Stereotactic ablative body radiotherapy for primary kidney cancer (TROG 15.03 FASTRACK II): a non-randomised phase 2 trial.

BACKGROUND: Stereotactic ablative body radiotherapy (SABR) is a novel non-invasive alternative for patients with primary renal cell cancer who do not undergo surgical resection. The FASTRACK II clinical trial investigated the efficacy of SABR for primary renal cell cancer in a phase 2 trial. METHODS: This international, non-randomised, phase 2 study was conducted in seven centres in Australia and one centre in the Netherlands. Eligible patients aged 18 years or older had biopsy-confirmed diagnosis of primary renal cell cancer, with only a single lesion; were medically inoperable, were at high risk of complications from surgery, or declined surgery; and had an Eastern Cooperative Oncology Group performance status of 0-2. A multidisciplinary decision that active treatment was warranted was required. Key exclusion criteria were a pre-treatment estimated glomerular filtration rate of less than 30 mL/min per 1·73 m2, previous systemic therapies for renal cell cancer, previous high-dose radiotherapy to an overlapping region, tumours larger than 10 cm, and direct contact of the renal cell cancer with the bowel. Patients received either a single fraction SABR of 26 Gy for tumours 4 cm or less in maximum diameter, or 42 Gy in three fractions for tumours more than 4 cm to 10 cm in maximum diameter. The primary endpoint was local control, defined as no progression of the primary renal cell cancer, as evaluated by the investigator per Response Evaluation Criteria in Solid Tumours (version 1.1). Assuming a 1-year local control of 90%, the null hypothesis of 80% or less was considered not to be worthy of proceeding to a future randomised controlled trial. All patients who commenced trial treatment were included in the primary outcome analysis. This trial is registered with ClinicalTrials.gov, NCT02613819, and has completed accrual. FINDINGS: Between July 28, 2016, and Feb 27, 2020, 70 patients were enrolled and initiated treatment. Median age was 77 years (IQR 70-82). Before enrolment, 49 (70%) of 70 patients had documented serial growth on initial surveillance imaging. 49 (70%) of 70 patients were male and 21 (30%) were female. Median tumour size was 4·6 cm (IQR 3·7-5·5). All patients enrolled had T1-T2a and N0-N1 disease. 23 patients received single-fraction SABR of 26 Gy and 47 received 42 Gy in three fractions. Median follow-up was 43 months (IQR 38-60). Local control at 12 months from treatment commencement was 100% (p<0·0001). Seven (10%) patients had grade 3 treatment-related adverse events, with no grade 4 adverse events observed. Grade 3 treatment-related adverse events were nausea and vomiting (three [4%] patients), abdominal, flank, or tumour pain (four [6%]), colonic obstruction (two [3%]), and diarrhoea (one [1%]). No treatment-related or cancer-related deaths occurred. INTERPRETATION: To our knowledge, this is the first multicentre prospective clinical trial of non-surgical definitive therapy in patients with primary renal cell cancer. In a cohort with predominantly T1b or larger disease, SABR was an effective treatment strategy with no observed local failures or cancer-related deaths. We observed an acceptable side-effect profile and renal function after SABR. These outcomes support the design of a future randomised trial of SABR versus surgery for primary renal cell cancer. FUNDING: Cancer Australia Priority-driven Collaborative Cancer Research Scheme.

A long-term high fat diet induces differential gene expression changes in spatially distinct adipose tissue of male mice.

The accumulation of visceral adipose tissue (VAT) is strongly associated with cardiovascular disease and diabetes. In contrast, individuals with increased subcutaneous adipose tissue (SAT) without corresponding increases in VAT are associated with a metabolic healthy obese phenotype. These observations implicate dysfunctional VAT as a driver of disease processes, warranting investigation into obesity-induced alterations of distinct adipose depots. To determine the effects of obesity on adipose gene expression, male mice (n=4) were fed a high fat diet to induce obesity or a normal laboratory diet (lean controls) for 12-14 months. Mesenteric VAT and inguinal SAT were isolated for bulk RNA-sequencing. AT from lean controls served as a reference to obesity-induced changes. The long-term high fat diet induced the expression of 169 and 814 unique genes in SAT and VAT, respectively. SAT from obese mice exhibited 308 differentially expressed genes (164 upregulated, 144 downregulated). VAT from obese mice exhibited 690 differentially expressed genes (262 genes upregulated, 428 downregulated). KEGG pathway and GO analyses revealed that metabolic pathways were upregulated in SAT vs. downregulated in VAT while inflammatory signaling was upregulated in VAT. We next determined common genes that were differentially regulated between SAT and VAT in response to obesity and identified four genes that exhibited this profile: elovl6 and kcnj15 were upregulated in SAT/downregulated in VAT while trdn and hspb7 were downregulated in SAT/ upregulated in VAT. We propose that these genes in particular should be further pursued to determine their roles in SAT vs. VAT with respect to obesity.

Cancer in Victorian prisoners: a description of cancer diagnoses, demographics, risk factors and barriers to optimal care.

BACKGROUND: The Victorian prison population is growing and ageing. Little has been documented about this group's cancer incidence, presentation or treatment. AIMS: To conduct a retrospective review of Victorian prisoners with cancer, including assessment of change over 15 years and adequacy of treatment delivery. METHODS: Detailed demographic, cancer and treatment data were collected for all prisoners with malignancy treated at St Vincent's Hospital Melbourne from 2002 to 2017. Detailed analysis of adherence to Optimal Care Guidelines was undertaken for a subset. Descriptive statistics were used. RESULTS: We identified 200 cancers in 191 prisoners. The population was predominantly male (185 of 191, 93%), with a median age of 54 years. Rates of cigarette smoking (118 of 191, 59%), mental illness (92 of 191, 46%) and intravenous drug use (59 of 191, 29.5%) were high. Exposure-related cancers predominated (nonmelanoma skin cancer, lung cancer and hepatoma). Most were symptomatic (154 of 191, 77%) and almost one-third had incurable disease at diagnosis (64 of 191, 32%). The number of prisoners with cancer increased over time (2002-2006 [T1], n = 31 vs 2012-2016 [T3], n = 101), as did the median age (45 years in T1 vs 55 years in T3) and rates of mental illness (10 of 31 [32%] in T1 vs 55 of 101 [54%] in T3). Delayed treatment initiation occurred in eight of 12 (66%) assessable patients, largely because of nonattendance. CONCLUSIONS: Victorian prisoners with cancer are at risk of poor outcomes because of late presentation, delayed treatment initiation and medical comorbidities. Tailored interventions are urgently required to improve the provision of timely, comprehensive cancer care to this vulnerable and growing population.

Larval parasitism in a specialist herbivore is explained by phenological synchrony and host plant availability.

Parasitism is a key factor in the population dynamics of many herbivorous insects, although its impact on host populations varies widely, for instance, along latitudinal and altitudinal gradients. Understanding the sources of geographical variation in host-parasitoid interactions is crucial for reliably predicting the future success of the interacting species under a context of global change. Here, we examine larval parasitism in the butterfly Aglais urticae in south-west Europe, where it is a mountain specialist. Larval nests were sampled over 2 years along altitudinal gradients in three Iberian mountain ranges, including the Sierra Nevada, home to its southernmost European population. Additional data on nettle condition and adult butterflies were obtained in the study areas. These data sources were used to investigate whether or not differences in parasitism rates are related to the geographical position and phenology of the host, and to the availability of the host plants. Phenological differences in the host populations between regions were related to the severity of summer drought and the corresponding differences in host plant availability. At the trailing-edge of its distribution, the butterfly's breeding season was restricted to the end of winter and spring, while in its northern Iberian range the season was prolonged until mid-summer. Although parasitism was an important source of mortality in all regions, parasitism rates and parasitoid richness were highest in the north and lowest in the south. Moreover, within a region, there was a notable increase in parasitism rates over time, which probably led to selection against an additional late summer host generation in northern regions. Conversely, the shorter breeding season in Sierra Nevada resulted in a loss of synchrony between the host and one important late season parasitoid, Sturmia bella, which may partly explain the high density of this butterfly species at the trailing-edge of its range. Our results support the key role of host phenology in accounting for differences in parasitism rates between populations. They also provide insights into how climate through host plant availability affects host phenology and, ultimately, the impact of parasitism on host populations.

Stereotactic ablative radiotherapy versus standard radiotherapy in stage 1 non-small-cell lung cancer (TROG 09.02 CHISEL): a phase 3, open-label, randomised controlled trial.

BACKGROUND: Stereotactic ablative body radiotherapy (SABR) is widely used to treat inoperable stage 1 non-small-cell lung cancer (NSCLC), despite the absence of prospective evidence that this type of treatment improves local control or prolongs overall survival compared with standard radiotherapy. We aimed to compare the two treatment techniques. METHODS: We did this multicentre, phase 3, randomised, controlled trial in 11 hospitals in Australia and three hospitals in New Zealand. Patients were eligible if they were aged 18 years or older, had biopsy-confirmed stage 1 (T1-T2aN0M0) NSCLC diagnosed on the basis of 18F-fluorodeoxyglucose PET, and were medically inoperable or had refused surgery. Patients had to have an Eastern Cooperative Oncology Group performance status of 0 or 1, and the tumour had to be peripherally located. Patients were randomly assigned after stratification for T stage and operability in a 2:1 ratio to SABR (54 Gy in three 18 Gy fractions, or 48 Gy in four 12 Gy fractions if the tumour was <2 cm from the chest wall) or standard radiotherapy (66 Gy in 33 daily 2 Gy fractions or 50 Gy in 20 daily 2·5 Gy fractions, depending on institutional preference) using minimisation, so no sequence was pre-generated. Clinicians, patients, and data managers had no previous knowledge of the treatment group to which patients would be assigned; however, the treatment assignment was subsequently open label (because of the nature of the interventions). The primary endpoint was time to local treatment failure (assessed according to Response Evaluation Criteria in Solid Tumors version 1.0), with the hypothesis that SABR would result in superior local control compared with standard radiotherapy. All efficacy analyses were based on the intention-to-treat analysis. Safety analyses were done on a per-protocol basis, according to treatment that the patients actually received. The trial is registered with ClinicalTrials.gov (NCT01014130) and the Australia and New Zealand Clinical Trials Registry (ACTRN12610000479000). The trial is closed to new participants. FINDINGS: Between Dec 31, 2009, and June 22, 2015, 101 eligible patients were enrolled and randomly assigned to receive SABR (n=66) or standard radiotherapy (n=35). Five (7·6%) patients in the SABR group and two (6·5%) in the standard radiotherapy group did not receive treatment, and a further four in each group withdrew before study end. As of data cutoff (July 31, 2017), median follow-up for local treatment failure was 2·1 years (IQR 1·2-3·6) for patients randomly assigned to standard radiotherapy and 2·6 years (IQR 1·6-3·6) for patients assigned to SABR. 20 (20%) of 101 patients had progressed locally: nine (14%) of 66 patients in the SABR group and 11 (31%) of 35 patients in the standard radiotherapy group, and freedom from local treatment failure was improved in the SABR group compared with the standard radiotherapy group (hazard ratio 0·32, 95% CI 0·13-0·77, p=0·0077). Median time to local treatment failure was not reached in either group. In patients treated with SABR, there was one grade 4 adverse event (dyspnoea) and seven grade 3 adverse events (two cough, one hypoxia, one lung infection, one weight loss, one dyspnoea, and one fatigue) related to treatment compared with two grade 3 events (chest pain) in the standard treatment group. INTERPRETATION: In patients with inoperable peripherally located stage 1 NSCLC, compared with standard radiotherapy, SABR resulted in superior local control of the primary disease without an increase in major toxicity. The findings of this trial suggest that SABR should be the treatment of choice for this patient group. FUNDING: The Radiation and Optometry Section of the Australian Government Department of Health with the assistance of Cancer Australia, and the Cancer Society of New Zealand and the Cancer Research Trust New Zealand (formerly Genesis Oncology Trust).

The Victorian Comprehensive Cancer Centre lung cancer clinical audit: collecting the UK National Lung Cancer Audit data from hospitals in Australia.

BACKGROUND: Clinical audit may improve practice in cancer service provision. The UK National Lung Cancer Audit (NLCA) collects data for all new cases of thoracic cancers. AIM: To collect similar data for our Victorian patients from six hospitals within the Victorian Comprehensive Cancer Centre and associated Western and Central Melbourne Integrated Cancer Service. METHODS: We conducted a retrospective audit of all newly diagnosed patients with lung cancer and mesothelioma in 2013 across the six Victorian Comprehensive Cancer Centre/Western and Central Melbourne Integrated Cancer Service hospitals. The objectives were to adapt the NLCA data set for use in the Australian context, to analyse the findings using descriptive statistics and to determine feasibility of implementing a routine, ongoing audit similar to that in the UK. Individual data items were adapted from the NLCA by an expert steering committee. Data were collated from the Victorian Cancer Registry, Victorian Admitted Episodes Dataset and individual hospital databases. Individual medical records were audited for missing data. RESULTS: Eight hundred and forty-five patients were diagnosed across the sites in 2013. Most were aged 65-80 (55%) and were male (62%). Most had non-small-cell lung cancer (81%) with 9% diagnosed with small cell lung cancer and 2% with mesothelioma. Data completeness varied significantly between fields. For those with higher levels of completeness, headline indicators of clinical care were comparable with NLCA data. The Victorian population seem to lack access to specialist lung cancer nurse services. CONCLUSION: Lung cancer care at participating hospitals appeared to be comparable with the UK in 2013. In future, prospective data collection should be harmonised across sites and correlated with survival outcomes. One area of concern was a lack of documented access to specialist nursing services.

Does low body fat percentage in neonates greater than the 5th percentile birthweight increase the risk of hypoglycaemia and neonatal morbidity?

AIM: Low body fat percentage (BF%) has been shown to predict morbidity and possible hypoglycaemia in newborns. Hypoglycaemia in neonates is associated with significant neonatal morbidity. Early detection and prevention are critical. To identify if low BF% (>1 standard deviation below the mean) in non-small-for-gestational-age neonates (>5th percentile body weight) increases the risk of short-term morbidity, with specific attention to hypoglycaemia. METHODS: All term neonates who had their BF% measured as part of the Newborn Early Assessment Programme between 28 January 2014 and 9 August 2016 were included in the study. Neonates whose weight was below the 5th percentile and neonates of diabetic mothers were excluded as blood sugar level monitoring is routinely performed on these babies. Neonatal morbidity and blood sugar levels were obtained from electronic records, and the individual patient's paper records were reviewed. A composite score for neonatal morbidity (poor feeding AND hypothermia AND prolonged length of stay) was calculated. Statistics were analysed using SPSS. RESULTS: A total of 247 neonates met the inclusion criteria (3.3% of total births). Hypoglycaemia was found in 8.5% of the study population. The risk of hypoglycaemia did not change significantly in neonates with birthweight of the 5th-10th percentile and >10th percentile (8 vs. 8.8%); 4.9% of babies met the combined morbidity criteria. CONCLUSIONS: Non-small-for-gestational-age babies (>5th percentile) with low BF% are at risk of hypoglycaemia and short-term morbidity. These infants will not be identified by current hypoglycaemia screening methods in centres that do not measure BF%.

Stereotactic ablative body radiotherapy for inoperable primary kidney cancer: a prospective clinical trial.

OBJECTIVE: To assess the feasibility and safety of stereotactic ablative body radiotherapy (SABR) for renal cell carcinoma (RCC) in patients unsuitable for surgery. Secondary objectives were to assess oncological and functional outcomes. MATERIALS AND METHODS: This was a prospective interventional clinical trial with institutional ethics board approval. Inoperable patients were enrolled, after multidisciplinary consensus, for intervention with informed consent. Tumour response was defined using Response Evaluation Criteria In Solid Tumors v1.1. Toxicities were recorded using Common Terminology Criteria for Adverse Events v4.0. Time-to-event outcomes were described using the Kaplan-Meier method, and associations of baseline variables with tumour shrinkage was assessed using linear regression. Patients received either single fraction of 26 Gy or three fractions of 14 Gy, dependent on tumour size. RESULTS: Of 37 patients (median age 78 years), 62% had T1b, 35% had T1a and 3% had T2a disease. One patient presented with bilateral primaries. Histology was confirmed in 92%. In total, 33 patients and 34 kidneys received all prescribed SABR fractions (89% feasibility). The median follow-up was 24 months. Treatment-related grade 1-2 toxicities occurred in 26 patients (78%) and grade 3 toxicity in one patient (3%). No grade 4-5 toxicities were recorded and six patients (18%) reported no toxicity. Freedom from local progression, distant progression and overall survival rates at 2 years were 100%, 89% and 92%, respectively. The mean baseline glomerular filtration rate was 55 mL/min, which decreased to 44 mL/min at 1 and 2 years (P < 0.001). Neutrophil:lymphocyte ratio correlated to % change in tumour size at 1 year, r2 = 0.45 (P < 0.001). CONCLUSION: The study results show that SABR for primary RCC was feasible and well tolerated. We observed encouraging cancer control, functional preservation and early survival outcomes in an inoperable cohort. Baseline neutrophil:lymphocyte ratio may be predictive of immune-mediated response and warrants further investigation.

Determinants of parasitoid communities of willow-galling sawflies: habitat overrides physiology, host plant and space.

Studies on the determinants of plant-herbivore and herbivore-parasitoid associations provide important insights into the origin and maintenance of global and local species richness. If parasitoids are specialists on herbivore niches rather than on herbivore taxa, then alternating escape of herbivores into novel niches and delayed resource tracking by parasitoids could fuel diversification at both trophic levels. We used DNA barcoding to identify parasitoids that attack larvae of seven Pontania sawfly species that induce leaf galls on eight willow species growing in subarctic and arctic-alpine habitats in three geographic locations in northern Fennoscandia, and then applied distance- and model-based multivariate analyses and phylogenetic regression methods to evaluate the hierarchical importance of location, phylogeny and different galler niche dimensions on parasitoid host use. We found statistically significant variation in parasitoid communities across geographic locations and willow host species, but the differences were mainly quantitative due to extensive sharing of enemies among gallers within habitat types. By contrast, the divide between habitats defined two qualitatively different network compartments, because many common parasitoids exhibited strong habitat preference. Galler and parasitoid phylogenies did not explain associations, because distantly related arctic-alpine gallers were attacked by a species-poor enemy community dominated by two parasitoid species that most likely have independently tracked the gallers' evolutionary shifts into the novel habitat. Our results indicate that barcode- and phylogeny-based analyses of food webs that span forested vs. tundra or grassland environments could improve our understanding of vertical diversification effects in complex plant-herbivore-parasitoid networks.

Critical theory as an approach to the ethics of information security.

Information security can be of high moral value. It can equally be used for immoral purposes and have undesirable consequences. In this paper we suggest that critical theory can facilitate a better understanding of possible ethical issues and can provide support when finding ways of addressing them. The paper argues that critical theory has intrinsic links to ethics and that it is possible to identify concepts frequently used in critical theory to pinpoint ethical concerns. Using the example of UK electronic medical records the paper demonstrates that a critical lens can highlight issues that traditional ethical theories tend to overlook. These are often linked to collective issues such as social and organisational structures, which philosophical ethics with its typical focus on the individual does not tend to emphasise. The paper suggests that this insight can help in developing ways of researching and innovating responsibly in the area of information security.

An illustrated key to European genera of Microgastrinae parasitoid wasps (Hymenoptera, Braconidae) with a recent historical and biological perspective and a guide to available species-level identification resources.

An illustrated key is provided for the identification of the 20 genera of Microgastrinae so far known to occur in Europe. A brief review of 20th century progress on the group is given. Morphological terms are explained and illustrated, with special reference to the different systems of wing venation employed by past workers on Microgastrinae in Europe, and recommendations are made for future work. For each genus, an outline of species richness, host usage, developmental biology, and particular morphological features is given, and some species that may be difficult to place are highlighted. Available keys for species identification within genera are referenced, with comments, and attention is drawn to species more recently recorded or described up to January 2024. The value of accurate rearing data for parasitoids is emphasised. The references discussed provide a comprehensive overview of the most useful literature for future morphological work on European Microgastrinae. Glyptapantelesmoldavicus (Tobias), comb. nov. is proposed.

Resolution of the Aleiodesseriatus (Herrich-Schäffer, 1838)-aggregate in the western Palaearctic (Hymenoptera, Braconidae, Rogadinae), with description of a new species.

Two European species are recognised and characterised within the traditional Aleiodesseriatus species concept, based initially on DNA barcoding but with supporting, although slight and sometimes unreliable, morphological differences. Aleiodespseudoseriatus sp. nov. is described and a neotype is designated for Rogasseriatus Herrich-Schäffer, 1838. Specimens from the Russian Far East were also DNA barcoded and were found to belong to a new species distinct from the two European taxa. The two European species were found to use different lithosiine hosts.

Scratching the tip of the iceberg: integrative taxonomy reveals 30 new species records of Microgastrinae (Braconidae) parasitoid wasps for Germany, including new Holarctic distributions.

Substantial parts of the European and German insect fauna still remain largely unexplored, the so-called "dark taxa". In particular, midges (Diptera) and parasitoid wasps (Hymenoptera) are abundant and species-rich throughout Europe, yet are often neglected in biodiversity research. One such dark taxon is Microgastrinae wasps (Hymenoptera: Braconidae), a group of parasitoids of lepidopteran caterpillars with 252 species reported in Germany so far. As part of the German Barcode of Life Project GBOL III: Dark Taxa, reverse DNA barcoding and integrative taxonomic approaches were used to shed some light on the German Fauna of Microgastrinae wasps. In our workflow, DNA barcoding was used for molecular clustering of our specimens in a first step, morphological examination of the voucher specimens in a second step, and host data compared in a third step. Here, 30 species are reported for the first time in Germany, adding more than 10% to the known German fauna. Information for four species is provided in a new Holarctic context, reporting them for the Nearctic or, respectively, Palaearctic region, and 26 additional country records are added from sequenced material available in the collections accessible to us. Molecular clusters that show signs of discrepancies are discussed. Results show that we are just scratching the tip of the iceberg of the unexplored Microgastrinae diversity in Germany.

Low rate of severe-end-stage kidney disease after SABR for localised primary kidney cancer.

BACKGROUND: Stereotactic ablative body radiotherapy (SABR) is an emerging treatment for patients with primary renal cell carcinoma (RCC). However, its impact on renal function is unclear. This study aimed to evaluate incidence and clinical factors predictive of severe to end-stage chronic kidney disease (CKD) after SABR for RCC. METHODS AND MATERIALS: This was a Single institutional retrospective analysis of patients with diagnosed primary RCC receiving SABR between 2012-2020. Adult patients with no metastatic disease, baseline estimated glomerular filtration rate (eGFR) of ≥ 30 ml/min/1.73 m2, and at least one post-SABR eGFR at six months or later were included in this analysis. Patients with upper tract urothelial carcinoma were excluded. Primary outcome was freedom from severe to end-stage CKD, determined using the Kaplan-Meier estimator. The impact of baseline CKD, age, hypertension, diabetes, tumor size and fractionation schedule were assessed by Cox proportional hazard models. RESULTS: Seventy-eight consecutive patients were included, with median age of 77.8 years (IQR 70-83), tumor size of 4.5 cm (IQR 3.9-5.8) and follow-up of 42.2 months (IQR 23-60). Baseline median eGFR was 58 mls/min; 55% (n = 43) of patients had baseline CKD stage 3 and the remainder stage 1-2. By last follow-up, 1/35 (2.8%) of baseline CKD 1-2, 7/27 (25.9%) CKD 3a and 11/16 (68.8%) CKD 3b had developed CKD stage 4-5. The estimated probability of freedom from CKD stage 4-5 at 1 and 5 years was 89.6% (CI 83.0-97.6) and 65% (CI 51.4-81.7) respectively. On univariable analysis, worse baseline CKD (p < 0.0001) and multi-fraction SABR (p = 0.005) were predictive for development of stage 4-5 CKD though only the former remained significant in multivariable model. CONCLUSION: In this elderly cohort with pre-existing renal dysfunction, SABR achieved satisfactory nephron sparing with acceptable rates of severe to end-stage CKD. It can be an attractive option in patients who are medically inoperable.

The impact of pre-treatment smoking status on survival after chemoradiotherapy for locally advanced non-small-cell lung cancer.

INTRODUCTION: Smoking is a risk factor for the development of lung cancer and reduces life expectancy within the general population. Retrospective studies suggest that non-smokers have better outcomes after treatment for lung cancer. We used a prospective database to investigate relationships between pre-treatment smoking status and survival for a cohort of patients with stage III non-small-cell lung cancer (NSCLC) treated with curative-intent concurrent chemoradiotherapy (CRT). METHODS: All patients treated with CRT for stage III NSCLC at a major metropolitan cancer centre were prospectively registered to a database. A detailed smoking history was routinely obtained at baseline. Kaplan-Meier statistics were used to assess overall survival and progression-free survival in never versus former versus current smokers. RESULTS: Median overall survival for 265 eligible patients was 2.21 years (95 % Confidence Interval 1.78, 2.84). It was 5.5 years (95 % CI 2.1, not reached) for 25 never-smokers versus 1.9 years (95 % CI 1.5, 2.7) for 182 former smokers and 2.2 years (95 % CI 1.3, 2.7) for 58 current smokers. Hazard ratio for death was 2.43 (95 % CI 1.32-4.50) for former smokers and 2.75 (95 % CI 1.40, 5.40) for current smokers, p = 0.006. Actionable tumour mutations (EGFR, ALK, ROS1) were present in more never smokers (14/25) than former (9/182) or current (3/58) smokers. TKI use was also higher in never smokers but this was not significantly associated with superior survival (Hazard ratio 0.71, 95 % CI 0.41, 1.26). CONCLUSIONS: Never smokers have substantially better overall survival than former or current smokers after undergoing CRT for NSCLC.

Treatment of brain metastases in lung cancer: strategies to avoid/reduce late complications of whole brain radiation therapy.

OPINION STATEMENT: Brain metastases occur in 20-40 % of lung cancer patients. The use of whole brain radiation therapy (WBRT) has been shown to ameliorate many neurological symptoms, facilitate corticosteroid reduction, enhance quality of life (QOL), and prolong survival. The acute and early delayed side effects of WBRT are generally mild and inconsequential, whereas late complications often are progressive, irreversible, and may have a profound effect on neurocognitive function and QOL. Nevertheless, WBRT remains the cornerstone for treatment of multiple brain metastases due to its efficacy and the paucity of other treatment options. In avoidance of WBRT and its potential toxicity, patients of good performance status and ≤3 metastases may be treated reasonably with focal therapy alone (surgery or radiosurgery) without a compromise in survival. In patients with multiple brain metastases and those undergoing prophylactic cranial irradiation (PCI), established methods to mitigate the late complications of WBRT include total dose observation, dose per fraction restrictions, and avoidance of concomitant chemotherapy. Current areas of active research that hold great potential for benefit include hippocampal-sparing radiotherapy and the use of neuroprotective agents.

Metagenomic Analysis of a Concrete Bridge Reveals a Microbial Community Dominated by Halophilic Bacteria and Archaea.

Concrete hosts a small but diverse microbiome that changes over time. Shotgun metagenomic sequencing would enable assessment of both the diversity and function of the microbial community in concrete, but a number of unique challenges make this difficult for concrete samples. The high concentration of divalent cations in concrete interferes with nucleic acid extraction, and the extremely low biomass in concrete means that DNA from laboratory contamination may be a large fraction of the sequence data. Here, we develop an improved method for DNA extraction from concrete, with higher yield and lower laboratory contamination. To show that this method provides DNA of sufficient quality and quantity to do shotgun metagenomic sequencing, DNA was extracted from a sample of concrete obtained from a road bridge and sequenced with an Illumina MiSeq system. This microbial community was dominated by halophilic Bacteria and Archaea, with enriched functional pathways related to osmotic stress responses. Although this was a pilot-scale effort, we demonstrate that metagenomic sequencing can be used to characterize microbial communities in concrete and that older concrete structures may host different microbes than recently poured concrete. IMPORTANCE Prior work on the microbial communities of concrete focused on the surfaces of concrete structures such as sewage pipes or bridge pilings, where thick biofilms were easy to observe and sample. Because the biomass inside concrete is so low, more recent analyses of the microbial communities inside concrete used amplicon sequencing methods to describe those communities. However, to understand the activity and physiology of microbes in concrete, or to develop living infrastructure, we must develop more direct methods of community analysis. The method developed here for DNA extraction and metagenomic sequencing can be used for analysis of microbial communities inside concrete and can likely be adapted for other cementitious materials.

Early circulating tumor DNA dynamics at the commencement of curative-intent radiotherapy or chemoradiotherapy for NSCLC.

Background: The kinetics of circulating tumor DNA (ctDNA) release following commencement of radiotherapy or chemoradiotherapy may reflect early tumour cell killing. We hypothesised that an increase in ctDNA may be observed after the first fraction of radiotherapy and that this could have clinical significance. Materials and methods: ctDNA analysis was performed as part of a prospective, observational clinical biomarker study of non-small cell lung cancer (NSCLC) patients, treated with curative-intent radiotherapy or chemoradiotherapy. Blood was collected at predefined intervals before, during (including 24 h after fraction 1 of radiotherapy) and after radiotherapy/chemoradiotherapy. Mutation-specific droplet digital PCR assays used to track ctDNA levels during and after treatment. Results: Sequential ctDNA results are available for 14 patients with known tumor-based mutations, including in EGFR, KRAS and TP53, with a median follow-up of 723 days (range 152 to 1110). Treatments delivered were fractionated radiotherapy/chemoradiotherapy, in 2-2.75 Gy fractions (n = 12), or stereotactic ablative body radiotherapy (SABR, n = 2). An increase in ctDNA was observed after fraction 1 in 3/12 patients treated with fractionated radiotherapy with a complete set of results, including in 2 cases where ctDNA was initially undetectable. Neither SABR patient had detectable ctDNA immediately before or after radiotherapy, but one of these later relapsed systemically with a high detected ctDNA concentration. Conclusions: A rapid increase in ctDNA levels was observed after one fraction of fractionated radiotherapy in three cases. Further molecular characterization will be required to understand if a "spike" in ctDNA levels could represent rapid initial tumor cell destruction and could have clinical value as a surrogate for early treatment response and/or as a means of enriching ctDNA for mutational profiling.

Characterisation of some species groups of Brachymeria (Hymenoptera: Chalcididae), with a review of the B. tibialis-group and description of a new species parasitizing Zygaena pupae (Lepidoptera: Zygaenidae).

The Brachymeria tibialis species group is newly recognized and diagnosed together with the Brachymeria annulata, femorata, kassiliensis and lasus species groups also newly defined. In these diagnoses a few morphological characters of the ventral part of the mesosoma, discovered in this study, are proposed to help differentiate the groups. The B. tibialis species group itself includes solely B. tibialis (Walker) and B. zygaenae Delvare Shaw n. sp., which was until now mixed with it. The biology and hosts of both species are summarized.

Facilitating primary care non-antiretroviral drug prescribing in people living with HIV: The 'THINK ARV' initiative.

OBJECTIVES: Older people living with HIV (PLWH) have higher rates of multimorbidity, polypharmacy and an associated increased risk of potential drug-drug interactions (DDIs). We describe the development, implementation and evaluation of an intervention to increase community prescribers' access to specialist prescribing advice. METHODS: Phase One: a survey evaluating General Practitioners' (GPs') knowledge of, and confidence detecting DDIs affecting PLWH, was circulated to eight General Practices in one UK city. Phase Two: co-production was used to develop the THINK ARV intervention for prescribers in city-wide General Practices: a dedicated mobile phone and e-mail advice service staffed by HIV specialist pharmacists. Queries were audited for 6 months pre- and post-intervention. A user-satisfaction survey was emailed to enquirers. RESULTS: Phase One: 42 GPs responded, of whom 62% requested further support identifying DDIs among PLWH. Phase Two: the number of queries received increased from 25 (6 months before 'THINK ARV' launch) to 63 in the following 6 months (152% increase). 94% of the queries were specifically about DDIs. CONCLUSIONS: Increasing community prescribers' access to specialist telephone and e-mail advice resulted in increased awareness and detection of DDIs. Similar interventions could be embedded within different healthcare settings to optimise medicines and avoid potential patient harm.