Implications of pretreatment extramural venous invasion in rectal cancer patients: A population-based study.

AIM: Extramural venous invasion detected by MRI (mrEMVI) has in several expert centre studies been identified as an important prognostic factor in rectal cancer, and in guiding neoadjuvant therapy. However, population-based evidence for mrEMVI as a predictor for recurrent disease is lacking. METHOD: This was a multicentre retrospective study based on the Swedish Colorectal Cancer Registry. The study period encompassed patients operated with abdominal resection for rectal cancer 2017-2021, with follow-up until January 2023. Patients diagnosed at hospitals with radiological registry data coverage <90% or with metastatic disease were excluded. Pretreatment mrEMVI constituted exposure, while recurrence-free survival was the main outcome. Distant and local recurrence, and overall survival were secondary outcomes, and pretreatment and postoperative scenarios were explored using multivariable Cox regression with multiple imputation. Hazard ratios (HRs) with 95% confidence intervals (CIs) were reported. RESULTS: A total of 2737 patients from 13 hospitals were eligible for analysis. Pretreatment mrEMVI was reported in 14.5% of patients, while 71.9% had negative findings and 13.6% had missing data. In the pretreatment scenario, mrEMVI was an independent predictor for worse recurrence-free survival with an adjusted HR of 1.64 (95% CI: 1.31-2.06). In the postoperative MDT setting, the influence of mrEMVI on recurrence-free survival decreased with an adjusted HR of 1.27 (95% CI: 1.00-1.61). CONCLUSION: mrEMVI at diagnosis is an independent predictor of recurrence-free survival in an unselected population of rectal cancer patients undergoing abdominal resection.

Preoperative beta blockers and other drugs in relation to anastomotic leakage after anterior resection for rectal cancer.

AIM: Previous research has indicated that preoperative beta blocker therapy is associated with a decreased risk of complications after surgery for rectal cancer. This is thought to arise because of the anti-inflammatory activity of the drug. These results need to be reproduced and analyses extended to other drugs with such properties, as this information might be useful in clinical decision-making. The main aim of this work was to replicate previous findings of beta blocker use as a prognostic marker for postoperative leakage. We also investigated whether drug exposure might induce anastomotic leaks. METHOD: This is a retrospective multicentre cohort study, comprising 1126 patients who underwent anterior resection for rectal cancer between 2014 and 2018. The use of any preoperative beta blocker was treated as the primary exposure, while anastomotic leakage within 12 months of surgery was the outcome. Secondary exposures comprised angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, statins and metformin. Using multivariable regression, we performed a replication analysis with a predictive aim for beta blockers only, while adjustment for confounding was done in more causally oriented analyses for all drugs. We estimated incidence rate ratio (IRR) and relative risk (RR) with 95% confidence intervals (CIs). RESULTS: Anastomotic leakage occurred in 20.6% of patients. Preoperative beta blockers were used by 22.7% of the cohort, while the leak distribution was almost identical between exposure groups. In the main replication analysis, no association could be detected (IRR 0.95, 95% CI 0.68-1.33). In the causally oriented analyses, only metformin affected the risk of leakage (RR 1.59, 95% Cl 1.31-1.92). CONCLUSION: While previous research has suggested that preoperative beta blocker use could be prognostic of anastomotic leakage, this study could not detect any such association. On the contrary, our results indicate that preoperative beta blocker use neither predicts nor causes anastomotic leakage after anterior resection for rectal cancer.

Short-term results in a population based study indicate advantage for minimally invasive rectal cancer surgery versus open.

BACKGROUND: The aim of this study was to determine if minimally invasive surgery (MIS) for rectal cancer is non-inferior to open surgery (OPEN) regarding adequacy of cancer resection in a population based setting. METHODS: All 9,464 patients diagnosed with rectal cancer 2012-2018 who underwent curative surgery were included from the Swedish Colorectal Cancer Registry. PRIMARY OUTCOMES: Positive circumferential resection margin (CRM < 1 mm) and positive resection margin (R1). Non-inferiority margins used were 2.4% and 4%. SECONDARY OUTCOMES: 30- and 90-day mortality, clinical anastomotic leak, re-operation < 30 days, 30- and 90-day re-admission, length of stay (LOS), distal resection margin < 1 mm and < 12 resected lymph nodes. Analyses were performed by intention-to-treat using unweighted and weighted multiple regression analyses. RESULTS: The CRM was positive in 3.8% of the MIS group and 5.4% of the OPEN group, risk difference -1.6% (95% CI -1.623, -1.622). R1 was recorded in 2.8% of patients in the MIS group and in 4.4% of patients in the OPEN group, risk difference -1.6% (95% CI -1.649, -1.633). There were no differences between the groups in adjusted unweighted and weighted analyses. All analyses demonstrated decreased mortality and re-admissions at 30 and 90 days as well as shorter LOS following MIS. CONCLUSIONS: In this population based setting MIS for rectal cancer was non-inferior to OPEN regarding adequacy of cancer resection with favorable short-term outcomes.

Evolution of surgical approach to rectal cancer resection: A multinational registry assessment.

PURPOSE: Surgical approach to rectal cancer has evolved in recent decades, with introduction of minimally invasive surgery (MIS) techniques and local excision. Since implementation might differ internationally, this study is aimed at evaluating trends in surgical approach to rectal cancer across different countries over the last 10 years and to gain insight into patient, tumour and treatment characteristics. METHODS: Pseudo-anonymised data of patients undergoing resection for rectal cancer between 2010 and 2019 were extracted from clinical audits in the Netherlands (NL), Sweden (SE), England-Wales (EW) and Australia-New Zealand (AZ). RESULTS: Ninety-nine thousand five hundred ninety-seven patients were included (38,413 open, 55,155 MIS and 5416 local excision). An overall increase in MIS was observed from 29.9% in 2010 to 72.1% in 2019, with decreasing conversion rates (17.5-9.0%). The MIS proportion was highly variable between countries in the period 2010-2014 (54.4% NL, 45.3% EW, 39.8% AZ, 14.1% SE, P < 0.001), but variation reduced over time (2015-2019 78.8% NL, 66.3% EW, 64.3% AZ, 53.2% SE, P < 0.001). The proportion of local excision for the two periods was highly variable between countries: 4.7% and 11.8% in NL, 3.9% and 7.4% in EW, 4.7% and 4.6% in AZ, 6.0% and 2.9% in SE. CONCLUSIONS: Application and speed of implementation of MIS were highly variable between countries, but each registry demonstrated a significant increase over time. Local excision revealed inconsistent trends over time.

Development of the integrated fish endocrine disruptor test (iFEDT)-Part A: Merging of existing fish test guidelines.

There has been increasing interest in endocrine-disrupting chemicals (EDCs) among scientists and public authorities over the last 30 years, notably because of their wide use and the increasing evidence of detrimental effects on humans and the environment. However, test systems for the detection of potential EDCs as well as testing strategies still require optimization. Thus, the aim of the present project was the development of an integrated test protocol that merges the existing OECD test guidelines (TGs) 229 (fish short-term reproduction assay) and 234 (fish sexual development test) and implements thyroid-related endpoints for fish. The integrated fish endocrine disruptor test (iFEDT) represents a comprehensive approach for fish testing, which covers reproduction, early development, and sexual differentiation, and will thus allow the identification of multiple endocrine-disruptive effects in fish. Using zebrafish (Danio rerio) as a model organism, two exposure tests were performed with well-studied EDCs: 6-propyl-2-thiouracil (PTU), an inhibitor of thyroid hormone synthesis, and 17α-ethinylestradiol (EE2), an estrogen receptor agonist. In part A of this article, the effects of PTU and EE2 on established endpoints of the two existing TGs are reported, whereas part B focuses on the novel thyroid-related endpoints. Results of part A document that, as expected, both PTU and EE2 had strong effects on various endocrine-related endpoints in zebrafish and their offspring. Merging of TGs 229 and 234 proved feasible, and all established biomarkers and endpoints were responsive as expected, including reproductive and morphometric changes (PTU and EE2), vitellogenin levels, sex ratio, gonad maturation, and histopathology (only for EE2) of different life stages. A validation of the iFEDT with other well-known EDCs will allow verification of the sensitivity and usability and confirm its capacity to improve the existing testing strategy for EDCs in fish. Integr Environ Assess Manag 2024;20:817-829. © 2023 The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals LLC on behalf of Society of Environmental Toxicology & Chemistry (SETAC).

Anastomotic Leakage in Relation to Type of Mesorectal Excision and Defunctioning Stoma Use in Anterior Resection for Rectal Cancer.

BACKGROUND: Anastomotic leakage after anterior resection for rectal cancer is more common after total mesorectal excision compared to partial mesorectal excision but might be mitigated by a defunctioning stoma. OBJECTIVE: The aim is to assess how anastomotic leakage is affected by type of mesorectal excision and defunctioning stoma use. DESIGN: This is a retrospective multicenter cohort study evaluating anastomotic leakage after anterior resection. Multivariable Cox regression with HRs and 95% CIs was used to contrast mesorectal excision types and defunctioning stoma use with respect to anastomotic leakage, with adjustment for confounding. SETTINGS: This multicenter study included patients from 11 Swedish hospitals between 2014 and 2018. PATIENTS: Patients who underwent anterior resection for rectal cancer were included. MAIN OUTCOMES MEASURES: Anastomotic leakage rates within and after 30 days of surgery are described up to 1 year after surgery. RESULTS: Anastomotic leakage occurred in 24.2% and 9.0% of 1126 patients operated with total and partial mesorectal excision, respectively. Partial compared to total mesorectal excision was associated with a reduction in leakage, with an adjusted HR of 0.46 (95% CI, 0.29-0.74). Early leak rates within 30 days were 14.9% with and 12.5% without a stoma, whereas late leak rates after 30 days were 7.5% with and 1.9% without a stoma. After adjustment, defunctioning stoma was associated with a lower early leak rate (HR 0.47; 95% CI, 0.28-0.77). However, the late leak rate was nonsignificantly higher in patients with defunctioning stomas (HR 1.69; 95% CI, 0.59-4.85). LIMITATIONS: This study was limited by its retrospective observational study design. CONCLUSIONS: Anastomotic leakage is common up to 1 year after anterior resection for rectal cancer, where partial mesorectal excision is associated with a lower leak rate. Defunctioning stomas seem to decrease the occurrence of leakage, although partially by only delaying the diagnosis. See Video Abstract . FUGA ANASTOMTICA SEGN EL TIPO DE EXCISIN MESORRECTAL Y LA CONFECCIN DE OSTOMA DE PROTECCIN EN LA RESECCIN ANTERIOR POR CNCER DE RECTO: ANTECEDENTES:La fuga anastomótica después de una resección anterior por cáncer de recto es más frecuente después de la excisión total del mesorrecto comparada con la excisión parcial del mismo, pero podría mitigarse con la confección de ostomías de protección.OBJETIVO:El objetivo es evaluar cómo la fuga anastomótica se ve afectada según el tipo de excisión mesorrectal y la confección de una ostomía de protección.DISEÑO:Estudio de cohortes multicéntrico y retrospectivo que evalúa la fuga anastomótica después de la resección anterior. Se aplicó la regresión multivariada de Cox con los índices de riesgo (HR) y los intervalos de confianza (IC) al 95% para contrastar los tipos de excisión mesorrectal y el uso de otomías de protección con respecto a la fuga anastomótica, realizando ajustes respecto a las variables de confusión.AJUSTES:El presente estudio multicéntrico incluyó pacientes de 11 hospitales suecos entre 2014 y 2018.PACIENTES:Se incluyeron todos aquellos sometidos a resección anterior por cáncer de recto.PRINCIPALES MEDIDAS DE RESULTADOS:Las tasas de fuga anastomótica dentro y después de los 30 días de la cirugía fueron descritos hasta un año mas tarde al acto quirúrgico.RESULTADOS:La fuga anastomótica ocurrió en el 24,2% y el 9,0% de 1126 pacientes operados por excisión total y parcial del mesorrecto respectivamente.La excisión parcial del mesorrecto en comparación con la total se asoció con una reducción de la fuga, HR ajustado de 0,46 (IC del 95 %: 0,29 a 0,74). Las tasas de fuga temprana dentro de los 30 días fueron del 14,9 % con y el 12,5 % sin estoma, mientras que las tasas de fuga tardía después de 30 días fueron del 7,5 % con y el 1,9 % sin estoma.Después del ajuste de variables de confusión, las ostomías de protección se asociaron con una tasa de fuga temprana más baja (HR 0,47; IC 95 %: 0,28-0,77). Sin embargo, la tasa de fuga tardía no fue significativamente mayor en pacientes ostomizados (HR 1,69; IC 95%: 0,59-4,85).LIMITACIONES:Las limitaciones del presente estudio estuvieron vinculadas con el diseño de tipo observacional y retrospectivo.CONCLUSIONES:La fuga anastomótica es común hasta un año después de la resección anterior por cáncer de recto, donde la excisión parcial del mesorrecto se asocia con una menor tasa de fuga. La confección de ostomías de protección parece disminuir la aparición de fuga anastomótica, aunque en parte sólo retrasen el diagnóstico. (Traducción-Dr. Xavier Delgadillo ).

Development of the integrated fish endocrine disruptor test-Part B: Implementation of thyroid-related endpoints.

Given the vital role of thyroid hormones (THs) in vertebrate development, it is essential to identify chemicals that interfere with the TH system. Whereas, among nonmammalian laboratory animals, fish are the most frequently utilized test species in endocrine disruptor research, for example, in guidelines for the detection of effects on the sex hormone system, there is no test guideline (TG) using fish as models for thyroid-related effects; rather, amphibians are used. Therefore, the objective of the present project was to integrate thyroid-related endpoints for fish into a test protocol combining OECD TGs 229 (Fish Short-Term Reproduction Assay) and 234 (Fish Sexual Development Test). The resulting integrated Fish Endocrine Disruption Test (iFEDT) was designed as a comprehensive approach to covering sexual differentiation, early development, and reproduction and to identifying disruption not only of the sexual and/or reproductive system but also the TH system. Two 85-day exposure tests were performed using different well-studied endocrine disruptors: 6-propyl-2-thiouracil (PTU) and 17α-ethinylestradiol (EE2). Whereas the companion Part A of this study presents the findings on effects by PTU and EE2 on endpoints established in existing TGs, the present Part B discusses effects on novel thyroid-related endpoints such as TH levels, thyroid follicle histopathology, and eye development. 6-Propyl-2-thiouracil induced a massive proliferation of thyroid follicles in any life stage, and histopathological changes in the eyes proved to be highly sensitive for TH system disruption especially in younger life stages. For measurement of THs, further methodological development is required. 17-α-Ethinylestradiol demonstrated not only the well-known disruption of the hypothalamic-pituitary-gonadal axis, but also induced effects on thyroid follicles in adult zebrafish (Danio rerio) exposed to higher EE2 concentrations, suggesting crosstalk between endocrine axes. The novel iFEDT has thus proven capable of simultaneously capturing endocrine disruption of both the steroid and thyroid endocrine systems. Integr Environ Assess Manag 2024;20:830-845. © 2023 The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals LLC on behalf of Society of Environmental Toxicology & Chemistry (SETAC).

Deletion of IFT20 exclusively in the RPE ablates primary cilia and leads to retinal degeneration.

Vision impairment places a serious burden on the aging society, affecting the lives of millions of people. Many retinal diseases are of genetic origin, of which over 50% are due to mutations in cilia-associated genes. Most research on retinal degeneration has focused on the ciliated photoreceptor cells of the retina. However, the contribution of primary cilia in other ocular cell types has largely been ignored. The retinal pigment epithelium (RPE) is a monolayer epithelium at the back of the eye intricately associated with photoreceptors and essential for visual function. It is already known that primary cilia in the RPE are critical for its development and maturation; however, it remains unclear whether this affects RPE function and retinal tissue homeostasis. We generated a conditional knockout mouse model, in which IFT20 is exclusively deleted in the RPE, ablating primary cilia. This leads to defective RPE function, followed by photoreceptor degeneration and, ultimately, vision impairment. Transcriptomic analysis offers insights into mechanisms underlying pathogenic changes, which include transcripts related to epithelial homeostasis, the visual cycle, and phagocytosis. Due to the loss of cilia exclusively in the RPE, this mouse model enables us to tease out the functional role of RPE cilia and their contribution to retinal degeneration, providing a powerful tool for basic and translational research in syndromic and non-syndromic retinal degeneration. Non-ciliary mechanisms of IFT20 in the RPE may also contribute to pathogenesis and cannot be excluded, especially considering the increasing evidence of non-ciliary functions of ciliary proteins.

Splenic flexure mobilization and anastomotic leakage in anterior resection for rectal cancer: A multicentre cohort study.

BACKGROUND AND OBJECTIVE: Some colorectal surgeons advocate routine splenic flexure mobilization (SFM) when performing anterior resection for rectal cancer to ensure a tension-free anastomosis. Meta-analyses of smaller studies suggest that this approach does not influence anastomotic leakage rates, but larger multicentre studies are needed to confirm the safety of a selective strategy. The aim of this study is to evaluate the impact of SFM on anastomotic leakage. METHODS: This is a retrospective multicentre cohort study, comprising 1109 patients operated with anterior resection for rectal cancer in 2014-2018. Exposure was SFM, while anastomotic leakage within a year constituted the outcome. Stratified analyses were performed for type of mesorectal excision and surgical approach, as well as sensitivity analysis considering vascular tie placement. Multivariable Cox regression with hazard ratios (HRs) and 95% confidence intervals (CIs) was employed to adjust for confounding, while multiple imputation was used for missing data. RESULTS: SFM was performed in 381 patients (34.4%). Anastomotic leakage occurred in 83 (21.8%) and 123 (20.3%) patients operated with and without SFM, respectively. SFM was neither clearly detrimental nor beneficial regarding anastomotic leakage (adjusted HR = 0.82; 95% CI: 0.59-1.15), with no apparent differences for total or partial mesorectal excision and minimally invasive or open surgery. Concurrent high vascular ligation did not impact these results, and there was no evidence of interaction from centers with a more common use of SFM. CONCLUSIONS: SFM did not seem to influence the risk of anastomotic leakage after anterior resection for rectal cancer, regardless of type of mesorectal excision, use of minimally invasive surgery, or high vascular ligation.

The modified Glasgow Prognostic Score indicates an increased risk of anastomotic leakage after anterior resection for rectal cancer.

BACKGROUND: Preoperative inflammation might cause and also be a marker for anastomotic leakage after anterior resection for rectal cancer. Available biomarker indices such as the modified Glasgow Prognostic Score (mGPS) or the C-reactive protein-to-albumin ratio (CAR) may be clinically useful for leakage assessment. METHODS: Patients who underwent anterior resection for rectal cancer during 2014-2018 from a multicentre retrospective cohort were included. Data from the Swedish Colorectal Cancer registry and chart review at each hospital were collected. In a subset of patients, preoperative laboratory assessments were available, constituting the exposures mGPS and CAR. Anastomotic leakage within 12 months was the outcome. Causally oriented analyses were conducted with adjustment for confounding, as well as predictive models. RESULTS: A total of 418 patients were eligible for analysis. Most patients had mGPS = 0 (84.7%), while mGPS = 1 (10.8%) and mGPS = 2 (4.5%) were less common. mGPS = 2 (OR: 4.11; 95% CI: 1.69-10.03) seemed to confer anastomotic leakage, while this was not seen for mGPS = 1 (OR 1.09; 95% CI: 0.53-2.25). A cut off point of CAR > 0.36 might be indicative of leakage (OR 2.25; 95% CI: 1.21-4.19). Predictive modelling using mGPS rendered an area-under-the-curve of 0.73 (95% CI: 0.67-0.79) at most. DISCUSSION: Preoperative inflammation seems to be involved in the development of anastomotic leakage after anterior resection for cancer. Inclusion into prediction models did not result in accurate leakage prediction, but high degrees of systemic inflammation might still be important in clinical decision-making.

Defunctioning loop ileostomy in anterior resection for rectal cancer and subsequent renal failure: nationwide population-based study.

BACKGROUND: Electrolyte disturbances and dehydration are common after anterior resection for rectal cancer with a defunctioning loop ileostomy. High-quality population-based studies on the impact of a defunctioning loop ileostomy on renal failure are lacking. METHODS: This was a nationwide observational study, based on the Swedish Colorectal Cancer Registry of patients undergoing anterior resection for rectal cancer between 2008 and 2016, with follow-up until 2017. Patients with severe co-morbidity, with age greater than 80 years, and with pre-existing renal failure were excluded. Loop ileostomy at index surgery constituted exposure, while a diagnosis of renal failure was the outcome. Acute and chronic events were analysed separately. Inverse probability weighting with adjustment for confounding derived from a causal diagram was employed. Hazards ratios (HRs) with 95 per cent c.i. are reported. RESULTS: A total of 5355 patients were eligible for analysis. At 5-year follow-up, all renal failure events (acute and chronic) were 7.2 per cent and 3.3 per cent in the defunctioning stoma and no stoma groups respectively. In the weighted analysis, a HR of 11.59 (95 per cent c.i. 5.68 to 23.65) for renal failure in ostomates was detected at 1 year, with the largest effect from acute renal failure (HR 24.04 (95 per cent c.i. 8.38 to 68.93)). Later follow-up demonstrated a similar pattern, but with smaller effect sizes. CONCLUSION: Patients having a loop ileostomy in combination with anterior resection for rectal cancer are more likely to have renal failure, especially early after surgery. Strategies are needed, such as careful fluid management protocols, and further research into alternative stoma types or reduction in stoma formation.

CRCBaSe: a Swedish register-based resource for colorectal adenocarcinoma research.

OBJECTIVES: To facilitate high-quality register-based research on colorectal cancer (CRC) in Sweden by constructing a database consisting of CRC patients, matched comparators, and relatives. MATERIAL AND METHODS: Patients with adenocarcinoma in the colon and/or rectum were identified in the Swedish Colorectal Cancer Register, a nationwide quality-of-care register. For each patient, six comparators from the general population were matched on birth year, sex, year of CRC diagnosis, and county. Comparators were free from CRC at the time of matching, but could later become cases. For both patients and comparators, first-degree relatives (parents, siblings, and children) were identified. Information from nationwide population-based registers was retrieved and linked to each individual in the database using the personal identification number unique to all Swedish residents. RESULTS: A total of 76,831 CRC patients diagnosed between 1995 and 2016 were identified (51% colon, 49% rectal; before 2007 only rectal cancer patients were included). Among all patients, 37% were stage I-II, 22% stage III, and 22% stage IV. The median follow-up time was 11.9 years (inter-quartile range, IQR: 8.6-15.3). Together with comparators and relatives, the database contains 2,413,139 individuals with information on demographics, dates and causes of death, in- and outpatient healthcare records, cancer diagnoses, prescribed and dispensed drugs, childbirths (among women), and social security information (such as sick leave and early retirement). CONCLUSION: The Colorectal Cancer Database Sweden (CRCBaSe) is a large and unique register-based data research platform, which opens up for clinically important, large epidemiological studies with innovative design in the field of colorectal adenocarcinoma.

A Horizon Scan to Support Chemical Pollution-Related Policymaking for Sustainable and Climate-Resilient Economies.

While chemicals are vital to modern society through materials, agriculture, textiles, new technology, medicines, and consumer goods, their use is not without risks. Unfortunately, our resources seem inadequate to address the breadth of chemical challenges to the environment and human health. Therefore, it is important we use our intelligence and knowledge wisely to prepare for what lies ahead. The present study used a Delphi-style approach to horizon-scan future chemical threats that need to be considered in the setting of chemicals and environmental policy, which involved a multidisciplinary, multisectoral, and multinational panel of 25 scientists and practitioners (mainly from the United Kingdom, Europe, and other industrialized nations) in a three-stage process. Fifteen issues were shortlisted (from a nominated list of 48), considered by the panel to hold global relevance. The issues span from the need for new chemical manufacturing (including transitioning to non-fossil-fuel feedstocks); challenges from novel materials, food imports, landfills, and tire wear; and opportunities from artificial intelligence, greater data transparency, and the weight-of-evidence approach. The 15 issues can be divided into three classes: new perspectives on historic but insufficiently appreciated chemicals/issues, new or relatively new products and their associated industries, and thinking through approaches we can use to meet these challenges. Chemicals are one threat among many that influence the environment and human health, and interlinkages with wider issues such as climate change and how we mitigate these were clear in this exercise. The horizon scan highlights the value of thinking broadly and consulting widely, considering systems approaches to ensure that interventions appreciate synergies and avoid harmful trade-offs in other areas. We recommend further collaboration between researchers, industry, regulators, and policymakers to perform horizon scanning to inform policymaking, to develop our ability to meet these challenges, and especially to extend the approach to consider also concerns from countries with developing economies. Environ Toxicol Chem 2023;42:1212-1228. © 2023 Crown copyright and The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC. This article is published with the permission of the Controller of HMSO and the King's Printer for Scotland.

Short term results in a population based study indicate advantage for laparoscopic colon cancer surgery versus open.

The aim of this study was to compare LAP with OPEN regarding short-term mortality, morbidity and completeness of the cancer resection for colon cancer in a routine health care setting using population based register data. All 13,683 patients who were diagnosed 2012-2018 and underwent elective surgery for right-sided or sigmoid colon cancer were included from the Swedish Colorectal Cancer Registry and the National Patient Registry. Primary outcome was 30-day mortality. Secondary outcomes were 90-day mortality, length of hospital stay, reoperation, readmission and positive resection margin (R1). Weighted and unweighted multi regression analyses were performed. There were no difference in 30-day mortality: LAP (0.9%) and OPEN (1.3%) (OR 0.89, 95% CI 0.62-1.29, P = 0.545). The weighted analyses showed an increased 90-day mortality following OPEN, P < 0.001. Re-operations and re-admission were more frequent after OPEN and length of hospital stay was 2.9 days shorter following LAP (P < 0.001). R1 resections were significantly more common in the OPEN group in the unweighted and weighted analysis with P = 0.004 and P < 0.001 respectively. Therefore, the favourable short-term outcomes following elective LAP versus OPEN resection for colon cancer in routine health care indicate an advantage of laparoscopic surgery.

Long-term oncological outcomes for minimally invasive surgery versus open surgery for colon cancer-a population-based nationwide study with a non-inferiority design.

AIM: The study aimed to compare 5-year overall survival in a national cohort of patients undergoing curative abdominal resection for colon cancer by minimally invasive surgery (MIS) or by the open (OPEN) technique. METHODS: All patients diagnosed between 2010 and 2016 in Sweden with pathological Union International Contre le Cancer Stages I-III colon cancer localized in the caecum, ascending colon, hepatic flexure or sigmoid colon and those who underwent curative right sided hemicolectomy, sigmoid resection or high anterior resection by MIS or OPEN were included. Patients were identified in the Swedish Colorectal Cancer Registry from which all data were retrieved. The analyses were performed as intention-to-treat and the relationship between surgical technique (MIS or OPEN) and overall mortality within 5 years was analysed. For the primary research question a non-inferiority hypothesis was assumed with a statistical power of 90%, a one-side type I error of 2.5% and a non-inferiority margin of 2%. For the secondary analyses, multilevel survival regression models with the patients matched by propensity scores were employed, adjusted for patient- and tumour-related variables. RESULTS: A total of 11 605 pathological Union International Contre le Cancer Stages I-III patients were included with 3297 MIS (28.4%) and 8308 OPEN (71.6%) and were followed until 31 December 2020. The primary analysis demonstrated superiority for MIS compared to OPEN. The multilevel survival regression analyses confirmed that 5-year overall survival was higher in MIS with a hazard ratio of 0.874 (95% confidence interval 0.791-0.965), and if excluding pT4 the outcome was similar, with a hazard ratio of 0.847 (95% confidence interval 0.756-0.948). CONCLUSION: This observational study demonstrated that MIS was favourable to OPEN with regard to 5-year overall survival. These results support the use of laparoscopic colon cancer surgery in routine practice.

Thyroid-like hormone signaling in invertebrates and its potential role in initial screening of thyroid hormone system disrupting chemicals.

This review examines the presence and evolution of thyroid-like systems in selected aquatic invertebrates to determine the potential use of these organisms in screens for vertebrate thyroid hormone axis disrupting chemicals (THADCs). Such a screen might support the phasing out of some vertebrate testing. Although arthropods including crustaceans do not contain a functional thyroid signaling system, elements of such a system exist in the aquatic phyla mollusks, echinoderms, tunicates, and cephalochordates. These phyla can synthesize thyroid hormone, which has been demonstrated in some groups to induce the nuclear thyroid hormone receptor (THR). Thyroid hormone may act in these phyla through interaction with a membrane integrin receptor. Thyroid hormone regulates inter alia metamorphosis but, unlike in vertebrates, this does not occur via receptor activation by the ligands triiodothyronine (T3) and thyroxine (T4). Instead, the unliganded nuclear receptor itself controls metamorphosis in mollusks, echinoderms, and tunicates, whereas the T3 derivative tri-iodothyroacetic acid (TRIAC) acts as a THR ligand in cephalochordates. In view of this, it may be possible to develop an invertebrate-based screen that is sensitive to vertebrate THADCs that interfere with thyroid hormone synthesis or metabolism along with interaction with membrane receptors. The review makes some recommendations for the need to develop an appropriate test method. Integr Environ Assess Manag 2023;19:63-82. © 2022 The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals LLC on behalf of Society of Environmental Toxicology & Chemistry (SETAC).

Low-dose aspirin use and colorectal cancer survival in 32,195 patients-A national cohort study.

BACKGROUND: Results from previous studies indicate that use of aspirin may improve colorectal cancer (CRC) survival. The aim of this study was to assess whether use of aspirin influences overall survival or CRC-specific survival in an unselected cohort of patients diagnosed with CRC. METHODS: The study was performed using the Colorectal Cancer Data Base Sweden (CRCBaSe), a mega-linkage originating from the Swedish Colorectal Cancer Register, with additional linkages to other national health care registers. All patients diagnosed with primary CRC stage I-III treated with curative surgery, aged 18-85 years at diagnosis, from 2007 through 2016 were identified. Information on low-dose aspirin use was extracted from the Swedish Prescribed Drug Register. Exposure was defined as dispensed prescription for at least 6 months. Aspirin exposure was analyzed at the time of surgery (yes/no) and as a time-varying exposure during follow-up. Follow-up was restricted to a maximum 6 years, to model 5-year survival. Cox regression models were fitted to estimate hazard ratios (HRs) with 95% confidence intervals (CIs). Adjustments were performed for sex, age, year of diagnosis, Charlson comorbidity index, hypertension, and ASA score as potential confounders. RESULTS: A total of 32,195 patients diagnosed with CRC were included. 6764 (21%) were exposed to aspirin at the time of CRC surgery. The median time of follow-up was 4.2 years. Aspirin use at the time of surgery was not associated with all-cause (adjusted HR = 1.03, 95% CI: 0.97-1.08) nor CRC-specific mortality (adjusted HR = 0.99, 95% CI: 0.91-1.07). Aspirin use during follow-up was associated with increased all-cause (adjusted HR = 1.09, 95% CI: 1.04-1.15) but not CRC-specific mortality (adjusted HR = 0.98, 95% CI: 0.91-1.06). A CRC-specific effect associated with aspirin was noted from approximately 3 years following surgery. CONCLUSIONS: In this large nation-wide cohort study there was no convincing association between aspirin use after CRC and OS or CRC-specific survival.

Long term oncological outcomes for laparoscopic versus open surgery for rectal cancer - A population-based nationwide noninferiority study.

AIM: The aim of this work was to compare the 5-year overall survival in a national cohort of patients undergoing curative abdominal resection for rectal cancer by laparoscopic (LAP) or open (OPEN) surgery. METHOD: All patients diagnosed with clinical Stage I-III rectal cancer and who underwent LAP or OPEN abdominal curative surgery in Sweden between 2010 and 2016 were retrieved from the Swedish Colorectal Cancer Registry. A noninferiority study design was employed with a statistical power of 90%, a one-side type I error of 2.5% and a noninferiority margin of 2%. The analyses were performed as intention-to-treat and the relationship between surgical technique and overall mortality within 5 years was analysed. Multilevel regression models with the patients matched by propensity scores adjusted for patient- and tumour-related variables were used. RESULTS: A total of 8410 Stage I-III cancer patients were included. This group underwent 2094 LAP (24.9%) and 6316 OPEN (75.1%) procedures and were followed until 31 December 2020. Multivariable Cox regression demonstrated that 5-year overall survival was higher in the LAP group [hazard ratio (HR) 0.877; 95% CI 0.775-0.993]. [Correction added on 21 November 2022, after first online publication: In the preceding sentence, the CI value for LAP group has been corrected from "0.877" to "0.775" in this version.] The outcome was similar when multiple imputation and propensity score matching were employed. When cT4 patients were excluded there was no difference (HR 0.885; 95% CI 0.790-1.033). At 5-years' follow-up local recurrence was not different, at 2.9% for the LAP group and 3.6% for the OPEN group (p = 0.075), while metastatic disease was more frequent in the OPEN group (19.6% compared with 15.6% for LAP; p < 0.001). CONCLUSION: This study demonstrated that the LAP technique was not inferior to OPEN surgery with regard to overall 5-year survival. These results support the use of laparoscopic surgery.

Preoperative biomarkers related to inflammation may identify high-risk anastomoses in colorectal cancer surgery: explorative study.

BACKGROUND: Colorectal anastomotic leakage can be considered a process of failed wound healing, for which related biomarkers might be a promising research area to decrease leak rates. METHODS: Patients who had elective surgery with a primary anastomosis for non-metastatic colorectal cancer, at two university hospitals between 1 January 2010 and 31 December 2015 were included. Patients with an anastomotic leak were identified and matched (1:1) to complication-free controls on the basis of sex, age, tumour stage, tumour location, and operating hospital. Preoperative blood samples were analysed by use of protein panels associated with systemic or enteric inflammation by proteomics, and enzyme-linked immunosorbent assays. Multivariable projection methods were used in the statistical analyses and adjusted for multiple comparisons to reduce false positivity. Rectal cancer tissue samples were evaluated with immunohistochemistry to determine local expression of biomarkers that differed significantly between cases and controls. RESULTS: Out of 726 patients undergoing resection, 41 patients with anastomotic leakage were matched to 41 controls. Patients with rectal cancer with leakage displayed significantly elevated serum levels of 15 proteins related to inflammation. After controlling for a false discovery rate, levels of C-X-C motif chemokine 6 (CXCL6) and C-C motif chemokine 11 (CCL11) remained significant. In patients with colonic cancer with leakage, levels of high-sensitivity C-reactive protein (hs-CRP) were increased before surgery. Local expression of CXCL6 and CCL11, and their receptors, were similar in rectal tissues between cases and controls. CONCLUSION: Patients with anastomotic leakage could have an upregulated inflammatory response before surgery, as expressed by elevated serological levels of CXCL6 and CCL11 for rectal cancer and hs-CRP levels in patients with colonic cancer respectively.