, data were obtained from 240 piglets of 12 pens. The pens were provided with a sensor-controlled, automatic feeding device, which dosed a ready-mixed mash in a trough. In each of 2 of the pens, the feed was mixed with warm water at 36 degrees C, during the first week of weaning. This heated mash had a temperature of 34 degrees C at the outlet of the automatic feeding device (experimental group). In the 2 control groups, the water was not heated and the temperature of the mash was 14 degrees C at the outlet of the automatic feeding device. From the second week of weaning, the mash had a temperature of 14 degrees C at the outlet of the automatic feeding device in all 4 pens. Piglets were weighed at weaning, at weekly intervals through 49 d after weaning, and on d 139 after weaning. Behavior of the whole group, as well as behavior of selected focal animals, was evaluated for the first 48 h after weaning. In addition, skin condition of piglets was assessed on day of weaning and on d 7, 14, and 21 after weaning. The amount of feed consumed by the piglets was recorded on a daily basis throughout the whole period of nursery. Over the total period of the study, piglets in the experimental group gained 3.98 +/- 1.66 kg (P = 0.047) more than the control group. The difference was particularly clear during the nursery period (49 d) when the experimental group gained 0.89 +/- 0.23 kg more than the control group (P = 0.03). Although piglets in the control group consumed 37.15 +/- 0.15 kg of feed over the complete nursery period, the experimental group consumed 42.56 +/- 0.15 kg per piglet (P = 0.023). By heating the mash feed in the first week after weaning, both growth performance as well as feed consumption of piglets could be increased. No difference in feed conversion and feeding behavior was found between groups.

Socializing piglets before weaning: effects on behavior of lactating sows, pre- and postweaning behavior, and performance of piglets.

This study evaluated how socializing piglets before weaning affects behavior of lactating sows and the pre- and postweaning behavior and performance of piglets. Two farrowing rooms, each with 6 pens, and 1 nursery with 4 pens were used. In total, data were obtained from 24 sows and their litters. In each farrowing room, the solid barriers between 3 farrowing pens were removed on d 12 after farrowing, and the sows remained confined in their crates (experimental group). In the other 3 farrowing pens of each farrowing room, sows and their litters were kept under conventional conditions until weaning (control group). All piglets were weaned 28 d after birth. After weaning, piglets from each group remained together in 1 pen of the nursery. The behavior of sows (lying, standing, sitting, nursing) and piglets (lying, active, suckling) in the farrowing rooms was observed for 24 h before and for 48 h after removal of the barriers between the pens. In addition, behavior (active, lying, feeding, agonistic behavior) of piglets was observed in the nursery during the initial 48-h period after weaning. Each piglet was weighed on d 5, 12, and 28 after birth and thereafter weekly until the fifth week of rearing. In the farrowing room, mixing of litters did not influence behavior of piglets and sows. Preweaning weight gain of the piglets did not differ (P = 0.60) between the treatments. In the initial 48 h after weaning, less agonistic behavior (P < 0.001) was observed in piglets belonging to the experimental group. During 5 wk of rearing, piglets in the experimental group gained more weight compared with the control group (P = 0.05). The advantage shown by the experimental group became especially conspicuous in the first week after weaning (P = 0.05). By socializing unfamiliar piglets before weaning, stress due to mixing could at least be distanced in time from the other burdens of weaning, thereby improving performance.

[Musculoskeletal pain as the most prominent feature in myotonic dystrophy type 2]. / Muskuloskelettaler Schmerz als Hauptsymptom bei myotoner Dystrophie Typ 2.

BACKGROUND: Myotonic dystrophy type 2/proximal myotonic myopathy (DM 2/PROMM) is an autosomal dominant multisystem disorder characterized by proximal muscle weakness, myotonia and musculoskeletal pain. PATIENTS AND METHODS: We describe five patients with DM 2/PROMM in whom musculoskeletal pain was the most prominent feature. We used the McGill Pain Questionnaire for standardized pain assessment. RESULTS: The patients reported multiple types of musculoskeletal pain including tenderness, cold-enhanced and exercise-related musculoskeletal pain. Exercise-induced or -enhanced musculoskeletal pain was indicated as the most disabling feature. CONCLUSIONS: Myotonic dystrophy type 2 should be considered as one of the differential diagnoses in patients with musculoskeletal pain. Family history and laboratory tests provide critical diagnostic clues.

Early abnormalities of evoked potentials and future disability in patients with multiple sclerosis.

Evoked potentials (EP) have a role in making the diagnosis of multiple sclerosis (MS) but their implication for predicting the future disease course in MS is under debate. EP data of 94 MS patients examined at first presentation, and after five and ten years were retrospectively analysed. Patients were divided into two groups in relation to the prior duration of disease at the time point of first examination: group 1 patients (n=44) were first examined within two years after disease onset, and group 2 patients (n=50) at later time points. As primary measures sum scores were calculated for abnormalities of single and combined EP (visual (VEP), somatosensory (SEP), magnetic motor evoked potentials (MEP)). In patients examined early after disease onset (group 1), a significant predictive value for abnormal EP was found with MEP and SEP sum scores at first presentation correlating significantly with Expanded Disability Status Scale (EDSS) values after five years, while the VEP sum score was not. The cumulative number of abnormal MEP, SEP and VEP results also indicated higher degrees of disability (EDSS > or = 3.5) after five years. Combined pathological SEP and MEP findings at first presentation best predicted clinical disability (EDSS > or = 3.5) after five years (odds ratio 11.0). EP data and EDSS at first presentation were not significantly linked suggesting that EP abnormalities at least in part represented clinically silent lesions not mirrored by EDSS. For patients in later disease phases (group 2), no significant associations between EP data at first presentation and EDSS at five and ten years were detected. Together with clinical findings and MR imaging, combined EP data may help to identify patients at high risk of long-term clinical deterioration and guide decisions as to immunomodulatory treatment.

LGMD 2I due to the common mutation 826C>A in the FKRP gene presenting as myopathy with vacuoles and paired-helical filaments.

We report on two unrelated patients clinically presenting with late-onset progressive limb girdle weakness; cardiomyopathy was seen in one patient. Muscle biopsy revealed a necrotic myopathy with numerous rimmed vacuoles, ultrastructurally typical paired-helical filaments, and reduced immunohistochemical staining for alpha-dystroglycan. Quadriceps sparing hereditary inclusion body myopathy due to mutations in GNE gene, and OPMD due to PABPN1 mutations were excluded, genetically. We detected a homozygous mutation of the FKRP gene (826C>A) in both patients. Mutations of FKRP have been reported in congenital muscular dystrophies, LGMD2I, cardiomyopathy and hyperCKemia, but not in myopathies with vacuoles and paired-helical filaments. Therefore, our findings further extend the morphological variability of muscular dystrophies due to FKRP mutations.