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Proton pump inhibitors (PPIs) are the mainstay of therapy for all gastric acid related diseases and are commonly used in current clinical practice. Although widely regarded as safe, PPIs have been associated with a variety of adverse effects, including hypomagnesaemia. The postulated mechanism of PPI-related hypomagnesaemia involves inhibition of intestinal magnesium absorption via transient receptor potential melastin (TRPM) 6 and 7 cation channels. PPI-induced hypomagnesaemia (PPIH) has become a well recognized phenomenon since it was first reported in 2006. Clinical concerns arise from growing number of case reports presenting PPIH as a consequence of long-term PPI use, with more than 30 cases published to date. In this article, we report 2 cases of PPIH associated with the use of pantoprazole. Both patients presented with severe hypomagnesaemia and hypocalcaemia. One of them had associated hypokalemia and cardiac arrhythmia. A casual relation with PPIs postulated and supported by resolution of electrolyte abnormalities after discontinuation of PPIs.

Background:Adjuvant chemotherapy improves survival for patients with resected pancreatic cancer. Elderly patients are under-represented in Phase III clinical trials, and as a consequence the efficacy of adjuvant therapy in older patients with pancreatic cancer is not clear. We aimed to assess the use and efficacy of adjuvant chemotherapy in older patients with pancreatic cancer.Methods:We assessed a community cohort of 439 patients with a diagnosis of pancreatic ductal adenocarcinoma who underwent operative resection in centres associated with the Australian Pancreatic Cancer Genome Initiative.Results:The median age of the cohort was 67 years. Overall only 47% of all patients received adjuvant therapy. Patients who received adjuvant chemotherapy were predominantly younger, had later stage disease, more lymph node involvement and more evidence of perineural invasion than the group that did not receive adjuvant treatment. Overall, adjuvant chemotherapy was associated with prolonged survival (median 22.1 vs 15.8 months; P<0.0001). Older patients (aged 70) were less likely to receive adjuvant chemotherapy (51.5% vs 29.8%; P<0.0001). Older patients had a particularly poor outcome when adjuvant therapy was not delivered (median survival=13.1 months; HR 1.89, 95% CI: 1.27-2.78, P=0.002).Conclusion:Patients aged 70 are less likely to receive adjuvant therapy although it is associated with improved outcome. Increased use of adjuvant therapy in older individuals is encouraged as they constitute a large proportion of patients with pancreatic cancer. [ABSTRACT FROM AUTHOR]

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Activation of renal interstitial fibroblasts is critically involved in the development of tubulointerstitial fibrosis in chronic kidney diseases. In this study, we investigated the effect of trichostatin A (TSA), a specific histone deacetylase (HDAC) inhibitor, on the activation of renal interstitial fibroblasts in a rat renal interstitial fibroblast line (NRK49F) and the development of renal fibrosis in a murine model of unilateral ureteral obstruction (UUO). α-Smooth muscle actin (α-SMA) and fibronectin, two hallmarks of fibroblast activation, were highly expressed in cultured NRK-49F cells, and their expression was inhibited in the presence of TSA. Similarly, administration of TSA suppressed the expression of α-SMA and fibronectin and attenuated the accumulation of renal interstitial fibroblasts in the kidney after the obstructive injury. Activation of renal interstitial fibroblasts was accompanied by phosphorylation of signal transducer and activator of transcription 3 (STAT3), and TSA treatment also abolished these responses. Furthermore, inhibition of the STAT3 pathway with AG490 inhibited expression of α-SMA and fibronectin in NRK-49F cells. Finally, ISA treatment inhibited tubular cell apoptosis and caspase-3 activation in the obstructive kidney. Collectively, we suggest that pharmacological HDAC inhibition may induce antifibrotic activity by inactivation of renal interstitial fibroblasts and inhibition of renal tubular cell death. STAT3 may mediate those actions of HDACs. [ABSTRACT FROM AUTHOR]

Approach to patients who manifest with features of Cushing’s syndrome often begin with exclusion of exposure to excessive exogenous source of glucocorticoids (GC). Most guidelines advocate no further assessment if excessive exogenous GC use is present. We present a case of a 66-year-old lady who was noted to have typical features of Cushing’s syndrome. As she gave a very clear history of ingesting exogenous GC for a year, no further work up was undertaken. Despite cessation of GC for a year, she continued to have thin skin and easy bruising. Upon admission for hypertensive emergency, her clinician took note of her changes and investigated her for endogenous Cushing’s syndrome. Her cortisol post overnight dexamethasone suppression test was 707 nmol/l. Post low dose dexamethasone suppression test yielded a cortisol of 1133.2 nmol/l. 24 hours urine cortisol was 432.2 nmol/l. Plasma ACTH was 1.1 pmol/l, indicating an ACTH independent Cushing’s syndrome. We proceeded with Computed tomography scan (CT scan) of adrenals which revealed a right adrenal adenoma measuring 4.4 × 3.4 × 4.0 cm. Right retroperiteneoscopic adrenalectomy was done. Histopathology examination was consistent with adrenal cortical adenoma with foci of myelolipoma. Post adrenalectomy she developed hypocortisolism secondary to contralateral adrenal suppression which lasted up to the present date. Her cutaneous and musculoskeletal manifestations improved substantially. Co-occurrence of endogenous and exogenous Cushing’s syndromes is uncommon but should be considered in patients whose Cushingnoid features do not resolve after cessation of exogenous GC.

Previous research on the multicommodity minimum cost flow problem (MMCFP) has assumed that there are two types of values associated with an arc. The first is the capacity of the arc and the second is the unit flow cost along the arc. This paper adds the third attribute--the degree of difficulty--into the conventional model of the MMCFP. In this way, a new problem, which is more general and difficult than the conventional MMCFP, is formed. However, we show that these two problems are indeed polynomially equivalent. With the equivalence, the techniques developed for solving the conventional MMCFP can be used to solve the new but more general problem. [ABSTRACT FROM AUTHOR]

For ectopic adrenocorticotropic hormone (ACTH) syndrome (EAS), when surgery is not feasible, or in cases of severe biochemical disturbances, immunosuppression or mental instability, medical therapy with agents such as etomidate is indicated. We present our experience in using etomidate for a 41-year old female with EAS secondary to a malignant mediastinal paraganglioma. We were able to demonstrate that etomidate can be used effectively to control severe hypercortisolism in a lower dose than previously described.

Zoonotic tuberculosis caused by Mycobacterium bovis (M. bovis), a member of Mycobacterium tuberculosis complex (MTBC) has increasingly gathered attention as a public health risk, particularly in developing countries with higher disease prevalence. M. bovis is capable of infecting multiple hosts encompassing a number of domestic animals, in particular cattle as well as a broad range of wildlife reservoirs. Humans are the incidental hosts of M. bovis whereby its transmission to humans is primarily through the consumption of cattle products such as unpasteurized milk or raw meat products that have been contaminated with M. bovis or the transmission could be due to close contact with infected cattle. Also, the transmission could occur through aerosol inhalation of infective droplets or infected body fluids or tissues in the presence of wound from infected animals. The zoonotic risk of M. bovis in humans exemplified by miscellaneous studies across different countries suggested the risk of occupational exposure towards M. bovis infection, especially those animal handlers that have close and unreserved contact with cattle and wildlife populations These animal handlers comprising of livestock farmers, abattoir workers, veterinarians and their assistants, hunters, wildlife workers as well as other animal handlers are at different risk of contracting M. bovis infection, depending on the nature of their jobs and how close is their interaction with infected animals. It is crucial to identify the underlying transmission risk factors and probable transmission pathways involved in the zoonotic transmission of M. bovis from animals to humans for better designation and development of specific preventive measures and guidelines that could reduce the risk of transmission and to protect these different occupational-related/populations at risk. Effective control and disease management of zoonotic tuberculosis caused by M. bovis in humans are also hindered by various challenges and factors involved at animal–human interface. A closer look into factors affecting proper disease control and management of M. bovis are therefore warranted. Hence, in this narrative review, we have gathered a number of different studies to highlight the risk of occupational exposure to M. bovis infection and addressed the limitations and challenges underlying this context. This review also shed lights on various components and approaches in tackling M. bovis infection at animal–human interface. [ABSTRACT FROM AUTHOR]

This paper presents the cyclic behavior of circular concrete columns confined with a proposed FRP-wrapped spiral corrugated tube (FWSCT) that serves as a permanent ribbed surface between FRP and concrete. Five FWSCT column specimens with GFRP layers and axial load ratios as design parameters were tested for the flexural and shear performances. The FWSCT specimens that did not use transverse steel hoops in the entire column used longitudinal reinforcement for the flexural capacity and FWSCT for the shear capacity. Specimen FWSCT-0 was confined with only a spiral corrugated steel tube without GFRP wraps; Specimens FWSCT-1, FWSCT-3, FWSCT-5 and FWSCT-8 were confined with a spiral corrugated steel tube and additional 1, 3, 5 and 8 GFRP layers, respectively. Test results showed that Specimen FWSCT-0 experienced shear failure at about 1% drift; Specimen FWSCT-1 experienced flexural shear failure at about 4% drift, while Specimens FWSCT-3, FWSCT-5 and FWSCT-8 exhibited rupture of longitudinal reinforcement at drift ratios of 7% to 8%, without shear failure. A plastic hinge was developed in un-wrapped column ends, further extending into the footing. An analytical method that used the residual shear model and a proposed plastic hinge length reasonably predicts the flexural and shear capacities of FWSCT columns. [ABSTRACT FROM AUTHOR]

Stat3 and its isoforms belong to a family of cytoplasmic transcription factors that affect the synthesis of various proteins. Caspases are cysteinyl-aspartate proteases that function under apoptotic and non-apoptotic conditions. We now report that, in addition to transcriptional splicing, Stat3 fragmentation can be mediated by caspases. Caspase activation in DU14S cells was achieved by staurosporine (STS) exposure, and Western analysis revealed a reduction in full-length Stat3 (fl-Stat3) expression that was caspase- mediated. This proteolytic relationship was further studied by exposing pun- fled Stat3 protein to a mixture of active caspases under cell-free conditions. This demonstrated that caspases directly cleaved Stat3 and Stat3 cleavage was accompanied by the apparent formation of cleavage fragment(s). Stat3 cleavage fragments, reflecting multiple caspase cleavage sites, also were observed in vitro following STS exposure in DU14S cells and in HEK293T cells transfected to express Stat3 truncation mutants. The impact of cleavage on Stat3 transcriptional activity next was assessed and revealed that cleavage of fl-Stat3 was accompanied by reductions in Stat3-DNA binding, Stat3-driven reporter protein (luciferase) activity, and the expression of selected Stat3-dependent genes. Further, reduced Stat3 expression correlated with increased sensitivity to apoptotic stimuli. In concomitant experiments, reporter activity was assessed in Stat3 truncation mutant-expressing HEK293T cells and revealed that, under non-apoptotic conditions, expression of different Stat3 fragments induced differential effects on Stat3-driven luciferase activity. These findings demonstrate that fl-Stat3 undergoes proteolytic processing by caspases that reduces its expression and leads to the formation of cleavage fragments that may modulate Stat3 transcriptional activity. [ABSTRACT FROM AUTHOR]

Background: STereotactic Arrhythmia Radioablation (STAR) is a novel noninvasive method for treating arrythmias in which external beam radiation is directed towards subregions of the heart. Challenges for accurate STAR targeting include small target volumes and relatively large patient motion, which can lead to radiation related patient toxicities. 4D Cone-beam CT (CBCT) images are used for stereotactic lung treatments to account for respiration-related patient motion. 4D-CBCT imaging could similarly be used to account for respiration-related patient motion in STAR; however, the poor contrast of heart tissue in CBCT makes identifying cardiac substructures in 4D-CBCT images challenging. If cardiac structures can be identified in pre-treatment 4D-CBCT images, then the location of the target volume can be more accurately identified for different phases of the respiration cycle, leading to more accurate targeting and a reduction in patient toxicities., Purpose: The aim of this simulation study is to investigate the accuracy of different cardiac substructure segmentation methods for 4D-CBCT images., Methods: Repeat 4D-CT scans from 13 lung cancer patients were obtained from The Cancer Imaging Archive. Synthetic 4D-CBCT images for each patient were simulated by forward projecting and reconstructing each respiration phase of a chosen "testing" 4D-CT scan. Eighteen cardiac structures were segmented from each respiration phase image in the testing 4D-CT using the previously validated platipy toolkit. The platipy segmentations from the testing 4D-CT were defined as the ground truth segmentations for the synthetic 4D-CBCT images. Five different 4D-CBCT cardiac segmentation methods were investigated: 3D Rigid Alignment, 4D Rigid Alignment, Direct CBCT Segmentation, Contour Transformation, and Synthetic CT Segmentation methods. For all methods except the Direct CBCT segmentation method, a separate 4D-CT (Planning CT) was used to assist in generating 4D-CBCT segmentations. Segmentation performance was measured using the Dice similarity coefficient (DSC), Hausdorff distance (HD), mean surface distance (MSD), and volume ratio (VR) metrics., Results: The mean ± standard deviation DSC for all cardiac substructures for the 3D Rigid Alignment, 4D Rigid Alignment, Direct CBCT Segmentation, Contour Transformation, and Synthetic CT Segmentation methods were 0.48 ± 0.29, 0.52 ± 0.29, 0.37 ± 0.32, 0.53 ± 0.29, 0.57 ± 0.28, respectively. Similarly, the HD values were 10.9 ± 3.6 , 9.9 ± 2.6 , 17.3 ± 5.3 , 9.9 ± 2.8 , 9.3 ± 3.0 mm, the MSD values were 2.9 ± 0.6 , 2.9 ± 0.6 , 6.3 ± 2.5 , 2.5 ± 0.6 , 2.4 ± 0.8 mm, and the VR Values were 0.81 ± 0.12, 0.78 ± 0.14, 1.10 ± 0.47, 0.72 ± 0.15, 0.98 ± 0.44, respectively. Of the five methods investigated the Synthetic CT segmentation method generated the most accurate segmentations for all calculated segmentation metrics., Conclusion: This simulation study investigates the accuracy of different cardiac substructure segmentation methods for 4D-CBCT images. Accurate 4D-CBCT cardiac segmentation will provide more accurate information on the location of cardiac anatomy during STAR treatments which can lead to safer and more effective STAR. As the data and segmentation methods used in this study are all open source, this study provides a useful benchmarking tool to evaluate other CBCT cardiac segmentation methods., (© 2024 American Association of Physicists in Medicine.)

Tremendous amount of sludge is generated annually from freshwater treatment or sewage. The high temperature slagging co-gasification converts the sludge to slag showing the potential application for construction material. In this study, the physico-chemical properties of 4 types of slags generated from the co-gasification of municipal solid waste (MSW) with sludge from freshwater treatment or sewage, and ashes from sludge incineration are comprehensively analyzed. Leaching performance of the sludge-derived slag and mortar (with slag as the fine aggregate), as determined based on Toxicity Characteristic Leaching Procedure (TCLP), batch leaching and column leaching tests, indicates the slag can be considered safe for reutilization. Compressive strength test demonstrates that the mortars perform excellently and have the potential to replace sand in concrete production. The consolidation coefficient of slag (1.6 - 39.1 m 2 /year) is lower than the sandy silt but higher than clay. Additionally, the coefficient of permeability (∼1.96 × 10 -3 m/s), angle of shearing resistance (∼39°), and undrained shear strength (375.5 ± 54.8 kPa) of the slag are comparable to sand. The life cycle assessment (LCA) is also conducted to evaluate the environmental impacts and benefits of reutilizing sludge-derived slag as an alternative material for concrete production and land reclamation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Pancreatic cancer (PC) is a lethal disease with few effective treatment options. Many anti-cancer therapies have been tested in the locally advanced and metastatic setting, with mixed results. This review synthesises all the randomised data available to help better inform patient and clinician decision-making. It updates the previous version of the review, published in 2018., Objectives: To assess the effects of chemotherapy, radiotherapy, or both on overall survival, severe or life-threatening adverse events, and quality of life in people undergoing first-line treatment of advanced pancreatic cancer., Search Methods: We searched for published and unpublished studies in CENTRAL, MEDLINE, Embase, and CANCERLIT, and handsearched various sources for additional studies. The latest search dates were in March and July 2023., Selection Criteria: We included randomised controlled trials comparing chemotherapy, radiotherapy, or both with another intervention or best supportive care. Participants were required to have locally advanced, unresectable pancreatic cancer or metastatic pancreatic cancer not amenable to curative intent treatment. Histological confirmation was required. Trials were required to report overall survival., Data Collection and Analysis: We used standard methodological procedures expected by Cochrane., Main Results: We included 75 studies in the review and 51 in the meta-analysis (11,333 participants). We divided the studies into seven categories: any anti-cancer treatment versus best supportive care; various chemotherapy types versus gemcitabine; gemcitabine-based combinations versus gemcitabine alone; various chemotherapy combinations versus gemcitabine plus nab-paclitaxel; fluoropyrimidine-based studies; miscellaneous studies; and radiotherapy studies. In general, the included studies were at low risk for random sequence generation, detection bias, attrition bias, and reporting bias, at unclear risk for allocation concealment, and high risk for performance bias. Compared to best supportive care, chemotherapy likely results in little to no difference in overall survival (OS) (hazard ratio (HR) 1.08, 95% confidence interval (CI) 0.88 to 1.33; absolute risk of death at 12 months of 971 per 1000 versus 962 per 1000; 4 studies, 298 participants; moderate-certainty evidence). The adverse effects of chemotherapy and impacts on quality of life (QoL) were uncertain. Many of the chemotherapy regimens were outdated. Eight studies compared non-gemcitabine-based chemotherapy regimens to gemcitabine. These showed that 5-fluorouracil (5FU) likely reduces OS (HR 1.69, 95% CI 1.26 to 2.27; risk of death at 12 months of 914 per 1000 versus 767 per 1000; 1 study, 126 participants; moderate certainty), and grade 3/4 adverse events (QoL not reported). Fixed dose rate gemcitabine likely improves OS (HR 0.79, 95% CI 0.66 to 0.94; risk of death at 12 months of 683 per 1000 versus 767 per 1000; 2 studies, 644 participants; moderate certainty), and likely increase grade 3/4 adverse events (QoL not reported). FOLFIRINOX improves OS (HR 0.51, 95% CI 0.43 to 0.60; risk of death at 12 months of 524 per 1000 versus 767 per 1000; P < 0.001; 2 studies, 652 participants; high certainty), and delays deterioration in QoL, but increases grade 3/4 adverse events. Twenty-eight studies compared gemcitabine-based combinations to gemcitabine. Gemcitabine plus platinum may result in little to no difference in OS (HR 0.94, 95% CI 0.81 to 1.08; risk of death at 12 months of 745 per 1000 versus 767 per 1000; 6 studies, 1140 participants; low certainty), may increase grade 3/4 adverse events, and likely worsens QoL. Gemcitabine plus fluoropyrimidine improves OS (HR 0.88, 95% CI 0.81 to 0.95; risk of death at 12 months of 722 per 1000 versus 767 per 1000; 10 studies, 2718 participants; high certainty), likely increases grade 3/4 adverse events, and likely improves QoL. Gemcitabine plus topoisomerase inhibitors result in little to no difference in OS (HR 1.01, 95% CI 0.87 to 1.16; risk of death at 12 months of 770 per 1000 versus 767 per 1000; 3 studies, 839 participants; high certainty), likely increases grade 3/4 adverse events, and likely does not alter QoL. Gemcitabine plus taxane result in a large improvement in OS (HR 0.71, 95% CI 0.62 to 0.81; risk of death at 12 months of 644 per 1000 versus 767 per 1000; 2 studies, 986 participants; high certainty), and likely increases grade 3/4 adverse events and improves QoL. Nine studies compared chemotherapy combinations to gemcitabine plus nab-paclitaxel. Fluoropyrimidine-based combination regimens improve OS (HR 0.79, 95% CI 0.70 to 0.89; risk of death at 12 months of 542 per 1000 versus 628 per 1000; 6 studies, 1285 participants; high certainty). The treatment arms had distinct toxicity profiles, and there was little to no difference in QoL. Alternative schedules of gemcitabine plus nab-paclitaxel likely result in little to no difference in OS (HR 1.10, 95% CI 0.82 to 1.47; risk of death at 12 months of 663 per 1000 versus 628 per 1000; 2 studies, 367 participants; moderate certainty) or QoL, but may increase grade 3/4 adverse events. Four studies compared fluoropyrimidine-based combinations to fluoropyrimidines alone, with poor quality evidence. Fluoropyrimidine-based combinations are likely to result in little to no impact on OS (HR 0.84, 95% CI 0.61 to 1.15; risk of death at 12 months of 765 per 1000 versus 704 per 1000; P = 0.27; 4 studies, 491 participants; moderate certainty) versus fluoropyrimidines alone. The evidence suggests that there was little to no difference in grade 3/4 adverse events or QoL between the two groups. We included only one radiotherapy (iodine-125 brachytherapy) study with 165 participants. The evidence is very uncertain about the effect of radiotherapy on outcomes., Authors' Conclusions: Combination chemotherapy remains standard of care for metastatic pancreatic cancer. Both FOLFIRINOX and gemcitabine plus a taxane improve OS compared to gemcitabine alone. Furthermore, the evidence suggests that fluoropyrimidine-based combination chemotherapy regimens improve OS compared to gemcitabine plus nab-paclitaxel. The effects of radiotherapy were uncertain as only one low-quality trial was included. Selection of the most appropriate chemotherapy for individuals still remains unpersonalised, with clinicopathological stratification remaining elusive. Biomarker development is essential to assist in rationalising treatment selection for patients., (Copyright © 2024 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Purpose: Lung cancer remains underrepresented in cancer survivorship research. This study aimed to understand survivors' physical/psychological challenges, experiences of immunotherapy (IO) and targeted therapy (TT), and psychological adjustment through application of the Roberts et al. (2017) advanced cancer adaptation of Folkman and Greer's appraisal and coping model., Methods: Adults 6-24 months post-initial treatment completion were recruited via an Australian cohort study. Participant demographic, clinical, quality of life, and distress data were obtained through the cohort database. Qualitative interviews were conducted and analyzed using Framework methods. Roberts et al. (2017)'s model informed data interpretation and presentation., Results: Twenty interviews were conducted (10 females; average age 69 years). Participants' diagnostic stages varied (stage I = 2, stage II = 4, stage III = 8, stage IV = 6); most had received IO/TT (n = 14) and were on average 17 months (range 10-24) post-diagnosis. Three themes were identified and mapped to the Roberts' framework: (1) Ongoing illness events: most participants reported functioning well despite ongoing physical effects. Those on IO/TT reported side effects; some were unexpected/serious. (2) Adjusting to life with lung cancer: most expressed hope for the future while simultaneously preparing for disease progression. Those receiving IO/TT experienced uncertainty given limited survival information. (3) Learning to live with lung cancer: participants described emotion, problem, and meaning based on coping strategies., Conclusions: Findings may guide development of supportive care resources/interventions focused on uncertainty, IO/TT communication and decision-making, and coping., Implications for Cancer Survivors: Many people with lung cancer are living well with their ongoing illness. Despite challenges, many survivors are adapting to issues as they arise and are maintaining a sense of hope and optimism., (© 2023. The Author(s).)

Radiotherapy is an essential part of treatment for many patients with thoracic cancers. However, proximity of the heart to tumour targets can lead to cardiac side effects, with studies demonstrating link between cardiac radiation dose and adverse outcomes. Although reducing cardiac dose can reduce associated risks, most cardiac constraint recommendations in clinical use are generally based on dose to the whole heart, as dose assessment at cardiac substructure levels on individual patients has been limited historically. Furthermore, estimation of an individual's cardiac risk is complex and multifactorial, which includes radiation dose alongside baseline risk factors, and the impact of systemic therapies. This review gives an overview of the epidemiological impact of cancer and cardiac disease, risk factors contributing to radiation-related cardiotoxicity, the evidence for cardiac side effects and future directions in cardiotoxicity research. A better understanding of the interactions between risk factors, balancing treatment benefit versus toxicity and the ongoing management of cardiac risk is essential for optimal clinical care. The emerging field of cardio-oncology is thus a multidisciplinary collaborative effort to enable better understanding of cardiac risks and outcomes for better-informed patient management decisions., (© 2024 The Author(s). Journal of Medical Imaging and Radiation Oncology published by John Wiley & Sons Australia, Ltd on behalf of Royal Australian and New Zealand College of Radiologists.)

Objectives: The coronavirus disease 2019 (COVID-19) pandemic disrupted healthcare systems worldwide, causing substantial changes to routine healthcare delivery. National and international modelling studies have predicted adverse impacts of this disruption. This study aimed to assess the real-world impact of the COVID-19 pandemic on quality of care and outcomes for patients with lung cancer in New South Wales (NSW)., Study Type: Pre-post observational cohort study using data prospectively collected for the Embedding Research (and Evidence) in Cancer Healthcare (EnRICH) Program., Methods: The study population comprised 2000 patients with lung cancer from six specialist cancer centres in metropolitan and regional NSW. We split this population into two cohorts: the pre-COVID-19 cohort (1143 patients diagnosed from 8 September 2016 to 10 March 2020) and the post-COVID-19 cohort (857 patients diagnosed from 11 March 2020 to 28 October 2021). The main outcome measures were lung cancer clinical quality indicators, 1-year and 2-year overall survival, and patient-reported health-related quality of life and psychological distress., Results: Patient and disease characteristics (e.g. age, gender, cancer stage) were similar for the pre-and post-COVID-19 cohorts, except for histology (non-small cell lung cancer (NSCLC) 88% in the pre-COVID-19 cohort and 84% in the post-COVID-19 cohort; p = 0.008) and region of residence (62% and 55%, respectively, lived in metropolitan areas; p = 0.002). Compared to the pre-COVID-19 cohort, fewer patients in the post-COVID-19 cohort received a diagnosis within 28 days of the first investigation of symptoms (clinical diagnosis: 77% compared with 72%; p = 0.017, pathological diagnosis: 60% compared with 53%; p = 0.005). However, the median time from the first investigation of symptoms to treatment initiation did not differ. One- and 2-year overall survival, quality of life and psychological distress did not differ between cohorts., Conclusions: This analysis found that the COVID-19 pandemic did not significantly adversely affect quality of care and outcomes for patients with lung cancer in NSW. Reassuringly, these results suggest that prioritising urgent health services, such as cancer care and implementing protective mitigation measures were effective in avoiding the predicted adverse outcomes of healthcare service disruption., Competing Interests: None declared

Background and Purpose: Stereotactic ablative body radiotherapy (SABR) is increasingly used for early-stage lung cancer, however the impact of dose to the heart and cardiac substructures remains largely unknown. The study investigated doses received by cardiac substructures in SABR patients and impact on survival., Materials and Methods: SSBROC is an Australian multi-centre phase II prospective study of SABR for stage I non-small cell lung cancer. Patients were treated between 2013 and 2019 across 9 centres. In this secondary analysis of the dataset, a previously published and locally developed open-source hybrid deep learning cardiac substructure automatic segmentation tool was deployed on the planning CTs of 117 trial patients. Physical doses to 18 cardiac structures and EQD2 converted doses (α/β = 3) were calculated. Endpoints evaluated include pericardial effusion and overall survival. Associations between cardiac doses and survival were analysed with the Kaplan-Meier method and Cox proportional hazards models., Results: Cardiac structures that received the highest physical mean doses were superior vena cava (22.5 Gy) and sinoatrial node (18.3 Gy). The highest physical maximum dose was received by the heart (51.7 Gy) and right atrium (45.3 Gy). Three patients developed grade 2, and one grade 3 pericardial effusion. The cohort receiving higher than median mean heart dose (MHD) had poorer survival compared to those who received below median MHD (p = 0.00004). On multivariable Cox analysis, male gender and maximum dose to ascending aorta were significant for worse survival., Conclusions: Patients treated with lung SABR may receive high doses to cardiac substructures. Dichotomising the patients according to median mean heart dose showed a clear difference in survival. On multivariable analyses gender and dose to ascending aorta were significant for survival, however cardiac substructure dosimetry and outcomes should be further explored in larger studies., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objective: To analyse the rate of contralateral nodal metastasis in human papillomavirus (HPV)-associated oropharyngeal carcinoma and identify the patient cohorts that would benefit from bilateral neck treatment., Methods: A retrospective cohort review was performed on 110 HPV-positive oropharyngeal carcinoma patients who underwent transoral robotic surgery and bilateral neck dissections from 2012 to 2022. The primary outcome was to investigate the pathological incidence and location of contralateral neck node metastasis., Results: The contralateral nodal disease rate was 12.7 per cent ( n = 14), of which 2 patients (2 per cent) were occult findings, with comparable results between tongue base and tonsil sub-groups. The most commonly involved contralateral nodal station was level II (11 of 110 patients, 10 per cent). The presence of extra-nodal extension and multiple ipsilateral positive nodes was associated with increased risk of contralateral nodal disease., Conclusion: The incidence of contralateral nodal and occult disease in the studied cohort is low. The characteristics of patients who may benefit from bilateral neck treatment were demonstrated.

Introduction: ALK-positive lung cancers represent a molecularly diverse disease. With drug exposure, driving selection pressure, and resistance pathways, disease relapse will emerge. There is compelling rationale to investigate novel treatment strategies, informed by dynamic circulating tumor DNA (ctDNA) monitoring., Methods: The single-arm, pilot study ALKTERNATE investigated fixed alternating cycles of lorlatinib intercalated with crizotinib in individuals resistant to second-generation ALK inhibitors. Dynamic ctDNA explored the correlation with disease response and disease recurrence and defined disease resistance. The primary outcome was time-to-treatment failure, a composite of tolerability, feasibility, and efficacy. Secondary outcomes included standard survival measures, toxicity, pharmacokinetic analysis, and patient-reported outcomes. Tertiary outcomes were proteogenomic analyses of tissue and plasma., Results: A total of 15 individuals were enrolled; three encountered primary resistance to lorlatinib induction. There were 12 participants who received alternating therapy, and this approach revealed safety, feasibility, and effectiveness. Patient-reported outcomes were maintained or improved on therapy, and toxicity was consistent with previous reports. The pharmacokinetic measures were similar to the single-arm drug experience. Median time-to-treatment failure was 10 months; overall survival was 23 months. ctDNA profiles indicated inferior survival in those with preexistent TP53 mutations and those without clear or cleared ctDNA at trial induction. The study defined a vastly heterogeneous population with an abundance of ALK coexisting with non-ALK resistance variants., Conclusions: ALKTERNATE revealed feasibility with a novel alternating ALK inhibitor strategy in ALK-positive NSCLC. Results support progressing inquiry into this approach and propose a flexible design with drug(s) selected and alternating time frames, informed by real-time plasma profiling. Moving this concept to treatment naive may also optimize impact., Competing Interests: ALKTERNATE received grant funding and provision of drug from Pfizer. The following authors have received personal financial payment from Pfizer for consultancy and/or honoraria: MI, AN, SK, AM, BJS, NP., (© 2024 The Authors.)