Impact of mesorectal extranodal tumor deposits in magnetic resonance imaging on outcome of rectal cancer patients.

AIM: Mesorectal extranodal tumor deposits (TDs) are identified in many rectal cancers. Their radiological features differ from metastatic lymph nodes, and they can be detected with magnetic resonance imaging (MRI). The purpose of this study was to determine the prevalence of rectal cancer TDs detected with MRI and their impact on overall (OS), cancer-specific (CSS), and disease-free survival (DFS) and the local recurrence rate. METHOD: In this retrospective cohort study, we screened all 525 consecutive rectal cancer patients who underwent surgery during 2017-2018 in a tertiary center. Patients with synchronous metastases or who had not undergone MRI were excluded. We analyzed the OS, CSS, and DFS as well as local recurrences. RESULTS: Of the 480 included patients, TDs were detected in the images of 81 (16.9 %). Extramural venous invasion (EMVI) and TDs were frequently found together (n = 50, 61.7 % of all cases with TDs). The presence of TDs alone [hazard ratio (HR) 1.66 (1.03-2.68)] or TDs and/or EMVI [HR 1.63 (1.01-2.62)] were risk factors for adverse DFS in multivariate Cox regression analysis. The OS and CSS rates were poorer among patients with TDs compared to those without, p = 0.009 and p < 0.001, respectively. TDs were also a risk factor for local recurrence in the univariate analysis. CONCLUSIONS: TDs detected with imaging are a risk factor for impaired DFS and associated with impaired CSS and OS of rectal cancer patients and should be taken into consideration in clinical decision-making.

Microbiota and mucosal gene expression of fecal microbiota transplantation or placebo treated patients with chronic pouchitis.

Altered microbiota and impaired host immune function have been linked to the pathogenesis of pouchitis. We used 16S rRNA gene sequencing and RNA sequencing data from a previous randomized clinical trial (RCT) on fecal microbiota transplantation (FMT) therapy in 26 chronic pouchitis patients with one-year follow-up. We analyzed changes in both luminal and mucosal microbiota composition, as well as in host mucosal gene expression to gain insights into the host-microbiota interactions possibly underlying clinical outcomes of the patients. Antibiotic type and pattern of use were significant drivers of the luminal microbiota at baseline. Differential gene expression analysis indicated transition from ileal to colonic gene expression in the pouch, and upregulation in inflammation- and immune system-related pathways in the pouch. At 4 weeks, the non-relapsed FMT patients had a lower microbiota dissimilarity to the donor than the non-relapsed placebo patients (p = .02). While two FMT-treated patients showed a shift toward the donor's microbiota during the one-year follow-up, the overall FMT microbiota modulation effect was low. Patient's luminal and mucosal microbiota profiles were unstable in both FMT and placebo groups. Expression of the chemokine receptor CXCR4 was downregulated at 52 weeks compared to the baseline in the non-relapsed patients in both FMT and placebo groups. Microbiota modulation by FMT seems to be low in this patient group. The microbiota composition or alterations did not explain the relapse status of the patients. Some evidence for remission-related host gene expression pattern was found; specifically, CXCR4 expression may have a role in sustained remission.

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.

Fecal Microbiota Transplantation in Chronic Pouchitis: A Randomized, Parallel, Double-Blinded Clinical Trial.

BACKGROUND: In ulcerative colitis, a pouchitis is the most common long-term adverse effect after proctocolectomy and ileal pouch-anal anastomosis. Approximately 5% of patients develop chronic antibiotic-dependent or antibiotic-refractory pouchitis without any effective treatment. The aim of this trial was to investigate the efficacy and safety of fecal microbiota transplantation in the treatment of chronic pouchitis. METHODS: This was a single-center, double-blinded, parallel group trial comparing donor fecal microbiota transplantation with placebo (autologous transplant) in chronic pouchitis. Twenty-six patients were recruited at the Helsinki University Hospital between December 2017 and August 2018 and were randomly allocated a 1:1 ratio to either donor fecal microbiota transplantation or placebo. The protocol included 2 transplantations into the pouch on weeks 0 and 4, and patients were followed up for 52 weeks. RESULTS: Nine patients in the intervention group and 8 patients in the placebo group relapsed during the 52-week follow-up, and the relapse-free survival did not differ between the groups (P = 0.183, log-rank; hazard ratio, 1.90 [95% confidence interval, 0.73-4.98; P = 0.190]). In the subgroup analysis of patients using continuous antibiotics before the study, the relapse-free survival was shorter in the intervention group (P = 0.004, log-rank; hazard ratio, 13.08 [95% confidence interval, 1.47-116.60; P = 0.021]). No major adverse effects were reported. CONCLUSIONS: The fecal microbiota transplantation treatment regime used in our study was not effective in the treatment of chronic pouchitis. The safety profile of fecal microbiota transplantation was good. CLINICALTRIALS.GOV IDENTIFIER: NCT03378921.

Dysplasia in the mucosal biopsy specimen is still a warning sign of cancer in ulcerative colitis.

OBJECTIVES: Patients with ulcerative colitis are at increased risk for colorectal cancer, especially at younger ages. Our aim was to determine, in our patient cohort, the clinicopathological features, incidence, and prognosis of ulcerative colitis-associated colorectal cancer. MATERIALS AND METHODS: A single-center, population-based study including all 1241 patients with ulcerative colitis who underwent surgery in Helsinki University Hospital, 1991-2018. All data were from medical records, collected retrospectively. RESULTS: In total, 71 patients with ulcerative colitis-associated cancer were operated on in Helsinki University Hospital during 1991-2018; 108 patients undergoing surgery during 2002-2018 showed dysplasia in the surgical specimen. Cancer was diagnosed preoperatively in 47 patients (66.2%). Ten patients (14.1%) had synchronous colorectal cancer, and 24 (33.8%) had synchronous dysplasia. The incidence of colorectal cancer has not changed during the study period (p = .113). Overall survival was 71.8%, and the 5-year colorectal cancer-specific survival was 81.5%. CONCLUSION: The incidence of ulcerative colitis-associated colorectal cancer remained constant in our study population over three decades. The prognosis of ulcerative colitis-associated colorectal cancer and the prognosis of sporadic colorectal cancer were comparable. One-third of the cancers were not diagnosed in preoperative colonoscopy, and the indication for surgery in such cases was dysplasia. We therefore do not recommend the endoscopic management of ulcerative colitis-associated dysplasia.

Thyroid Carcinomas That Occur in Familial Adenomatous Polyposis Patients Recurrently Harbor Somatic Variants in APC, BRAF, and KTM2D.

Background: Familial adenomatous polyposis (FAP) is a condition typically caused by pathogenic germline mutations in the APC gene. In addition to colon polyps, individuals with FAP have a substantially increased risk of developing papillary thyroid cancer (PTC). Little is known about the events underlying this association, and the prevalence of somatic "second-hit" mutations in APC is controversial. Methods: Whole-genome sequencing was performed on paired thyroid tumor and normal DNA from 12 FAP patients who developed PTC. Somatic mutation profiles were compared with clinical characteristics and previously sequenced sporadic PTC cases. Germline variant profiling was performed to assess the prevalence of variants in genes previously shown to have a role in PTC predisposition. Results: All 12 patients harbored germline mutations in APC, consistent with FAP. Seven patients also had somatic mutations in APC, and seven patients harbored somatic mutations in KMT2D, which encodes a lysine methyl transferase. Mutation of these genes is extremely rare in sporadic PTCs. Notably, only two of the tumors harbored the somatic BRAF p.V600E mutation, which is the most common driver mutation found in sporadic PTCs. Six tumors displayed a cribriform-morular variant of PTC (PTC-CMV) histology, and all six had somatic mutations in APC. Additionally, nine FAP-PTC patients had rare germline variants in genes that were previously associated with thyroid carcinoma. Conclusions: Our data indicate that FAP-associated PTCs typically have distinct mutations compared with sporadic PTCs. Roughly half of the thyroid cancers that arise in FAP patients have somatic "second-hits" in APC, which is associated with PTC-CMV histology. Somatic BRAF p.V600E variants also occur in some FAP patients, a novel finding. We speculate that in carriers of heterozygous pathogenic mutations of tumor suppressor genes such as APC, a cooperating second-hit somatic variant may occur in a different gene such as KTM2D or BRAF, leading to differences in phenotypes. The role of germline variance in genes other than APC (9 of the 12 patients in this series) needs further research.

Durability of Kock continent ileostomy.

PURPOSE: The purpose of this study was to determine the cumulative success rate of Kock continent ileostomy and the reasons leading to excision and to compare the results with pelvic pouch and ileal pouch-anal anastomosis. METHODS: The data were collected from the histories of 96 patients, who underwent a Kock continent ileostomy operation from 1972 to 2000 at Helsinki University Central Hospital. The failure rate was calculated by the Kaplan-Meier method. RESULTS: Overall, the continent ileostomy was converted to conventional stoma in 21 patients (24 percent). The cumulative success rate was 96 percent at 1 year, 86 percent at 10 years, 77 percent at 15 years, and 71 percent at 29 years. The most common reason for pouch excision was partial or total nipple-valve sliding. Eighty-five re-reconstructions were performed among 57 patients (59 percent), the most common indication being nipple-valve dysfunction. Of these patients, 14 later ended up with pouch excision. The success rate of continent ileostomy was significantly lower than that of ileoanal anastomosis (P < 0.01). CONCLUSION: The durability of continent ileostomy is mainly related to the mechanism of the nipple valve and not to ileitis or other systemic effects of the basic disease. Kock continent ileostomy can offer satisfactory long-term function in more than two-thirds of patients up to 30 years.