ESO-ESMO fifth international consensus guidelines for breast cancer in young women (BCY5).

We dedicate this manuscript in memory of a dear friend and colleague Bella Kaufman. The fifth International Consensus Symposium for Breast Cancer in Young Women (BCY5) took place virtually in October 2020, organized by the European School of Oncology (ESO) and the European Society of Medical Oncology (ESMO). Consensus recommendations for the management of breast cancer in young women were updated from BCY4 with incorporation of new evidence to inform the guidelines. Areas of research priorities as well as specificities in different geographic and minority populations were identified. This manuscript summarizes the ESO-ESMO international consensus recommendations, which are also endorsed by the European Society of Breast Specialists (EUSOMA).

ESO-ESMO 4th International Consensus Guidelines for Breast Cancer in Young Women (BCY4).

The 4th International Consensus Conference for Breast Cancer in Young Women (BCY4) took place in October 2018, in Lugano, Switzerland, organized by the European School of Oncology (ESO) and the European Society of Medical Oncology (ESMO). Consensus recommendations for the management of breast cancer in young women were updated from BCY3 with incorporation of new evidence to inform the guidelines. Areas of research priorities were also identified. This article summarizes the ESO-ESMO international consensus recommendations, which are also endorsed by the European Society of Breast Specialists (EUSOMA).

Bullseye's representation of cerebral white matter hyperintensities.

BACKGROUND AND PURPOSE: Visual rating scales have limited capacities to depict the regional distribution of cerebral white matter hyperintensities (WMH). We present a regional-zonal volumetric analysis alongside a visualization tool to compare and deconstruct visual rating scales. MATERIALS AND METHODS: 3D T1-weighted, T2-weighted spin-echo and FLAIR images were acquired on a 3T system, from 82 elderly participants in a population-based study. Images were automatically segmented for WMH. Lobar boundaries and distance to ventricular surface were used to define white matter regions. Regional-zonal WMH loads were displayed using bullseye plots. Four raters assessed all images applying three scales. Correlations between visual scales and regional WMH as well as inter and intra-rater variability were assessed. A multinomial ordinal regression model was used to predict scores based on regional volumes and global WMH burdens. RESULTS: On average, the bullseye plot depicted a right-left symmetry in the distribution and concentration of damage in the periventricular zone, especially in frontal regions. WMH loads correlated well with the average visual rating scores (e.g. Kendall's tau [Volume, Scheltens]=0.59 CI=[0.53 0.62]). Local correlations allowed comparison of loading patterns between scales and between raters. Regional measurements had more predictive power than global WMH burden (e.g. frontal caps prediction with local features: ICC=0.67 CI=[0.53 0.77], global volume=0.50 CI=[0.32 0.65], intra-rater=0.44 CI=[0.23 0.60]). CONCLUSION: Regional-zonal representation of WMH burden highlights similarities and differences between visual rating scales and raters. The bullseye infographic tool provides a simple visual representation of regional lesion load that can be used for rater calibration and training.

Performance of grain sorghum hybrids under drought stress using GGE biplot analyses.

The objective of this study was to estimate the adaptability and stability of grain sorghum hybrids grown under post-flowering water stress and non-stress conditions. The trials were carried out in Nova Porteirinha-MG during the season of 2014 and 2015, and in Teresina-PI in the 2014 season. Twenty-nine-grain sorghum hybrids were evaluated, in a randomized complete block design, with three replications. Plots consisted of four lines with 3 m long. The grain yield data were submitted to the individual variance analysis, having considered the effects of the hybrids as fixed and the other effects as random. The joint analysis was carried out, and when the interaction genotypes x environments was significant, the grain yield data were submitted to the adaptability and stability analysis by the GGE biplot method. A substantial reduction in the grain yield in environments with water stress was found. The highest yielding hybrids under water stress conditions in Nova Porteirinha-MG were 50A50, AG1080, AG1090, DKB550, DKB590, Jade, and BM737, and the highest yielding hybrids under the water stress in Teresina-PI were 1G282, 1G244, and A9721R. Considering all environments, the highest yielding hybrids were 1G282, DKB540, A9721R, 1G100, and AG1090.

Identification of sorghum hybrids with high phenotypic stability using GGE biplot methodology.

The aim of this study was to identify sorghum hybrids that have both high yield and phenotypic stability in Brazilian environments. Seven trials were conducted between February and March 2011. The experimental design was a randomized complete block with 25 treatments and three replicates. The treatments consisted of 20 simple pre-commercial hybrids and five witnesses of grain sorghum. Sorghum genotypes were analyzed by the genotype main effects + genotype environment interaction (GGE) biplot method if significant genotype x environment interaction, adaptability, and phenotypic stability were detected. GGE biplot methodology identified two groups of environments, the first composed of Água Comprida-MG, Montividiu-GO, and Vilhena- RO and the second of Guaíra-SP and Sete Lagoas-MG. The BRS 308 and 1G282 genotypes were found to have high grain yield, adaptability, and phenotypic stability and are thus indicated for cultivation in the first and second groups of environments, respectively.

The Kite Latissimus Dorsi Flap for Breast Reconstruction: An Attempt to Reduce Lateral Chest Wall Deformity and Axillary Bulking.

UNLABELLED: The latissimus dorsi flap is a commonly used tissue transfer for volume replacement in partial or total breast reconstruction. In this era of cosmetic awareness and oncoplastic breast surgery, two main defects are related to the conventional technique: the back scar and the bulkiness on the lateral chest wall, under the axilla. Axillary bulking, a disturbing defect for the majority of patients, is a persistent consequence, independent of the technique used, even when the proximal tendon is cut. We describe a new approach, the kite latissimus dorsi flap, consisting of harvesting the flap, partially or totally, with pedicle dissection from the muscle, extending dissection, perforator style if needed, until the external border of the breast (anterior axillary line) is reached. The muscle is then cut at that level, leaving no unnecessary volume under the axilla, which would cause bulkiness and chest wall deformity. LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266.

In vivo imaging of tau pathology using multi-parametric quantitative MRI.

As the number of people diagnosed with Alzheimer's disease (AD) reaches epidemic proportions, there is an urgent need to develop effective treatment strategies to tackle the social and economic costs of this fatal condition. Dozens of candidate therapeutics are currently being tested in clinical trials, and compounds targeting the aberrant accumulation of tau proteins into neurofibrillary tangles (NFTs) are the focus of substantial current interest. Reliable, translatable biomarkers sensitive to both tau pathology and its modulation by treatment along with animal models that faithfully reflect aspects of the human disease are urgently required. Magnetic resonance imaging (MRI) is well established as a valuable tool for monitoring the structural brain changes that accompany AD progression. However the descent into dementia is not defined by macroscopic brain matter loss alone: non-invasive imaging measurements sensitive to protein accumulation, white matter integrity and cerebral haemodynamics probe distinct aspects of AD pathophysiology and may serve as superior biomarkers for assessing drug efficacy. Here we employ a multi-parametric array of five translatable MRI techniques to characterise the in vivo pathophysiological phenotype of the rTg4510 mouse model of tauopathy (structural imaging, diffusion tensor imaging (DTI), arterial spin labelling (ASL), chemical exchange saturation transfer (CEST) and glucose CEST). Tau-induced pathological changes included grey matter atrophy, increased radial diffusivity in the white matter, decreased amide proton transfer and hyperperfusion. We demonstrate that the above markers unambiguously discriminate between the transgenic group and age-matched controls and provide a comprehensive profile of the multifaceted neuropathological processes underlying the rTg4510 model. Furthermore, we show that ASL and DTI techniques offer heightened sensitivity to processes believed to precede detectable structural changes and, as such, provides a platform for the study of disease mechanisms and therapeutic intervention.

Guidelines for time-to-event end point definitions in breast cancer trials: results of the DATECAN initiative (Definition for the Assessment of Time-to-event Endpoints in CANcer trials)†.

BACKGROUND: Using surrogate end points for overall survival, such as disease-free survival, is increasingly common in randomized controlled trials. However, the definitions of several of these time-to-event (TTE) end points are imprecisely which limits interpretation and cross-trial comparisons. The estimation of treatment effects may be directly affected by the definitions of end points. The DATECAN initiative (Definition for the Assessment of Time-to-event Endpoints in CANcer trials) aims to provide recommendations for definitions of TTE end points. We report guidelines for randomized cancer clinical trials (RCTs) in breast cancer. PATIENTS AND METHODS: A literature review was carried out to identify TTE end points (primary or secondary) reported in publications of randomized trials or guidelines. An international multidisciplinary panel of experts proposed recommendations for the definitions of these end points based on a validated consensus method that formalize the degree of agreement among experts. RESULTS: Recommended guidelines for the definitions of TTE end points commonly used in RCTs for breast cancer are provided for non-metastatic and metastatic settings. CONCLUSION: The use of standardized definitions should facilitate comparisons of trial results and improve the quality of trial design and reporting. These guidelines could be of particular interest to those involved in the design, conducting, reporting, or assessment of RCT.

Breast cancer under age 40: a different approach.

Breast cancer (BC) under age 40 is a complex disease to manage due to the additionally fertility-related factors to be taken in consideration. More than 90% of young patients with BC are symptomatic. Women<40 years are more likely to develop BC with worse clinicopathological features and more aggressive subtype. This has been frequently associated with inferior outcomes. Recently, the prognostic significance of age<40 has been shown to differ according to the BC subtype, being associated with worst recurrence-free survival (RFS) and overall survival (OS) for luminal BC. The biology of BC<40 has also been explored through analysis of large genomic data set, and specific pathways overexpressed in these tumors have been identified which can lead to the development of targeted therapy in the future. A multidisciplinary tumor board should determine the optimal locoregional and systemic management strategies for every individual patient with BC before the start of any therapy including surgery. This applies to both early (early breast cancer (EBC)) and advanced (advanced breast cancer (ABC)) disease, before the start of any therapy. Mastectomy even in young patients confers no overall survival advantage when compared to breast-conserving treatment (BCT), followed by radiotherapy. Regarding axillary approach, indications are identical to other age groups. Young age is one of the most important risk factors for local recurrence after both breast-conserving surgery (BCS) and mastectomy, associated with a higher risk of distant metastasis and death. Radiation after BCS reduces local recurrence from 19.5 to 10.2% in BC patients 40 years and younger. The indications for and the choice of systemic treatment for invasive BC (both early and advanced disease) should not be based on age alone but driven by the biological characteristics of the individual tumor (including hormone receptor status, human epidermal growth factor receptor 2 (HER-2) status, grade, and proliferative activity), disease stage, and patient's comorbidities. Recommendations regarding the use of genomic profiles such as MammaPrint, Oncotype Dx, and Genomic grade index in young women are similar to the general BC population. Especially in the metastatic setting, patient preferences should always be taken into account, as the disease is incurable. The best strategy for these patients is the inclusion into well-designed, independent, prospective randomized clinical trials. Metastatic disease should always be biopsied whenever feasible for histological confirmation and reassessment of biology. Endocrine therapy is the preferred option for hormone receptor-positive disease (HR+ve), even in presence of visceral metastases, unless there is concern or proof of endocrine resistance or there is a need for rapid disease response and/or symptom control. Recommendations for chemotherapy (CT) should not differ from those for older patients with the same characteristics of the metastatic disease and its extent. Young age by itself should not be an indication to prescribe more intensive and combination CT regimens over the sequential use of monotherapy. Poly(ADP-ribose) polymerase inhibitors (PARP inhibitors) represent an important group of promising drugs in managing patients with breast cancer susceptibility gene (BRCA)-1- or BRCA-2-associated BC. Specific age-related side effects of systemic treatment (e.g., menopausal symptoms, change in body image, bone morbidity, cognitive function impairment, fertility damage, sexual dysfunction) and the social impact of diagnosis and treatment (job discrimination, taking care for children) should also be carefully addressed when planning systemic long-lasting therapy, such as endocrine therapy. Survivorship concerns for young women are different compared to older women, including issues of fertility, preservation, and pregnancy.

Stability and adaptability of grain sorghum hybrids in the off-season.

We analyzed productivity data obtained from experiments on grain sorghum conducted in 7 locations of its cultivation in Brazil. A total of 25 hybrids were analyzed, of which 22 were pre-commercial and 3 were cultivars. The Wricke and Purchase et al. methods were highly consistent in identifying individuals with low contributions to genotype x environment interactions. The Lin and Binns method proved to be easily applicable and interpretable but it was not efficient in detecting individuals with specific adaptations. An additive main effect and multiplicative interaction (AMMI) model indicated the suitability of cultivar 1G282 for the cities of Guaíra, Sete Lagoas, and Vilhena, and hybrids 0307087 and 0307091 for the southeast of Goiás. The associations of the Eberhart and Russell method with AMMI indicated that 0307071, 0307131, 0307511, and 0307651 showed adaptability to favorable environments. Hybrid 0009061 stood out as the most adaptable and stable cultivar.

Selection indices to identify drought-tolerant grain sorghum cultivars.

Twenty-five cultivars of grain sorghum [Sorghum bicolor (L.) Moench] were examined under both drought stress and normal conditions in 4 experiments. In each condition, genotypes were evaluated in a factorial experiment using a randomized complete block design with 3 replications. Eight drought tolerance indices including stability tolerance index, mean productivity (MP), geometric MP, harmonic mean, stress susceptibility index, tolerance index, yield index, and yield stability index were estimated for each genotype based on grain yield under drought (Ys) and irrigated conditions (Yp). The results indicated that there were positive and significant correlations among Yp and Ys with geometric MP, MP, harmonic mean, and stability tolerance index, indicating that these factors are better predictors of Yp and Ys than tolerance index, stress susceptibility index, yield stability index, and yield index. Based on adjusted means at Yp and Ys, indices geometric MP, MP, harmonic mean, and stability tolerance index, unweighted pair group method with arithmetic mean cluster and biplot analysis, the most tolerant cultivars were '9929020', '9929034', and 'N 95B'.

Sometimes it is better to just make it simple. De-escalation of oncoplastic and reconstructive procedures.

Simple breast conservation surgery (sBCS) has technically advanced onto oncoplastic breast procedures (OBP) to avoid mastectomy and improve breast cancer patients' psychosocial well-being and cosmetic outcome. Although OBP are time-consuming and expensive, we are witnessing an increase in their use, even for cases that could be managed with sBCS. The choice between keeping it simple or opting for more complex oncoplastic procedures is difficult. This review proposes a pragmatic approach in assisting this decision. Medical literature suggests that OBP and sBCS might be similar regarding local recurrence and overall survival, and patients seem to have higher satisfaction levels with the aesthetic outcome of OBP when compared to sBCS. However, the lack of comprehensive high-quality research assessing their safety, efficacy, and patient-reported outcomes hinders these supposed conclusions. Postoperative complications after OBP may delay the initiation of adjuvant RT. In addition, precise displacement of the breast volume is not effectively recorded despite surgical clips placement, making accurate dose delivery tricky for radiation oncologists, and WBRT preferable to APBI in complex OBP cases. With a critical eye on financial toxicity, patient satisfaction, and oncological outcomes, OBP must be carefully integrated into clinical practice. The thoughtful provision of informed consent is essential for decision-making between sBCS and OBP. As we look into the future, machine learning and artificial intelligence can potentially help patients and doctors avoid postoperative regrets by setting realistic aesthetic expectations.

Long-term cosmetic changes after breast-conserving treatment of patients with stage I-II breast cancer and included in the EORTC 'boost versus no boost' trial.

BACKGROUND: In breast cancer treated with breast-conserving radiotherapy, the influence of the boost dose on cosmetic outcome after long-term follow-up is unknown. PATIENTS AND METHODS: We included 348 patients participating in the EORTC 'boost versus no boost' mega trial with a minimum follow-up of 6 years. Digitalised pictures were analysed using specific software, enabling quantification of seven relative asymmetry features associated with different aspects of fibrosis. RESULTS: After 3 years, we noted a statistically significantly poorer outcome for the boost patients for six features compared with those of the no boost patients. Up to 9 years of follow-up, results continued to worsen in the same magnitude for the both patient groups. We noted the following determinants for poorer outcome: (i) boost treatment, (ii) larger excision volumes, (iii) younger age, (iv) tumours located in the central lower quadrants of the breast and (v) a boost dose administered with photons. CONCLUSIONS: A boost dose worsens the change in breast appearance in the first 3 years. Moreover, the development of fibrosis associated with whole-breast irradiation, as estimated with the relative asymmetry features, is an ongoing process until (at least) 9 years after irradiation.

Moderate penetrance genes complicate genetic testing for breast cancer diagnosis: ATM, CHEK2, BARD1 and RAD51D.

Breast cancer risk associated with germline likely pathogenic/pathogenic variants (PV) varies by gene, often by penetrance (high >50% or moderate 20-50%), and specific locus. Germline PVs in BRCA1 and BRCA2 play important roles in the development of breast and ovarian cancer in particular, as well as in other cancers such as pancreatic and prostate cancers and melanoma. Recent studies suggest that other cancer susceptibility genes, including ATM, CHEK2, PALB2, RAD51C and RAD51D confer differential risks of breast and other specific cancers. In the era of multigene panel testing, advances in next-generation sequencing technologies have notably reduced costs in the United States (US) and enabled sequencing of BRCA1/2 concomitantly with additional genes. The use of multigene-panel testing is beginning to expand in Europe as well. Further research into the clinical implications of variants in moderate penetrance genes, particularly in unaffected carriers, is needed for appropriate counselling and risk management with data-driven plans for surveillance and/or risk reduction. For individuals at high risk without any pathogenic or likely pathogenic variant in cancer susceptibility genes or some carriers of pathogenic variants in moderate-risk genes such as ATM and CHEK2, polygenic risk scores offer promise to help stratify breast cancer risk and guide appropriate risk management options. Cancer patients whose tumours are driven by the loss of function of both copies of a predisposition gene may benefit from therapies targeting the biological alterations induced by the dysfunctional gene e.g. poly ADP ribose polymerase (PARP) inhibitors and other novel pathway agents in cancers with DNA repair deficiencies. A better understanding of mechanisms by which germline variants drive various malignancies may lead to improvements in both therapeutic and preventive management options.