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Abstract: Global Positioning System (GPS) data acquired between 1996 and 2004 and fault plane solutions for four seismic zones are analyzed to obtain the velocity and strain rate fields for western Bulgaria. The GPS derived velocities suggest that southwestern Bulgaria moves to the S to SSE at a rate of ∼1 mm/year with respect to northern Bulgaria and southern Romania, defining an approximately ESE-trending extensional boundary that marks the northernmost extent of the Aegean extensional domain. The boundary includes the E–W trending Sub-Balkan graben system of central Bulgaria and its westward continuation into the Sofia graben. Active faults within the boundary region trend ENE to WNW, and they have normal or oblique normal and strike–slip displacements consistent with the velocity field. Within the western part of the boundary region, extension is transferred to the north of the Sofia graben across the westernmost part of the Stara Planina Mountains and the ridges of the western Sredna Gora. The geodetically derived N–S extension is in agreement with the seismic data that show a variable pattern, but with projections of the T axes mostly lying within the N–S quadrant. The predominant type of faulting is caused by sub-horizontal extensional stresses in an approximate N–S direction. This is consistent with extension and oblique strike–slip interpreted from geological studies that show numerous WNW, ENE to E–W-trending active normal faults in western Bulgaria. [Copyright &y& Elsevier]

The ENE-tilted Mesta half-graben contains a ∼3-km-thick section of Priabonian (Late Eocene) to Oligocene sedimentary and volcanic rocks that rest unconformably on basement metamorphic rocks along its west side. Basal strata dip 50–60° E and dip at progressively lower angles upward, indicating synrotational deposition. The southern part of the half-graben contains nested volcanic caldera complexes, formed during the deposition of the middle part of the sedimentary sequence, which have been rotated by about half the total rotation of the sedimentary succession. The half-graben is bounded on the east by a fault that steepens from more deeply exposed structural levels in the south (8–18° W) to shallower exposed structural levels in the north (∼70° W) and together with the rotation of Paleogene strata during deposition indicate the Mesta half-graben is underlain by a listric detachment fault, the Mesta detachment. Subhorizontal Middle Miocene strata that unconformably overlie tilted Paleogene strata yield an upper age limit to the extension. West and northwest of the Mesta half-graben are many other NNW-trending NE-tilted Paleogene half-grabens which we suggest are part of an important extended area in SW Bulgaria and eastern Macedonia that lies above one or more west-dipping detachment faults and date the beginning of Aegean extension in the southern Balkan region as at least as old as Priabonian. The Mesta detachment is oblique to the trend of a contemporaneous Paleogene magmatic arc in the southern Balkans and the origin of the detachment is probably related to gravitationally induced spreading of thickened hot arc crust and Hellenic trench roll back. [Copyright &y& Elsevier]

Background The use of supportive granulocyte colony-stimulating factor (G-CSF) to reduce the risk of neutropenic complications in high-risk cancer patients is consistently recommended by several clinical practice guidelines. However, in a previous meta-analysis, G-CSF prophylaxis was associated with an increased risk of secondary malignancies while reducing long-term mortality. We present here an updated systematic review and meta-analysis. Materials and methods A systematic literature search was carried out to identify randomized controlled trials of cancer patients receiving conventional-dose chemotherapy, assigned to primary G-CSF support or a control group without initial G-CSF, with at least 2 years of follow-up. Studies were categorized into one of the four groups, based on the chemotherapy regimen and study design. An updated meta-analysis was carried out; relative risk (RR) and 95% confidence intervals (CIs) for all-cause mortality and secondary malignancies were calculated. Results Of 2604 articles screened, 14 eligible studies were identified and combined with studies identified in the previous systematic literature searches. The updated meta-analysis included a total of 68 studies presenting 71 separate comparisons. Survival was significantly improved in patients receiving primary G-CSF support, compared with patients without primary G-CSF support (mortality RR=0.92; 95% CI 0.90–0.95; ARD=−3.3%; 95% CI −4.2–−2.4; P  <   0.0001). The largest improvement in survival was observed with dose-dense chemotherapy regimens with G-CSF support, compared with controls receiving no G-CSF support (mortality RR=0.86; 95% CI 0.80–0.92; P  <   0.0001). Patients who received primary G-CSF support experienced a significantly higher risk of secondary malignancies, compared with controls (RR=1.85; 95% CI 1.19–2.88; ARD=0.47; 95% CI 0.21–0.73; P  <   0.01). Conclusions Our findings demonstrate that overall survival is improved in patients receiving intensified chemotherapy with primary G-CSF support, compared with those receiving standard chemotherapy. Primary G-CSF support was also associated with a higher risk of developing secondary malignancies, including secondary acute myeloid leukemia and myelodysplastic syndrome. [ABSTRACT FROM AUTHOR]

Background: Following the functional and physicochemical characterization of a proposed biosimilar, comparative clinical studies help to confirm biosimilarity by demonstrating similar safety and efficacy to the reference product in a sensitive patient population. Patients and methods: LA-EP2006 is a proposed biosimilar that has been developed for pegfilgrastim, a long-acting form of granulocyte colony-stimulating factor for the prevention of neutropenia. The current analysis reports data pooled from two independent, multinational, prospective, randomized, controlled, double-blind phase III studies of similar design comparing the safety and efficacy of reference pegfilgrastim with LA-EP2006 in patients with breast cancer receiving myelotoxic (neo)adjuvant TAC (docetaxel, doxorubicin, and cyclophosphamide) chemotherapy and requiring granulocyte colony-stimulating factor. Results: A total of 624 patients were randomized in the PROTECT-1 and PROTECT-2 studies (NCT01735175; NCT01516736) (LA-EP2006: n=314; reference: n=310). Baseline characteristics of patients were well balanced across treatment groups. The primary end point, mean duration of severe neutropenia in the first chemotherapy cycle was similar in both the LA-EP2006 and reference groups (1.0561.055 days versus 1.0160.958 days), with a treatment difference of -0.04 days [95% confidence interval (CI): -0.19 to 0.11] that met the equivalence criteria (the 95% CI were within the defined margin of61 day). Secondary end points, such as the nadir of absolute neutrophil count and the incidence of febrile neutropenia, were also similar between LA-EP2006 and reference pegfilgrastim. The safety and tolerability profile of LA-EP2006 was similar to that observed with reference pegfilgrastim, and there were no reports of neutralizing antibodies. Conclusions: This pooled analysis confirms, as a part of totality of evidence approach, that the proposed biosimilar pegfilgrastim LA-EP2006 has a comparable efficacy and safety profile to reference pegfilgrastim in patients with breast cancer receiving TAC chemotherapy. [ABSTRACT FROM AUTHOR]

Background: Biosimilars of filgrastim are in widespread clinical use in Europe. This phase III study compares biosimilar filgrastim (EP2006), with the US-licensed reference product, Neupogen®, in breast cancer patients receiving (neo)adjuvant myelosuppressive chemotherapy (TAC). Patients and methods: A total of 218 patients receiving 5 μg/kg/day filgrastim over six chemotherapy cycles were randomized 1:1:1:1 into four arms. Two arms received only one product (nonalternating), biosimilar or reference, and two arms (alternating) received alternating treatments during each cycle (biosimilar then reference or vice versa). The primary end point was duration of severe neutropenia (DSN) during cycle 1. Results: The baseline characteristics were balanced between the four treatment arms. Noninferiority of biosimilar versus the reference was demonstrated: DSN (days) in cycle 1 was 1.17 ± 1.11 (biosimilar, N = 101) and 1.20 ± 1.02 (reference, N = 103), 97.5% confidence interval lower boundary for the difference was -0.26 days (above the predefined limit of -1 day). No clinically meaningful differences were observed regarding any other efficacy parameter: incidence of febrile neutropenia (FN); hospitalization due to FN; incidence of infections; depth and time of absolute neutrophil count (ANC) nadir and time to ANC recovery during cycle 1 and across all cycles. The pattern and frequency of adverse events were similar across all treatments. Conclusion: This study demonstrates that biosimilar and the reference filgrastim are similar with no clinically meaningful differences regarding efficacy and safety in prevention of severe neutropenia. Biosimilar filgrastim could represent an important alternative to the reference product, potentially benefiting public health by increasing access to filgrastim treatment. [ABSTRACT FROM AUTHOR]