Feasibility of targeted therapies in the adjuvant setting of early breast cancer in men: real-world data from a population-based registry.

BACKGROUND: Following the positive iDFS and OS results of the phase III clinical trials monarchE, NATALEE and OlympiA, new oral anticancer agents (the CDK4/6 inhibitors abemaciclib, ribociclib as well as the PARP inhibitor olaparib) have recently been introduced into the treatment of high-risk early breast cancer (eBC). However, only few male patients were included in these trials (0.4%, 0.6% and 0.3%, respectively). The objective of this real-world analysis was to determine the proportion of male patients with eBC fulfilling the clinical high-risk criteria of above-mentioned trials. PATIENTS AND METHODS: We conducted a data inquiry and analysis with the Cancer Registry of Baden-Württemberg of men with breast cancer diagnosed between January 1, 2015 and December 31, 2021. Men with eBC were identified and the number of patients at clinical high-risk according to the inclusion criteria of monarchE, NATALEE and OlympiA was assessed. RESULTS: Of 397 men with eBC, 354 (89.1%) had a HR + /Her2- and 4 (1.0%) a triple-negative subtype. 84 patients (21.2%) met the clinical high-risk criteria according to the monarchE, 189 (47.6%) those according to the NATALEE and 50 (12.6%) those according to the OlympiA trial. CONCLUSION: In a large real-world sample, more men with eBC are at clinical high risk according to the inclusion criteria of monarchE, NATALEE and OlympiA than would be expected in women. This is most likely due to more advanced stages at initial diagnosis in men. To evaluate whether CDK4/6 and PARP inhibitors improve prognosis also in men should be the topic of future real- world analyses.

Adjuvant Olaparib for Germline BRCA Carriers With HER2-Negative Early Breast Cancer: Evidence and Controversies.

In the OlympiA study, 1 year of adjuvant olaparib significantly extended invasive disease-free survival and overall survival. The benefit was consistent across subgroups, and this regimen is now recommended after chemotherapy for germline BRCA1/2 mutation (gBRCA1/2m) carriers with high-risk, HER2-negative early breast cancer. However, the integration of olaparib in the landscape of agents currently available in the post(neo)adjuvant setting-ie, pembrolizumab, abemaciclib, and capecitabine-is challenging, as there are no data suggesting how to select, sequence, and/or combine these therapeutic approaches. Furthermore, it is unclear how to best identify additional patients who could benefit from adjuvant olaparib beyond the original OlympiA criteria. Since it is unlikely that new clinical trials will answer these questions, recommendations for clinical practice can be made through indirect evidence. In this article, we review available data that could help guide treatment decisions for gBRCA1/2m carriers with high-risk, early-stage breast cancer.

Differences in induced thermotolerance among populations of Olympia oysters.

An organism's ability to cope with thermal stress is an important predictor of survival in a changing climate. One way in which organisms may acclimatize to thermal stress in the short-term is through induced thermotolerance, whereby exposure to a sublethal heat shock enables the organism to subsequently survive what might otherwise be a lethal event. Whether induced thermotolerance is related to basal thermotolerance is not well understood for marine organisms. Furthermore, whether populations often differ in their capacity for induced thermotolerance is also unclear. Here, we tested for differences in basal thermotolerance and induced thermotolerance among six populations of Olympia oysters (Ostrea lurida) from three California estuaries. Oysters were raised under common-garden laboratory conditions for a generation and then exposed to two treatments (control or sublethal heat shock) followed by a spectrum of temperatures that bound the upper critical temperature in order to determine LT50 (temperature at which 50% of the population dies). All populations exhibited induced thermotolerance by increasing their LT50 to a similar maximum temperature when extreme thermal stress was preceded by a sublethal heat shock. However, populations differed in their basal thermotolerance and their plasticity in thermotolerance. Populations with the highest basal thermotolerance were least able to modify upper critical temperature, while the population with the lowest basal thermotolerance exhibited the greatest plasticity in the upper critical temperature. Our results highlight that populations with high basal thermotolerance may be most vulnerable to climate warming because they lack the plasticity required to adjust their upper thermal limits.

Life Expectancy of Olympic Wrestling Champions in Comparison to the General Population.

Although it was presumed that moderate exercise is a healthy practice but long term high intensity exercise is not, studies observed a life expectancy benefit for both high-intensity endurance and fast power sports athlets, but the data for contact sports are conflicting. Therefore, the author aimed to investigate the life expectancy of Olympic wrestling champions in comparison to the general population. Characteristics, vital status and life-span of the male Olympic wrestling champions was collected (1896-2016). The life expectancy of Olympic champions was compared with matched individuals of the general population (by country, age, and year of birth) obtained from the human mortality database ( http://www.mortality.org ). Overall, 341 male Olympic wrestling champions with median age of 25 (IQR 24-28) years at their Olympic victory were included in this analysis. In total, 142 (41.6%) came of rich countries. The survival was not affected by weight class and country of origin. A significant life expectancy benefit for Olympic champions in comparison to the general population was observed. Male Olympic wrestling champions lived in mean 19.1 ± 19.1 years longer than the matched individuals of the general population (respectively of their country of origin). A substantially lower mortality in male Olympic wrestling champions, compared with the general male population was observed. However, the results do not allow us to draw conclusions about the causes of this survival benefit.

Timing of stressors alters interactive effects on a coastal foundation species.

The effects of climate-driven stressors on organismal performance and ecosystem functioning have been investigated across many systems; however, manipulative experiments generally apply stressors as constant and simultaneous treatments, rather than accurately reflecting temporal patterns in the natural environment. Here, we assessed the effects of temporal patterns of high aerial temperature and low salinity on survival of Olympia oysters (Ostrea lurida), a foundation species of conservation and restoration concern. As single stressors, low salinity (5 and 10 psu) and the highest air temperature (40°C) resulted in oyster mortality of 55.8, 11.3, and 23.5%, respectively. When applied on the same day, low salinity and high air temperature had synergistic negative effects that increased oyster mortality. This was true even for stressor levels that were relatively mild when applied alone (10 psu and 35°C). However, recovery times of two or four weeks between stressors eliminated the synergistic effects. Given that most natural systems threatened by climate change are subject to multiple stressors that vary in the timing of their occurrence, our results suggest that it is important to examine temporal variation of stressors in order to more accurately understand the possible biological responses to global change.

Testing local and global stressor impacts on a coastal foundation species using an ecologically realistic framework.

Despite the abundance of literature on organismal responses to multiple environmental stressors, most studies have not matched the timing of experimental manipulations with the temporal pattern of stressors in nature. We test the interactive effects of diel-cycling hypoxia with both warming and decreased salinities using ecologically realistic exposures. Surprisingly, we found no evidence of negative synergistic effects on Olympia oyster growth; rather, we found only additive and opposing effects of hypoxia (detrimental) and warming (beneficial). We suspect that diel-cycling provided a temporal refuge that allowed physiological compensation. We also tested for latent effects of warming and hypoxia to low-salinity tolerance using a seasonal delay between stressor events. However, we did not find a latent effect, rather a threshold survival response to low salinity that was independent of early life-history exposure to warming or hypoxia. The absence of synergism is likely the result of stressor treatments that mirror the natural timing of environmental stressors. We provide environmental context for laboratory experimental data by examining field time series environmental data from four North American west coast estuaries and find heterogeneous environmental signals that characterize each estuary, suggesting that the potential stressor exposure to oysters will drastically differ over moderate spatial scales. This heterogeneity implies that efforts to conserve and restore oysters will require an adaptive approach that incorporates knowledge of local conditions. We conclude that studies of multiple environmental stressors can be greatly improved by integrating ecologically realistic exposure and timing of stressors found in nature with organismal life-history traits.

Real-world prevalence, treatment and survival of "high risk" early breast cancer, with mandatory testing of gBRCA1/2 mutation according to the OlympiA trial inclusion criteria: Data from a population-based registry.

BACKGROUND: The results of the OlympiA study led to the approval of a PARP inhibitor (olaparib) as adjuvant treatment for early breast cancer (eBC) at high risk of relapse in patients with a germline BRCA1/2 mutation (gBRCAm). However, the proportion of patients in routine practice who meet the "high-risk" criteria applied in the OlympiA study, and for whom gBRCAm testing would now be mandatory, remains unknown. PATIENTS AND METHODS: In this population-based study, we use unique data from the French specialized Côte d'Or Breast and Gynecological Cancer Registry, to assess the real-life proportion, and long-term prognosis of patients treated for eBC between 2005 and 2015 with standard treatment, and at "high risk" of relapse according to the OlympiA trial criteria. RESULTS: We included 3483 patients treated for HER2-negative eBC (N = 380 with ER-, and N = 3103 with ER + tumor). We found N = 62 (1.8 %) patients with gBRCA1/2 mutations. A total of 494 patients (14.2 %) were classified as "high risk" according to the Olympia criteria; 55 % with ER-tumors, and 9.1 % with ER + tumors, respectively. Despite more intensive systemic treatments in "high risk" patients, 10-year overall survival was much worse in these "high risk" patients compared to the others: 60.1 % vs 83.8 % in ER-tumors, and 55.4 % vs 84.1 % in ER + tumors. Our estimates of net survival show an even greater difference. CONCLUSION: This study provides real-life insights into the prevalence and prognosis of patients with high-risk eBC, in a context where the approval of adjuvant olaparib requires careful reorganization of care, so as not to overlook a patient with gBRCAm who could benefit from adjuvant olaparib.

In situ habitat clearance rates and particle size preference of indigenous Olympia oysters (Ostrea lurida) and non-native Pacific oysters (Magallana gigas) in North American Pacific coast estuaries.

The Olympia oyster, Ostrea lurida, is the target of many restoration projects along estuaries on the North American Pacific coast, while the non-native Pacific oyster, Magallana gigas, dominates oyster aquaculture globally. Both species provide filtration functions that were investigated in three California bays using a whole-habitat, in situ approach, a laboratory particle selection experiment, and a regional physiological comparison. Measurements of chlorophyll α, temperature, salinity, and turbidity upstream and downstream, as well as point samples of seston total particulate matter and organic content to estimate habitat clearance rates (HCR, L hr-1 m-2) were collected. From February 2018 to June 2019, twenty-two trials were conducted across four sites. HCRs were highly variable within and among sites, ranging from site averages of -464 to 166 L hr-1 m-2, and not significantly different among sites, indicating field filtration performance of O. lurida habitat and M. gigas aquaculture is similar. Using a random forest regression, site was the most important predictor of HCR, with a variable importance score of 25.7 % (SD = 4.6 %). O. lurida and M. gigas had significantly different particle size selection preferences, likely affecting the quality of their filtration. This study's findings suggest that restoring O. lurida habitat may provide similar filtration benefits as M. gigas aquaculture, but the unique hydrodynamics and food quality of individual bays, as well as regional differences in filter feeder communities, must be considered in managing oyster habitat for filtration functions.

Morphometric and topographic data of small and medium size landforms in the Northern Circumpolar Region of Mars.

A substantial dataset containing topographic landforms at Olympia Undae and Scandia Cavi in the Northern circumpolar region of Mars was created by Sanchez-Bayton et al. (2022) [1]. This dataset contains the essential morphometric parameters of 200 small and medium-size landforms. In particular, it includes cratered, non-cratered, and complex irregular structures. Experimental Data Records (EDR) were obtained from the Mars Express, Mars Reconnaissance Orbiter, and Mars Global Surveyor missions, and the analysed dataset was produced thanks to the Java Mission-planning and Analysis for Remote Sensing (JMARS) software. This dataset constitutes a significant improvement in the characterisation of the small and medium-size topographic structures in the Northern circumpolar region of Mars and it contributes towards better understanding of the Northern circumpolar area. This dataset is of great value for modellers and other studies of the Martian surface processes, related to volcanic structures, aeolian processes driving to erosion or deposition, sublimation and subglacial processes, and several impact events.

Importance of Early Next-Generation Sequencing in Microsatellite Unstable Colon Cancer With a High Tumor Mutation Burden.

Colon cancer is one of the leading causes of cancer-related deaths. Microsatellite instability (MSI) or deficient mismatch repair proteins with a high tumor mutation burden (TMB) colon cancer are less responsive to chemotherapy. Targeted therapies based on early next-generation sequencing (NGS) in metastatic colon cancer can help significantly in overall prognosis. Here, we report a case of colon cancer that illustrated significant TMB and MSI and responded poorly to treatment due to delay in NGS testing.

Population structure, genetic connectivity, and adaptation in the Olympia oyster (Ostrea lurida) along the west coast of North America.

Effective management of threatened and exploited species requires an understanding of both the genetic connectivity among populations and local adaptation. The Olympia oyster (Ostrea lurida), patchily distributed from Baja California to the central coast of Canada, has a long history of population declines due to anthropogenic stressors. For such coastal marine species, population structure could follow a continuous isolation-by-distance model, contain regional blocks of genetic similarity separated by barriers to gene flow, or be consistent with a null model of no population structure. To distinguish between these hypotheses in O. lurida, 13,424 single nucleotide polymorphisms (SNPs) were used to characterize rangewide population structure, genetic connectivity, and adaptive divergence. Samples were collected across the species range on the west coast of North America, from southern California to Vancouver Island. A conservative approach for detecting putative loci under selection identified 235 SNPs across 129 GBS loci, which were functionally annotated and analyzed separately from the remaining neutral loci. While strong population structure was observed on a regional scale in both neutral and outlier markers, neutral markers had greater power to detect fine-scale structure. Geographic regions of reduced gene flow aligned with known marine biogeographic barriers, such as Cape Mendocino, Monterey Bay, and the currents around Cape Flattery. The outlier loci identified as under putative selection included genes involved in developmental regulation, sensory information processing, energy metabolism, immune response, and muscle contraction. These loci are excellent candidates for future research and may provide targets for genetic monitoring programs. Beyond specific applications for restoration and management of the Olympia oyster, this study lends to the growing body of evidence for both population structure and adaptive differentiation across a range of marine species exhibiting the potential for panmixia. Computational notebooks are available to facilitate reproducibility and future open-sourced research on the population structure of O. lurida.

Complete mitochondrial genome of the Olympia oyster Ostrea lurida (Bivalvia, Ostreidae).

The complete mitochondrial (mt) genome of the Olympia oyster Ostrea lurida (16,344 bp), an economically important bivalve, was newly sequenced and annotated. Ostrea lurida is the largest reported Ostrea oyster mt genomes to date and has a comparatively highest overall A + T content (65%) among the available genomes of marine oysters. High levels of variability of nad2 and nad6 genes and that of major non-coding region (MNR) indicate their potential value as useful molecular markers for population and conservation genetic studies in the future. Phylogenetic analyses based on concatenated nucleotide sequences from all 13 PCGs and 2 rRNA genes show that the European flat oyster Ostrea edulis is sister to the Asian slipper oyster Ostrea denselamellosa, while O. lurida is put at the most basal position of the clade, and indicate that Ostrea are closer to Saccostrea than Crassostrea, although gene arrangement shows a closer relationship between Ostrea and Crassostrea. The observations of the evolutionary pattern of start codon usage among the three congeneric oysters indicate that variation in start codon usage is species-correlated rather than gene-correlated, and to some extent, bears useful phylogenetic information.