pERK, pAKT and p53 as tissue biomarkers in erlotinib-treated patients with advanced pancreatic cancer: a translational subgroup analysis from AIO-PK0104

Background: The role of pERK, pAKT and p53 as biomarkers in patients with advanced pancreatic cancer has not yet been defined. Methods: Within the phase III study AIO-PK0104 281 patients with advanced pancreatic cancer received an erlotinib-based 1st-line regimen. Archival tissue from 153 patients was available for central immunohistochemistry staining for pERK, pAKT and p53. Within a subgroup analysis, biomarker data were correlated with efficacy endpoints and skin rash using a Cox regression model. Results: Fifty-five out of 153 patients were classified as pERK(low) and 98 patients as pERK(high); median overall survival (OS) was 6.2 months and 5.7 months, respectively (HR 1.29, p = 0.16). When analysing pERK as continuous variable, the pERK score was significantly associated with OS (HR 1.06, 95% CI 1.0-1.12, p = 0.05). Twenty-one of 35 patients were pAKT(low) and 14/35 pAKT(high) with a corresponding median OS of 6.4 months and 6.8 months, respectively (HR 1.03, p = 0.93). Four out of 50 patients had a complete loss of p53 expression, 20 patients a regular expression and 26 patients had tumors with p53 overexpression. The p53 status had no impact on OS (p = 0.91); however, a significant improvement in progression-free survival (PFS) (6.0 vs 1.8 months, HR 0.24, p = 0.02) and a higher rate of skin rash (84% vs 25%, p = 0.02) was observed for patients with a regular p53 expression compared to patients with a complete loss of p53. Conclusion: pERK expression may have an impact on OS in erlotinib-treated patients with advanced pancreatic cancer; p53 should be further investigated for its potential role as a predictive marker for PFS and skin rash

Collective cancer invasion forms an integrin-dependent radioresistant niche

Cancer fatalities result from metastatic dissemination and therapy resistance, both processes that depend on signals from the tumor microenvironment. To identify how invasion and resistance programs cooperate, we used intravital microscopy of orthotopic sarcoma and melanoma xenografts. We demonstrate that these tumors invade collectively and that, specifically, cells within the invasion zone acquire increased resistance to radiotherapy, rapidly normalize DNA damage, and preferentially survive. Using a candidate-based approach to identify effectors of invasion-associated resistance, we targeted beta 1 and alpha V beta 3/beta 5 integrins, essential extracellular matrix receptors in mesenchymal tumors, which mediate cancer progression and resistance. Combining radiotherapy with beta 1 or alpha V integrin monotargeting in invading tumors led to relapse and metastasis in 40-60% of the cohort, in line with recently failed clinical trials individually targeting integrins. However, when combined, anti-beta 1/alpha V integrin dual targeting achieved relapse-free radiosensitization and prevented metastatic escape. Collectively, invading cancer cells thus withstand radiotherapy and DNA damage by beta 1/alpha V beta 3/beta 5 integrin cross-talk, but efficient radiosensitization can be achieved by multiple integrin targeting

Fear and rumours regarding placental biopsies in a malaria-in-pregnancy trial in Benin.

BACKGROUND: A multi-country, community-based trial on scheduled screening and treatment for malaria in pregnancy was conducted in Benin, The Gambia and Burkina Faso. Despite standardized procedures and outcomes, the study became subject to rumours and accusations of placenta being sold for mystical and financial gain by trial staff, leading to drop-out rates of 30% and the consequent halting of placental biopsy sampling in Benin. This paper explores the role of socio-cultural beliefs related to placenta and identified additional factors contributing these rumours. METHODS: A qualitative comparative emergent-theory design was used to assess social factors related to trial implementation and uptake in the three countries. Data from participant observation, informal conversations, group discussions and interviews were triangulated and analysed with NVivo Qualitative Analysis software. RESULTS: Despite similar sociocultural beliefs about the sacred nature of the placenta in all three study countries, these beliefs did not affect participation rates in Burkina Faso and The Gambia and placenta-related rumours only emerged in Benin. Therefore, the presence of beliefs is not a sufficient condition to have generated placenta-selling fears. The rumours in Benin reflected the confluence of placenta-related beliefs and factors related to the implementation of the trial (including a catalysing adverse event and miscommunication during the informed consent procedure). Furthermore, distinct socio-political factors contributed to the emergence of rumours, including the historical distrust in governmental organizations and the tense relationship between some of the actors involved in the trial. CONCLUSION: Transdisciplinary social science research designs should accompany the implementation of the trial. The integration of multiple stakeholders' knowledge and involvement is required to define and solve upcoming barriers

Robotic-assisted surgery for prostatectomy – does the diffusion of robotic systems contribute to treatment centralization and influence patients’ hospital choice?

Abstract Background Between 2008 and 2018, the share of robotic-assisted surgeries (RAS) for radical prostatectomies (RPEs) has increased from 3 to 46% in Germany. Firstly, we investigate if this diffusion of RAS has contributed to RPE treatment centralization. Secondly, we analyze if a hospital’s use of an RAS system influenced patients’ hospital choice. Methods To analyze RPE treatment centralization, we use (bi-) annual hospital data from 2006 to 2018 for all German hospitals in a panel-data fixed effect model. For investigating RAS systems’ influence on patients’ hospital choice, we use patient level data of 4614 RPE patients treated in 2015. Employing a random utility choice model, we estimate the influence of RAS as well as specialization and quality on patients’ marginal utilities and their according willingness to travel. Results Despite a slight decrease in RPEs between 2006 and 2018, hospitals that invested in an RAS system could increase their case volumes significantly (+ 82% compared to hospitals that did not invest) contributing to treatment centralization. Moreover, patients are willing to travel longer for hospitals offering RAS (+ 22% than average travel time) and for specialization (+ 13% for certified prostate cancer treatment centers, + 9% for higher procedure volume). The influence of outcome quality and service quality on patients’ hospital choice is insignificant or negligible. Conclusions In conclusion, centralization is partly driven by (very) high-volume hospitals’ investment in RAS systems and patient preferences. While outcome quality might improve due to centralization and according specialization, evidence for a direct positive influence of RAS on RPE outcomes still is ambiguous. Patients have been voting with their feet, but research yet has to catch up

Middle Miocene magmatic activity in the Sophia Basin, Arctic Ocean – evidence from dredged basalt at the flanks of Mosby Seamount

The area to the northwest of Svalbard was affected by repeated tectono-magmatic processes starting from the Cretaceous formation of the High Arctic Large Igneous Province, to Late Cretaceous/early Cenozoic birth of the Eurasian Basin towards the establishment of a full seafloor-spreading regime along the Lena Trough/Fram Strait in Middle Miocene. These processes also affected the Sophia Basin located in-between the Yermak Plateau and the northern Svalbard Shelf. In 2013 a little piece of basalt could be dredged from the southern flank of the Mosby Seamount, the central landmark within the Sophia Basin. Geochemical analyses support our assumption that the rock fragment has a local origin and that it was not rafted towards the sample site by ice. The trace element composition implies that the basalt had incorporated marine sediments and also Fe-Mn crusts or nodules. According to geochronological data the basalt erupted ~13 Ma, contemporaneous to incipient seafloor spreading in the nearby Lena Trough and volcanic activity in northern Svalbard. Assuming a link of the dredged basalt with seismic indication of sediment covered lava flows and sill intrusion around Mosby Seamount, its middle Miocene age can be used to better constrain the regional seismo-stratigraphy

Strategies for reducing potentially avoidable hospitalizations for ambulatory care-sensitive conditions

Purpose Hospitalizations for ambulatory care-sensitive conditions (ACSCs) are seen as potentially avoidable with optimal primary care. Little is known, however, about how primary care physicians rate these hospitalizations and whether and how they could be avoided. This study explores the complex causality of such hospitalizations from the perspective of primary care physicians. Methods We conducted semistructured interviews with 12 primary care physicians from 10 primary care clinics in Germany regarding 104 hospitalizations of 81 patients with ACSCs at high risk of rehospitalization. Results Participating physicians rated 43 (41%) of the 104 hospitalizations to be potentially avoidable. During the interviews the cause of hospitalization fell into 5 principal categories: system related (eg, unavailability of ambulatory services), physician related (eg, suboptimal monitoring), medical (eg, medication side effects), patient related (eg, delayed help-seeking), and social (eg, lack of social support). Subcategories frequently associated with physicians' rating of hospitalizations for ACSCs as potentially avoidable were after-hours absence of the treating physician, failure to use ambulatory services, suboptimal monitoring, patients' fearfulness, cultural background and insufficient language skills of patients, medication errors, medication nonadherence, and overprotective caregivers. Comorbidities and medical emergencies were frequent causes attributed to ACSC-based hospitalizations that were rated as being unavoidable. Conclusions Primary care physicians rated a significant proportion of hospitalizations for ACSCs to be potentially avoidable. Strategies to avoid these hospitalizations may target after-hours care, optimal use of ambulatory services, intensified monitoring of high-risk patients, and initiatives to improve patients' willingness and ability to seek timely help, as well as patients' medication adherence

Middle Miocene magmatic activity in the Sophia Basin, Arctic Ocean—evidence from dredged basalt at the flanks of Mosby Seamount

The area to the northwest of Svalbard was repeatedly affected by tectono-magmatic events during the opening of the Arctic Ocean including the formation of the Cretaceous High Arctic Large Igneous Province, the Late Cretaceous/early Cenozoic birth of the Eurasian Basin, and the establishment of a full seafloor-spreading regime along the Lena Trough/Fram Strait in the middle Miocene. These processes also affected the Sophia Basin located between the Yermak Plateau and the northern Svalbard Shelf. In 2013 a piece of basalt was dredged from the southern flank of the Mosby Seamount, the central landmark within the Sophia Basin. According to Ar–Ar dating on fresh plagioclase the basalt erupted at ~ 13 Ma, contemporaneous with incipient seafloor spreading in the nearby Lena Trough and volcanic activity on northern Svalbard. If the dredged basalt is temporally related to sediment-covered lava flows and sill intrusions around Mosby Seamount, which were revealed by seismic reflections, then the age of the sedimentary cover must be middle Miocene or younger. This finding will improve the regional seismo-stratigraphy

Provenance and characteristics of rocks from the Yermak Plateau, Arctic Ocean: Petrographic, geochemical and geochronological constraints

The Yermak Plateau is a prominent bathymetric feature of the Arctic Ocean. To the west it is bordered by the Fram Strait, which forms the only deep-water connection between the Arctic and the other global oceans. Origin, crustal nature and age of the Yermak Plateau are largely unknown. For this study, we investigated dredged rocks of two sites from the Yermak Plateau. Based on petrography, geochemistry, and geochronology, we distinguished between ice-transported and in-situ rocks. Ice-transported material was most likely derived from outcrops of the High Arctic Large Igneous Province (HALIP) on Franz Josef Land, the Siberian trap province, and presumably from northern Svalbard. Our data from the in-situ rocks, in conjunction with previously published geophysical data, show that the investigated parts of the Yermak Plateau are composed of stretched continental crust strongly affected by alkaline magmatism. The continental rocks represent a direct continuation of the exposures on northern Svalbard. Alkaline magmatism took place at ~ 51 Ma and was related to continental rifting in an extensional setting. The melts were formed by low degrees of partial melting of the sub-continental lithospheric mantle and are probably associated with the high-amplitude magnetic anomalies described for the northeastern Yermak Plateau. Extension of the Yermak Plateau was contemporaneous with spreading of the adjacent young Eurasian Basin, and occurred during the peak of compressional deformation affecting North Greenland, Svalbard, and Ellesmere Island. These contrasting regimes were probably compensated by transpression and strike-slip movements along the DeGeer and Wegener Faults. The date of ~ 51 Ma for extension-related magmatism also provides age constraints for the extension-related formation of the Sophia Basin (and thus for water exchange between the Eurasian Basin, the area of the DeGeer Fault and the young Norwegian-Greenland Sea), and for the sediments covering the horst-and-graben structures of the Yermak Plateau

Regionale Strukturanalyse des Schul- und Hochschulsystems in Niedersachsen Grunddaten fuer die Schulentwicklungs- und Hochschulrahmenplanung. Teilbd. 2

UuStB Koeln(38)-920106410 / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekSIGLEDEGerman

Regionale Strukturanalyse des Schul- und Hochschulsystems in Niedersachsen Grunddaten fuer die Schulentwicklungs- und Hochschulrahmenplanung. Teilbd. 1

UuStB Koeln(38)-910108316 / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekSIGLEDEGerman