Introduction

Ongoing screening programs should be monitored and evaluated regularly to ensure a favorable balance between their harms and benefits. In 2022, the Dutch Health Council performed an evaluation commissioned by the Minister of Health of the first seven years of the population-based colorectal cancer (CRC) screening program in the Netherlands.

Aims & Methods

This study describes the key performance indicators used for this large evaluation in 2022. Population-based CRC screening in the Netherlands was initiated in 2014 with a phased roll-out by birth cohort, inviting individuals aged 55 to 75 to perform a faecal immunochemical test (FIT) using a positivity cut-off of 47 µg Hb/g faeces every two years. We calculated key performance indicators based on individual-level data from participants between 2014 and 2020 (up to four screening rounds) and presented outcomes by sex, round and prior faecal haemoglobin concentration (fHb). Also, we calculated the overall and advanced (stage III and IV) CRC incidence rate in 2013, 2015 and 2018 for advanced CRC incidence rate and 2019 for overall CRC incidence rate. Last, FIT episode sensitivity was calculated for three screening rounds between 2014 and 2018.

Results

FIT participation was high, especially among women, but slightly decreased over time. (Table 1) Colonoscopy participation remained stable (~85%). FIT positivity rate decreased from 5.6% to 4.3% after the first round and was higher for men than women. Similar patterns were observed for PPV and detection rates. The false-positivity rate was stable over three screening rounds (2.7 for men and 2.1 for women). The colonoscopy complication rate was less than 1%. For individuals with prior fHb just below the cut-off (15.0-46.9 µg Hb/g), FIT positivity and detection rates were significantly higher than for individuals with lower fHb. After the introduction of the screening program, the age-standardized overall CRC incidence rate initially increased from 214.3 in 2013 to 259.2 in 2015 but subsequently decreased below the level before screening to 181.5 in 2019. The same pattern was also visible for the advanced CRC incidence rate which increased from 117.0 in 2013 to 122.8 in 2015 and decreased to 94.7 in 2018.

Table 1 Key performance indicators in the evaluation by the Health Council of the population-based CRC screening program in the Netherlands.

Conclusion

Based on these key performance indicators, the Health Council concluded that the Dutch CRC screening program has a favorable harm-benefit ratio. The Council recommended future research into increasing participation in underserved populations or improving the program with a personalized invitation or screening strategy.

Introduction

Liver cancer ranks as the sixth most common malignant tumor worldwide and the third leading cause of cancer-related deaths. Hepatocellular carcinoma (HCC), accounting for approximately 90% of primary liver cancers, is among the most lethal malignancies, with a mortality-to-incidence ratio as high as 0.92. Metastasis remains a pivotal determinant of HCC patient prognosis and therapeutic efficacy, making in-depth exploration of its underlying mechanisms a critical foundation for improving clinical outcomes. Ribosomes, composed of ribosomal RNA (rRNA) and ribosomal proteins (RPs), are central to protein synthesis. Emerging evidence highlights that ribosomal heterogeneity influences tumor biology through differentially regulating protein translation. However, the specific mechanisms by which ribosomal proteins contribute to HCC metastasis remain poorly characterized, underscoring a significant gap in oncological research.

Aims & Methods

We performed a screen for ribosomal genes associated with survival in HCC patients using multiple databases through a comprehensively bioinformatics analysis. We estimated the correlation between RPS8 expression and clinicopathological features of patients in HCC. We explored the biological function of RPS8 in HCC cells via lentiviral in vitro. We further assessed the tumorigenicity of RPS8 using both subcutaneous tumor formation in nude mouse and orthotopic liver tumorigenesis in NCG mouse. multi-omics were applied for exploring the mechanism of RPS8 in HCC.

Results

Comprehensive pathological evaluation of HCC clinical specimens revealed overexpression of RPS8 in tumor tissues, which exhibited significant associations with higher tumor stage, poorly differentiated histology , microvascular invasion,and reduced overall survival.Functional studies demonstrated that knockdown of RPS8 suppressed proliferation, migration, and invasion in HCC cell lines . Overexpression of RPS8 could enhance the malignant behavior of HCC cells. Moreover, RPS8 depletion reduced subcutaneous tumor volume and orthotopic liver tumor metastasis to lungs. Mechanistically, proteomic analysis and RIP-seq revealed interferon-stimulated gene 15 (ISG15) exhibited the most significant downregulation at the protein level upon RPS8 knockdown and RPS8 directly binds to ISG15 mRNA. GO and KEGG analysis indicate that RPS8 promotes HCC invasion and metastasis by modulating cell motility and migration. Among the top five differentially expressed proteins, CCDC25, a neutrophil extracellular trap (NET) repceptor, exhibited the most significant downregulation upon RPS8 knockdown. ISG15 can bind with target proteins to form ISGlation, thus preventing the ubiquitinlation. Bioinformatic predictions have identified six potential ubiquitination modification sites in CCDC25. Additionally, molecular docking analyses suggest the presence of potential ubiquitination modification sites within the binding interface between ISG15 and CCDC25. We then performed CCDC25 overexpression in RPS8-knockdown HCC cells and CCDC25 knockout in RPS8-overexpressing HCC cells. Downregulation or upregulation of CCDC25 partially reversed the oncogenic effects of RPS8 respectively, supporting CCDC25 as a critical downstream mediator of RPS8-driven HCC progression. Finally, we found that NETs from HCC patients could promote in vivo metastasis of control cells, but showed less efficacy in RPS8-knockdown cells.

Conclusion

Ribosomal protein RPS8 promotes HCC metastasis through upregulating ISG15 to stabilize NETs receptor CCDC25 protein. These findings provide a promising therapeutic strategy targeting .

References

1.Kang J, Brajanovski N, Chan KT et al. Ribosomal proteins and human diseases: molecular mechanisms and targeted therapy. Signal Transduction and Targeted Therapy 2021; 6.
2. Larionova TD, Bastola S, Aksinina TE et al. Alternative RNA splicing modulates ribosomal composition and determines the spatial phenotype of glioblastoma cells. Nature Cell Biology 2022; 24:1541-1557.
3.Kang JA, Kim YJ, Jeon YJ. The diverse repertoire of ISG15: more intricate than initially thought. Experimental & Molecular Medicine 2022; 54:1779-1792.
4.Yang L, Liu Q, Zhang X et al. DNA of neutrophil extracellular traps promotes cancer metastasis via CCDC25. Nature 2020; 583:133-138.
5.Zhan X, Wu R, Kong XH et al. Elevated neutrophil extracellular traps by HBV‐mediated S100A9‐TLR4/RAGE‐ROS cascade facilitate the growth and metastasis of hepatocellular carcinoma. Cancer Communications 2022; 43:225-245.

Introduction

EUS-guided gall bladder drainage (EUS-GBD) with an electrocautery-enhanced lumen-apposing metal stent (EC-LAMS) is emerging as a method of establishing gall bladder drainage in patients who lack fitness for surgery¹.
The aim of the study was to assess the efficacy, safety and long-term outcomes in patients who underwent EUS-GBD with an EC-LAMS.

Aims & Methods

A retrospective review of consecutive patients who underwent EUS-GBD with EC-LAMS at 11 tertiary institutions across the United Kingdom and Ireland between January 2016 and December 2022 was undertaken.

Results

Sixty two patients (71.0% female; n=44) with a median age of 74.6 years (range 33-95 years) were included. The predominant approach was transduodenal (59.7%; n=37), while the most common indication was non-malignant cholecystitis (56.5%; n=35).
The mean follow-up period was 2.1 years (range 0.04-6.9 years); 72.6% (n=45) were alive at the end of the follow-up period.
Technical success, defined as successful gall bladder access followed by adequate transmural EC-LAMS deployment, was achieved in 95.2% (n=59). Clinical success, defined as resolution of clinical parameters of acute cholecystitis (as per Tokyo 2018 diagnostic criteria) within 96 hours was achieved in 94.7% (n=54).
The 30-day adverse event rate was 4.8% (n=3), with 3.2% (n=2) experiencing a severe/fatal event (as per ASGE lexicon). A further adverse event (1 severe) occurred in 14.8% (n=4) of those who were followed up for a year and in 7.1% (n=1) of those who were followed up for two years.
Of those with benign disease, the EC-LAMS was removed in 15.0% (n=3) of cases who were followed up for at least one year. This was associated with an adverse event (recurrent cholecystitis) in only one case.

Conclusion

EUS-GBD with EC-LAMS at tertiary institutions is a highly effective and relatively safe technique in patients who are not fit for surgery. Technical failures or adverse events can usually be managed conservatively or with endoscopic therapy.

References

References:

1. Luo X, Sharaiha R, Teoh AYB. Endoscopic Management of Acute Cholecystitis. Gastrointest Endosc Clin N Am. 2022 Jul;32(3):527-543.

Introduction

Work-life integration is a critical issue many individuals face in the workforce, particularly in professions with high demands, such as healthcare. Physicians, in particular, experience significant challenges in managing their professional and personal lives due to long work hours, unpredictable schedules, and the emotional toll of caring for patients. The resulting work-life conflicts can negatively impact their well-being, job satisfaction, and patient care. Despite recognizing this issue, there is still a lack of research on the extent of work-life conflicts and their effects on physicians.

Aims & Methods

We distributed a voluntary and anonymous survey via e-mail to all members of the German Society for Digestive and Metabolic Diseases (DGVS - Deutsche Gesellschaft für Gastroenterologie, Verdauungs- und Stoffwechselerkrankungen). Sociodemographics and data on parental status, number of children, and used support structures were gathered. The Work-Family Conflict Scale (ISSP) was used to measure the compatibility of family and job. Query logic branched depending on responses, and single and multiple-choice questions were used, as well as Likert scales.

Results

At the point of this interim analysis, 586 respondents finished the survey and were included for statistical analysis. Of the respondents, 45% were women, 71% were parents, and 60.3% had children living in the household. The mean age was 47 years (SD 11,0). In most cases, respondents lived with a working partner (93%), with male respondents more likely to have a stay-at-home partner (8,9% versus 2,9%). A corresponding trend was observed in partners working part-time (Overall: 41.5%. Partners of male physicians 58,9%, partners of female physicians 17,2%). In the ISSP, there were high levels of work-life conflict (scale 1-4, average work/life 3,06 life/work 1,79). Female respondents reported statistically significantly higher work/life, but only numerically higher life/work conflicts than male respondents. (work/life 3,18 versus 2,94, p ˂ 0.001; life/work 1,88 versus 1,77 p = 0.080; two tailed Chi Square). Parents were affected significantly more often by work-life and life-work conflicts.

Conclusion

This study provides valuable insights into the challenges faced by physicians in balancing their professional and personal lives. Finding ways to manage work-life conflicts and maintain a healthy balance is critical for the well-being and longevity of physicians, as well as the quality of care they provide to their patients. Healthcare employers should support their employees in achieving a satisfactory work-life balance.