| 1. |
- Luen, S J, et al.
(författare)
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Genomic characterisation of hormone receptor-positive breast cancer arising in very young women.
- 2023
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Ingår i: Annals of oncology : official journal of the European Society for Medical Oncology. - : Elsevier BV. - 1569-8041. ; 34:4, s. 397-409
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Tidskriftsartikel (refereegranskat)abstract
- Very young premenopausal women diagnosed with hormone receptor-positive, HER2-negative (HR+HER2-) early breast cancer (EBC) have higher rates of recurrence and death for reasons that remain largely unexplained.Genomic sequencing was applied to HR+HER2- tumours from patients enrolled in the SOFT clinical trial to determine genomic drivers that are enriched in young premenopausal women. Genomic alterations were characterised using next-generation sequencing from a subset of 1,276 patients (deep targeted sequencing, N=1258; whole-exome sequencing in a young-age, case-control subsample, N=82). We defined copy number (CN) subgroups and assessed for features suggestive of homologous recombination deficiency (HRD). Genomic alteration frequencies were compared between young premenopausal women (<40 years) and older premenopausal women (≥40 years), and assessed for associations with distant recurrence-free interval (DRFI), and overall survival (OS).Younger women (<40 years, N=359) compared with older women (≥40 years, N=917) had significantly higher frequencies of mutations in GATA3 (19%vs16%) and CN-amplifications (47%vs26%), but significantly lower frequencies of mutations in PIK3CA (32%vs47%), CDH1 (3%vs9%), and MAP3K1 (7%vs12%). Additionally, significantly higher frequencies of features suggestive of HRD (27%vs21%), and a higher proportion of PIK3CA mutations with concurrent CN-amplifications (23%vs11%).Genomic features suggestive of HRD, PIK3CA mutations with CN-amplifications, and CN-amplifications associated with significantly worse DRFI and OS compared with those without these features. These poor prognostic features were enriched in younger patients: present in 72% of patients aged <35 years, 54% aged 35-39 years, and 40% ≥40 years. Poor prognostic features (N=584[46%]) vs none (N=692[54%]) had an 8-year DRFI of 84%vs94% and OS of 88%vs96%. Younger women (<40) had the poorest outcomes: 8-year DRFI 74%vs85% and OS of 80%vs93% respectively.These results provide insights into genomic alterations that are enriched in young women with HR+HER2-EBC, provide rationale for genomic subgrouping, and highlight priority molecular targets for future clinical trials.
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| 2. |
- Colleoni, M., et al.
(författare)
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Low-Dose Oral Cyclophosphamide and Methotrexate Maintenance for Hormone Receptor-Negative Early Breast Cancer: International Breast Cancer Study Group Trial 22-00
- 2016
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Ingår i: Journal of Clinical Oncology. - : American Society of Clinical Oncology (ASCO). - 0732-183X .- 1527-7755. ; 34:28, s. 3400-9
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Tidskriftsartikel (refereegranskat)abstract
- Purpose To evaluate the benefit of low-dose cyclophosphamide and methotrexate (CM) maintenance, which previously demonstrated antitumor activity and few adverse effects in advanced breast cancer, in early breast cancer. International Breast Cancer Study Group (IBCSG) Trial 22-00, a randomized phase III clinical trial, enrolled 1,086 women (1,081 intent-to-treat) from November 2000 to December 2012. Women with estrogen receptor- and progesterone receptor-negative (< 10% positive cells by immunohistochemistry) early breast cancer any nodal and human epidermal growth factor receptor 2 status, were randomly assigned anytime between primary surgery and 56 days after the first day of last course of adjuvant chemotherapy to CM maintenance (cyclophosphamide 50 mg/day orally continuously and methotrexate 2.5 mg twice/day orally on days 1 and 2 of every week for 1 year) or to no CM. The primary end point was disease-free survival (DFS), which included invasive recurrences, second (breast and nonbreast) malignancies, and deaths. After a median of 6.9 years of follow-up, DFS was not significantly better for patients assigned to CM maintenance compared with patients assigned to no CM, both overall (hazard ratio [HR], 0.84; 95% CI, 0.66 to 1.06;P = .14) and in triple-negative (TN) disease (n = 814; HR, 0.80; 95% CI, 0.60 to 1.06). Patients with TN, node-positive disease had a nonstatistically significant reduced HR (n = 340; HR, 0.72; 95% CI, 0.49 to 1.05). Seventy-one (13%) of 542 patients assigned to CM maintenance did not start CM. Of 473 patients who received at least one CM maintenance dose (including two patients assigned to no CM), 64 (14%) experienced a grade 3 or 4 treatment-related adverse event; elevated serum transaminases was the most frequently reported (7%), followed by leukopenia (2%). CM maintenance did not produce a significant reduction in DFS events in hormone receptor-negative early breast cancer. The trend toward benefit observed in the TN, node-positive subgroup supports additional exploration of this strategy in the TN, higher-risk population. (C) 2016 by American Society of Clinical Oncology.
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| 3. |
- Possidente, Luca, et al.
(författare)
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3D Beam Element for the Analysis of Torsional Problems of Steel-Structures in Fire
- 2020
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Ingår i: Journal of Structural Engineering. - : American Society of Civil Engineers (ASCE). - 0733-9445 .- 1943-541X. ; 146:7
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Tidskriftsartikel (refereegranskat)abstract
- The paper presents the development of a three-dimensional (3D) beam element for the analysis of steel structures in fire that properly accounts for the degradation of the torsional strength and stiffness owing to thermal exposure. The element is well-suited for the analysis of members that are subjected to significant torsional effects, as steel members with open cross-sections subjected to torsion, lateral-torsional buckling, and torsional buckling. The element is based on a corotational formulation and small strains assumption, while the local formulation was developed according to both the Timoshenko and Bernoulli beam theories. The stress-strain relationship and thermal expansion of steel were implemented according to Eurocode EN 1993-1-2 (CEN 2005). A comprehensive numerical analysis was performed and results for several case studies are presented in the paper to assess the performance of the 3D beam element. The outcomes indicated very good agreement when compared with shell-based models, highlighting promising capabilities of modeling steel structures in fire. Moreover, the proposed element showed more accurate results with respect to beam elements included into two commercial software, i.e., ABAQUS and SAFIR.
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| 4. |
- Possidente, Luca, et al.
(författare)
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A 3D beam element to study torsion of steel open sections exposed to fire
- 2019
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Ingår i: Advances in Engineering Materials, Structures and Systems. - : CRC Press. - 9780429426506 - 9781138386969 ; , s. 561-565
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Konferensbidrag (refereegranskat)abstract
- In the analysis of structures in fire, numerical models must account for the effects of increasing temperatures. Although different finite elements capable of effectively tackling the problem are available, 3D beam elements employed in many commercial software do not properly account for the degradation of the torsional properties with temperature. In this context, an enhanced 3D beam element based on a co-rotational formulation is proposed. The element was specifically developed for steel elements and is well suited for the analysis of structures that exhibit a significant torsional behavior. The Timoshenko beam theory was employed and the steel stress-strain law and thermal expansion were implemented according to EN1993-1-2. Two different case studies are presented in this paper. Numerical analyses by means of two different software (ABAQUS and SAFIR) were performed and compared to the results. The outcomes confirmed the effectiveness of the proposed element.
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| 5. |
- Possidente, L., et al.
(författare)
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Fire buckling curves for torsionally sensitive steel members subjected to axial compression
- 2022
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Ingår i: Journal of Structural Fire Engineering. - : Emerald. - 2040-2317 .- 2040-2325. ; 13:2, s. 171-193
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Buckling should be carefully considered in steel assemblies with members subjected to compressive stresses, such as bracing systems and truss structures, in which angles and built-up steel sections are widely employed. These type of steel members are affected by torsional and flexural-torsional buckling, but the European (EN 1993-1-2) and the American (AISC 360-16) design norms do not explicitly treat these phenomena in fire situation. In this work, improved buckling curves based on the EN 1993-1-2 were extended by exploiting a previous work of the authors. Moreover, new buckling curves of AISC 360-16 were proposed. Design/methodology/approach: The buckling curves provided in the norms and the proposed ones were compared with the results of numerical investigation. Compressed angles, tee and cruciform steel members at elevated temperature were studied. More than 41,000 GMNIA analyses were performed on profiles with different lengths with sections of class 1 to 3, and they were subjected to five uniform temperature distributions (400–800 C) and with three steel grades (S235, S275, S355). Findings: It was observed that the actual buckling curves provide unconservative or overconservative predictions for various range of slenderness of practical interest. The proposed curves allow for safer and more accurate predictions, as confirmed by statistical investigation. Originality/value: This paper provides new design buckling curves for torsional and flexural-torsional buckling at elevated temperature since there is a lack of studies in the field and the design standards do not appropriately consider these phenomena.
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| 6. |
- Possidente, Luca, et al.
(författare)
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Torsional and flexural-torsional buckling of compressed steel members in fire
- 2020
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Ingår i: Journal of constructional steel research. - : Elsevier. - 0143-974X .- 1873-5983. ; 171
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Tidskriftsartikel (refereegranskat)abstract
- Torsional and flexural-torsional buckling of compressed steel members are relevant phenomena for monosymmetric and built-up cross-sections frequently employed in bracing systems or in truss structures. Despite the great interest shown by researchers relative to the instability of steel elements in fire, there is a lack of studies on the torsional and flexural-torsional buckling behaviour of steel members in compression at elevated temperature, and no provisions are given in EN 1993-1-2. In this work, a comprehensive numerical investigation of the behaviour of axially compressed angles, Tee and cruciform steel cross-sections at elevated temperature was performed. In this respect, a parametric study was carried out on Class 1 to 3 profiles subjected to uniform temperature distribution. It was found that the buckling curve given in EN 1993-1-2 provides unconservative results for slenderness ranges of practical interest. Improved buckling curves to better predict the behaviour of angles, Tee and cruciform compressed cross-sections at elevated temperature were proposed.
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| 7. |
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| 8. |
- Tondini, N., et al.
(författare)
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A 2D beam element for the analysis of flexural buckling of steel structures at elevated temperatures
- 2018
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Ingår i: Applications of Fire Engineering - Proceedings of the International Conference of Applications of Structural Fire Engineering, ASFE 2017. - : CRC Press/Balkema. - 9781138092914 ; , s. 199-208
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Konferensbidrag (refereegranskat)abstract
- The paper describes the development of a two-dimensional (2D) nonlinear beam finite element that includes advanced path-following capabilities for detecting bifurcation instability of steel elements subjected to fire loading. A co-rotational formulation was used for describing the beam kinematic. The degradation of the steel mechanical properties at high temperature according to the Eurocode 1993-1-2 was considered by integrating the material constitutive law based on a predetermined temperature field in the cross section. Advanced path-following methods were implemented to analyse the elastic-plastic post-buckling behaviour of compressed steel elements at high temperature without the need of introducing geometrical imperfections. To highlight the practical implications, a parametric analysis showed that the element could reproduce the EN1993-1-2 buckling curve. The obtained outcomes were validated against experimental and numerical data obtained with commercial software ABAQUS and SAFIR.
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| 9. |
- Yang, Xin, et al.
(författare)
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Cancer risks associated with germline PALB2 pathogenic variants : An international study of 524 families
- 2020
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Ingår i: Journal of Clinical Oncology. - 0732-183X. ; 38:7, s. 674-685
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE To estimate age-specific relative and absolute cancer risks of breast cancer and to estimate risks of ovarian, pancreatic, male breast, prostate, and colorectal cancers associated with germline PALB2 pathogenic variants (PVs) because these risks have not been extensively characterized. METHODS We analyzed data from 524 families with PALB2 PVs from 21 countries. Complex segregation analysis was used to estimate relative risks (RRs; relative to country-specific population incidences) and absolute risks of cancers. The models allowed for residual familial aggregation of breast and ovarian cancer and were adjusted for the family-specific ascertainment schemes. RESULTS We found associations between PALB2 PVs and risk of female breast cancer (RR, 7.18; 95% CI, 5.82 to 8.85; P = 6.5 × 10-76), ovarian cancer (RR, 2.91; 95% CI, 1.40 to 6.04; P = 4.1 × 10-3), pancreatic cancer (RR, 2.37; 95% CI, 1.24 to 4.50; P = 8.7 × 10-3), and male breast cancer (RR, 7.34; 95% CI, 1.28 to 42.18; P = 2.6 3 1022). There was no evidence for increased risks of prostate or colorectal cancer. The breast cancer RRs declined with age (P for trend = 2.0 × 10-3). After adjusting for family ascertainment, breast cancer risk estimates on the basis of multiple case families were similar to the estimates from families ascertained through population-based studies (P for difference = .41). On the basis of the combined data, the estimated risks to age 80 years were 53% (95% CI, 44% to 63%) for female breast cancer, 5% (95% CI, 2% to 10%) for ovarian cancer, 2%-3% (95% CI females, 1% to 4%; 95% CI males, 2% to 5%) for pancreatic cancer, and 1% (95% CI, 0.2% to 5%) for male breast cancer. CONCLUSION These results confirm PALB2 as a major breast cancer susceptibility gene and establish substantial associations between germline PALB2 PVs and ovarian, pancreatic, and male breast cancers. These findings will facilitate incorporation of PALB2 into risk prediction models and optimize the clinical cancer risk management of PALB2 PV carriers.
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