Inhibition of aquaporin-9 ameliorates severe acute pancreatitis and associated lung injury by NLRP3 and Nrf2/HO-1 pathways.

Inflammation, apoptosis and oxidative stress play crucial roles in the deterioration of severe acute pancreatitis-associated acute respiratory distress syndrome (SAP-ARDS). Unfortunately, despite a high mortality rate of 45 %[1], there are limited treatment options available for ARDS outside of last resort options such as mechanical ventilation and extracorporeal support strategies[2]. This study investigated the potential therapeutic role and mechanisms of AQP9 inhibitor RG100204 in two animal models of severe acute pancreatitis, inducing acute respiratory distress syndrome: 1) a sodium-taurocholate induced rat model, and 2) and Cerulein and lipopolysaccharide induced mouse model. RG100204 treatment led to a profound reduction in inflammatory cytokine expression in pancreatic, and lung tissue, in both models. In addition, infiltration of CD68 + and CD11b + cells into these tissues were reduced in RG100204 treated SAP animals, and edema and SAP associated tissue damage were improved. Moreover, we demonstrate that RG100204 reduced apoptosis in the lungs of rat SAP animals, and reduces NF-κB signaling, NLRP3, expression, while profoundly increasing the Nrf2-dependent anti oxidative stress response. We conclude that AQP9 inhibition is a promising strategy for the treatment of pancreatitis and its systemic complications, such as ARDS.

ARHGAP4 as a Prognostic Biomarker for Colon Liver Metastases After Surgical Resection.

BACKGROUND/AIM: To select and stratify patients for optimal treatment plans is challenging. Identification of cancer-related biomarkers that serve as predictors for prognosis and treatment response is essential to better predict treatment outcome and find future targets for therapy. Previous data has suggested ARHGAP4 as a relevant biomarker in colorectal cancer (CRC). The purpose of this study was to assess how ARHGAP4 expression affected patients undergoing surgery for colon liver metastasis (CLM) in terms of overall survival (OS). PATIENTS AND METHODS: A total of 251 patients undergoing resection of CLM from 2006 to 2017 were included. Corresponding resected tumor specimens were examined for ARHGAP4 expression levels by immunohistochemistry (IHC). The correlation between ARHGAP4 expression and postoperative survival was analyzed. RESULTS: High expression levels of ARHGAP4 were seen in 60% of patients. High expression levels of ARHGAP4 were correlated with adverse prognosis after hepatectomy due to CLM. Survival data generated using Cox proportional hazard model showed a statistically significant difference between high and low ARHGAP4 expression groups by univariate (HR=1.5, 95% CI=1.1-2.2) and multivariate (HR=1.5, 95% CI=1.0-2.1) analysis. In multivariate Cox regression, high ARHGAP4 expression, preoperative CEA levels and presence of vascular invasion by pathological examinations were independent predictive factors of overall survival. CONCLUSION: ARHGAP4 is a novel prognostic biomarker after resection of CLM.

Validation of the Appendicitis Inflammatory Response (AIR) score during pregnancy: A nested case-control study.

OBJECTIVES: Appendicitis poses diagnostic challenges. A correct diagnosis is important during pregnancy to avoid unnecessary surgery on the one hand and delayed surgery on the other hand, as both may negatively affect pregnancy outcomes. Clinical scores for risk-stratified management of suspected appendicitis are well established in adults but have not been validated during pregnancy. This nested case-control study evaluated the diagnostic accuracy of the Appendicitis Inflammatory Response (AIR) score and imaging during pregnancy. METHODS: By cross-linking national Swedish health registries from a defined geographical area, we identified a cohort of 154 women who underwent appendectomy for suspected appendicitis during pregnancy and a matched cohort of 232 pregnant women admitted for acute abdominal pain and suspected appendicitis but with a discharge diagnosis of nonspecific abdominal pain (NSAP). All variables were extracted from medical records. The diagnostic value of AIR score and imaging was estimated for patients with a final diagnosis of appendicitis compared with patients with negative appendectomy and NSAP patients. RESULTS: The final diagnoses for the operated patients were uncomplicated and complicated appendicitis in 49.4% and 26.6%, respectively, and negative appendectomy in 24.0%. Nearly half of all the patients underwent diagnostic imaging (41%), mainly by ultrasonography. The sensitivity and specificity of diagnostic imaging were 44.9% (95% CI 32.9%-57.4%) and 42.2% (95% CI 31.9%-53.1%), respectively. The area under the receiver operating characteristic curve of AIR score was 0.88 (95% CI 0.84-0.92) for all appendicitis and 0.90 (95% CI 0.84-0.95) for complicated appendicitis. The sensitivity for complicated appendicitis was 100% at a score of ≥4. The specificity for all appendicitis was 97% at a score of ≥9. CONCLUSIONS: The results of this study suggest that the AIR score may be a suitable diagnostic tool for risk stratification of pregnant women with abdominal pain and suspected appendicitis but further validation among pregnant women is needed.

L-type Amino Acid Transporter 1 as a Therapeutic Target in Pancreatic Cancer.

Metabolic rewiring is a key feature of cancer cells to support the demands of growth and proliferation. The metabolism of amino acids is altered in many cancers, including pancreatic cancer. The cellular uptake of amino acids is regulated by amino acid transporters, such as L-type amino acid transporter 1 (LAT1). Accumulating evidence suggests that LAT1 is overexpressed in pancreatic cancer and confers a poor prognosis. Here we discuss the prospects of utilizing LAT1 as a novel target for pancreatic cancer therapy.

Surveillance after resection of pancreatic ductal adenocarcinoma: How to do it and what are the benefits?

BACKGROUND AND OBJECTIVE: Surveillance following resection with curative intent of pancreatic cancer varies widely, and supporting evidence is limited. Recurrence is although frequent, not at least during the first 2 years. Surveillance may be costly, but evidence on how this influences overall survival is not fully elucidated. METHODS, RESULTS: There are reports implying that signs of biological recurrence (increasing CA 19-9) precede radiologically demonstrated recurrence by months. CONCLUSIONS: The possibility of initiating salvage therapy earlier is discussed, potentially based on improved future biomarker panels.

Restoring tumor immunogenicity with dendritic cell reprogramming.

Decreased antigen presentation contributes to the ability of cancer cells to evade the immune system. We used the minimal gene regulatory network of type 1 conventional dendritic cells (cDC1) to reprogram cancer cells into professional antigen-presenting cells (tumor-APCs). Enforced expression of the transcription factors PU.1, IRF8, and BATF3 (PIB) was sufficient to induce the cDC1 phenotype in 36 cell lines derived from human and mouse hematological and solid tumors. Within 9 days of reprogramming, tumor-APCs acquired transcriptional and epigenetic programs associated with cDC1 cells. Reprogramming restored the expression of antigen presentation complexes and costimulatory molecules on the surfaces of tumor cells, allowing the presentation of endogenous tumor antigens on MHC-I and facilitating targeted killing by CD8+ T cells. Functionally, tumor-APCs engulfed and processed proteins and dead cells, secreted inflammatory cytokines, and cross-presented antigens to naïve CD8+ T cells. Human primary tumor cells could also be reprogrammed to increase their capability to present antigen and to activate patient-specific tumor-infiltrating lymphocytes. In addition to acquiring improved antigen presentation, tumor-APCs had impaired tumorigenicity in vitro and in vivo. Injection of in vitro generated melanoma-derived tumor-APCs into subcutaneous melanoma tumors delayed tumor growth and increased survival in mice. Antitumor immunity elicited by tumor-APCs was synergistic with immune checkpoint inhibitors. Our approach serves as a platform for the development of immunotherapies that endow cancer cells with the capability to process and present endogenous tumor antigens.

Female and Male Fertility after Colectomy and Reconstructive Surgery in Inflammatory Bowel Diesase: A National Cohort Study from Sweden.

BACKGROUND AND AIMS: Colectomy and reconstruction in patients with inflammatory bowel disease [IBD] may adversely affect fertility, but few population-based studies on this subject are available. METHODS: Fertility was assessed in 2989 women and 3771 men with IBD and prior colectomy during 1964-2014, identified from the Swedish National Patient Register, and in 35 092 matched individuals. RESULTS: Reconstruction with ileoanal pouch anastomosis [IPAA] was as common as ileorectal anastomosis [IRA] in ulcerative colitis [UC] and IBD-unclassified [IBD-U] but rare in Crohn's disease [CD]. Compared with the matched reference cohort, women with IBD had lower fertility overall after colectomy (hazard ratio [HR] 0.65, confidence interval [CI] 0.61-0.69), with least impact with leaving the rectum intact [HR 0.79, CI 0.70-0.90]. Compared with colectomy only, fertility in female patients remained unaffected after IRA [HR 0.86, CI 0.63-1.17 for UC, 0.86, CI 0.68-1.08 for IBD-U and 1.07, CI 0.70-1.63 for CD], but was impaired after IPAA, especially in UC [HR 0.67, CI 0.50-0.88], and after completion proctectomy [HR 0.65, CI 0.49-0.85 for UC, 0.68, CI 0.55-0.85 for IBD-U and 0.61, CI 0.38-0.96 for CD]. In men, fertility was marginally reduced following colectomy [HR 0.89, CI 0.85-0.94], regardless of reconstruction. CONCLUSIONS: Fertility was reduced in women after colectomy for IBD. The least impact was seen when a deviated rectum was left intact. IRA was associated with no further reduction in fertility, whereas proctectomy and IPAA were associated with the strongest impairment. IRA therefore seems to be the preferred reconstruction to preserve fertility in selected female patients. Fertility in men was only moderately reduced after colectomy.

Spontaneous Resolution of Uncomplicated Appendicitis may Explain Increase in Proportion of Complicated Appendicitis During Covid-19 Pandemic: a Systematic Review and Meta-analysis.

BACKGROUND: Reports of an increased proportion of complicated appendicitis during the Covid-19 pandemic suggest a worse outcome due to delay secondary to the restrained access to health care, but may be explained by a concomitant decrease in uncomplicated appendicitis. We analyze the impact of the pandemic on the incidences of complicated and uncomplicated appendicitis. METHOD: We did a systematic literature search in the PubMed, Embase and Web Of Science databases on December 21, 2022 with the search terms (appendicitis OR appendectomy) AND ("COVID" OR SARS-Cov2 OR "coronavirus"). Studies reporting the number of complicated and uncomplicated appendicitis during identical calendar periods in 2020 and the pre-pandemic year(s) were included. Reports with indications suggesting a change in how the patients were diagnosed and managed between the two periods were excluded. No protocol was prepared in advance. We did random effects meta-analysis of the change in proportion of complicated appendicitis, expressed as the risk ratio (RR), and of the change in number of patients with complicated and uncomplicated appendicitis during the pandemic compared with pre-pandemic periods, expressed as the incidence ratio (IR). We did separate analyses for studies based on single- and multi-center and regional data, age-categories and prehospital delay. RESULTS: The meta-analysis of 100,059 patients in 63 reports from 25 countries shows an increase in the proportion of complicated appendicitis during the pandemic period (RR 1.39, 95% confidence interval (95% CI 1.25, 1.53). This was mainly explained by a decreased incidence of uncomplicated appendicitis (incidence ratio (IR) 0.66, 95% CI 0.59, 0.73). No increase in complicated appendicitis was seen in multi-center and regional reports combined (IR 0.98, 95% CI 0.90, 1.07). CONCLUSION: The increased proportion of complicated appendicitis during Covid-19 is explained by a decrease in the incidence of uncomplicated appendicitis, whereas the incidence of complicated appendicitis remained stable. This result is more evident in the multi-center and regional based reports. This suggests an increase in spontaneously resolving appendicitis due to the restrained access to health care. This has important principal implications for the management of patients with suspected appendicitis.

Reoperations and Long-term Survival of Kock's Continent Ileostomy in Patients With IBD: A Population-Based National Cohort Study From Sweden.

BACKGROUND: Kock's continent ileostomy is an option after proctocolectomy for patients not suitable for IPAA or ileorectal anastomosis. Ulcerative colitis is the most common indication for continent ileostomy. OBJECTIVE: The aim of this study was to evaluate the long-term outcome of continent ileostomy. DESIGN: Retrospective cohort register study. SETTINGS: Data were obtained from the Swedish National Patient Registry. PATIENTS: All patients with IBD and a continent ileostomy were identified. Data on demographics, diagnosis, reoperations, and excisions of the continent ileostomy were obtained. Patients with inconsistent diagnostic coding were classified as IBD-unclassified. MAIN OUTCOME MEASURES: The main outcome measures were number of reoperations, time to reoperations, and time to excision of continent ileostomy. RESULTS: We identified 727 patients, 428 (59%) with ulcerative colitis, 45 (6%) with Crohn's disease, and 254 (35%) with IBD-unclassified. After a median follow-up time of 27 (interquartile range, 21-31) years, 191 patients (26%) never had revision surgery. Some 1484 reoperations were performed on 536 patients (74%), and the median number of reoperations was 1 (interquartile range, 0-3) per patient. The continent ileostomy was excised in 77 patients (11%). Reoperation within the first year after reconstruction was associated with a higher rate of revisions (incidence rate ratio, 2.90; p < 0.001) and shorter time to excision (HR 2.38; p < 0.001). Constructing the continent ileostomy after year 2000 was associated with increased revision and excision rates (incidence rate ratio, 2.7; p < 0.001 and HR 2.74; p = 0.013). IBD-unclassified was associated with increased revisions (incidence rate ratio, 1.3; p < 0.001)' and the proportion of IBD-unclassified patients almost doubled from the 1980s (32%) to after 2000 (50%). LIMITATIONS: Retrospective design, data from a register, and no data on quality of life were available were the limitations of this study. CONCLUSION: Continent ileostomy is associated with substantial need for revision surgery, but most patients keep their reconstruction for a long time. See Video Abstract at http://links.lww.com/DCR/C122 . REOPERACIONES Y SUPERVIVENCIA A LARGO PLAZO DE LA ILEOSTOMA CONTINENTE DE KOCK EN PACIENTES CON ENFERMEDAD INFLAMATORIA INTESTINAL UN ESTUDIO DE COHORTE NACIONAL BASADO EN LA POBLACIN DE SUECIA: ANTECEDENTES:La ileostomía continente de Kock es una opción después de la proctocolectomía para los pacientes que no son aptos para la anastomosis ileoanal con reservorio o la anastomosis ileorrectal. La colitis ulcerativa es la indicación más común para la ileostomía continente.OBJETIVO:El objetivo de este estudio fue evaluar el resultado a largo plazo de la ileostomía continente.DISEÑO:Estudio de registro de cohorte retrospectivo.AJUSTES:Los datos se obtuvieron del Registro Nacional de Pacientes de Suecia.PACIENTES:Se identificaron todos los pacientes con enfermedad inflamatoria intestinal e ileostomía continente. Se obtuvieron datos demograficos, diagnóstico, reoperaciones y extirpaciones de la ileostomía continente. Los pacientes con codificación diagnóstica inconsistente se clasificaron como no clasificados con EII.PRINCIPALES MEDIDAS DE RESULTADO:Las principales medidas de resultado fueron el número de reoperaciones, el tiempo hasta las reoperaciones y el tiempo hasta la escisión de la ileostomía continente.RESULTADOS:Identificamos 727 pacientes, 428 (59%) con colitis ulcerativa, 45 (6%) con enfermedad de Crohn y 254 (35%) con EII no clasificada. Después de una mediana de tiempo de seguimiento de 27 (IQR 21-31) años, 191 (26%) pacientes nunca se habían sometido a una cirugía de revisión. Se realizaron 1.484 reintervenciones en 536 (74%) pacientes, la mediana de reintervenciones fue de 1 (RIC 0-3) por paciente. La ileostomía continente se extirpó en 77 (11%) pacientes. La reoperación dentro del primer año después de la reconstrucción se asoció con una mayor tasa de revisiones (IRR 2,90 p < 0,001) y un tiempo más corto hasta la escisión (HR 2,38 p < 0,001). La construcción de la ileostomía continente después del año 2000 se asoció con mayores tasas de revisión y escisión (IRR 2,7 p < 0,001 y HR 2,74 p = 0,013). La EII no clasificada se asoció con un aumento de las revisiones (IRR 1,3 p < 0,001) y la proporción de pacientes con EII no clasificada casi se duplicó desde la década de 1980 (32%) hasta después de 2000 (50%).LIMITACIONES:Diseño retrospectivo, datos de registro. No hay datos disponibles sobre la calidad de vida.CONCLUSIÓN:La ileostomía continente se asocia con una necesidad sustancial de cirugía de revisión, pero la mayoría de los pacientes logran mantener su reconstrucción durante mucho tiempo. Consulte Video Resumen en http://links.lww.com/DCR/C122 . (Traducción-Dr. Yolanda Colorado ).

Changes in apparent diffusion coefficient and pathological response in colorectal liver metastases after preoperative chemotherapy.

BACKGROUND: The pathological response to preoperative chemotherapy of colorectal liver metastases (CRLMs) is predictive of long-term prognosis after liver resection. Accurate preoperative assessment of chemotherapy response could enable treatment optimization. PURPOSE: To investigate whether changes in lesion-apparent diffusion coefficient (ADC) measured with diffusion-weighted magnetic resonance imaging (MRI) can be used to assess pathological treatment response in patients with CRLMs undergoing preoperative chemotherapy. MATERIAL AND METHODS: Patients who underwent liver resection for CRLMs after preoperative chemotherapy between January 2011 and December 2019 were retrospectively included if they had undergone MRI before and after preoperative chemotherapy on the same 1.5-T MRI scanner with diffusion-weighted imaging with b-values 50, 400, and 800 s/mm2. The pathological chemotherapy response was assessed using the tumor regression grade (TRG) by AJCC/CAP. Lesions were divided into two groups: pathological responding (TRG 0-2) and non-responding (TRG 3). The change in lesion ADC after preoperative chemotherapy was compared between responding and non-responding lesions. RESULTS: A total of 27 patients with 49 CRLMs were included, and 24/49 lesions showed a pathological chemotherapy response. After chemotherapy, ADC increased in both pathological responding (pretreatment ADC: 1.26 [95% confidence interval (CI)=1.06-1.37] vs. post-treatment ADC: 1.33 [95% CI=1.13-1.56] × 10-3 mm2/s; P = 0.026) and non-responding lesions (1.12 [95% CI=0.980-1.21] vs. 1.20 [95% CI=1.09-1.43] × 10-3 mm2/s; P = 0.018). There was no difference in median relative difference in ADC after chemotherapy between pathological responding and non-responding lesions (15.8 [95% CI=1.42-26.3] vs. 7.17 [95% CI=-4.31 to 31.2]%; P = 0.795). CONCLUSION: Changes in CRLM ADCs did not differ between pathological responding and non-responding lesions.

Model-based screening for pancreatic cancer in Sweden.

BACKGROUND: Detecting pancreatic cancer at an earlier stage may contribute to an increased survival. Patients with stage I pancreatic cancer have a 5-year survival rate of 36%, while stage IV patients have a 5-year survival rate of 1% in Sweden. Research into novel blood-based biomarkers for pancreatic cancer is highly intensive and innovative, but has yet to result in any routine screening test. The aim of this study was to evaluate the specificity and sensitivity of a hypothetical blood test for pancreatic cancer used for screening purposes and the economic aspects of testing. METHOD: A model of a screening test was created, with varying specificity and sensitivity both set at 80%, 85%, 90%, 95% or 99% and applied to selected risk groups. Excessive costs of false positive screening outcomes, QALYs, ICERs and total costs were calculated. RESULTS: Individuals with family history and genetic mutations associated with pancreatic cancer, new-onset diabetes ≥50 years of age and early symptoms had the highest positive predictive values and ICERs beneath the willingness-to-pay-level of EUR 100,000/QALY. Screening of the general population and smokers resulted in a high rate of false positive cases and extensive extra costs. CONCLUSIONS: General screening for pancreatic cancer is not cost-effective, while screening of certain high-risk groups may be economically justified given the availability of a high-performing blood-based test.

Histopathological investigation of colon liver metastases - which factors affect survival after surgery?

INTRODUCTION: Novel therapeutic options have improved prognosis for patients with colonic liver metastases (CLM) over the last decades. Despite this, the challenge to select and stratify patients for optimal treatment regimen persists. This study aimed to evaluate established and novel histopathological features and investigate the impact on overall survival (OS) and recurrence in patients undergoing surgery for CLM. METHODS: Two hundred and sixty patients who underwent resection of CLM with curative intent 2006-2017 were included in the study. Clinicopathological characteristics were retrieved from patient medical records. The following histopathological parameters were investigated: vascular/lymphatic invasion, perineural invasion, tumor regression grade (TRG), tumor growth pattern, pseudocapsule and acellular mucin. Histopathological traits were correlated to OS. RESULTS: Vascular and lymphatic invasion, as well as perineural invasion, significantly correlated with an adverse prognosis hazard ratio (HR) = 1.7, 95% confidence interval (CI) 1.23-2.40 and HR = 1.7, 95% CI 1.20-2.51, respectively. Results retrieved from the study could not propose any novel explorative histopathological features (TRG, tumor growth pattern, pseudocapsule and acellular mucin) to be of significant value as comes correlation with patient OS. DISCUSSION: Classical histopathological characteristics of previously reported influence on survival were confirmed, while more novel factors that has been proposed, like tumor growth pattern, tumor regression and grade and presence of a pseudocapsule, were not. Further studies are thus needed to identify better ways of understanding the impact of tumor microenvironment and tumor biology on patient outcome and not at least for stratification and improved treatment response.