Susceptibility of Two Southern Ocean Phytoplankton Key Species to Iron Limitation and High Light

Although iron (Fe) availability primarily sets the rate of phytoplankton growth and primary and export production in the Southern Ocean, other environmental factors, most significantly light, also affect productivity. As light availability strongly influences phytoplankton species distribution in low Fe-waters, we investigated the combined effects of increasing light (20, 200, and 500 μmol photons m-2 s-1) in conjunction with different Fe (0.4 and 2 nM) availability on the physiology of two ecologically relevant phytoplankton species in the Southern Ocean, Chaetoceros debilis (Bacillariophyceae) and Phaeocystis antarctica (Haptophyceae). Fe-deficient cells of P. antarctica displayed similar high growth rates at all irradiances. In comparison, Fe-deplete C. debilis cells grew much slower under low and medium irradiance and were unable to grow at the highest irradiance. Interestingly, Fe-deficient C. debilis cells were better protected against short-term excessive irradiances than P. antarctica. This tolerance was apparently counteracted by strongly lowered growth and particulate organic carbon production rates of the diatom relative to the prymnesiophyte. Overall, our results show that P. antarctica was the more tolerant species to changes in the availability of Fe and light, providing it a competitive advantage under a high light regime in Fe-deficient waters as projected for the future

Early Exanthema Upon Vemurafenib Plus Cobimetinib Is Associated With a Favorable Treatment Outcome in Metastatic Melanoma: A Retrospective Multicenter DeCOG Study

Background: The combination of BRAF and MEK inhibitors has become standard of care in the treatment of metastatic BRAF V600-mutated melanoma. Clinical factors for an early prediction of tumor response are rare. The present study investigated the association between the development of an early exanthema induced by vemurafenib or vemurafenib plus cobimetinib and therapy outcome. Methods: This multicenter retrospective study included patients with BRAF V600-mutated irresectable AJCC-v8 stage IIIC/D to IV metastatic melanoma who received treatment with vemurafenib (VEM) or vemurafenib plus cobimetinib (COBIVEM). The development of an early exanthema within six weeks after therapy start and its grading according to CTCAEv4.0 criteria was correlated to therapy outcome in terms of best overall response, progression-free (PFS), and overall survival (OS). Results: A total of 422 patients from 16 centers were included (VEM, n=299; COBIVEM, n=123). 20.4% of VEM and 43.1% of COBIVEM patients developed an early exanthema. In the VEM cohort, objective responders (CR/PR) more frequently presented with an early exanthema than non-responders (SD/PD); 59.0% versus 38.7%; p=0.0027. However, median PFS and OS did not differ between VEM patients with or without an early exanthema (PFS, 6.9 versus 6.0 months, p=0.65; OS, 11.0 versus 12.4 months, p=0.69). In the COBIVEM cohort, 66.0% of objective responders had an early exanthema compared to 54.3% of non-responders (p=0.031). Median survival times were significantly longer for patients who developed an early exanthema compared to patients who did not (PFS, 9.7 versus 5.6 months, p=0.013; OS, not reached versus 11.6 months, p=0.0061). COBIVEM patients with a mild early exanthema (CTCAEv4.0 grade 1-2) had a superior survival outcome as compared to COBIVEM patients with a severe (CTCAEv4.0 grade 3-4) or non early exanthema, respectively (p=0.047). This might be caused by the fact that 23.6% of patients with severe exanthema underwent a dose reduction or discontinuation of COBIVEM compared to only 8.9% of patients with mild exanthema. Conclusions: The development of an early exanthema within 6 weeks after treatment start indicates a favorable therapy outcome upon vemurafenib plus cobimetinib. Patients presenting with an early exanthema should therefore be treated with adequate supportive measures to provide that patients can stay on treatment

Immune Checkpoint Blockade for Metastatic Uveal Melanoma: Re-Induction following Resistance or Toxicity

Re-induction with immune checkpoint blockade (ICB) needs to be considered in many patients with uveal melanoma (UM) due to limited systemic treatment options. Here, we provide hitherto the first analysis of ICB re-induction in UM. A total of 177 patients with metastatic UM treated with ICB were included from German skin cancer centers and the German national skin cancer registry (ADOReg). To investigate the impact of ICB re-induction, two cohorts were compared: patients who received at least one ICB re-induction (cohort A, n = 52) versus those who received only one treatment line of ICB (cohort B, n = 125). In cohort A, a transient benefit of overall survival (OS) was observed at 6 and 12 months after the treatment start of ICB. There was no significant difference in OS between both groups (p = 0.1) with a median OS of 16.2 months (cohort A, 95% CI: 11.1–23.8) versus 9.4 months (cohort B, 95% CI: 6.1–14.9). Patients receiving re-induction of ICB (cohort A) had similar response rates compared to those receiving ICB once. Re-induction of ICB may yield a clinical benefit for a small subgroup of patients even after resistance or development of toxicities

Stringent monitoring can decrease mortality of immune checkpoint inhibitor induced cardiotoxicity

BackgroundImmune checkpoint inhibitor (ICI)-induced myocarditis is a rare immune-related adverse event (irAE) with a fatality rate of 40%–46%. However, irMyocarditis can be asymptomatic. Thus, improved monitoring, detection and therapy are needed. This study aims to generate knowledge on pathogenesis and assess outcomes in cancer centers with intensified patient management.MethodsPatients with cardiac irAEs from the SERIO registry (www.serio-registry.org) were analyzed for demographics, ICI-related information (type of ICI, therapy line, combination with other drugs, onset of irAE, and tumor response), examination results, irAE treatment and outcome, as well as oncological endpoints. Cardiac biopsies of irMyocarditis cases (n = 12) were analyzed by Nanostring and compared to healthy heart muscle (n = 5) and longitudinal blood sampling was performed for immunophenotyping of irMyocarditis-patients (n = 4 baseline and n = 8 during irAE) in comparison to patients without toxicity under ICI-therapy (n = 4 baseline and n = 7 during ICI-therapy) using flow cytometry.ResultsA total of 51 patients with 53 cardiac irAEs induced by 4 different ICIs (anti-PD1, anti-PD-L1, anti-CTLA4) were included from 12 centers in 3 countries. Altogether, 83.0% of cardiac irAEs were graded as severe or life-threatening, and 11.3% were fatal (6/53). Thus, in centers with established consequent troponin monitoring, work-up upon the rise in troponin and consequent treatment of irMyocarditis with corticosteroids and –if required–second-line therapy mortality rate is much lower than previously reported. The median time to irMyocarditis was 36 days (range 4–1,074 days) after ICI initiation, whereas other cardiotoxicities, e.g. asystolia or myocardiopathy, occurred much later. The cytokine-mediated signaling pathway was differentially regulated in myocardial biopsies as compared to healthy heart based on enrichment Gene Ontology analysis. Additionally, longitudinal peripheral blood mononuclear cell (PBMC) samples from irMyocarditis-patients indicated ICI-driven enhanced CD4+ Treg cells and reduced CD4+ T cells. Immunophenotypes, particularly effector memory T cells of irMyocarditis-patients differed from those of ICI-treated patients without side effects. LAG3 expression on T cells and PD-L1 expression on dendritic cells could serve as predictive indicators for the development of irMyocarditis.ConclusionInterestingly, our cohort shows a very low mortality rate of irMyocarditis-patients. Our data indicate so far unknown local and systemic immunological patterns in cardiotoxicity

Real‐world outcomes using PD‐1 antibodies and BRAF + MEK inhibitors for adjuvant melanoma treatment from 39 skin cancer centers in Germany, Austria and Switzerland

Abstract Background Programmed death‐1 (PD‐1) antibodies and BRAF + MEK inhibitors are widely used for adjuvant therapy of fully resected high‐risk melanoma. Little is known about treatment efficacy outside of phase III trials. This real‐world study reports on clinical outcomes of modern adjuvant melanoma treatment in specialized skin cancer centers in Germany, Austria and Switzerland. Methods Multicenter, retrospective study investigating stage III–IV melanoma patients receiving adjuvant nivolumab (NIV), pembrolizumab (PEM) or dabrafenib + trametinib (D + T) between 1/2017 and 10/2021. The primary endpoint was 12‐month recurrence‐free survival (RFS). Further analyses included descriptive and correlative statistics, and a multivariate linear‐regression machine learning model to assess the risk of early melanoma recurrence. Results In total, 1198 patients from 39 skin cancer centers from Germany, Austria and Switzerland were analysed. The vast majority received anti PD‐1 therapies (n = 1003). Twelve‐month RFS for anti PD‐1 and BRAF + MEK inhibitor‐treated patients were 78.1% and 86.5%, respectively (hazard ratio [HR] 1.998 [95% CI 1.335–2.991]; p = 0.001). There was no statistically significant difference in overall survival (OS) in anti PD‐1 (95.8%) and BRAF + MEK inhibitor (96.9%) treated patients (p > 0.05) during the median follow‐up of 17 months. Data indicates that anti PD‐1 treated patients who develop immune‐related adverse events (irAEs) have lower recurrence rates compared to patients with no irAEs (HR 0.578 [95% CI 0.443–0.754], p = 0.001). BRAF mutation status did not affect overall efficacy of anti PD‐1 treatment (p > 0.05). In both, anti PD‐1 and BRAF + MEK inhibitor treated cohorts, data did not show any difference in 12‐month RFS and 12‐month OS comparing patients receiving total lymph node dissection (TLND) versus sentinel lymph node biopsy only (p > 0.05). The recurrence prediction model reached high specificity but only low sensitivity with an AUC = 0.65. No new safety signals were detected. Overall, recorded numbers and severity of adverse events were lower than reported in pivotal phase III trials. Conclusions Despite recent advances in adjuvant melanoma treatment, early recurrence remains a significant clinical challenge. This study shows that TLND does not reduce the risk of early melanoma recurrence and should only be considered in selected patients. Data further highlight that variables collected during clinical routine are unlikely to allow for a clinically relevant prediction of individual recurrence risk

Optimizing immune checkpoint blockade in metastatic uveal melanoma: exploring the association of overall survival and the occurrence of adverse events

IntroductionDespite recent advancements in the treatment of metastatic uveal melanoma (UM), the availability of further treatment options remains limited and the prognosis continues to be poor in many cases. In addition to tebentafusp, immune checkpoint blockade (ICB, PD-1 (+/-) CTLA-4 antibodies) is commonly used for metastatic UM, in particular in HLA-A 02:01-negative patients. However, ICB comes at the cost of potentially severe immune-related adverse events (irAE). Thus, the selection of patient groups that are more likely to benefit from ICB is desirable.MethodsIn this analysis, 194 patients with metastatic UM undergoing ICB were included. Patients were recruited from German skin cancer sites and the ADOReg registry. To investigate the association of irAE occurrence with treatment response, progression-free survival (PFS), and overall survival (OS) two cohorts were compared: patients without irAE or grade 1/2 irAE (n=137) and patients with grade 3/4 irAE (n=57).ResultsIn the entire population, the median OS was 16.4 months, and the median PFS was 2.8 months. Patients with grade 3/4 irAE showed more favorable survival than patients without or grade 1/2 irAE (p=0.0071). IrAE occurred in 44.7% (87/194), and severe irAE in 29.4% (57/194) of patients. Interestingly, irColitis and irHepatitis were significantly associated with longer OS (p=0.0031 and p=0.011, respectively).ConclusionsThis data may indicate an association between irAE and favorable survival outcomes in patients with metastatic UM undergoing ICB treatment and suggests that a reduced tolerance to tumor antigens could be linked to reduced tolerance to self-antigens

Seawater carbonate chemistry and particulate organic carbon accumulation of two Antarctic diatom species

Impacts of rising atmospheric CO2 concentrations and increased daily irradiances from enhanced surface water stratification on phytoplankton physiology in the coastal Southern Ocean remain still unclear. Therefore, in the two Antarctic diatoms Fragilariopsis curta and Odontella weissflogii the effects of moderate and high natural solar radiation combined with either ambient or future pCO2 on cellular particulate organic carbon (POC) contents and photophysiology were investigated. Results showed that increasing CO2 concentrations had greater impacts on diatom physiology than exposure to increasing solar radiation. Irrespective of the applied solar radiation regime, cellular POC quotas increased with future pCO2 in both diatoms. Lowered maximum quantum yields of photochemistry in PSII (Fv/Fm) indicated a higher photosensitivity under these conditions, being counteracted by increased cellular concentrations of functional photosynthetic reaction centers. Overall, our results suggest that both bloom‐forming Antarctic coastal diatoms might increase carbon contents under future pCO2 conditions despite reduced physiological fitness. This indicates a higher potential for primary productivity by the two diatom species with important implications for the CO2 sequestration potential of diatom communities in the future coastal Southern Ocean

Fast Processing Affects the Relaxation of Polymers: The Slow Arrhenius Process Can Probe Stress at the Molecular Level

info:eu-repo/semantics/publishe

Impact of light and iron availability on Antarctic phytoplankton ecophysiology

Although iron (Fe) availability sets primarily the rate of phytoplankton growth and primary and export production in the Southern Ocean, other environmental factors, most significantly light, also affect productivity. Due to wind-induced vertical mixing, the total irradiance dose can be reduced, but exposing phytoplankton also to periods of excessive irradiance when residing near the surface. As these dynamic alterations between low and high irradiance in low Fe-waters are important drivers of species distribution, we investigated the effects of light (20, 200 and 500 μmol photons m−2 s−1) in combination with low and high Fe availability (0.4 and 2 nM Fe) on the physiology of the two ecologically relevant species Chaetoceros debilis and Phaeocystis antarctica. Fe-limited cells of P. antarctica displayed similar high growth rates at all irradiances. In comparison, Fe-limited C. debilis cells grew much slower under low and medium irradiance and were unable to grow at the highest irradiance. Compared to C. debilis Fe-limited P. antarctica cells fixed more particulate organic carbon at all irradiances. When exposed to short-term excessive irradiances C. debilis could cope better than P. antarctica under low Fe conditions, but this was at the expense of lowered carbon production. Overall, our results show that P. antarctica was more tolerant to changes in the availability of Fe and light, providing it a competitive advantage under a dynamic light regime in Fe-deficient waters