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 surgery for pancreatic cancer: a global scoping review of guidelines and a nordic Survey of contemporary practice.

OBJECTIVES: Most patients with pancreatic cancer who have undergone surgical resection eventually develop disease recurrence. |This study aimed to investigate whether there is evidence to support routine surveillance after pancreatic cancer surgery, with a secondary aim of analyzing the implementation of surveillance strategies in the Nordic countries. MATERIALS AND METHODS: A scoping review was conducted to identify clinical practice guidelines globally and research studies relating to surveillance after pancreatic cancer resection. This was followed by a survey among 20 pancreatic units from four Nordic countries to assess their current practice of follow-up for operated patients. RESULTS: Altogether 16 clinical practice guidelines and 17 research studies were included. The guidelines provided inconsistent recommendations regarding postoperative surveillance of pancreatic cancer. The clinical research data were mainly based on retrospective cohort studies with low level of evidence and lead-time bias was not addressed. Active surveillance was recommended in Sweden and Denmark, but not in Norway beyond the post-operative/adjuvant period. Finland had no national recommendations for surveillance. The Nordic survey revealed a wide variation in reported practice among the different units. About 75% (15 of 20 units) performed routine postoperative surveillance. Routine CA 19-9 testing was used by 80% and routine CT by 67% as part of surveillance. About 73% of centers continued follow-up until 5 years postoperatively. CONCLUSION: Evidence for routine long-term (i.e. 5 years) surveillance after pancreatic cancer surgery remains limited. Most pancreatic units in the Nordic countries conduct regular follow-up, but protocols vary.

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 ).

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.

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.

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.

Postpancreatectomy Acute Pancreatitis (PPAP): Definition and Grading From the International Study Group for Pancreatic Surgery (ISGPS).

OBJECTIVE: The ISGPS aimed to develop a universally accepted definition for PPAP for standardized reporting and outcome comparison. BACKGROUND: PPAP is an increasingly recognized complication after partial pancreatic resections, but its incidence and clinical impact, and even its existence are variable because an internationally accepted consensus definition and grading system are lacking. METHODS: The ISGPS developed a consensus definition and grading of PPAP with its members after an evidence review and after a series of discussions and multiple revisions from April 2020 to May 2021. RESULTS: We defined PPAP as an acute inflammatory condition of the pancreatic remnant beginning within the first 3 postoperative days after a partial pancreatic resection. The diagnosis requires (1) a sustained postoperative serum hyperamylasemia (POH) greater than the institutional upper limit of normal for at least the first 48 hours postoperatively, (2) associated with clinically relevant features, and (3) radiologic alterations consistent with PPAP. Three different PPAP grades were defined based on the clinical impact: (1) grade postoperative hyperamylasemia, biochemical changes only; (2) grade B, mild or moderate complications; and (3) grade C, severe life-threatening complications. DISCUSSIONS: The present definition and grading scale of PPAP, based on biochemical, radiologic, and clinical criteria, are instrumental for a better understanding of PPAP and the spectrum of postoperative complications related to this emerging entity. The current terminology will serve as a reference point for standard assessment and lend itself to developing specific treatments and prevention strategies.

Pancreatic cancer - the past, the present, and the future.

BACKGROUND: Pancreatic cancer has been and still is associated with a very poor prognosis. This is due to a lack of major breakthroughs with respect to early diagnosis, prognostication, prediction, as well as novel, targeted therapies. The benefits of surgery and chemotherapy are evident, but the fact that only some 10% of all patients have early, localized disease highlights the unmet need for new early detection methods. An improved understanding of tumor biology and the development of molecular markers detectable both in the circulation and in cancer tissues may underlie the development of new tools for optimizing both diagnosis and treatment. MATERIAL AND METHODS: Review of the literature. RESULTS AND CONCLUSION: If we do not improve precision oncology for pancreatic ductal adenocarcinoma, the prognosis will still remain dismal and the" burden" on society will increase substantially.

Esophageal perforations - a population-based nationwide study in Sweden with survival analysis.

BACKGROUND: Esophageal perforation is a rare and life-threatening condition with several treatment options. The aim was to assess the incidence, type of treatment and mortality of esophageal perforations in Sweden and to identify risk factors for 90-day mortality. METHOD: All patients admitted with an esophageal perforation from 2007 to 2017 were identified from the National Patient Register. Mortality was assessed by linkage with the Cause of Death Registry. We analyze the incidence and the impact of age, sex, comorbidities on mortality. RESULTS: 879 patients with esophageal perforation were identified, giving an incidence rate of 1.09 per 100,000 person-years. The median age at diagnosis was 68.8 years and 60% were men. The mortality was 26% at 90 days. Independent risk factors for death within 90 days were age (odds ratio (OR): 6.20; 95% (confidence interval) CI: 2.16-17.79 at 60-74 years and OR: 11.58; 95% CI: 4.04-33.15 at 75 years or older), peripheral vascular disease (OR: 2.92; 95% CI: 1.44-5.92) and underlying malignant disease (OR: 5.91; 95% CI: 3.86-9.03). In patients younger than 45 years, survival was lower among women than among men (at 5 years 73 and 93%, respectively). The cause of death among young women was often drug-related or suicide. CONCLUSIONS: 90-day mortality was 26%, old age, vascular disease and underlying malignant disease were risk factors.

Impact of COVID-19 on the incidence of CT-diagnosed appendicitis and its complications in the UK and Sweden.

AIM: To compare the number of appendicitis cases and its complications, during the first months of the COVID-19 pandemic in Sweden and the UK and the corresponding time period in 2019. METHOD: Reports of emergency abdominopelvic CT performed at 56 Swedish hospitals and 38 British hospitals between April and July 2020 and a corresponding control cohort from 2019 were reviewed. Two radiologists and two surgeons blinded to the date of cohorts analyzed all reports for diagnosis of appendicitis, perforation, and abscess. A random selection of cases was chosen for the measurement of inter-rater agreement. RESULT: Both in Sweden (6111) and the UK (5591) fewer, abdominopelvic CT scans were done in 2020 compared to 2019 (6433 and 7223, respectively); p < 0.001. In the UK, the number of appendicitis was 36% lower in April-June 2020 compared to 2019 but not in Sweden. Among the appendicitis cases, there was a higher number of perforations and abscesses in 2020, in Sweden. In the UK, the number of perforations and abscesses were initially lower (April-June 2020) but increased in July 2020. There was a substantial inter-rater agreement for the diagnosis of perforations and abscess formations (K = 0.64 and 0.77). CONCLUSION: In Sweden, the number of appendicitis was not different between 2019 and 2020; however, there was an increase of complications. In the UK, there was a significant decrease of cases in 2020. The prevalence of complications was lower initially but increased in July. These findings suggest variability in delay in diagnosis of appendicitis depending on the country and time frame studied.

Swedish national guidelines for chronic pancreatitis.

Chronic pancreatitis (CP) should be suspected in the case of recurrent upper abdominal pain of unknown origin and/or clinical signs of exocrine pancreatic insufficiency (EPI). Alcohol is the most common etiological factor associated with CP, others being smoking, male gender, and hereditary forms. CP is often associated with recurrent episodes of acute exacerbations.As of today, there is no accepted clinical definition of CP. However, irreversible morphological changes within the pancreas often occur, including dilatation of the main and branch pancreatic ducts, calcifications in ducts and parenchyma, parenchymal atrophy, and development of pseudocysts, though less so in the early phase of CP.

Projected economic burden of pancreatic cancer in Sweden in 2030.

BACKGROUND: Pancreatic cancer is predicted to become the second most common cause of cancer-related death by 2030. The objective of this study was to estimate the economic burden of pancreatic cancer for the years 2018 and 2030 based on changing demographics and incidence rates in Sweden. METHOD: The incidence of pancreatic cancer in Sweden and additional relevant data were obtained from official statistics. A linear regression model and the mean incidence rates 2008-2018 were applied to calculate the incidence in 2030. An economic model based on the human capital method was created to calculate the indirect cost of pancreatic cancer in 2018 and 2030. Costs associated with surgery, radiology, oncology, and palliative care constituted the direct costs. A sensitivity analysis was performed. RESULTS: The incidence of pancreatic cancer in Sweden in the year 2018 was 1352 patients and projected to between 1554 (+15%) and 1736 (+28%) in 2030. The total cost was calculated to €125 million in 2018 and between €210 million (+68%) and €225 million (+80%) in 2030. The indirect cost in the ≤65-year-old group was €328,344 in 2018 and between €380,738 and €382,109 per individual in 2030. CONCLUSIONS: The economic burden of pancreatic cancer is expected to increase in Sweden by 2030 due to the increasing incidence of the disease and changing demographics. Pancreatic cancer is a growing health care problem in urgent need of advancements in prevention, early detection, treatment, and control of the disease.

Validation of the Appendicitis Inflammatory Response (AIR) Score.

BACKGROUND: Patients with suspicion of appendicitis present with a wide range of severity. Score-based risk stratification can optimise the management of these patients. This prospective study validates the Appendicitis Inflammatory Response (AIR) score in patients with suspicion of appendicitis. METHOD: Consecutive patients over the age of five with suspicion of appendicitis presenting at 25 Swedish hospital's emergency departments were prospectively included. The diagnostic properties of the AIR score are estimated. RESULTS: Some 3878 patients were included, 821 with uncomplicated and 724 with complicated appendicitis, 1986 with non-specific abdominal pain and 347 with other diagnoses. The score performed better in detecting complicated appendicitis (ROC area 0.89 (95% confidence interval (CI) 0.88-0.90) versus 0.83 (CI 0.82-0.84) for any appendicitis, p < 0.001), in patients below age 15 years and in patients with >47 h duration of symptoms (ROC area 0.93, CI 0.90-0.95 for complicated and 0.87, CI 0.84-0.90 for any appendicitis in both categories). Complicated appendicitis is unlikely at AIR score <4 points (Negative Predictive Value 99%, CI 98-100%). Appendicitis is likely at AIR score >8 points, especially in young patients (positive predictive value (PPV) 96%, CI 90-100%) and men (PPV 89%, CI 84-93%). CONCLUSIONS: The AIR score has high sensitivity for complicated appendicitis and identifies subgroups with low probability of complicated appendicitis or high probability of appendicitis. The discriminating capacity is high in children and patients with long duration of symptoms. It performs equally well in both sexes. This verifies the AIR score as a valid decision support. Trial registration number https://clinicaltrials.gov/ct2/show/NCT00971438.

Mass spectrometry-based analysis of formalin-fixed, paraffin-embedded distal cholangiocarcinoma identifies stromal thrombospondin-2 as a potential prognostic marker.

BACKGROUND: Distal cholangiocarcinoma is an aggressive malignancy with a dismal prognosis. Diagnostic and prognostic biomarkers for distal cholangiocarcinoma are lacking. The aim of the present study was to identify differentially expressed proteins between distal cholangiocarcinoma and normal bile duct samples. METHODS: A workflow utilizing discovery mass spectrometry and verification by parallel reaction monitoring was used to analyze surgically resected formalin-fixed, paraffin-embedded samples from distal cholangiocarcinoma patients and normal bile duct samples. Bioinformatic analysis was used for functional annotation and pathway analysis. Immunohistochemistry was performed to validate the expression of thrombospondin-2 and investigate its association with survival. RESULTS: In the discovery study, a total of 3057 proteins were identified. Eighty-seven proteins were found to be differentially expressed (q < 0.05 and fold change ≥ 2 or ≤ 0.5); 31 proteins were upregulated and 56 were downregulated in the distal cholangiocarcinoma samples compared to controls. Bioinformatic analysis revealed an abundance of differentially expressed proteins associated with the tumor reactive stroma. Parallel reaction monitoring verified 28 proteins as upregulated and 18 as downregulated in distal cholangiocarcinoma samples compared to controls. Immunohistochemical validation revealed thrombospondin-2 to be upregulated in distal cholangiocarcinoma epithelial and stromal compartments. In paired lymph node metastases samples, thrombospondin-2 expression was significantly lower; however, stromal thrombospondin-2 expression was still frequent (72%). Stromal thrombospondin-2 was an independent predictor of poor disease-free survival (HR 3.95, 95% CI 1.09-14.3; P = 0.037). CONCLUSION: Several proteins without prior association with distal cholangiocarcinoma biology were identified and verified as differentially expressed between distal cholangiocarcinoma and normal bile duct samples. These proteins can be further evaluated to elucidate their biomarker potential and role in distal cholangiocarcinoma carcinogenesis. Stromal thrombospondin-2 is a potential prognostic marker in distal cholangiocarcinoma.

YAP1 is an independent prognostic marker in pancreatic cancer and associated with extracellular matrix remodeling.

BACKGROUND: Pancreatic cancer is a major cause of cancer-related mortality. The identification of effective biomarkers is essential in order to improve management of the disease. Yes-associated protein 1 (YAP1) is a downstream effector of the Hippo pathway, a signal transduction system implicated in tissue repair and regeneration, as well as tumorigenesis. Here we evaluate the biomarker potential of YAP1 in pancreatic cancer tissue. METHODS: YAP1 was selected as a possible biomarker for pancreatic cancer from global protein sequencing of fresh frozen pancreatic cancer tissue samples and normal pancreas controls. The prognostic utility of YAP1 was evaluated using mRNA expression data from 176 pancreatic cancer patients in The Cancer Genome Atlas (TCGA), as well as protein expression data from immunohistochemistry analysis of a local tissue microarray (TMA) cohort comprising 140 pancreatic cancer patients. Ingenuity Pathway Analysis was applied to outline the interaction network for YAP1 in connection to the pancreatic tumor microenvironment. The expression of YAP1 target gene products was evaluated after treatment of the pancreatic cancer cell line Panc-1 with three substances interrupting YAP-TEAD interaction, including Super-TDU, Verteporfin and CA3. RESULTS: Mass spectrometry based proteomics showed that YAP1 is the top upregulated protein in pancreatic cancer tissue when compared to normal controls (log2 fold change 6.4; p = 5E-06). Prognostic analysis of YAP1 demonstrated a significant correlation between mRNA expression level data and reduced overall survival (p = 0.001). In addition, TMA and immunohistochemistry analysis suggested that YAP1 protein expression is an independent predictor of poor overall survival [hazard ratio (HR) 1.870, 95% confidence interval (CI) 1.224-2.855, p = 0.004], as well as reduced disease-free survival (HR 1.950, 95% CI 1.299-2.927, p = 0.001). Bioinformatic analyses coupled with in vitro assays indicated that YAP1 is involved in the transcriptional control of target genes, associated with extracellular matrix remodeling, which could be modified by selected substances disrupting the YAP1-TEAD interaction. CONCLUSIONS: Our findings indicate that YAP1 is an important prognostic biomarker for pancreatic cancer and may play a regulatory role in the remodeling of the extracellular matrix.

Genomic Profiling of Stage II Colorectal Cancer Identifies Candidate Genes Associated with Recurrence-Free Survival, Tumor Location, and Differentiation Grade.

BACKGROUND: Identification of high-risk stage II colorectal cancer (CRC) patients, potential candidates for adjuvant chemotherapy, is challenging. Current clinical guidelines rely mainly on histopathological markers with relatively weak prognostic value. This motivates further search for prognostic markers. METHODS: This explorative study aimed to identify potential candidate gene mutations to facilitate differentiation between subgroups of patients with CRC stage II. Panel-based massive parallel sequencing was used to genetically characterize tumor tissues from 85 patients radically operated for CRC stage II, of which 12 developed recurrent cancer during follow-up. Genetic data was compared between patients with or without cancer recurrence, between tumors located in colon and in rectum, and for association with tumor differentiation grade. RESULTS: Genetic variation in ATM, C11ORF65 was associated with recurrence-free survival. Previous reports regarding the association between BRAF mutation and a higher age at diagnosis, and tumor location in colon were confirmed. APC, BRAF, or KRAS mutation was associated with tumor differentiation grade. Multiple correspondence analyses revealed no obvious clustering of patients with the studied clinical characteristics, indicating that the genetic signatures observed here were unique for each individual. CONCLUSIONS: Taken together, we have demonstrated the utility of panel-based massive parallel sequencing to explore the pathogenesis of CRC stage II. We have identified promising candidate gene mutations associated with cancer recurrence, tumor location, and differentiation grade in patients with CRC stage II, which merit further investigation.

Expression of peritumoral SPARC during distal cholangiocarcinoma progression and correlation with outcome.

Objectives: Distal cholangiocarcinoma (dCCA) is a malignancy with a dismal prognosis. One of the hallmarks is the presence of a rich desmoplastic stroma believed to contribute to tumor progression and treatment resistance. Secreted protein acidic and rich in cysteine (SPARC) is a matricellular glycoprotein implicated in tumor-stroma interaction with prognostic correlation across several malignancies. The aim of the present study was to evaluate the expression pattern and prognostic significance of SPARC in resected dCCA and paired lymph node metastasis.Materials and methods: SPARC expression was evaluated in 59 resected dCCA samples and 25 paired lymph node metastases as well as 10 benign bile duct samples using immunohistochemistry. Stromal SPARC expression was scored semi quantitatively. Survival was estimated using the Kaplan-Meier method with associated log-rank test.Results: SPARC expression was absent in normal bile ducts. In dCCA, peritumoral stromal SPARC was detectable in 47/59 (80%) of samples with 40/59 (68%) classified as high stromal SPARC expression. There was a significantly lower proportion of SPARC positive stroma in paired lymph node metastasis 17/25 (68%) than the corresponding primary tumors 24/25 (96%) (p = .016). Stromal SPARC expression was associated with the presence of lymph node metastasis; high SPARC expression 31/40 (78%) versus low SPARC expression 9/19 (47%) (p = .013). In the present material there was no significant association between stromal SPARC expression and survival.Conclusions: Stromal SPARC expression occurs frequently in dCCA. Although significantly lower than in primary tumors stromal SPARC is frequently retained in paired lymph node metastasis suggesting a possible role in the metastatic process of dCCA.

Expression of fibroblast activation protein and the clinicopathological relevance in distal cholangiocarcinoma.

Objectives: The current survival of patients with distal cholangiocarcinoma (dCCA) is poor. There is a need to develop new prognostic and predictive biomarkers to improve the survival of patients. Fibroblast activation protein (FAP) expression has been associated with survival in several solid malignancies. The goal of this study was to evaluate the expression pattern and prognostic significance of FAP in dCCA.Materials and methods: FAP expression was examined in 57 resected dCCA specimens and 28 paired lymph node metastasis specimens, as well as 10 benign bile ducts using immunohistochemistry. FAP expression was scored in the epithelial and stromal component of the dCCA specimens. The association between FAP expression and prognosis was evaluated using univariable and multivariable statistical modeling.Results: FAP expression was absent in the benign controls. FAP expression was evident in the epithelial 43 (75%) and stromal compartment 34 (60%) of dCCA. There was no association between epithelial or stromal FAP expression and clinicopathological factors. Epithelial FAP expression (HR 0.4 95% CI 0.20-0.78; p=.007) but not stromal FAP expression was significantly associated with better survival in univariable and multivariable analysis.Conclusions: FAP overexpression is evident in dCCA. There was a positive association between epithelial FAP expression and better survival which merits further evaluation.

Genetic polymorphism patterns suggest a genetic driven inflammatory response as pathogenesis in appendicitis.

PURPOSE: The pathogenesis of appendicitis is not well understood. Environmental factors are regarded most important, but epidemiologic findings suggest a role of inflammatory and genetic mechanisms. This study determines the association of single nucleotide polymorphisms (SNPs) of inflammatory genes with appendicitis. METHODS: As part of a larger prospective study on the diagnostic value of inflammatory variables in appendicitis, the genotype frequency of 28 polymorphisms in 26 inflammatory response genes from the appendicitis and control patients was analyzed in blood samples from 343 patients, 100 with appendicitis, and 243 with non-specific abdominal pain, using TaqMan SNP genotyping assays. RESULTS: Associations with appendicitis were found for SNPs IL-13 rs1800925 with odds ratio (OR) 6.02 (95% CI 1.52-23.78) for T/T versus C/C + T/T, for IL-17 rs2275913 with OR 2.38 (CI 1.24-4.57) for A/A vs G/G + GA, for CCL22 rs223888 with OR 0.12 (0.02-0.90), and for A/A vs G/G + GA. Signs of effect modification of age for the association with appendicitis were found for IL-13 rs1800925 and CTLA4 rs3087243. Stratified analysis showed difference in association with severity of disease for IL-17 rs2275913 and CD44 rs187115. CONCLUSIONS: The association of gene variants on risk of appendicitis and its severity suggest an etiologic role of genetically regulated inflammatory response. This may have implications for understanding the prognosis of untreated appendicitis as a possible self-limiting disorder and for understanding the inverse association of appendicitis with ulcerative colitis.