Improved outcomes of large B-cell lymphoma patients treated with CD19 CAR T in the UK over time.

The success of CD19 Chimeric antigen receptor (CAR) T-cell therapy in large B-cell lymphoma (LBCL) has been partially offset by toxicity and logistical challenges, which off-the-shelf agents like CD20xCD3 bispecific antibodies might potentially overcome. However, when using CAR T outcomes as the 'standard-of-care comparator̕ for relapsed/refractory (r/r) LBCL, a potential learning curve with implementing a novel, complex therapy like CAR T needs to be considered. To address this, we analysed 726 UK patients intended to be treated with CD19 CAR T for r/r LBCL and compared outcomes between the first year of the national CAR T programme (Era 1; 2019) and the more recent treatment era (Era 2; 2020-2022). We identified significant improvements for Era 2 versus Era 1 in dropout rate (17% vs. 27%, p = 0.001), progression-free survival (1-year PFS 50% vs. 32%, p < 0.001) and overall survival (1-year OS 60% vs. 40%, p < 0.001). We also observed increased use of bridging therapy, improvement in bridging outcomes, more tocilizumab/corticosteroid use, reduced high-grade cytokine release syndrome (4% vs. 9%, p = 0.01) and intensive care unit admissions (20% vs. 32%, p = 0.001). Our results demonstrate significant improvement in CAR T outcomes over time, highlighting the importance of using up-to-date clinical data when comparing CAR T against new treatment options for r/r LBCL.

CAR T in patients with large B-cell lymphoma not fit for autologous transplant.

Large B-cell lymphoma (LBCL) patients with comorbidities and/or advanced age are increasingly considered for treatment with CD19 CAR T, but data on the clinical benefit of CAR T in the less fit patient population are still limited. We analysed outcomes of consecutive patients approved for treatment with axicabtagene ciloleucel (axi-cel) or tisagenlecleucel (tisa-cel) by the UK National CAR T Clinical Panel, according to fitness for autologous stem cell transplant (ASCT). 81/404 (20%) of approved patients were deemed unfit for ASCT. Unfit patients were more likely to receive tisa-cel versus axi-cel (52% vs. 48%) compared to 20% versus 80% in ASCT-fit patients; p < 0.0001. The drop-out rate from approval to infusion was significantly higher in the ASCT-unfit group (34.6% vs. 23.5%; p = 0.042). Among infused patients, response rate, progression-free and overall survival were similar in both cohorts. CAR T was well-tolerated in ASCT-unfit patients with an incidence of grade ≥3 cytokine release syndrome and neurotoxicity of 2% and 11%, respectively. Results from this multicentre real-world cohort demonstrate that CD19 CAR T can be safely delivered in carefully selected older patients and patients with comorbidities who are not deemed suitable for transplant.

In situ calibration of passive sampling methods for urban micropollutants using targeted multiresidue GC and LC screening systems.

In this study, ChemcatcherTM (CC) and Polar Organic Chemical Integrative Samplers (POCIS) passive samplers were chosen to investigate trace organic chemical residues in urban streams of the megacity of Sydney, Australia. In situ calibration with these passive samplers investigated 1392 organic chemicals. Six sets of CC passive samplers fitted with SDB-XC or SDB-RPS disks and six POCIS containing Oasis HLB sorbent were deployed at three sites. Every week for six weeks across three deployments, composite water samples were retrieved from autosamplers, along with one set of CC/POCIS passive samplers. Samples were analysed by Automated Identification and Quantification System (AIQS) GC/MS or LC/QTOF-MS database methods with 254 chemicals detected. The most frequently detected compounds under GC/MS analysis were aliphatic, pesticides, phenols, PAHs, sterols and fatty acid methyl esters while from LC/QTOF-MS analysis these were pesticides, pharmaceuticals, and personal care products. Sampling rates (Rs) ranged between <0.001 - 0.132 L day-1 (CC SDB-XC, 18 chemicals), <0.001 - 0.291 L day-1 (CC SDB-RPS, 28 chemicals), and <0.001 - 0.576 L day-1 (POCIS Oasis HLB, 30 chemicals). Assessment of deployment duration indicated that about half of the chemicals that were continuously detected across all deployment weeks had maximal simple linear regression R2 values at four weeks for CC SDB-RPS (seven of 13 chemicals) and at three weeks for POCIS Oasis HLB (seven of 14 chemicals). Where ranges of Rs recorded from the estuarine site were able to be compared to ranges of Rs from one or both freshwater sites, only tributyl phosphate had a higher range of Rs out of 21 possible chemical comparisons, and suggested salinity was an unlikely influence on Rs. Whereas relatively higher rainfall of the third round of deployment aligned with higher Rs across the estuarine and freshwater sites for CC SDB-RPS and POCIS for nearly all possible comparisons.

Unusually high sedimentary metal concentrations in intermittently closed and open lakes and lagoons (ICOLLs) in the northern lagoons of Sydney (Australia).

The environmental status of three Intermittently Closed and Open Lakes and Lagoons (ICOLLs) (Manly, Curl Curl and Dee Why Lagoons) in northern Sydney (Australia) were assessed using sedimentary metals. Results identified the highest sedimentary metal enrichment in the Australian central east coast estuaries, with only a moderate ecological risk. A comparison with surficial sediment concentrations from 1996 to 2008 indicated declining metal concentrations, which is largely supported by subsurface metals data. Extensive low-lying areas of the catchments were historically reclaimed by infilling wetlands, which may have resulted in contaminated groundwater influx to the lagoons. An analysis of the sedimentary metals mix in lagoons surrounded by extensive infilling and estuaries with minor reclamation were statistically distinct. ICOLLs are environmentally sensitive due to large catchment/estuary ratios and restricted access to the ocean. A full set of baseline data is provided to support future monitoring of anthropogenic impacts on the system.

Comparison of mangrove (Avicennia marina) metal tissue concentrations to ambient sediment with an extensive range of contaminant levels in a highly-modified estuary (Sydney estuary, Australia).

Statistically distinct 'high', 'moderate' and 'low' metal contamination positions were distinguished across five Sydney estuary embayments for total sedimentary metal concentrations of Ni, Pb and Zn. While statistically distinct total sedimentary As, Cd, Co and Cu concentrations were indicated for the 'low' position samples. Mangrove (Avicennia marina) pneumatophore tissue metal concentrations from 'high' position trees were statistically distinct for Cd, Ni, Pb and Zn, while root tissue samples from 'low' position trees were statistically distinct for As, Cd and Zn. Outcomes from CAP, simple linear regression and DISTLM modelling indicated sedimentary metals were predominantly assimilated into mangrove root tissue, with smaller uptake into pneumatophore tissue. A comparison of floristic tissue metal concentrations indicated mangrove (A. marina) root tissue assimilated higher sedimentary metal concentrations than leaf and root tissue of seagrasses (Zostera capricorni and Halophila ovalis), which had relatively higher metal concentrations than those from pneumatophore and leaf mangrove tissue.

Deepwater ocean outfalls: A sustainable solution for sewage discharge for mega-coastal cities (Sydney, Australia): Influence of deepwater ocean outfalls on shelf benthic infauna.

In the early 1990s, a cliff-face disposal-system discharging approximately 940 ML/day, or 80% of sewage generated by the City of Sydney (Australia) (population 3.3 million) was replaced by three deepwater ocean outfalls. An 18-year benthic infauna monitoring study was undertaken to address earlier concerns of long-term accumulation from sewage discharges and potential adverse effects on the marine environment. Assessment of outfall community structure indicated organic input from discharges has not resulted in sediment anoxia. The current post-commissioning investigation detected a gradual change in community structure from north to south in the study area, which was also displayed in taxonomic turnover south of the Malabar outfall. Temporal fluctuation in community structure detected at the three outfall and three reference locations in the current study was also noted in the pre-commissioning study at these locations. Evidence provided by this study indicated the Sydney deepwater ocean outfalls do not cause significant ecological impact.

Deepwater ocean outfalls: A sustainable solution for sewage discharge for mega-coastal cities (Sydney, Australia): A synthesis.

In 1990-91 three deepwater ocean outfalls replaced three cliff-face outfalls discharging approximately 940 ML/day, or 80% of sewage generated by the City of Sydney (Australia) (population 3.3 million). Operation of these outfalls was assessed for the first two years and performed well, mitigating most of the environmental problems previously experienced from shoreline discharge. However, a concern remained for the unknown long-term effects on the marine environment. The current series of articles examine over 20 years of monitoring, for possible accumulative effects. Oceanographic modelling provided an understanding of particle settling, dispersion and distribution of discharged wastewater and monitoring assessed potential impact of offshore discharges on beach bathing water quality, sediment chemistry and benthic infauna. These four articles demonstrate that properly designed ocean outfalls are a viable, sustainable solution to sewage disposal for mega-coastal cities, however, continued monitoring is required to assess possible long-term environmental degradation.

Deepwater ocean outfalls: A sustainable solution for sewage discharge for mega-coastal cities (Sydney, Australia): Influences on beach water quality.

Shoreline discharge representing approximately 80% of sewage generated by Sydney (Australia) was replaced with three deepwater ocean outfalls between 1990 and 1991. Beachwatch bacterial monitoring data collected between 1989 and 2016 were analysed to assess the impact of commissioning on bathing water quality along 32 km of coastline. Bacterial contamination was reduced by 26-99% during the first 32 months post-commissioning and in the longer post-commissioning period, 1993 to 2016, bathing water quality improved for 31 beaches. Relatively stable bathing water quality was observed for five other beaches after the 2001 upgrade of another shoreline wastewater treatment plant. Bacterial contamination of bathing water in this 24-year post-commissioning period was most influenced by rainfall in the 24-h to 9 am on the day of sampling. Bacterial contamination from surfacing shore-blown wastewater plumes was not evident, whereas stormwater-delivered bacterial contamination was apparent and varied between beaches.

Metal concentrations in Sydney Cockle (Anadara trapezia) tissue and ambient sediment in a highly-modified estuary (Sydney estuary, Australia).

The influence of sedimentary metals on the cockle A. trapezia tissue was examined using a strong difference in sedimentary metal concentrations in an embayment (Hen and Chicken Bay) highly contaminated in Cu and an adjacent cove (Iron Cove), strongly enriched in Cd, Cu, Pb and Zn within the heavily-urbanised Sydney estuary catchment (Australia). Statistically significant differences were recorded for cockle tissue metal concentrations between the study locations reflecting differences in surficial sediment metal concentrations. Low metal uptake was apparent in A. trapezia tissue, which were considerably less than background sedimentary concentrations and was of low-risk for human consumption. Dissimilar bioconcentration of Cd, Cu, Pb and Zn was apparent in tissue of cockles (A. trapezia), prawns (Metapenaeus bennettae), mussels (Mytilus galloprovincialis) and oysters (Saccostrea glomerata), due possibly to different feeding patterns and biogeochemical conditions in bottom sediments.

Deepwater ocean outfalls: A sustainable solution for sewage discharge for mega-coastal cities (Sydney, Australia): Influence of deepwater ocean outfalls on shelf sediment chemistry.

A cliff-face disposal system discharging approximately 940 ML/day, or 80% of sewage generated by the City of Sydney (Australia) (population 3.3 million) was replaced by three deepwater ocean outfalls in the early 1990s. Enrichment of anthropogenic chemicals from cliff-face discharges raised concerns regarding long-term accumulation of sewage particulates and associated contaminants in offshore sediments and for reduced beach water quality. The current post-commissioning investigation detected a southward gradient of sediment fining and increased total organic carbon in the study region. Deepwater ocean discharges have not contributed to an accumulation of fines, or to increased metallic/nonmetallic chemicals of concern with no elevated risk of adverse biological effects beyond pre-commissioning conditions. Instead, the best modelled relationship was recorded between benthic infauna and sedimentary fines and not to contaminants. Historic sea dumping prior to 1932 in the north of the study area has resulted in enrichment of some non-bioavailable sedimentary metals.

Metal concentrations in seagrass (Halophila ovalis) tissue and ambient sediment in a highly modified estuarine environment (Sydney estuary, Australia).

Research into sediment-seagrass tissue metal relationships has been undertaken in Sydney estuary due to the recognized role contamination plays in threats to seagrass health. Seagrass (Halophila ovalis) leaf tissue concentrations are elevated in Cu, Pb and Zn and contain the highest reported root Cr concentrations. Seagrass metal concentrations were significantly different between species H. ovalis and Zostera capricorni; between root and leaf tissue; and between sampling locations. Greatest tissue enrichment was for Pb, however metals were not enriched in seagrass relative to surficial sediment. Fine and total sediment metal concentrations were temporally consistent between collection years 2013/15, whereas root tissue metals changed between years and sites and leaf metal contents were temporally inconsistent. Extractable metal concentrations in fine sediment (<62.5 µm) showed moderate significant correlation with root tissue and a weak significant relationship with leaf tissue, whereas total sediment metal showed no such relationships. Management implications are provided.

The relationship between metal concentrations in seagrass (Zostera capricorni) tissue and ambient fine sediment in modified and near-pristine estuaries (Sydney estuaries, Australia).

Seagrass (Zostera capricorni) tissue metal concentrations in Sydney estuary are some of the highest reported for urban environments. A strong declining metal (As, Co, Cr, Cu, Mn, Pb and Zn) concentration gradient in fine sediment from highly modified to the near-pristine estuarine environments was matched by a concurrent and statistically significant, moderately strong, relationship with declining metal concentrations for leaf, rhizomes and root tissue types. Leaf tissue more consistently expressed metal concentration uptake from sediment. Rhizome tissue contained the highest concentrations for all metals, except Mn, while leaf concentrations were higher for Cr and Zn and roots were more elevated in Cr and Pb. Tissue Cr, Pb and Zn were close to background for reference sites for leaves. Maximum tissue enrichment over background was 25, 19, 47 and 8 times for Cr, Cu, Pb and Zn. Bio-sediment accumulation factors were generally <1 for all metals.

The recovery of oyster (Saccostrea glomerata) populations in Sydney estuary (Australia).

The current work documented a significant and widespread increase in the abundance of the Sydney rock oyster Saccostrea glomerata, in Sydney estuary (Australia) by undertaking surveys of oyster density in the estuary in 1989 and annually from 1994 to 2006. Oyster density at six control sites located in nearby National Parks unaffected by boating and stormwater discharges were compared to 17 study sites widely distributed within Sydney estuary. No oyster populations were evident in Sydney estuary in 1989; however, by 1994 oysters had colonised areas of the lower and central estuary and by 2002 densities were statistically similar to control sites. The timing of estuary-wide increases in oyster abundance suggests that the partial banning of tributyltin in 1989 for vessels under 25 m long may have played a major role in the increase of S. glomerata in this estuary.

A childhood asthma death in a clinical trial: potential indicators of risk.

A 9 yr old girl with a history of eczema and asthma was admitted to our specialist asthma service and recruited into a trial designed to investigate systemic as well as therapeutic benefits of inhaled corticosteroids. Eight months after referral the patient died from an acute asthma attack. This childhood asthma death during an inhaled steroid trial has facilitated identification of risk factors. Despite good clinical response to inhaled corticosteroids, the patient was distinguishable from the other patients by: increased variability of the morning and evening peak flow rates; increased reactivity, though not sensitivity, to histamine; and an unprecedented rise in serum soluble interleukin-2 receptor levels immediately after commencing inhaled steroids. The immunological basis for corticosteroid resistance and immunohistochemical studies on postmortem specimens from asthma deaths suggest that T-cell activation markers may be indicators of the fatality prone asthmatic.

Variations in serum soluble IL-2 receptor concentration.

Soluble interleukin-2 receptor (sIL-2R) concentrations were measured in the sera of 18 healthy adult volunteers, 40 healthy children aged 5 months -16 years 8 months and cord blood from 10 babies, using two commercially available ELISA kits (T-cell Sciences and Serotec). In the presence of normal C-reactive protein (CRP) children (aged 0-16 years 8 months) had significantly higher sIL-2R concentrations than adults aged (18-37 years). In children up to the age of 16 years there was a significant negative correlation between age and sIL-2R (r = -0.725 p < 0.0001 T-Cell Sciences, r = -0.646 p < 0.0001 Serotec). A comparison was also made between the two kits, which indicated that both kits yielded reproducible results but the T-Cell Sciences kit had a larger working concentration range than the Serotec kit. Following 12-h sampling in adult volunteers, a lower concentration of sIL-2R was observed at 4 am compared with 10 am (p = 0.0052) which indicates diurnal variation. These observations emphasize the importance of the study of normals as part of any research, and raises further questions regarding the many factors which influence immune function.

Raised serum soluble interleukin-2 receptor concentrations in cystic fibrosis patients with and without evidence of lung disease.

Soluble interleukin-2 receptor (sIL-2R-CD25) concentrations were measured in the sera of 115 children with cystic fibrosis and 45 aged matched controls. Above the age of 4 years children with cystic fibrosis had significantly raised concentrations irrespective of disease status as judged by Shwachman score, lung function, or evidence of pseudomonas colonisation. It is believed that these data indicate that T lymphocyte activation can be detected before there is clinical evidence of lung inflammation due to infection in cystic fibrosis. They support the notion that early use of anti-inflammatory (immunosuppressive) drugs may have a role in delaying the progress of lung damage in cystic fibrosis.