Symptoms and Needs of Patients with Advanced Lung Cancer: Early Prevalence Assessment

Background: Little is known on symptom burden, psychosocial needs, and perception of prognosis in advanced lung cancer patients at the time of diagnosis, although early assessment is strongly recommended within the setting of daily routine care. Methods: Twelve study sites cross-sectionally assessed symptoms and psychosocial needs of patients suffering from newly diagnosed incurable lung cancer. Assessment comprised NCCN distress thermometer, FACT-L, SEIQoL-Q, PHQ-4, and shortened and modified SCNS-SF-34 questionnaires. Additional prognostic information from both patients and physicians were collected. Results: A total of 208 patients were evaluated. Mean age was 63.6 years, 58% were male, 84% suffered from stage IV lung cancer, and 71% had an ECOG performance status of 0–1. Mean distress level was 5.4 (SD 2.5), FACT-L total score was 86 (21.5), and TOI 50.5 (14.9). PHQ-4 was 4.6 (3.3), and shortened and modified SCNS-SF-34 showed 9 (8.7) unmet needs per patient. According to their physicians’ perspective, 98.1% of patients were reflecting on and 85.2% were accepting incurability, while 26.5% of patients considered the treatment to be of curative intent. Conclusion: Our findings emphasize substantial domains of symptom burden seen in newly diagnosed, incurable lung cancer patients. Oncologists should be aware of these features and address prognostic issues early in the disease trajectory to facilitate opportunities to improve coping, advance care planning, and appropriate integration of palliative care, thus improving quality of life

Interactions of myeloma cells with osteoclasts and osteoblasts and influence of proteasome inhibitors on myeloma bone disease

Komplexe Interaktionen zwischen Myelomzellen und Zellen des Knochenmarkmikromilieus führen zu einer Entkopplung der Osteoblasten- und Osteoklastenaktivität mit einem gesteigerten Knochenabbau und Auftreten von Osteolysen. Wir konnten zum einen zeigen, dass Myelomzellen RANKL exprimieren, den stärksten Aktivator der Osteoklasten, und dass die Stärke der RANKL Expression mit der Ausprägung der Knochendestruktion korreliert. Die Myelomzellen stimulieren außerdem die Bildung von RANKL durch Stromazellen und führen zum Abbau des RANKL-Antagonisten OPG. Zum anderen haben wir nachweisen können, dass Myelomzellen das Protein DKK-1 sezernieren, einen Inhibitor des Wnt/ ß Catenin-Signalweges, der essentiell für die Osteoblastendifferenzierung ist. Unsere Untersuchungen zeigten, dass DKK-1 bei Myelompatienten vermehrt im Serum nachweisbar ist, und dass die Stärke der Expression mit dem Vorhandensein von Osteolysen korreliert. Die Kombination dieser Wechselwirkungen führt zu einem vermehrten Knochenabbau ohne adäquate Knochenneubildung. Im Gegenzug stimulieren die Zellen des Mikroenvironments die Proliferation und das Überleben von Myelomzellen sowie deren Migrations- und Invasionsfähigkeit. Auf der Basis dieser Daten wurden verschiedene Therapieansätze zur Behandlung der myelominduzierten Knochendestruktion entwickelt, u.a. ein rekombinanter Antikörper gegen RANKL (Denosumab) sowie ein Antikörper gegen DKK-1. Eine weitere Substanz, die den gesteigerten Knochenabbau beim Myelom günstig beeinflussen könnte, ist der Proteasominhibitor Bortezomib. Wir konnten zeigen, dass Bortezomib einerseits die Reifung und Aktivität von Osteoklasten hemmt und andererseits die Differenzierung und Funktion von Osteoblasten stimuliert. Damit konnten neue Pathomechanismen zur Genese der Knochendestruktion beim multiplen Myelom identifiziert werden, die zur Entwicklung vielversprechender Therapieansätze der myelombedingten Knochendestruktion geführt haben.Interactions between myeloma cells and cells of the bone marrow microenvironment lead to osteoclast activation and osteoblast inhibition (uncoupling), resulting in lytic bone lesions. We could show that myeloma cells express RANKL, a potent stimulator of osteoclast activity, and that the expression of RANKL correlates with osteolytic bone disease. In addition, myeloma cells induce RANKL expression by stromal cells and lead to degradation and reduced expression of the RANKL antagonist OPG. Furthermore, we could show that myeloma cells produce DKK-1, an inhibitor of Wnt/ ß catenin signalling pathway, which is crucial for osteoblast differentiation, and that serum DKK-1 is elevated in myeloma patients and correlates with the extend of bone disease. In return, cells of the bone marrow microenvironment stimulate proliferation, survival, migration and invasion of myeloma cells. Based on these findings, novel therapies have been developed targeting myeloma bone disease, as denosumab, a recombinant antibody against RANKL, or an anti-DKK-1- antibody. The proteasome inhibitor bortezomib is another drug that could influence bone metabolism in myeloma patients. We could show that bortezomib on one hand inhibits osteoclast differentiation and activity, and on the other hand stimulates osteoblast differentiation. With the identification of these new pathomechnisms, novel targets for the treatment of myeloma bone disease could be defined

Magnetic and petrographic properties of ODP Site 120-747 (Table 1)

Carbonate sediments from the Kerguelen Plateau (ODP Leg 120) of Eocene to Pliocene age were investigated with rock magnetic, petrographic and geochemical methods to determine the carriers of remanent magnetization. Magnetic methods showed that the major magnetic minerals were titanomagnetites slightly larger than single domain particles. Submicrometre to micrometre-size grains of titanomagnetite were identified as inclusions in volcanic glass particles or as crystals in lithic clasts. Volcanic fallout ash particles formed the major fraction of the magnetic extract from each sediment sample. Three groups of volcanic ashes were identified: trachytic ashes, basaltic ashes with sideromelane and tachylite shards, and palagonitic ashes. These three groups could be equally well defined based on their magnetic hysteresis properties and alternating field demagnetization curves. The highest coercivities of all samples were found for the tachylite, due to the submicrometre-size titanomagnetite inclusions in the matrix. Trachytic ashes had intermediate magnetic properties between the single-domain-type tachylites and the palagonitic (altered) basaltic ashes with low coercivities. Samples which contained mixtures of these different volcanic ashes could be distinguished from the three types of ashes based on their magnetic characteristics. There was neither evidence of biogenic magnetofossils in the transmission electron micrographs nor did we find magnetic particles derived from continental Antarctica. The presence of dispersed volcanic fallout ashes between visible ash layers suggests continuous explosive volcanic activity on the Kerguelen Plateau in the South Indian Ocean since the early Eocene. The continuous fallout of volcanic ash from explosive volcanism on the Kerguelen Archipelago is the source of the magnetic particles and thus responsible for the magnetostratigraphy of the nannofossil oozes drilled during Leg 120

Effects of Exercise and Omega-3-Supplemented, High-Protein Diet on Inflammatory Markers in Serum, on Gene Expression Levels in PBMC, and after Ex Vivo Whole-Blood LPS Stimulation in Old Adults

Inflammaging is related to cell senescence and reflects an erratic immune system, which promotes age-associated diseases. Exercise and nutrition, particularly omega-3 fatty acids, are able to affect inflammation. Therefore, we examined the effects of an 8-week exercise and dietary intervention on the inflammatory response in community-dwelling old adults. All participants received weekly vibration and home-based resistance exercise. Furthermore, participants were randomized to either a control, high-protein (1.2–1.5 g/kg), or high-protein, omega-3-enriched (2.2 g/day) diet. Before and after treatment, inflammatory markers in fasting serum and after whole-blood ex vivo lipopolysaccharide (LPS) stimulation were assessed. Gene expression levels of inflammatory markers were quantified in peripheral blood mononuclear cells (PBMC). Sixty-one participants (age: 70.6 ± 4.7 years; 47% men) completed the study. According to generalized linear mixed models, a high-protein, omega-3-enriched diet decreased circulating anti-inflammatory interleukin (IL-) 10 and IL-1 receptor antagonist (IL-1RA). Sex-stratified analyses showed also significantly reduced pro-inflammatory markers in men with a high-protein, omega-3-enriched diet. Gene expression of IL-1RA was significantly reduced after both protein-enriched diets compared with controls. In comparison to a high-protein diet, exercise alone showed lower LPS-induced release of c-c motif chemokine ligand-2 (CCL-2), which tended to be more pronounced in men compared with women. Eight weeks of a high-protein, omega-3-enriched diet combined with exercise decreased circulating anti-inflammatory markers, and pro-inflammatory markers in men. A high-protein diet attenuated anti-inflammatory markers on gene expression level in PBMC. Exercise alone resulted in a lower pro-inflammatory response to LPS-exposure in whole-blood cultures