Mitotic abnormalities precede microsatellite instability in lynch syndrome-associated colorectal tumourigenesis.

BACKGROUND: Lynch syndrome (LS) is one of the most common hereditary cancer syndromes worldwide. Dominantly inherited mutation in one of four DNA mismatch repair genes combined with somatic events leads to mismatch repair deficiency and microsatellite instability (MSI) in tumours. Due to a high lifetime risk of cancer, regular surveillance plays a key role in cancer prevention; yet the observation of frequent interval cancers points to insufficient cancer prevention by colonoscopy-based methods alone. This study aimed to identify precancerous functional changes in colonic mucosa that could facilitate the monitoring and prevention of cancer development in LS. METHODS: The study material comprised colon biopsy specimens (n = 71) collected during colonoscopy examinations from LS carriers (tumour-free, or diagnosed with adenoma, or diagnosed with carcinoma) and a control group, which included sporadic cases without LS or neoplasia. The majority (80%) of LS carriers had an inherited genetic MLH1 mutation. The remaining 20% included MSH2 mutation carriers (13%) and MSH6 mutation carriers (7%). The transcriptomes were first analysed with RNA-sequencing and followed up with Gorilla Ontology analysis and Reactome Knowledgebase and Ingenuity Pathway Analyses to detect functional changes that might be associated with the initiation of the neoplastic process in LS individuals. FINDINGS: With pathway and gene ontology analyses combined with measurement of mitotic perimeters from colonic mucosa and tumours, we found an increased tendency to chromosomal instability (CIN), already present in macroscopically normal LS mucosa. Our results suggest that CIN is an earlier aberration than MSI and may be the initial cancer driving aberration, whereas MSI accelerates tumour formation. Furthermore, our results suggest that MLH1 deficiency plays a significant role in the development of CIN. INTERPRETATION: The results validate our previous findings from mice and highlight early mitotic abnormalities as an important contributor and precancerous marker of colorectal tumourigenesis in LS. FUNDING: This work was supported by grants from the Jane and Aatos Erkko Foundation, the Academy of Finland (330606 and 331284), Cancer Foundation Finland sr, and the Sigrid Jusélius Foundation. Open access is funded by Helsinki University Library.

The ability of magnetic resonance imaging to predict lymph node metastases and the risk of recurrence in rectal cancer.

AIM: This study aimed to examine the diagnostic accuracy and prognostic value of magnetic resonance imaging (MRI) detected lymph nodes in rectal cancer. METHOD: We evaluated 806 rectal cancer patients consecutively operated on between 2015 and 2018 at Helsinki University Hospital. In total, 485 patients met the inclusion criteria of presenting with stage I-III disease and were intended for curative treatment at the time of diagnosis. The effect of MRI-detected clinical lymph node status (cN) on cumulative overall survival (OS), disease-specific survival (DSS) and disease-free survival (DFS) was calculated using the Kaplan-Meier analysis. RESULTS: Negative predictive value (NPV) of MRI-lymphnode negativity was 74.8%. Positive predictive value of lymph node metastasis was only 48.6%. In the Kaplan-Meier survival analysis, OS (p = 0.989), DSS (p = 0.911), and DFS (p = 0.109) did not significantly differ according to MRI nodal status. However, cumulative disease-free survival significantly (p < 0.001) differed according to the histopathological lymph node metastasis status (pN). CONCLUSIONS: MRI detected lymph node positivity appears insufficiently precise and cannot predict disease recurrence or survival. Therefore, it should not serve as an independent risk factor when considering neoadjuvant treatment options for rectal cancer patients.

The prognostic value of extramural venous invasion in preoperative MRI of rectal cancer patients.

AIM: This study aimed to examine the prognostic value of extramural venous invasion observed in preoperative MRI on survival and recurrences. METHOD: In total, 778 rectal cancer patients were evaluated in multidisciplinary meetings in Helsinki University Hospital during the years 2016-2018. 635 patients met the inclusion criteria of stage I-III disease and were intended for curative treatment at the time of diagnosis. 128 had extramural venous invasion in preoperative MRI. RESULTS: The median follow-up time was 2.5 years. In a univariate analysis extramural venous invasion was associated with poorer disease-specific survival (hazard ratio [HR] 2.174, 95% CI 1.118-4.224, P = 0.022), whereas circumferential margin ≤1 mm, tumour stage ≥T3c or nodal positivity were not. Disease recurrence occurred in 17.3% of the patients: 13.4% had metastatic recurrence only, 1.7% mere local recurrence and 2.2% both metastatic and local recurrence. In multivariate analysis, extramural venous invasion (HR 1.734, 95% CI 1.127-2.667, P = 0.012) and nodal positivity (HR 1.627, 95% CI 1.071-2.472, P = 0.023) were risk factors for poorer disease-free survival (DFS). Circumferential margin ≤1 mm was a risk factor for local recurrence in multivariate analysis (HR 5.675, 95% CI 1.274-25.286, P = 0.023). CONCLUSION: In MRI, circumferential margin ≤1 mm is a risk factor for local recurrence, but the risk is quite well controlled with chemoradiotherapy and extended surgery. Extramural venous invasion instead is a significant risk factor for poorer DFS and new tools to reduce the systemic recurrence risk are needed.

Mechanical and oral antibiotic bowel preparation versus no bowel preparation for elective colectomy (MOBILE): a multicentre, randomised, parallel, single-blinded trial.

BACKGROUND: Decreased surgical site infections (SSIs) and morbidity have been reported with mechanical and oral antibiotic bowel preparation (MOABP) compared with no bowel preparation (NBP) in colonic surgery. Several societies have recommended routine use of MOABP in patients undergoing colon resection on the basis of these data. Our aim was to investigate this recommendation in a prospective randomised context. METHODS: In this multicentre, parallel, single-blinded trial, patients undergoing colon resection were randomly assigned (1:1) to either MOABP or NBP in four hospitals in Finland, using a web-based randomisation technique. Randomly varying block sizes (four, six, and eight) were used for randomisation, and stratification was done according to centre. The recruiters, treating physicians, operating surgeons, data collectors, and analysts were masked to the allocated treatment. Key exclusion criteria were need for emergency surgery; bowel obstruction; colonoscopy planned during surgery; allergy to polyethylene glycol, neomycin, or metronidazole; and age younger than 18 years or older than 95 years. Study nurses opened numbered opaque envelopes containing the patient allocated group, and instructed the patients according to the allocation group to either prepare the bowel, or not prepare the bowel. Patients allocated to MOABP prepared their bowel by drinking 2 L of polyethylene glycol and 1 L of clear fluid before 6 pm on the day before surgery and took 2 g of neomycin orally at 7 pm and 2 g of metronidazole orally at 11 pm the day before surgery. The primary outcome was SSI within 30 days after surgery, analysed in the modified intention-to-treat population (all patients who were randomly allocated to and underwent elective colon resection with an anastomosis) along with safety analyses. The trial is registered with ClinicalTrials.gov, NCT02652637, and EudraCT, 2015-004559-38, and is closed to new participants. FINDINGS: Between March 17, 2016, and Aug 20, 2018, 738 patients were assessed for eligibility. Of the 417 patients who were randomised (209 to MOABP and 208 to NBP), 13 in the MOABP group and eight in the NBP were excluded before undergoing colonic resection; therefore, the modified intention-to-treat analysis included 396 patients (196 for MOABP and 200 for NBP). SSI was detected in 13 (7%) of 196 patients randomised to MOABP, and in 21 (11%) of 200 patients randomised to NBP (odds ratio 1·65, 95% CI 0·80-3·40; p=0·17). Anastomotic dehiscence was reported in 7 (4%) of 196 patients in the MOABP group and in 8 (4%) of 200 in the NBP group, and reoperations were necessary in 16 (8%) of 196 compared with 13 (7%) of 200 patients. Two patients died in the NBP group and none in the MOABP group within 30 days. INTERPRETATION: MOABP does not reduce SSIs or the overall morbidity of colon surgery compared with NBP. We therefore propose that the current recommendations of using MOABP for colectomies to reduce SSIs or morbidity should be reconsidered. FUNDING: Vatsatautien Tutkimussäätiö Foundation, Mary and Georg Ehrnrooth's Foundation, and Helsinki University Hospital research funds.

Association of Clinical Factors with the Costs of Kidney Transplantation in the Current Era.

BACKGROUND Kidney transplantation is reported to save costs compared to maintenance dialysis. We analyzed the current actual costs of kidney transplantation compared to dialysis, and analyzed risk factors for higher costs after transplantation. MATERIAL AND METHODS Altogether, 338 kidney transplant recipients between 2009 and 2014 were included in this study. All individual-level cost data from specialized health care and data from all reimbursed medication and travel costs were acquired from official records. Cost data were compared before and after transplantation within the same patients starting from dialysis initiation and continued until the end of follow-up at the end of 2015. RESULTS Total annual costs were median 53 275 EUR per patient in dialysis, 59 583 EUR for the first post-transplantation year (P<0.001), and 12 045 EUR for the subsequent years (P<0.001 compared to dialysis). Median costs for specialized health care were 36 103 EUR/year per patient during dialysis, compared to median 51 640 EUR for the first post-transplantation year (P<0.001 compared to dialysis), whereas the median costs for the subsequent years declined to median 4895 EUR/year (P<0.001 compared to dialysis). The median annual costs for drug treatments and travel reimbursements during dialysis were higher compared to after transplantation (P<0.001). Delayed graft function and highly sensitized status were independent risk factor for higher costs during the first the post-transplantation year. CONCLUSIONS After the first posttransplant year the costs of a kidney transplant patient for the health care system are <1/3 of the costs seen during dialysis treatment. Delayed graft function and previous sensitization were associated with increased costs post-transplantation.

Short- and long-term survival after severe acute pancreatitis: A retrospective 17 years' cohort study from a single center.

PURPOSE: To study mortality in severe acute pancreatitis (SAP) and to identify risk factors for mortality. MATERIALS AND METHODS: A retrospective 17-years' cohort study of 435 consecutive adult patients with SAP treated at intensive care unit of a university hospital. RESULTS: Overall, 357 (82.1%) patients survived at 90 days follow-up. Three-hundred six (89.5%) patients under 60 years, 38 (60.3%) patients between 60 and 69 years, and 13 (43.3%) patients over 69 years of age survived at 90 days follow-up. Independent risk factors for death within 90-days were: 60 to 69 years of age (odds ratio [OR] 5.1), >69 years of age (OR 10.4), female sex (OR 2.0), heart disease (OR 2.9), chronic liver failure (OR 12.3), open abdomen treatment (OR 4.4) and sterile necrosectomy within 4 weeks (OR 14.7). The 10-year survival estimate was <70% in patients under 60 years and <30% in patients over 60 years. Underlying cause of death after the initial 90-day follow-up period was alcohol-related in 48 (57.1%) patients, and all of them had suffered from alcoholic SAP. CONCLUSIONS: Although younger patients have excellent short-term survival after SAP, the long-term survival estimate is disappointing mostly due to alcohol abuse.