Intestinal PTGS2 mRNA Levels, PTGS2 Gene Polymorphisms, and Colorectal Carcinogenesis

<div><p>Background & Aims</p><p>Inflammation is a major risk factor for development of colorectal cancer (CRC). Prostaglandin synthase cyclooxygenase-2 (COX-2) encoded by the <i>PTGS2</i> gene is the rate limiting enzyme in prostaglandin synthesis and therefore plays a distinct role as regulator of inflammation.</p><p>Methods</p><p><i>PTGS2</i> mRNA levels were determined in intestinal tissues from 85 intestinal adenoma cases, 115 CRC cases, and 17 healthy controls. The functional <i>PTGS2</i> polymorphisms A-1195G (rs689466), G-765C (rs20417), T8473C (rs5275) were assessed in 200 CRC cases, 991 adenoma cases and 399 controls from the Norwegian KAM cohort.</p><p>Results</p><p><i>PTGS2</i> mRNA levels were higher in mild/moderate adenoma tissue compared to morphologically normal tissue from the same individual (P<0.0001) and (P<0.035) and compared to mucosa from healthy individuals (P<0.0039) and (P<0.0027), respectively. In CRC patients, <i>PTGS2</i> mRNA levels were 8–9 times higher both in morphologically normal tissue and in cancer tissue, compared to healthy individuals (P<0.0001). <i>PTGS2</i> A-1195G variant allele carriers were at reduced risk of CRC (odds ratio (OR) = 0.52, 95% confidence interval (95% CI): 0.28–0.99, P = 0.047). Homozygous carriers of the haplotype encompassing the A-1195G and G-765C wild type alleles and the T8473C variant allele <i>(PTGS2</i> AGC) were at increased risk of CRC as compared to homozygous carriers of the <i>PTGS2</i> AGT (<u>A</u>-1195G, <u>G</u>-765C, <u>T</u>8473C) haplotype (OR = 5.37, 95% CI: 1.40–20.5, P = 0.014). No association between the investigated polymorphisms and <i>PTGS2</i> mRNA levels could be detected.</p><p>Conclusion</p><p>High intestinal <i>PTGS2</i> mRNA level is an early event in colorectal cancer development as it occurs already in mild/moderate dysplasia. <i>PTGS2</i> polymorphisms that have been associated with altered <i>PTGS2</i> mRNA levels/COX-2 activity in some studies, although not the present study, were associated with colorectal cancer risk. Thus, both <i>PTGS2</i> polymorphisms and <i>PTGS2</i> mRNA levels may provide information regarding CRC risk.</p></div

The multidrug resistance 1 (MDR1) gene polymorphism G-rs3789243-A is not associated with disease susceptibility in Norwegian patients with colorectal adenoma and colorectal cancer; a case control study

<p>Abstract</p> <p>Background</p> <p>Smoking, dietary factors, and alcohol consumption are known life style factors contributing to gastrointestinal carcinogenesis. Genetic variations in carcinogen handling may affect cancer risk. The multidrug resistance 1(<it>MDR1/ABCB1</it>) gene encodes the transport protein P-glycoprotein (a phase III xenobiotic transporter). P-glycoprotein is present in the intestinal mucosal lining and restricts absorption of certain carcinogens, among these polycyclic aromatic hydrocarbons. Moreover, P-glycoprotein transports various endogenous substrates such as cytokines and chemokines involved in inflammation, and may thereby affect the risk of malignity. Hence, genetic variations that modify the function of P-glycoprotein may be associated with the risk of colorectal cancer (CRC). We have previously found an association between the <it>MDR1 </it>intron 3 G-rs3789243-A polymorphism and the risk of CRC in a Danish study population. The aim of this study was to investigate if this <it>MDR1 </it>polymorphism was associated with risk of colorectal adenoma (CA) and CRC in the Norwegian population.</p> <p>Methods</p> <p>Using a case-control design, the association between the <it>MDR1 </it>intron 3 G-rs3789243-A polymorphism and the risk of colorectal carcinomas and adenomas in the Norwegian population was assessed in 167 carcinomas, 990 adenomas, and 400 controls. Genotypes were determined by allelic discrimination. Odds ratio (OR) and 95 confidence interval (95% CI) were estimated by binary logistic regression.</p> <p>Results</p> <p>No association was found between the <it>MDR1 </it>polymorphism (G-rs3789243-A) and colorectal adenomas or cancer. Carriers of the variant allele of MDR1 intron 3 had odds ratios (95% CI) of 0.97 (0.72–1.29) for developing adenomas, and 0.70 (0.41–1.21) for colorectal cancer, respectively, compared to homozygous wild type carriers.</p> <p>Conclusion</p> <p>The <it>MDR1 </it>intron 3 (G-rs3789243-A) polymorphism was not associated with a risk of colorectal adenomas or carcinomas in the present Norwegian study group. Thus, this <it>MDR1 </it>polymorphism does not seem to play an important role in colorectal carcinogenesis in this population.</p

Differential Expression of miRNAs in Colorectal Cancer: Comparison of Paired Tumor Tissue and Adjacent Normal Mucosa Using High-Throughput Sequencing

We present the results of a global study of dysregulated miRNAs in paired samples of normal mucosa and tumor from eight patients with colorectal cancer. Although there is existing data of miRNA contribution to colorectal tumorigenesis, these studies are typically small to medium scale studies of cell lines or non-paired tumor samples. The present study is to our knowledge unique in two respects. Firstly, the normal and adjacent tumor tissue samples are paired, thus taking into account the baseline differences between individuals when testing for differential expression. Secondly, we use high-throughput sequencing, thus enabling a comprehensive survey of all miRNAs expressed in the tissues. We use Illumina sequencing technology to perform sequencing and two different tools to statistically test for differences in read counts per gene between samples: edgeR when using the pair information and DESeq when ignoring this information, i.e., treating tumor and normal samples as independent groups. We identify 37 miRNAs that are significantly dysregulated in both statistical approaches, 19 down-regulated and 18 up-regulated. Some of these miRNAs are previously published as potential regulators in colorectal adenocarcinomas such as miR-1, miR-96 and miR-145. Our comprehensive survey of differentially expressed miRNAs thus confirms some existing findings. We have also discovered 16 dysregulated miRNAs, which to our knowledge have not previously been associated with colorectal carcinogenesis: the following significantly down-regulated miR-490-3p, -628-3p/-5p, -1297, -3151, -3163, -3622a-5p, -3656 and the up-regulated miR-105, -549, -1269, -1827, -3144-3p, -3177, -3180-3p, -4326. Although the study is preliminary with only eight patients included, we believe the results add to the present knowledge on miRNA dysregulation in colorectal carcinogenesis. As such the results would serve as a robust training set for validation of potential biomarkers in a larger cohort study. Finally, we also present data supporting the hypothesis that there are differences in miRNA expression between adenocarcinomas and neuroendocrine tumors of the colon

Differential Expression of miRNAs in Colorectal Cancer: Comparison of Paired Tumor Tissue and Adjacent Normal Mucosa Using High-Throughput Sequencing

We present the results of a global study of dysregulated miRNAs in paired samples of normal mucosa and tumor from eight patients with colorectal cancer. Although there is existing data of miRNAs contributing to colorectal tumorigenesis, these studies are typically small to medium scale studies of cell lines or non-paired tumor samples. The present study is to our knowledge unique in two respects. Firstly, the normal and adjacent tumor tissue samples are paired, thus taking into account the baseline differences between individuals when testing for differential expression. Secondly, we use high-throughput sequencing, thus enabling a comprehensive survey of all miRNAs expressed in the tissues. We use Illumina sequencing technology to perform sequencing and two different tools to test for differences in read counts per gene between samples: DESeq for pooled sample testing and edgeR for paired sample testing. We identify 37 miRNAs that are significantly dysregulated in both statistical approaches. 19 down-regulated and 18 upregulated. Some of these miRNAs are previously published as potential regulators in colorectal adenocarcinomas such as miR-1, miR-96 and miR-145. Our comprehensive survey of differentially expressed miRNAs thus confirms some existing findings. We have also discovered 16 dysregulated miRNAs which to our knowledge have not previously been associated with colorectal carcinogenesis. These results add to the present knowledge on miRNA dysregulation in colorectal carcinogenesis by identifying molecules that may either be important regulators of this cancer or be useful as biomarkers. Finally, we also present data supporting the hypothesis that there are differences in miRNA expression between adenocarcinomas and neuroendocrine tumors of the colon

S227: INITIAL SAFETY DATA FROM THE PHASE 3 POLAR BEAR TRIAL IN ELDERLY OR FRAIL PATIENTS WITH DIFFUSE LARGE CELL LYMPHOMA, COMPARING R-POLA-MINI-CHP AND R-MINI-CHOP

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Tidlig diagnostisering av osteoporose hos postmenopausale kvinner med underarmsbrudd

Ortopedisk avdeling ved Klinikk Bærum sykehus, Vestre Viken HF (VVHF) har ingen interne rutiner for osteoporosevurdering av kvinner over 50 år etter lavenergibrudd i underarmen. Dette er et problem som ledelsen i VVHF erkjenner, og hvor vi i avdelingen ser et behov for endret praksis. Osteoporose er i dette prosjektet definert som en skjelettlidelse med redusert beinstyrke, som predisponerer for brudd. I følge Verdens helseorganisasjon (WHO) er osteoporose beintetthet lavere enn 2,5 standardavvik under gjennomsnittet til unge friske kvinner, såkalt T-score (WHO-kriteriet). Betegnelsen etablert osteoporose brukes hvis det foreligger lavenergibrudd i tillegg til osteoporose. Dual Energy X-ray Absorptiometry (DXA) er den mest brukte metoden for å måle beintetthet. Prinsippet går ut på at to fotoner med ulik energi passerer gjennom beinvev, og tapt energi måles (attenuasjon). Attenuasjonen vil øke med beintettheten. Resultatene oppgis som et absolutt (Bone Mineral Density) og et relativt mål (T-score) (1). Kvinner er mer utsatt enn menn for å få osteoporose grunnet østrogenmangel etter menopause. I tillegg vil alder i seg selv være en risikofaktor da beintapet øker med alder (2). I målgruppen for dette prosjektet inkluderes for enkelhets skyld alle kvinner over 50 år uavhengig av menopausal status. Med underarmsbrudd menes brudd som involverer radius og/eller ulna. I henhold til anatomisk klassifikasjon av AO Foundation inkluderer dette alle brudd med koder 21 – 23 (3). Lavenergibrudd er i denne sammenheng brudd etter fall fra samme nivå eller som oppstår uten at sterke ytre krefter er involvert (4). Per dags dato kommer pasienter i vår målgruppe til 6-ukers poliklinisk kontroll ved Ortopedisk avdeling etter et brudd uten at systematiske osteoporosetiltak blir satt i gang. Vi ønsker å optimalisere tidlig diagnostisering av osteoporose hos kvinner som har høy risiko for nye brudd. I denne prosjektbeskrivelsen vil vi belyse kunnskapsgrunnlaget for endret praksis, hvordan situasjonen er i dag samt evaluere hvordan praksis i vår avdeling kan endres. Målet med en slik endring er å forebygge nye brudd i denne pasientgruppen. Dette vil mest sannsynlig også kunne redusere morbiditet og mortalitet, samtidig som det vil være kostnadseffektivt i et samfunnsøkonomisk perspektiv

Using process indicators to monitor documentation of patient-centred variables in an integrated oncology and palliative care pathway—results from a cluster randomized trial

Background. Despite robust evidence from randomized controlled trials (RCTs) demonstrating clinical and patient-reported benefits of integrated oncology and palliative care, the tumour-centred focus is predominant. This single–centre process evaluation monitors documentation of required patient-centred variables during an RCT. Methods. Performance status, patient self-reported symptoms, weight and summaries to general practitioners were assessed from June 2017 to July 2020 in three consultation types: first oncological after study inclusion and palliative and oncological consultations during chemotherapy. Descriptive statistics were used to monitor if the pre-defined program fulfilment of ≥85% documentation was reached. Results. 435 consultations were monitored in 76 patients; 60.5% males, 86.8% with GI cancers; 76 (17.5%) were from the first oncological consultations, 87 (20.0%) and 272 (62.5%) from palliative or subsequent oncological consultations. Program fulfilment differed across consultation types with 94.8% in the palliative consultations (83.3–100%), relative to 65.8% (62.5–75.0%) and 69.2% (57.0–84.3%) for first and subsequent oncological consultations over time, respectively. Use of self-reported symptoms was consistently lower in the oncological consultations. Conclusions. The documentation level of required core variables was not satisfactory, notwithstanding their high clinical relevance and continuous reminders during study. Pre-trial optimization strategies are paramount to promote integration and reduce professional and personal barriers towards a more patient-centred focus

Survival Trends of Right- and Left-Sided Colon Cancer across Four Decades: A Norwegian Population-Based Study

Background: Patients with right-sided colon cancer (RCC) and left-sided colon cancer (LCC) differ clinically and molecularly. The main objective was to investigate stage-stratified survival and recurrence of RCC and LCC across four 10-year periods. Methods: Patients diagnosed from 1977 to 2016 with colon adenocarcinoma were included from the Cancer Registry of Norway. Primary tumor location (PTL) was defined as RCC if proximal and LCC if distal to the splenic flexure. Multivariable regressions were used to estimate HRs for overall survival (OS), recurrence-free survival (RFS), survival after recurrence (SAR), and excess HRs (eHR) for relative survival (RS). Results: 72,224 patients were eligible for analyses [55.1% (n = 39,769/72,224) had RCC]. In 1977 to 1986, there was no difference between LCC and RCC in OS [HR, 1.01; 95% confidence interval (CI), 0.97–1.06; P = 0.581] or RS (eHR, 0.96; 95% CI, 0.90–1.02; P = 0.179). In 2007 to 2016, LCC had significantly better OS (HR, 0.84; 95% CI, 0.80–0.87; P < 0.001) and RS (eHR, 0.76; 95% CI, 0.72–0.81; P < 0.001) compared with RCC. The gradually diverging and significantly favorable prognosis for LCC was evident for distant disease across all time periods and for regional disease from 2007 onward. There was no difference in RFS between LCC and RCC in patients less than 75 years during 2007 to 2016 (HR, 0.99; 95% CI, 0.91–1.08; P = 0.819); however, SAR was significantly better for LCC (HR, 0.61; 95% CI, 0.53–0.71; P < 0.001). Conclusions: A gradually diverging and increasingly favorable prognosis was observed for patients with LCC with advanced disease over the past four decades. Impact: Current PTL survival disparities stress the need for further exploring targetable molecular subgroups across and within different PTLs to further improve patient outcomes