The Oncological Emergency Case: Paraneoplastic Hypoglycemia in Metastatic Breast Cancer - Case Report and Brief Review of the Literature

Background: Paraneoplastic hypoglycemia is a rare syndrome amoungtumorous diseases. It is often associated with a paraneoplasticsecretion of ‘big’ insulin-like growth factor-II. Methods: We describethis syndrome in a 60-year-old patient with advanced breast cancer 8years after primary diagnosis. Results and Conclusion: This non-isletcell tumor-induced hypoglycemia may be the only evidence for anotherwise clinically occult disease progression. Fast diagnosis andappropriate acute and causal treatment concepts should be part ofoncological management

The presence of PD-1 positive tumor infiltrating lymphocytes in triple negative breast cancers is associated with a favorable outcome of disease

Triple negative breast cancer patients have a poor course of disease not least because of limited treatment options however immunotherapy by targeting the PD-1/PD-L1 checkpoint system is a promising strategy to improve the outcome. Here we systematically investigated the expression of PD-1 on tumor infiltrating lymphocytes and PD-L1 on both tumor and infiltrated immune cells. Moreover, the PD-L1 gene status in tumor cells was assessed. 103 tissue microarray samples derived from triple negative breast cancer specimens were immunohistochemically stained against PD-1 and PD-L1. Dual marker fluorescence in-situ hybridization was applied to the PD-L1 gene and centromere region of chromosome 9. The disease free and overall survival rates were determined as a function of the PD-1/PD-L1 status. A slight gain of the PD-L1 gene region was found in 55% of all samples but an elevated PD-L1/cen9 ratio was rather rare (7%). An increased gene dose is not associated with an enhanced protein expression and the PD-L1 expression only weakly correlates with the amount of immune cell infiltration. Instead, we found an association of PD-L1 expression on tumor and immune cells, respectively. Notably, the PD-1 expression on immune cells is associated with a favorable disease free and overall survival. PD-1 expression indicates an enhanced immunological anti-tumor activity and represents a favorable prognostic impact. A deeper understanding of factors that affect the regulation and function of the PD-1/PD-L1 system is required to establish predictive variables and to utilize the system for therapeutic intervention of triple negative breast cancer patients

Impact of cavity shaving on residual tumor rates in patients with primary invasive carcinoma and carcinoma in situ in breast conserving surgery

Background Several international studies reported relatively high re-excision rates due to residual tumor in breast conserving surgery (BCS). Cavity shaving (CS) is a surgical strategy to reduce re-excision rates. This study aimed to investigate the effect of circumferential cavity shaving during BCS to reduce residual tumor. Material and Methods A total of 591 patients with early invasive carcinoma or carcinoma in situ of the breast (ICD-10, C50 or D05) who were diagnosed between 01/01/2017 and 31/12/2019 and underwent BCS in a certified breast cancer center of the University Regensburg were analyzed regarding surgical excision methods. Patients with CS during BCS and patients with targeted re-excision in a specific direction depending on the result of intraoperative mammography or sonography during BCS were compared. The risk of pathologic residual tumor (R1) was compared between both groups by means of a multivariable binary logistic regression model to determine if there is a benefit of a certain surgical method to avoid a second intervention for re-excision. We adjusted for age, tumor size, nodal status, histologic type, surgeon, breast side, and neoadjuvant chemotherapy. Results 80 (n = 13.54%) patients had CS and 511 (n = 86.46%) had a targeted re-excision in a specific direction during BCS according to intraoperative mammography or sonography. After comparing both techniques in a multivariable regression model, there was no significant difference regarding risk of residual tumor (p = 0.738) in the total cohort. However, CS showed a tendency to be favorable regarding rates of residual tumor in patients with invasive breast cancer between 60 and 70 years (p = 0.072) and smaller T1-tumors (p = 0.057) compared to targeted intraoperative re-excision following mammographic or sonographic assessment. Conclusion CS showed a tendency to reduce residual tumor compared to the standard technique of intraoperative re-excision in specific subgroups, although no statistical significance was reached. Further studies are needed to overcome potential limitations like surgeon-based bias and missing standardized definitions of CS to reduce residual tumor rates

Triple negative breast cancers express receptors for LHRH and are potential therapeutic targets for cytotoxic LHRH-analogs, AEZS 108 and AEZS 125

Background Triple negative breast cancer (TNBC) is a distinct subtype of breast cancer burdened with a dismal prognosis due to the lack of effective therapeutic agents. Receptors for LHRH (luteinizing hormone-releasing hormone) can be successfully targeted with AEZS-108 [AN-152], an analog of LHRH conjugated to doxorubicin. Our study evaluates the presence of this target LHRH receptor in human specimens of TNBC and investigates the efficacy and toxicity of AEZS-108 in vivo. We also studied in vitro activity of AEZS-125, a new LHRH analog conjugated with the highly potent natural compound, Disorazol Z. Methods 69 human surgical specimens of TNBC were investigated for LHRH-R expression by immunohistochemistry. Expression of LHRH-R in two TNBC cell lines was evaluated by real time RT-PCR. Cytotoxicity of AEZS-125 was evaluated by Cell Titer Blue cytoxicity assay. LHRH- receptor expression was silenced with an siRNA in both cell lines. For the in vivo experiments an athymic nude mice model xenotransplanted with the cell lines, MDA-MB-231 and HCC 1806, was used. The animals were randomised to three groups receiving solvent only (d 1, 7, 14, i.v.) for control, AEZS-108 (d 1, 7, 14, i.v.) or doxorubicin at an equimolar dose (d 1, 7, 14, i.v.). Results In human clinical specimens of TNBC, expression of the LHRH-receptor was present in 49% (n = 69). HCC 1806 and MDA-MB-231 TNBC cells expressed mRNA for the LHRH-receptor. Silencing of the LHRH-receptor significantly decreased the cytotoxic effect of AEZS-108. MDA-MB-231 and HCC 1806 tumors xenografted into nude mice were significantly inhibited by treatment with AEZS-108; doxorubicin at equimolar doses was ineffective. As compared to AEZS 108, the Disorazol Z – LHRH conjugate, AEZS-125, demonstrated an increased cytotoxicity in vitro in HCC 1806 and MDA-MB-231 TNBC; this was diminished by receptor blockade with synthetic LHRH agonist (triptorelin) pretreatment. Conclusion The current study confirms that LHRH-receptors are expressed by a significant proportion of TNBC and can be successfully used as homing sites for cytotoxic analogs of LHRH, such as AEZS-108 and AEZS-125

The Cold Peace: Russo-Western Relations as a Mimetic Cold War

In 1989–1991 the geo-ideological contestation between two blocs was swept away, together with the ideology of civil war and its concomitant Cold War played out on the larger stage. Paradoxically, while the domestic sources of Cold War confrontation have been transcended, its external manifestations remain in the form of a ‘legacy’ geopolitical contest between the dominant hegemonic power (the United States) and a number of potential rising great powers, of which Russia is one. The post-revolutionary era is thus one of a ‘cold peace’. A cold peace is a mimetic cold war. In other words, while a cold war accepts the logic of conflict in the international system and between certain protagonists in particular, a cold peace reproduces the behavioural patterns of a cold war but suppresses acceptance of the logic of behaviour. A cold peace is accompanied by a singular stress on notions of victimhood for some and undigested and bitter victory for others. The perceived victim status of one set of actors provides the seedbed for renewed conflict, while the ‘victory’ of the others cannot be consolidated in some sort of relatively unchallenged post-conflict order. The ‘universalism’ of the victors is now challenged by Russia's neo-revisionist policy, including not so much the defence of Westphalian notions of sovereignty but the espousal of an international system with room for multiple systems (the Schmittean pluriverse)

Does timing of neoadjuvant chemotherapy influence the prognosis in patients with early triple negative breast cancer?

Purpose For patients with triple negative breast cancer (TNBC), the optimal time to initiate neoadjuvant chemotherapy (TTNC) is unknown. This study evaluates the association between TTNC and survival in patients with early TNBC. Methods A retrospective study using data from of a cohort of TNBC patients diagnosed between January 1, 2010 to December 31, 2018 registered in the Tumor Centre Regensburg was performed. Data included demographics, pathology, treatment, recurrence, and survival. Interval to treatment was defined as days from pathology diagnosis of TNBC to first dose of neoadjuvant chemotherapy (NACT). The Kaplan–Meier and Cox regression methods were used to evaluate the impact of TTNC on overall survival (OS) and 5 year OS. Results A total of 270 patients were included. Median follow up was 3.5 years. The 5-year OS estimates according to TTNC were 77.4%, 66.9%, 82.3%, 80.6%, 88.3%, 58.3%, 71.1% and 66.7% in patients who received NACT within 0–14, 15–21, 22–28, 29–35, 36–42, 43–49, 50–56 and > 56 days after diagnosis. Patients who received systemic therapy early had the highest estimated mean OS of 8.4 years, while patients who received systemic therapy after more than 56 days survived an estimated 3.3 years. Conclusion The optimal time interval between diagnosis and NACT remains to be determined. However, starting NACT more than 42 days after diagnosis of TNBC seems to reduce survival. Therefore, it is strongly recommended to carry out the treatment in a certified breast center with appropriate structures, in order to enable an adequate and timely care

Forest microclimate dynamics drive plant responses to warming

Climate warming is causing a shift in biological communities in favor of warm-affinity species (i.e., thermophilization). Species responses often lag behind climate warming, but the reasons for such lags remain largely unknown. Here, we analyzed multidecadal understory microclimate dynamics in European forests and show that thermophilization and the climatic lag in forest plant communities are primarily controlled by microclimate. Increasing tree canopy cover reduces warming rates inside forests, but loss of canopy cover leads to increased local heat that exacerbates the disequilibrium between community responses and climate change. Reciprocal effects between plants and microclimates are key to understanding the response of forest biodiversity and functioning to climate and land-use changes

Replacements of small- by large-ranged species scale up to diversity loss in Europe’s temperate forest biome

The loss of biodiversity at the global scale has been difficult to reconcile with observations of no net loss at local scales. Vegetation surveys across European temperate forests show that this may be explained by the replacement of small-ranged species with large-ranged ones, driven by nitrogen deposition. Biodiversity time series reveal global losses and accelerated redistributions of species, but no net loss in local species richness. To better understand how these patterns are linked, we quantify how individual species trajectories scale up to diversity changes using data from 68 vegetation resurvey studies of seminatural forests in Europe. Herb-layer species with small geographic ranges are being replaced by more widely distributed species, and our results suggest that this is due less to species abundances than to species nitrogen niches. Nitrogen deposition accelerates the extinctions of small-ranged, nitrogen-efficient plants and colonization by broadly distributed, nitrogen-demanding plants (including non-natives). Despite no net change in species richness at the spatial scale of a study site, the losses of small-ranged species reduce biome-scale (gamma) diversity. These results provide one mechanism to explain the directional replacement of small-ranged species within sites and thus explain patterns of biodiversity change across spatial scales

Directional turnover towards larger-ranged plants over time and across habitats

Species turnover is ubiquitous. However, it remains unknown whether certain types of species are consistently gained or lost across different habitats. Here, we analysed the trajectories of 1827 plant species over time intervals of up to 78 years at 141 sites across mountain summits, forests, and lowland grasslands in Europe. We found, albeit with relatively small effect sizes, displacements of smaller- by larger-ranged species across habitats. Communities shifted in parallel towards more nutrient-demanding species, with species from nutrient-rich habitats having larger ranges. Because these species are typically strong competitors, declines of smaller-ranged species could reflect not only abiotic drivers of global change, but also biotic pressure from increased competition. The ubiquitous component of turnover based on species range size we found here may partially reconcile findings of no net loss in local diversity with global species loss, and link community-scale turnover to macroecological processes such as biotic homogenisation

T-cell recognition of chemicals, protein allergens and drugs: towards the development of in vitro assays

Chemicals can elicit T-cell-mediated diseases such as allergic contact dermatitis and adverse drug reactions. Therefore, testing of chemicals, drugs and protein allergens for hazard identification and risk assessment is essential in regulatory toxicology. The seventh amendment of the EU Cosmetics Directive now prohibits the testing of cosmetic ingredients in mice, guinea pigs and other animal species to assess their sensitizing potential. In addition, the EU Chemicals Directive REACh requires the retesting of more than 30,000 chemicals for different toxicological endpoints, including sensitization, requiring vast numbers of animals. Therefore, alternative methods are urgently needed to eventually replace animal testing. Here, we summarize the outcome of an expert meeting in Rome on 7 November 2009 on the development of T-cell-based in vitro assays as tools in immunotoxicology to identify hazardous chemicals and drugs. In addition, we provide an overview of the development of the field over the last two decades