Introduction
Severe immune‐related adverse events (irAEs) due to immune checkpoint inhibitors (ICIs) can lead to admission to the intensive care unit (ICU). In this retrospective study, we determined ...the incidence, treatment patterns and survival outcomes of this patient population at a comprehensive cancer center.
Methods
All patients admitted to the ICU due to irAEs from ICI treatment between January 2015 and July 2022 were included. Descriptive statistics were reported on patient characteristics and treatment patterns during hospital admission. Overall survival (OS) from the time of ICU discharge to death was estimated using the Kaplan–Meier method.
Results
Over the study period, 5561 patients received at least one ICI administration, of which 32 patients (0.6%) were admitted to the ICU due to irAEs. Twenty patients were treated with anti‐PD‐1 plus anti‐CTLA‐4 treatment, whereas 12 patients were treated with ICI monotherapy. The type of irAEs were de novo diabetes‐related ketoacidosis (n = 8), immune‐related gastrointestinal toxicity (n = 8), myocarditis or myositis (n = 10), nephritis (n = 3), pneumonitis (n = 2), and myelitis (n = 1). The median duration of ICU admission was 3 days (interquartile range: 2–6 days). Three patients died during ICU admission. The median OS of the patients who were discharged from the ICU was 18 months (95% confidence interval, 5.0—NA).
Conclusion
The incidence of irAEs leading to ICU admission in patients treated with ICI was low in this study. ICU mortality due to irAEs was low and a subset of this patient population even had long‐term survival.
In a process linked to DNA replication, duplicated chromosomes are entrapped in large, circular cohesin complexes and functional sister chromatid cohesion (SCC) is established by acetylation of the ...SMC3 cohesin subunit. Roberts Syndrome (RBS) and Warsaw Breakage Syndrome (WABS) are rare human developmental syndromes that are characterized by defective SCC. RBS is caused by mutations in the SMC3 acetyltransferase ESCO2, whereas mutations in the DNA helicase DDX11 lead to WABS. We found that WABS-derived cells predominantly rely on ESCO2, not ESCO1, for residual SCC, growth and survival. Reciprocally, RBS-derived cells depend on DDX11 to maintain low levels of SCC. Synthetic lethality between DDX11 and ESCO2 correlated with a prolonged delay in mitosis, and was rescued by knockdown of the cohesin remover WAPL. Rescue experiments using human or mouse cDNAs revealed that DDX11, ESCO1 and ESCO2 act on different but related aspects of SCC establishment. Furthermore, a DNA binding DDX11 mutant failed to correct SCC in WABS cells and DDX11 deficiency reduced replication fork speed. We propose that DDX11, ESCO1 and ESCO2 control different fractions of cohesin that are spatially and mechanistically separated.
Premature loss of sister chromatid cohesion at metaphase is a diagnostic marker for different cohesinopathies. Here, we report that metaphase spreads of many cancer cell lines also show premature ...loss of sister chromatid cohesion. Cohesion loss occurs independently of mutations in cohesion factors including SA2, a cohesin subunit frequently inactivated in cancer. In untransformed cells, induction of DNA replication stress by activation of oncogenes or inhibition of DNA replication is sufficient to trigger sister chromatid cohesion loss. Importantly, cell growth under conditions of replication stress requires the cohesin remover WAPL. WAPL promotes rapid RAD51-dependent repair and restart of broken replication forks. We propose that active removal of cohesin allows cancer cells to overcome DNA replication stress. This leads to oncogene-induced cohesion loss from newly synthesized sister chromatids that may contribute to genomic instability and likely represents a targetable cancer cell vulnerability.
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•Cohesion loss is a common feature of cancer cells•DNA replication stress induces cohesion loss•The cohesin remover WAPL is essential in replication stress conditions•WAPL promotes repair and restart of a broken replication fork
Benedict et al. show that in cancer cells the connection between newly synthesized chromatids (cohesion) is often less tight than in normal cells. They show that removal of cohesion in cancer cells is necessary to repair broken DNA replication forks and to sustain tumor cell expansion.
Abstract
Warsaw Breakage Syndrome (WABS) is a rare disorder related to cohesinopathies and Fanconi anemia, caused by bi-allelic mutations in
DDX11
. Here, we report multiple compound heterozygous ...WABS cases, each displaying destabilized DDX11 protein and residual DDX11 function at the cellular level. Patient-derived cell lines exhibit sensitivity to topoisomerase and PARP inhibitors, defective sister chromatid cohesion and reduced DNA replication fork speed. Deleting DDX11 in RPE1-TERT cells inhibits proliferation and survival in a TP53-dependent manner and causes chromosome breaks and cohesion defects, independent of the expressed pseudogene
DDX12p
. Importantly, G-quadruplex (G4) stabilizing compounds induce chromosome breaks and cohesion defects which are strongly aggravated by inactivation of DDX11 but not FANCJ. The DNA helicase domain of DDX11 is essential for sister chromatid cohesion and resistance to G4 stabilizers. We propose that DDX11 is a DNA helicase protecting against G4 induced double-stranded breaks and concomitant loss of cohesion, possibly at DNA replication forks.
The objective of this study was to investigate effects of calf transport age (14 vs. 28 d) and calf (e.g., sex and breed) and dam characteristics (e.g., parity and ease of birth) on health and ...performance of veal calves until slaughter age. Calves (n = 683) originated from 13 dairy farms in the Netherlands and were transported at either 14 or 28 d of age from the dairy farm to 8 Dutch veal farms. A health assessment of calves was performed on a weekly basis at the dairy farm and in wk 2, 10, 18, and 24 at the veal farm. Body weight of calves was measured on a weekly basis at the dairy farm and upon arrival at the veal farm. At the veal farm, use of antibiotics and other medicines during the rearing period (both at herd and individual level) was recorded and carcass weights were obtained from the slaughterhouse. Body weight upon arrival (Δ = 11.8 kg) and carcass weight at slaughter (Δ = 14.8 kg) were greater, and mortality risk (Δ = −3.1%) and prevalence of animals treated with medicines other than antibiotics (e.g., antiinflammatories, multivitamins, and anticoccidial drugs; Δ = −5.4%) were lower in calves transported at 28 d compared with calves transported at 14 d. Crossbreds other than Belgian Blue × Holstein Friesian received a higher number of individual treatments with antibiotics and other medicines (Δ = 14.8% and Δ = 15.1%, respectively) at the veal farm compared with Belgian Blue × Holstein Friesian calves. These findings suggest that calves transported at 28 d were more robust compared with calves transported at 14 d.
This study aimed to investigate effects of pretransport diet (rearing milk vs. electrolytes), type of vehicle (open vs. conditioned truck), and transport duration (6 vs. 18 h) on physiological status ...of young calves upon arrival at the veal farm. A total of 368 calves were transported in 2 consecutive batches from a collection center to a veal farm. Blood samples were collected from calves before transport; immediately posttransport (T0); and 4, 24, and 48 h, and 1, 3, and 5 wk posttransport. Blood was analyzed for glucose, urea, lactate, nonesterified fatty acids (NEFA), β-hydroxybutyrate (BHB), creatine kinase, albumin, total protein, osmolality, calcium, sodium, magnesium, and hematological variables. Body weight, rectal temperature, and skin elasticity were determined before and immediately posttransport. Blood glucose, NEFA, and urea concentrations at T0 showed an interaction between pretransport diet and transport duration. Milk-fed and electrolyte-fed calves transported for 18 h did not significantly differ in plasma glucose concentration or serum NEFA concentrations. However, after 6 h of transport, milk-fed calves had higher plasma glucose and lower serum NEFA concentrations (4.71 mmol/L and 586.5 µmol/L, respectively) than electrolyte-fed calves (3.56 mmol/L and 916 µmol/L, respectively). After 18 h of transport, milk-fed calves had lower urea concentrations (5.40 mmol/L) than electrolyte-fed calves (7.38 mmol/L). In addition, at T0, after 6 h of transport, milk-fed calves gained weight (Δ = 0.41 kg), whereas electrolyte-fed calves lost weight (Δ = −0.16 kg). After 18 h of transport, both milk-fed and electrolyte-fed calves showed body weight losses (Δ = −0.67 and −0.74 kg, respectively). Type of vehicle had a limited influence on blood parameters. Concentrations of NEFA and BHB reached the maximum values at T0 and then decreased until wk 5 posttransport. The increase in NEFA and BHB concentrations between prior to and just posttransport (T0) was less pronounced in calves transported for 6 h (746.1 µmol/L and 0.38 mmol/L, respectively) than in calves transported for 18 h (850.6 µmol/L and 0.50 mmol/L). Overall, the recovery rate of calves at the veal farm seemed rapid; all blood parameters returned to (below) pretransport values within 48 h posttransport. We concluded that feeding milk before short-term transport helps young veal calves cope with transport, whereas this is not the case during long-term transport.
Severe thrombocytopenia should be corrected by prophylactic platelet transfusion prior to central venous catheter (CVC) insertion, according to national and international guidelines. Even though ...correction is thought to prevent bleeding complications, evidence supporting the routine administration of prophylactic platelets is absent. Furthermore, platelet transfusion bears inherent risk. Since the introduction of ultrasound-guided CVC placement, bleeding complication rates have decreased. The objective of the current trial is, therefore, to demonstrate that omitting prophylactic platelet transfusion prior to CVC placement in severely thrombocytopenic patients is non-inferior compared to prophylactic platelet transfusion.
The PACER trial is an investigator-initiated, national, multicentre, single-blinded, randomised controlled, non-inferior, two-arm trial in haematologic and/or intensive care patients with a platelet count of between 10 and 50 × 10
/L and an indication for CVC placement. Consecutive patients are randomly assigned to either receive 1 unit of platelet concentrate, or receive no prophylactic platelet transfusion prior to CVC insertion. The primary endpoint is WHO grades 2-4 bleeding. Secondary endpoints are any bleeding complication, costs, length of intensive care and hospital stay and transfusion requirements.
This is the first prospective, randomised controlled trial powered to test the hypothesis of whether omitting forgoing platelet transfusion prior to central venous cannulation leads to an equal occurrence of clinical relevant bleeding complications in critically ill and haematologic patients with thrombocytopenia.
Nederlands Trial Registry, ID: NTR5653 ( http://www.trialregister.nl/trialreg/index.asp ). Registered on 27 January 2016. Currently recruiting. Randomisation commenced on 23 February 2016.
This study aimed to investigate effects of transport age of calves (14 vs. 28 d), and of calf and dam characteristics, on immunoglobulin titers and hematological variables of veal calves. Calves (n = ...683) were transported to a veal farm at 14 or 28 d of age. Natural antibodies N-IgG, N-IgM, and N-IgA against phosphorylcholine conjugated to bovine serum albumin (PC-BSA) were measured in serum of the dams 1 wk before calving and in first colostrum. These antibodies were also measured in serum of calves 1 wk after birth, 1 d before transport, and in wk 2 and 10 posttransport at the veal farm. Hematological variables were assessed in calves 1 d before transport and in wk 2 posttransport. One day before transport, titers of N-IgG, N-IgM, N-IgA, and neutrophil counts were higher, and lymphocyte counts were lower in 14-d-old calves compared with 28-d-old calves. In wk 2 at the veal farm, calves transported at 14 d of age had higher N-IgG titers and neutrophil counts, but lower N-IgM and N-IgA titers, and lymphocyte counts than calves transported at 28 d. In wk 1 and 1 d before transport, N-Ig in calves were positively related to N-Ig in colostrum. In wk 2 and 10 at the veal farm, N-IgG in calves was positively related to N-IgG in colostrum. The N-IgG titers in calves at the dairy farm were negatively related to the likelihood of being individually treated with antibiotics or other medicines at the veal farm. Our results suggest that calves transported to the veal farm at 28 d of age showed a more advanced development of their adaptive immunity than calves transported at 14 d of age. Quality of colostrum might have long-term consequences for N-IgG titers and immunity in veal calves.
Dairy calves, including surplus calves, are typically separated from their dam within hours of birth. The aim of this study was to assess the welfare impacts of raising surplus calves destined for ...veal with their dam for 2 or 4 weeks until transport. Surplus calves from one dairy farm were separated from their dam at birth (n = 39) or kept with the dam (n = 37) until transport to the veal farm at either 2 (n = 50) or 4 (n = 26) weeks of age, with abrupt separation for dam-reared calves. Calf measures of body weight, health, immunity, haematology and behaviour were recorded at the dairy and veal farms. Dam-reared calves had higher body weights in weeks 3, 4 and 5 at the DF, as well as at arrival at the veal farm, but by slaughter this advantage was lost. More dam-reared calves had fever in week 3 and showed signs of disease in week 5 at the dairy farm. Dam-reared calves did not differ in IgG, IgA or IgM levels but had higher counts of white blood cells, which could reflect a higher pathogen exposure rather than improved immunity. Dam-reared calves displayed more fear towards humans in a human approach test at 5 and 7 weeks after arrival at the veal farm, and more frequent social behaviours at the veal farm at 9 and 16 weeks of age. In conclusion, it seems that there may be both advantages and disadvantages to keeping veal calves with the dam in terms of welfare in the current system.
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