Cerebrospinal Fluid Leaks: Challenges in Localizing Spontaneous Spinal Leak Sites and Minimally Invasive Treatment.

The confirmation of cerebrospinal fluid (CSF) leaks in the setting of spontaneous intracranial hypotension (SIH) by imaging involves a growing toolset of multimodal advanced spinal and skull base imaging techniques, for which exists a unique set of challenges for each CSF leak type. Furthermore, the repertoire of minimally invasive CSF leak treatment beyond nontargeted epidural blood patch administration has grown widely, with varied practices across institutions. This review describes current diagnostic imaging and treatment modalities as they apply to the challenges of CSF leak localization and management.

A randomised controlled trial of Standard Of Care versus RadioAblaTion in Early Stage HepatoCellular Carcinoma (SOCRATES HCC).

BACKGROUND: Therapeutic options for early-stage hepatocellular carcinoma (HCC) in individual patients can be limited by tumor and location, liver dysfunction and comorbidities. Many patients with early-stage HCC do not receive curative-intent therapies. Stereotactic ablative body radiotherapy (SABR) has emerged as an effective, non-invasive HCC treatment option, however, randomized evidence for SABR in the first line setting is lacking. METHODS: Trans-Tasman Radiation Oncology Group (TROG) 21.07 SOCRATES-HCC is a phase II, prospective, randomised trial comparing SABR to other current standard of care therapies for patients with a solitary HCC ≤ 8 cm, ineligible for surgical resection or transplantation. The study is divided into 2 cohorts. Cohort 1 will compromise 118 patients with tumors ≤ 3 cm eligible for thermal ablation randomly assigned (1:1 ratio) to thermal ablation or SABR. Cohort 2 will comprise 100 patients with tumors > 3 cm up to 8 cm in size, or tumors ≤ 3 cm ineligible for thermal ablation, randomly assigned (1:1 ratio) to SABR or best other standard of care therapy including transarterial therapies. The primary objective is to determine whether SABR results in superior freedom from local progression (FFLP) at 2 years compared to thermal ablation in cohort 1 and compared to best standard of care therapy in cohort 2. Secondary endpoints include progression free survival, overall survival, adverse events, patient reported outcomes and health economic analyses. DISCUSSION: The SOCRATES-HCC study will provide the first randomized, multicentre evaluation of the efficacy, safety and cost effectiveness of SABR versus other standard of care therapies in the first line treatment of unresectable, early-stage HCC. It is a broad, multicentre collaboration between hepatology, interventional radiology and radiation oncology groups around Australia, coordinated by TROG Cancer Research. TRIAL REGISTRATION: anzctr.org.au, ACTRN12621001444875, registered 21 October 2021.

Real-world use of immune checkpoint inhibitors in advanced or recurrent endometrial cancer.

OBJECTIVE: The aim of this study was to describe real-world use of immune checkpoint inhibitors for women with advanced or recurrent endometrial cancer. METHODS: Adult women with advanced or recurrent endometrial cancer who received at least one line of systemic treatment between January 1, 2014 and November 1, 2020, then followed to May 31, 2021 in a nationwide electronic health record-derived de-identified database. Chi-Squared test or Welch's 2-sample t-tests were used to compare patient and clinical factors associated with immune checkpoint inhibitor treatment. Time to next treatment analyses were performed based on the treatment line of the immune checkpoint inhibitor. Sankey plots depicted patient-level temporal systemic treatment. RESULTS: During our study period, 326 women received their first immune checkpoint inhibitor treatment, increasing from 12 patients in 2016 to 148 in 2020. Factors associated with ever receiving immune checkpoint inhibitors included disease stage (p=0.002), mismatch repair (MMR)/microsatellite instability (MSI) status (p<0.001), performance status (p=0.001), and prior radiation receipt (p<0.001) and modality (p=0.003). The most common immune checkpoint inhibitor regimen was pembrolizumab (47.9%) followed by pembrolizumab and lenvatinib (34.7%). Immune checkpoint inhibitors were given as first, second, and third or greater lines of therapy in 24.5%, 41.7%, and 46.1% of evaluable patients. The median time to next treatment was significantly longer if given as an earlier line of treatment (p=0.008). There were significant differences in treatment line of immune checkpoint inhibitor by region (p=0.004), stage (p<0.001), and prior radiation receipt (p=0.014) and modality (p=0.009). Among 326 patients who received immune checkpoint inhibitors, 114 (34.9%) received subsequent treatment including chemotherapy (43.9%), additional immune checkpoint inhibitors (29.8%), and other (26.3%) with no differences in demographic or clinical characteristics based on the type of post-immune checkpoint inhibitor treatment. CONCLUSION: In an observational retrospective real-world database study, immune checkpoint inhibitors were used in 14.7% of patients with advanced or recurrent endometrial cancer across multiple lines of treatment, including after initial immune checkpoint inhibitor treatment.

Use of HSC Targeted LNP to Generate a Mouse Model of Lethal α-Thalassemia and Treatment via Lentiviral Gene Therapy.

-Thalassemia (AT) is one of the most commonly occurring inherited hematological diseases. However, few treatments are available, and allogeneic bone marrow transplantation (BMT) is the only available therapeutic option for patients with severe AT. Research into AT has remained limited due to a lack of adult mouse models, with severe AT typically resulting in in utero lethality. By using a lipid nanoparticle (LNP) targeting the receptor CD117 and delivering a Cre mRNA (mRNACreLNPCD117), we were able to delete floxed -globin genes at high efficiency in hematopoietic stem cells (HSC) ex vivo. These cells were then engrafted in the absence or presence of a novel α-globin expressing lentiviral vector (ALS20I). Myeloablated mice transplanted with mRNACreLNPCD117-treated HSC showed a complete knockout of -globin genes. They demonstrated a phenotype characterized by the synthesis of hemoglobin H (-tetramers,  or HbH), aberrant erythropoiesis, and abnormal organ morphology, culminating in lethality approximately eight weeks following engraftment. Mice receiving mRNACreLNPCD117-treated HSC with at least one copy of ALS20I survived long-term with normalization of erythropoiesis, decreased the production of HbH, and ameliorated the abnormal organ morphology. Furthermore, we tested ALS20I in erythroid progenitors derived from -globin-KO CD34+ and cells isolated from patients with both deletional and non-deletional HbH disease, demonstrating improvement in -globin/-globin mRNA ratio and reduction in the formation of HbH by HPLC. Our results demonstrate the broad applicability of LNP for disease modeling, characterization of a novel severe mouse model of AT, and the efficacy of ALS20I for treating AT.

Sleep, Nutrition, and Health Maintenance in Cardiothoracic Surgery.

Cardiothoracic surgeons work in high-intensity environments starting in surgical training and throughout their careers. They deal with critical patients. Their routine procedures are delicate, require extensive attention to detail, and can have detrimental effects on patients' lives. Cardiothoracic surgeons are required to perform at their best capacity incessantly. To do this, they must safeguard their mental and physical well-being. Preserving health through sleep, nutrition, exercise, and routine medical checkups ensures a cardiothoracic surgeon's well-being. Great personal effort and discipline is required to maintain health in a busy schedule. We offer our best recommendations from expert peers in the field.

A suite of enhancer AAVs and transgenic mouse lines for genetic access to cortical cell types.

The mammalian cortex is comprised of cells with different morphological, physiological, and molecular properties that can be classified according to shared properties into cell types. Defining the contribution of each cell type to the computational and cognitive processes that are guided by the cortex is essential for understanding its function in health and disease. We use transcriptomic and epigenomic cortical cell type taxonomies from mice and humans to define marker genes and enhancers, and to build genetic tools for cortical cell types. Here, we present a large toolkit for selective targeting of cortical populations, including mouse transgenic lines and recombinant adeno-associated virus (AAV) vectors containing genomic enhancers. We report evaluation of fifteen new transgenic driver lines and over 680 different enhancer AAVs covering all major subclasses of cortical cells, with many achieving a high degree of specificity, comparable with existing transgenic lines. We find that the transgenic lines based on marker genes can provide exceptional specificity and completeness of cell type labeling, but frequently require generation of a triple-transgenic cross for best usability/specificity. On the other hand, enhancer AAVs are easy to screen and use, and can be easily modified to express diverse cargo, such as recombinases. However, their use depends on many factors, such as viral titer and route of administration. The tools reported here as well as the scaled process of tool creation provide an unprecedented resource that should enable diverse experimental strategies towards understanding mammalian cortex and brain function.

Genome-wide Polygenic Risk Scores Predict Risk of Glioma and Molecular Subtypes.

BACKGROUND: Polygenic risk scores (PRS) aggregate the contribution of many risk variants to provide a personalized genetic susceptibility profile. Since sample sizes of glioma genome-wide association studies (GWAS) remain modest, there is a need to efficiently capture genetic risk using available data. METHODS: We applied a method based on continuous shrinkage priors (PRS-CS) to model the joint effects of over 1 million common variants on disease risk and compared this to an approach (PRS-CT) that only selects a limited set of independent variants that reach genome-wide significance (P<5×10-8). PRS models were trained using GWAS stratified by histological (10,346 cases, 14,687 controls) and molecular subtype (2,632 cases, 2,445 controls), and validated in two independent cohorts. RESULTS: PRS-CS was generally more predictive than PRS-CT with a median increase in explained variance (R2) of 24% (interquartile range=11-30%) across glioma subtypes. Improvements were pronounced for glioblastoma (GBM), with PRS-CS yielding larger odds ratios (OR) per standard deviation (OR=1.93, P=2.0×10-54 vs. OR=1.83, P=9.4×10-50) and higher explained variance (R2=2.82% vs. R2=2.56%). Individuals in the 80th percentile of the PRS-CS distribution had significantly higher risk of GBM (0.107%) at age 60 compared to those with average PRS (0.046%, P=2.4×10-12). Lifetime absolute risk reached 1.18% for glioma and 0.76% for IDH wildtype tumors for individuals in the 95th PRS percentile. PRS-CS augmented the classification of IDH mutation status in cases when added to demographic factors (AUC=0.839 vs. AUC=0.895, PΔAUC=6.8×10-9). CONCLUSIONS: Genome-wide PRS has potential to enhance the detection of high-risk individuals and help distinguish between prognostic glioma subtypes.

Immunomethylomic profiles of long-term head and neck squamous cell carcinoma survivors on immune checkpoint inhibitors.

Aim: This study addresses the challenge of predicting the response of head and neck squamous cell carcinoma (HNSCC) patients to immunotherapy. Methods: Using DNA methylation cytometry, we analyzed the immune profiles of six HNSCC patients who showed a positive response to immunotherapy over a year without disease progression. Results: There was an initial increase in CD8 T memory cells and natural killer cells during the first four cycles of immunotherapy, which then returned to baseline levels after a year. Baseline CD8 T cell levels were lower in HNSCC immunotherapy responders but became similar to those in healthy subjects after immunotherapy. Conclusion: These findings suggest that monitoring fluctuations in immune profiles could potentially identify biomarkers for immunotherapy response in HNSCC patients.

[Box: see text].

FDA Approval Summary: Repotrectinib for locally advanced or metastatic ROS1-positive non-small cell lung cancer.

On November 15, 2023, the U.S. Food and Drug Administration (FDA) granted traditional approval to repotrectinib (Augtyro®, Bristol Myers Squibb Corporation), for the treatment of adult patients with locally advanced or metastatic ROS1-positive non-small cell lung cancer (NSCLC). The approval was based on TRIDENT-1, a single arm trial with multiple cohorts of patients with ROS1 fusion-positive (hereafter "ROS1-positive") NSCLC, (NCT03093116), who were either treatment naïve or had received prior ROS1 TKI and/or platinum-based chemotherapy. The primary efficacy outcome measure is objective response rate (ORR) assessed by blinded independent central review (BICR) using response evaluation criteria in solid tumors (RECIST) version 1.1. ORR was assessed in 71 patients who were ROS1 TKI naïve and 56 patients who had received a prior ROS1 TKI. Among 71 patients who were ROS1 TKI naïve, the ORR was 79% (95% CI 68, 88); median duration of response was 34.1 months (95% CI 26, NE). In patients who had received a prior ROS1 TKI and no prior chemotherapy, the ORR was 38% (95% CI 25, 52). The median duration of response was 14.8 months (95% CI 7.6, NE) BICR-assessed responses were observed in CNS metastases in patients in both cohorts, and in patients who developed resistance mutations following prior TKI therapy. The most common (> 20%) adverse reactions were dizziness, dysgeusia, peripheral neuropathy, constipation, dyspnea, ataxia, fatigue, cognitive disorders, and muscular weakness. A unique feature of this ROS1 TKI approval is the inclusion of robust evidence of efficacy in patients with ROS1-positive NSCLC who had progressed on prior ROS1 TKIs.

Novel Transcriptional and DNA Methylation Abnormalities of SORT1 Gene in Non-Small Cell Lung Cancer.

Sortilin is an important regulator with potential tumour-suppressor function by limiting EGFR signalling. In this study, we undertook a comprehensive expression analysis of sortilin transcript variants and the DNA methylation status of their corresponding promoters in human non-small cell carcinomas (NSCLCs). RNA/DNA was extracted from 81 NSCLC samples and paired normal tissue. mRNA expression was measured by qPCR and DNA methylation determined by pyrosequencing. BigDye-terminator sequencing was used to confirm exon-8 alternative splicing. Results demonstrated that both SORT1A and SORT1B variants were downregulated in lung tumours. The SORT1A/SORT1B expression ratio was higher in tumours compared to normal tissue. SORT1B promoter hypermethylation was detected in lung tumours compared to normal lung (median difference 14%, Mann-Whitney test p = 10-6). Interestingly, SORT1B is hypermethylated in white blood cells, but a small and very consistent drop in methylation (6%, p = 10-15) was observed in the lung cancer cases compared to control subjects. We demonstrate that the SORT1B exon-8 splice variation, reported in sequence databases, is also a feature of SORT1A. The significantly altered quantitative and qualitative characteristics of sortilin mRNA in NSCLC indicate a significant involvement in tumour pathogenesis and may have significant impact for its utility as a predictive marker in lung cancer management.

Operative Time Associated With Increased Length of Stay After Single-level Cervical Disk Arthroplasty: An Analysis of 3681 Surgeries.

STUDY DESIGN: Level III evidence-retrospective cohort. OBJECTIVE: The purpose of this study was to (1) determine whether longer CDA operative time increases the risk of 30-day postoperative complications, (2) analyze the association between operative time and subsequent health care utilization, and (3) discharge disposition. BACKGROUND: Cervical disk arthroplasty (CDA) most commonly serves as an alternative to anterior cervical discectomy and fusion (ACDF) to treat cervical spine disease, however, with only 1600 CDAs performed annually relative to 132,000 ACDFs, it is a relatively novel procedure. METHODS: A retrospective query was performed identifying patients who underwent single-level CDA between January 2012 and December 2018 using a nationwide database. Differences in baseline patient demographics were identified through univariate analysis. Multivariate logistic regression was performed to identify associations between operative time (reference: 81-100 min), medical/surgical complications, and health care utilization. RESULTS: A total of 3681 cases were performed, with a mean patient age of 45.52 years and operative time of 107.72±49.6 minutes. Higher odds of length of stay were demonstrated starting with operative time category 101-120 minutes (odds ratio: 2.164, 95% CI: 1.247-3.754, P=0.006); however, not among discharge destination, 30-day unplanned readmission, or reoperation. Operative time <40 minutes was associated with 10.7x odds of nonhome discharge, while >240 minutes was associated with 4.4 times higher odds of LOS>2 days (P<0.01). Increased operative time was not associated with higher odds of wound complication/infection, pulmonary embolism, deep venous thrombosis, or urinary tract infections. CONCLUSIONS: Prolonged CDA operative time above the reference 81-100 minutes is independently associated with increased length of stay, but not other significant health care utilization parameters, including discharge disposition, readmission, or reoperation. There was no association between prolonged operative time and 30-day medical/surgical complications, including wound complications, infections, pulmonary embolism, or urinary tract infection.

Enteral Nutrition in Operated-On Gastric Cancer Patients: An Update.

It is well established that the preoperative nutritional status of gastric cancer (GC) patients significantly affects the prognosis of the operated patients, their overall survival, as well as the disease-specific survival. Existing data support that preoperative assessment of nutritional status and early correction of nutritional deficiencies exert a favorable effect on early postoperative outcomes. A variety of relevant indices are used to assess the nutritional status of GC patients who are candidates for surgery. The guidelines of almost all international organizations recommend the use of oral enteral nutrition (EN). Oncologically acceptable types of gastrectomy and methods of patient rehabilitation should take into account the expected postoperative nutritional status. The majority of data support that perioperative EN reduces complications and hospital stay, but not mortality. Oral EN in the postoperative period, albeit in small amounts, helps to reduce the weight loss that is a consequence of gastrectomy. Iron deficiency with or without anemia and low serum levels of vitamin B12 are common metabolic sequelae after gastrectomy and should be restored. EN also significantly helps patients undergoing neoadjuvant or adjuvant antineoplastic therapy. The occurrence of the so-called "postgastrectomy syndromes" requires dietary modifications and drug support. This review attempts to highlight the benefits of EN in GC patients undergoing gastrectomy and to emphasize the type of necessary nutritional management, based on current literature data.

Effects of supplemental methionine sources in finishing pig diets on growth performance, carcass characteristics, cutting yields, and meat quality.

Supplemental methionine (Met) is widely used within the swine industry; however, data are limited regarding the effect of Met sources on carcass cutability and meat quality. The objective was to determine the effects of L-Met (LM, 99%), DL-Met (DLM, 99%), or calcium salt of DL-Met hydroxyl analog (MHA, 84%) in finishing pig diets on carcass characteristics and meat quality. At 9 weeks of age, pigs (N = 240) were allocated to 60 single-sex pens for a four-phase finishing trial that lasted 104 d. Pigs were fed a common grower diet until day 56 where pens were randomly allotted to one of the three experimental diets. For the remaining 7 wk of the finisher phase, pigs (BW = 79.9 ±â€…0.80 kg) were fed diets containing LM, DLM, or MHA, with the supplemental Met source providing 25% of standardized ileal digestible (SID) Met + cysteine (Cys) requirement based on 65% bioefficacy for MHA in comparison with LM or DLM. One pig per pen was slaughtered at the study conclusion (on day 104), and the left sides of carcasses were fabricated into subprimal cuts to determine carcass-cutting yields. Loin quality including proximate composition and shear force were measured. Hot carcass weight was not different (P = 0.34) between treatments (LM 104.5 kg; DLM 103.0 kg; MHA 101.5 kg), moreover, loin eye area was not different (P = 0.98) between treatments (LM 52.65 cm²; DLM 52.49 cm²; MHA 52.81 cm²). Boneless carcass-cutting yield was not different (P = 0.56) between treatments (LM 54.97 kg; DLM 54.82 kg; MHA 54.52 kg). Loin pH was not different (P = 0.24) between treatments (LM 5.45; DLM 5.48; MHA 5.45). However, drip loss tended to be reduced (P = 0.11) by the DLM treatment (5.58%) compared with LM (7.03%) and MHA (6.68%) treatments. Shear force was not different (P = 0.85) between treatments (LM 3.03 kg; DLM 3.06 kg; MHA 3.10 kg). However, cook loss tended to be reduced (P = 0.06) by the DLM treatment (16.20%) compared with LM (18.18%) and MHA (18.50%) treatments. These data suggest that only minimal differences in carcass cutability and meat quality can be attributed to Met source in finishing pig diets when using 65% bioefficacy for MHA relative to L-Met or DL-Met.

Stakeholder perspectives on scaling robotic surgery in India: qualitative research.

Robotic surgery (RS) is a milestone in minimally invasive surgery. More than 500 surgeons are trained in RS in India, and more than 100 robotic systems have been installed across various centers. RS offers various benefits to patients and surgeons. Although it is rapidly advancing and has several advantages, a robotic system is a complex system that is equipped with complex instruments. Qualitative research aims to take a broad view of the perceptions of stakeholders of RS and to synthesize their views to gain insight into scaling RS. This qualitative study aimed to explore the perspectives of relevant stakeholders on RS to learn how to develop the field and make it more affordable. This study is based on grounded theory methodology and uses the standards for reporting qualitative research (SRQR) guidelines for reporting. Three premier hospitals that are pioneers in RS in India served as the study locations. Purposive sampling was used to collect data from surgeons, nurses, and insurance staff. The surgeons interviewed have national and international exposure and are consulting and performing robotic surgeries across India and internationally. We conducted one-on-one interviews and wrote memos to gather further information before approaching each stakeholder. Samples were determined based on theoretical saturation. Fellowship training, which includes simulation, bedside assistance, and individual cases under supervision, was found to be the standard training method. The stakeholders mentioned a few prerequisites for performing RS, such as prior laparoscopic experience, passion for surgical knowledge and skill, and proper case selection. The surgeons discussed some technical considerations of RS, such as medico-legal issues and mechanical faults associated with it. Although there is increased scope for establishing robotic surgery, surgeons feel that the cost of RS is high. From the interactions with the stakeholders, it is understood that robotic surgeons are the most significant players in RS. Robotic surgery demands more skills and more trained professionals to scale up. Key findings highlight the importance of fellowship training, prior laparoscopic experience, and proper case selection. While RS has potential for growth, high costs, and technical issues remain concerns. Insurance companies include robotic surgery in their policies under the category of "modernized medicine." Depending on the insurance plan that the patient selects, the necessity of the robotic surgery, and the surgeon's justification, the insurance company will pay for the patient's robotic surgery. To make it affordable for patients, complete insurance coverage is mandatory along with creating more awareness among patients. The growth of RS is inevitable in the future with other robotic companies emerging which will ultimately reduce the capital cost and robotic surgeons are pivotal in advancing RS.

The Biting Colon: An Unfortunate Nightmare for a Healthy but Anxious Patient.

A 48-year-old female with no significant past medical history presented to the emergency department with an uncommon scenario after accidentally ingesting a three-unit dental bridge, leading to its impaction within the lower gastrointestinal tract. Despite initial conservative management with laxatives aimed at facilitating spontaneous passage, the foreign body remained lodged in the colon. Subsequently, the patient underwent endoscopic intervention via colonoscopy, during which the dental bridge was successfully extracted. This case highlights the complexity of managing foreign body ingestions, particularly when impaction occurs in uncommon locations, such as the colon. We emphasize the importance of individualized care strategies and recognize the potential of endoscopic procedures in resolving clinical scenarios involving foreign body ingestions.

Resumen: Consenso internacional para la nomenclatura y clasificación de la válvula aórtica bicúspide congénita y su aortopatía, con fines clínicos, quirúrgicos, intervencionistas y de investigación / Summary: International consensus statement on nomenclature and classification of the congenital bicuspid aortic valve and its aortopathy, for clinical, surgical, interventional and research purposes

resumen está disponible en el texto completo

Abstract This consensus of nomenclature and classification for congenital bicuspid aortic valve and its aortopathy is evidence-based and intended for universal use by physicians (both pediatricians and adults), echocardiographers, advanced cardiovascular imaging specialists, interventional cardiologists, cardiovascular surgeons, pathologists, geneticists, and researchers spanning these areas of clinical and basic research. In addition, as long as new key and reference research is available, this international consensus may be subject to change based on evidence-based data1.

Florid follicular lymphoid hyperplasia of the palate: review of the literature and report of an illustrative case.

OBJECTIVE: The aim of this report was to review oral follicular lymphoid hyperplasia, with emphasis on palatal lesions. METHOD AND MATERIALS: A comprehensive search was performed on PubMed for case reports and case series of palatal follicular lymphoid hyperplasia published in the English language literature. Relevant data from collated articles was sought, including patient demographics, clinical manifestations, imaging modalities and findings, comorbidities, etiopathogenesis, lesional management, and lesional outcome. A new palatal case has also been provided to illustrate several features of this lesion. RESULTS: In total, 32 cases were assembled to establish clinicopathologic correlations, representing the largest aggregation of published cases. Most of the affected patients were at least 60 years old and with a decisive female predilection. The majority of lesions were ≤ 3 cm, appearing as normal color, purple-red or red, and varied from soft to firm. Notably, 32% of palatal follicular lymphoid hyperplasias were associated with denture wear, and lesional recurrence was recorded in 16% of cases. To date, none of the reported cases of palatal follicular lymphoid hyperplasia has undergone malignant transformation. CONCLUSIONS: Palatal follicular lymphoid hyperplasias often arise as a reactive process. Critical histopathologic and histochemical assessments are necessary to establish benignity. Postoperatively, clinicians should follow patients for at least 5 years for recurrence and remain vigilant for neoplastic change as several published accounts of non-oral follicular lymphoid hyperplasias have undergone malignant transformation, usually to lymphoma.

Assessment of TROP2, CEACAM5 and DLL3 in metastatic prostate cancer: Expression landscape and molecular correlates.

Therapeutic approaches targeting proteins on the surface of cancer cells have emerged as an important strategy for precision oncology. To capitalize on the potential impact of drugs targeting surface proteins, detailed knowledge about the expression patterns of the target proteins in tumor tissues is required. In castration-resistant prostate cancer (CRPC), agents targeting prostate-specific membrane antigen (PSMA) have demonstrated clinical activity. However, PSMA expression is lost in a significant number of CRPC tumors. The identification of additional cell surface targets is necessary to develop new therapeutic approaches. Here, we performed a comprehensive analysis of the expression heterogeneity and co-expression patterns of trophoblast cell-surface antigen 2 (TROP2), delta-like ligand 3 (DLL3), and carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) in CRPC samples from a rapid autopsy cohort. We show that DLL3 and CEACAM5 exhibit the highest expression in neuroendocrine prostate cancer (NEPC), while TROP2 is expressed across different CRPC molecular subtypes, except for NEPC. We further demonstrated that AR alterations were associated with higher expression of PSMA and TROP2. Conversely, PSMA and TROP2 expression was lower in RB1-altered tumors. In addition to genomic alterations, we show a tight correlation between epigenetic states, particularly histone H3 lysine 27 methylation (H3K27me3) at the transcriptional start site and gene body of TACSTD2 (encoding TROP2), DLL3, and CEACAM5, and their respective protein expression in CRPC patient-derived xenografts. Collectively, these findings provide insights into patterns and determinants of expression of TROP2, DLL3, and CEACAM5 with implications for the clinical development of cell surface targeting agents in CRPC.

Impact of single round of low dose CT lung cancer screening on cause of mortality in different socio-economic groups: a post-hoc analysis of long-term follow-up of the UKLS trial.

Background: Lower socioeconomic status, as measured by the Index of Multiple Deprivation (IMD), is associated with higher rates of smoking-related disease mortality, and with poor uptake of cancer screening. Here we explore whether socioeconomic status impacts the effectiveness of a single round of low-dose-CT screening, or impacts other causes of death, in the UKLS LDCT screening trial. Methods: IMD quintiles were defined according to UK-wide data, with the deprived group defined as the lower two quintiles (Q1-2) and the less deprived as Q3-5. Follow-up data was obtained for lung cancer diagnosis (median follow-up 9.1 years) and cause of death (median follow-up 9.9 years). Outcomes were compared based on IMD group and trial arm (CT or control). Findings: More deprived quintiles were less likely to respond to the questionnaire, but this population was more likely to be selected for screening by the LLP risk model. Lower IMD quintiles benefitted from low-dose-CT screening in terms of lung cancer survival (HR 1.89, 95% CI 1.16-3.08) to the same extent as upper quintiles (HR 1.87, 95% CI 1.07-3.26). However, there was a bigger impact on deaths due to COPD and emphysema in more deprived quintiles. Interpretation: Whilst LDCT screening benefit for lung cancer was similar, significant impact on the rates of death from other smoking-related diseases, notably COPD and emphysema, was seen primarily in lower socioeconomic groups. Future research is required to confirm how lung cancer screening benefits other disease outcomes. Funding: NIHR Health Technology Assessment Programme; NIHR Policy Research programme; Roy Castle Lung Cancer Foundation.