| 1. |
|
|
| 2. |
|
|
| 3. |
- Marina, Neyssa M., et al.
(författare)
-
Comparison of MAPIE versus MAP in patients with a poor response to preoperative chemotherapy for newly diagnosed high-grade osteosarcoma (EURAMOS-1) : an open-label, international, randomised controlled trial
- 2016
-
Ingår i: The Lancet Oncology. - 1470-2045. ; 17:10, s. 1396-1408
-
Tidskriftsartikel (refereegranskat)abstract
- Background We designed the EURAMOS-1 trial to investigate whether intensified postoperative chemotherapy for patients whose tumour showed a poor response to preoperative chemotherapy (≥10% viable tumour) improved event-free survival in patients with high-grade osteosarcoma. Methods EURAMOS-1 was an open-label, international, phase 3 randomised, controlled trial. Consenting patients with newly diagnosed, resectable, high-grade osteosarcoma aged 40 years or younger were eligible for randomisation. Patients were randomly assigned (1:1) to receive either postoperative cisplatin, doxorubicin, and methotrexate (MAP) or MAP plus ifosfamide and etoposide (MAPIE) using concealed permuted blocks with three stratification factors: trial group; location of tumour (proximal femur or proximal humerus vs other limb vs axial skeleton); and presence of metastases (no vs yes or possible). The MAP regimen consisted of cisplatin 120 mg/m2, doxorubicin 37·5 mg/m2 per day on days 1 and 2 (on weeks 1 and 6) followed 3 weeks later by high-dose methotrexate 12 g/m2 over 4 h. The MAPIE regimen consisted of MAP as a base regimen, with the addition of high-dose ifosfamide (14 g/m2) at 2·8 g/m2 per day with equidose mesna uroprotection, followed by etoposide 100 mg/m2 per day over 1 h on days 1–5. The primary outcome measure was event-free survival measured in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT00134030. Findings Between April 14, 2005, and June 30, 2011, 2260 patients were registered from 325 sites in 17 countries. 618 patients with poor response were randomly assigned; 310 to receive MAP and 308 to receive MAPIE. Median follow-up was 62·1 months (IQR 46·6–76·6); 62·3 months (IQR 46·9–77·1) for the MAP group and 61·1 months (IQR 46·5–75·3) for the MAPIE group. 307 event-free survival events were reported (153 in the MAP group vs 154 in the MAPIE group). 193 deaths were reported (101 in the MAP group vs 92 in the MAPIE group). Event-free survival did not differ between treatment groups (hazard ratio [HR] 0·98 [95% CI 0·78–1·23]); hazards were non-proportional (p=0·0003). The most common grade 3–4 adverse events were neutropenia (268 [89%] patients in MAP vs 268 [90%] in MAPIE), thrombocytopenia (231 [78% in MAP vs 248 [83%] in MAPIE), and febrile neutropenia without documented infection (149 [50%] in MAP vs 217 [73%] in MAPIE). MAPIE was associated with more frequent grade 4 non-haematological toxicity than MAP (35 [12%] of 301 in the MAP group vs 71 [24%] of 298 in the MAPIE group). Two patients died during postoperative therapy, one from infection (although their absolute neutrophil count was normal), which was definitely related to their MAP treatment (specifically doxorubicin and cisplatin), and one from left ventricular systolic dysfunction, which was probably related to MAPIE treatment (specifically doxorubicin). One suspected unexpected serious adverse reaction was reported in the MAP group: bone marrow infarction due to methotrexate. Interpretation EURAMOS-1 results do not support the addition of ifosfamide and etoposide to postoperative chemotherapy in patients with poorly responding osteosarcoma because its administration was associated with increased toxicity without improving event-free survival. The results define standard of care for this population. New strategies are required to improve outcomes in this setting. Funding UK Medical Research Council, National Cancer Institute, European Science Foundation, St Anna Kinderkrebsforschung, Fonds National de la Recherche Scientifique, Fonds voor Wetenschappelijk Onderzoek-Vlaanderen, Parents Organization, Danish Medical Research Council, Academy of Finland, Deutsche Forschungsgemeinschaft, Deutsche Krebshilfe, Federal Ministry of Education and Research, Semmelweis Foundation, ZonMw (Council for Medical Research), Research Council of Norway, Scandinavian Sarcoma Group, Swiss Paediatric Oncology Group, Cancer Research UK, National Institute for Health Research, University College London Hospitals, and Biomedical Research Centre.
|
|
| 4. |
- Bielack, Stefan S, et al.
(författare)
-
Methotrexate, Doxorubicin, and Cisplatin (MAP) Plus Maintenance Pegylated Interferon Alfa-2b Versus MAP Alone in Patients With Resectable High-Grade Osteosarcoma and Good Histologic Response to Preoperative MAP: First Results of the EURAMOS-1 Good Response Randomized Controlled Trial
- 2015
-
Ingår i: Journal of Clinical Oncology. - 1527-7755. ; 33:20, s. 2279-2287
-
Tidskriftsartikel (refereegranskat)abstract
- Purpose EURAMOS-1, an international randomized controlled trial, investigated maintenance therapy with pegylated interferon alfa-2b (IFN-α-2b) in patients whose osteosarcoma showed good histologic response (good response) to induction chemotherapy. Patients and Methods At diagnosis, patients age ≤ 40 years with resectable high-grade osteosarcoma were registered. Eligibility after surgery for good response random assignment included ≥ two cycles of preoperative MAP (methotrexate, doxorubicin, and cisplatin), macroscopically complete surgery of primary tumor, < 10% viable tumor, and no disease progression. These patients were randomly assigned to four additional cycles MAP with or without IFN-α-2b (0.5 to 1.0 μg/kg per week subcutaneously, after chemotherapy until 2 years postregistration). Outcome measures were event-free survival (EFS; primary) and overall survival and toxicity (secondary). Results Good response was reported in 1,041 of 2,260 registered patients; 716 consented to random assignment (MAP, n = 359; MAP plus IFN-α-2b, n = 357), with baseline characteristics balanced by arm. A total of 271 of 357 started IFN-α-2b; 105 stopped early, and 38 continued to receive treatment at data freeze. Refusal and toxicity were the main reasons for never starting IFN-α-2b and for stopping prematurely, respectively. Median IFN-α-2b duration, if started, was 67 weeks. A total of 133 of 268 patients who started IFN-α-2b and provided toxicity information reported grade ≥ 3 toxicity during IFN-α-2b treatment. With median follow-up of 44 months, 3-year EFS for all 716 randomly assigned patients was 76% (95% CI, 72% to 79%); 174 EFS events were reported (MAP, n = 93; MAP plus IFN-α-2b, n = 81). Hazard ratio was 0.83 (95% CI, 0.61 to 1.12; P = .214) from an adjusted Cox model. Conclusion At the preplanned analysis time, MAP plus IFN-α-2b was not statistically different from MAP alone. A considerable proportion of patients never started IFN-α-2b or stopped prematurely. Long-term follow-up for events and survival continues.
|
|
| 5. |
|
|
| 6. |
|
|
| 7. |
- Lorbek, G, et al.
(författare)
-
Lessons from hepatocyte-specific Cyp51 knockout mice: impaired cholesterol synthesis leads to oval cell-driven liver injury
- 2015
-
Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 5, s. 8777-
-
Tidskriftsartikel (refereegranskat)abstract
- We demonstrate unequivocally that defective cholesterol synthesis is an independent determinant of liver inflammation and fibrosis. We prepared a mouse hepatocyte-specific knockout (LKO) of lanosterol 14α-demethylase (CYP51) from the part of cholesterol synthesis that is already committed to cholesterol. LKO mice developed hepatomegaly with oval cell proliferation, fibrosis and inflammation, but without steatosis. The key trigger was reduced cholesterol esters that provoked cell cycle arrest, senescence-associated secretory phenotype and ultimately the oval cell response, while elevated CYP51 substrates promoted the integrated stress response. In spite of the oval cell-driven fibrosis being histologically similar in both sexes, data indicates a female-biased down-regulation of primary metabolism pathways and a stronger immune response in males. Liver injury was ameliorated by dietary fats predominantly in females, whereas dietary cholesterol rectified fibrosis in both sexes. Our data place defective cholesterol synthesis as a focus of sex-dependent liver pathologies.
|
|
| 8. |
- Wennrich, Volker, et al.
(författare)
-
Impact processes, permafrost dynamics, and climate and environmental variability in the terrestrial Arctic as inferred from the unique 3.6 Myr record of Lake El'gygytgyn, Far East Russia - A review
- 2016
-
Ingår i: Quaternary Science Reviews. - : Elsevier BV. - 0277-3791 .- 1873-457X. ; 147, s. 221-244
-
Tidskriftsartikel (refereegranskat)abstract
- Lake El'gygytgyn in Far East Russia is a 3.6 Myr old impact crater lake. Located in an area that has never been affected by Cenozoic glaciations nor desiccation, the unique sediment record of the lake represents the longest continuous sediment archive of the terrestrial Arctic. The surrounding crater is the only impact structure on Earth developed in mostly acid volcanic rocks. Recent studies on the impactite, permafrost, and sediment sequences recovered within the framework of the ICDP "El'gygytgyn Drilling Project" and multiple pre-site surveys yielded new insight into the bedrock origin and cratering processes as well as permafrost dynamics and the climate and environmental history of the terrestrial Arctic back to the mid-Pliocene. Results from the impact rock section recovered during the deep drilling clearly confirm the impact genesis of the El'gygytgyn crater, but indicate an only very reduced fallback impactite sequence without larger coherent melt bodies. Isotope and element data of impact melt samples indicate a F-type asteroid of mixed composition or an ordinary chondrite as the likely impactor. The impact event caused a long-lasting hydrothermal activity in the crater that is assumed to have persisted for c. 300 kyr. Geochemical and microbial analyses of the permafrost core indicate a subaquatic formation of the lower part during lake-level highstand, but a subaerial genesis of the upper part after a lake-level drop after the Allerod. The isotope signal and ion compositions of ground ice is overprinted by several thaw freeze cycles due to variations in the talik underneath the lake. Modeling results suggest a modern permafrost thickness in the crater of c. 340 m, and further confirm a pervasive character of the talik below Lake El'gygytgyn. The lake sediment sequences shed new leight into the Pliocene and Pleistocene climate and environmental evolution of the Arctic. During the mid-Pliocene, significantly warmer and wetter climatic conditions in western Beringia than today enabled dense boreal forests to grow around Lake Ergygytgyn and, in combination with a higher nutrient flux into the lake, promoted primary production. The exceptional warmth during the mid-Pliocene is in accordance with other marine and terrestrial records from the Arctic and indicates a period of enhanced "Arctic amplification". The favourable conditions during the mid-Pliocene were repeatedly interrupted by climate deteriorations, e.g., during Marine Isotope Stage (MIS) M2, when pollen data and sediment proxies indicate a major cooling and the onset of local permafrost around the lake. A gradual vegetation change after c. 3.0 Ma points to the onset of a long-term cooling trend during the Late Pliocene that culminated in major temperature drops, first during MIS G6, and later during MIS 104. These cold events coincide with the onset of an intensified Northern Hemisphere (NH) glaciation and the largest extent of the Cordilleran Ice Sheet, respectively. After the Pliocene/Pleistocene transition, local vegetation and primary production in Lake El'gygtygyn experienced a major change from relatively uniform conditions to a high-amplitude glacial-to-interglacial cyclicity that fluctuated on a dominant 41 kyr obliquity band, but changed to a 100 kyr eccentricity dominance during the Middle Pleistocene transition (MPT) at c. 1.2-0.6 Ma. Periods of exceptional warming in the Pleistocene record of Lake El'gygytgyn with dense boreal forests around and peaks of primary production in the lake are assigned to so-called "super-interglacial" periods. The occurrence of these super-interglacials well corresponds to collapses of the West Antarctic Ice Sheet (WAIS) recorded in ice-free periods in the ANDRILL core, which suggests strong intrahemispheric teleconnections presumably driven by changes in the thermocline ocean circulation.
|
|
