The Association of Mismatch Repair Status with Microscopically Positive (R1) Margins in Stage III Colorectal Cancer: A Retrospective Cohort Study.

BACKGROUND: There is mounting evidence that microscopically positive (R1) margins in patients with colorectal cancer (CRC) may represent a surrogate for aggressive cancer biology rather than technical failure during surgery. However, whether detectable biological differences exist between CRC with R0 and R1 margins is unknown. We sought to investigate whether mismatch repair (MMR) status differs between Stage III CRC with R0 or R1 margins. METHODS: Patients treated for Stage III CRC from January 1, 2016 to December 31, 2019 were identified by using the Danish Colorectal Cancer Group database. Patients were stratified according to MMR status (proficient [pMMR] vs. deficient [dMMR]) and margin status. Outcomes of interest included the R1 rate according to MMR and overall survival. RESULTS: A total of 3636 patients were included, of whom 473 (13.0%) had dMMR colorectal cancers. Patients with dMMR cancers were more likely to be elderly, female, and have right-sided cancers. R1 margins were significantly more common in patients with dMMR cancers (20.5% vs. 15.2%, p < 0.001), with the greatest difference seen in the rate of R1 margins related to the primary tumour (8.9% vs. 4.7%) rather than to lymph node metastases (11.6% vs. 10.5%). This association was seen in both right- and left-sided cancers. On multivariable analyses, R1 margins, but not MMR status, were associated with poorer survival, alongside age, pN stage, perineural invasion, and extramural venous invasion. CONCLUSIONS: In patients with Stage III CRC, dMMR status is associated with increased risks of R1 margins following potentially curative surgery, supporting the use of neoadjuvant immunotherapy in this patient group.

Do differences in surgical quality account for the higher rate of R1 margins to lymph node metastases in right- versus left-sided Stage III colon cancer: A retrospective cohort study.

AIM: Microscopically positive (R1) margins to lymph node metastases (R1LNM) are associated with poorer oncological outcomes in patients with Stage III colon cancer. R1LNM margins are more common in right-sided cancer, although the cause of this phenomenon is unknown. We sought to investigate whether differences in surgical quality account for the higher rate of R1LNM in right-sided cancers. METHOD: Patients treated for Stage III colon cancer from 1 January 2016 to 31 December 2018 were identified using the Danish national cancer registry. Indicators of surgical quality (mesocolic resection grade, median lymph node yield, and length to the distal colonic margin) were compared according to tumour site and margin status. RESULTS: In all, 1765 patients were included, 981 (55.6%) with right-sided cancers. R1LNM margins were more common in right-sided cancers (14.4% vs. 6.1%, P < 0.001). All three surgical quality indicators were higher in patients with right-sided cancers (mesocolic resection planes 81.7% vs. 69.5%, P < 0.001; median lymph node yield 28 vs. 25, P < 0.001; ≥5 cm to the distal colon margin 81.2% vs. 53.6%, P < 0.001). When stratified according to margin status, no differences in mesocolic resection planes or resectate length were noted, whilst median lymph node yield was higher in patients with R1LNM margins (29 vs. 27, P = 0.009). CONCLUSION: Surgical quality does not appear to be poorer in patients undergoing surgery for right-sided versus left-sided colon cancers in Denmark. Suboptimal surgery does not appear to be responsible for R1LNM margins, implying that these margins may be a surrogate for more aggressive biology.

The significance of subdivisions of microscopically positive (R1) margins in colorectal cancer: A retrospective study of a national cancer registry.

AIM: Microscopically positive (R1) margins are associated with poorer outcomes in patients with colorectal cancer. However, little is known of the differential impact of subdivisions of R1 margins, be they to the primary tumour (R1tumour) or to lymph node metastases/tumour deposits (R1LNM). METHODS: Patients treated for Stage III colorectal cancer from 1 January 2016 to 31 December 2019 were identified from the Danish national cancer registry. Patients were stratified into three groups according to margin status (R0 vs. R1tumour vs. R1LNM). The primary outcome was overall survival. RESULTS: In all, 4186 patients were included, comprising 3012 patients with colon cancer and 1174 patients with rectal cancer. The R1 resection rates were 16.5% and 18.2% in patients with colon and rectum cancer, respectively. In colon cancers, 3-year overall survival was reduced in patients with R1LNM (65.7%, 95% CI 62.8-68.6) or R1tumour margins (51.8%, 95% CI 47.3-56.3) compared with R0 resections (80.8%, 95% CI 79.9-81.6, P < 0.001). A similar impact on survival was seen in rectal cancers (R0, 84.2%, 95% CI 82.9-85.5; R1LNM, 72.2%, 95% CI 67.8-76.6; R1tumour, 56.6%, 95% CI 50.0-63.2, P < 0.001). Margin status was independently prognostic of survival in both colon (R1tumour, hazard ratio 2.08, 95% CI 1.50-2.89, P < 0.001; R1LNM, hazard ratio 1.48, 95% CI 1.11-1.97, P = 0.008) and rectal cancers (R1tumour, hazard ratio 2.35, 95% CI 1.42-3.90, P < 0.001; R1LNM, hazard ratio 1.54, 95% CI 0.95-2.48, P = 0.077). CONCLUSION: R1 subdivisions have distinct impacts on survival in Stage III colorectal cancer. Further focused research in these patient subgroups is warranted.

The impact of subdivisions of microscopically positive (R1) margins on patterns of relapse in stage III colorectal cancer - A retrospective cohort study.

AIM: Microscopically positive (R1) margins are associated with poorer outcomes in patients with colorectal cancer. However, the impact of subdivisions of R1 margins, be they to the primary tumour (R1 tumour) or to lymph node metastases (R1LNM), on patterns of relapse is unknown. METHODS: Patients treated for stage III colorectal cancer from 01 January 2016 to 31 December 2019 in four specialist centres were identified from the Danish national cancer registry. Patients were stratified into three groups according to margin status (R0 vs. R1 tumour vs. R1LNM). The primary outcomes were local recurrence-free survival (LRFS), distant metastases-free survival (DMFS) and disease-specific survival (DSS). RESULTS: A total of 1,164 patients were included, with R1 margins found in 237 (20.4%). Irrespective of tumour location, R1 tumour and R1LNM margins were independent prognostic factors for systemic relapse (R1 tumour HR 1.84, CI: 1.17-2.88, p = 0.008; R1LNM HR 1.59, CI: 1.12-2.27, p = 0.009) and disease-related death (R1 tumour HR 2.08, CI: 1.12-3.85, p = 0.020; R1LNM HR 1.84, CI: 1.12-3.02, p = 0.016). Whereas R1 tumour margins were associated with poorer 3-year LRFS in both colon and rectum cancer, R1LNM margins only reduced LRFS in patients with rectal cancer. Patterns of relapse differed between R1 subdivisions, with R1 tumour margins more likely to affect multiple anatomical sites, with a predilection for extra-hepatic/pulmonary metastases. CONCLUSION: Subdivisions of R1 margins have a distinct impact on the oncological outcomes and patterns of disease relapse in patients with stage III colorectal cancer.

Validation of a Novel EUS-FNB-Derived Organoid Co-Culture System for Drug Screening in Patients with Pancreatic Cancer.

Cancer-associated fibroblasts (CAFs) have been shown to impact the chemosensitivity of patient-derived tumor organoids (PDTOs). However, the published literature comparing PDTO response to clinical outcome does not include CAFs in the models. Here, a co-culture model was created using PDTOs and CAFs derived from endoscopic ultrasound-guided fine-needle biopsies (EUS-FNBs) for potential use in drug screening applications. Co-cultures were established, and growth was compared to monocultures using image metrics and a commercially available assay. We were able to establish and expand validated malignant PDTOs from 19.2% of adenocarcinomas from EUS-FNBs. CAFs could be established from 25% of the samples. The viability of PDTOs in the mixed cell co-culture could be isolated using image metrics. The addition of CAFs promoted PDTO growth in half of the established co-cultures. These results show that co-cultures can be established from tiny amounts of tissue provided by EUS-FNB. An increased growth of PDTOs was shown in co-cultures, suggesting that the present setup successfully models CAF-PDTO interaction. Furthermore, we demonstrated that standard validation techniques may be insufficient to detect contamination with normal cells in PDTO cultures established from primary tumor core biopsies.

Noninvasive Prediction of Advanced Fibrosis in Pediatric Liver Disease-Discriminatory Performance of 2D Shear Wave Elastography, Transient Elastography and Magnetic Resonance Elastography in Comparison to Histopathology.

Background: Elastography can be measured with different imaging techniques and is increasingly used for noninvasive assessment of hepatic fibrosis. Little is known about the performance, and interrelation of different elastographic techniques, in prediction of hepatic fibrosis in pediatric liver disease. Objectives: We aimed to determine the discriminatory value for advanced fibrosis (Metavir F3-4) and evaluate the applicability of 2D shear wave ultrasound elastography (USe), Transient Elastography (TE) and Magnetic Resonance elastography (MRe) in pediatric liver disease. Methods: In patients with pediatric liver disease aged 0−19 years, USe, TE and MRe were compared with histopathological fibrosis stage. Multivariate logistic regression models for advanced fibrosis were considered. Discriminative performance was assessed by the area under the receiver operating characteristic curve and the Brier Score. Primary analyses included complete cases. Multiple imputation was used as sensitivity analysis. Results: In 93 histologically evaluated patients USe, TE and MRe were performed 89, 93 and 61 times respectively. With increased liver stiffness values, significantly increased odds for presenting F3-4 were seen in individual models for ALT < 470 U/L, whereas the effect for ALT > 470 U/L was non-significant. Area under the curve and Brier Score for discrimination of advanced fibrosis were 0.798 (0.661−0.935) and 0.115 (0.064−0.166); 0.862 (0.758−0.966) and 0.118 (0.065−0.171); 0.896 (0.798−0.994) and 0.098 (0.049−0.148) for USe, TE and MRe respectively. No significant increase in discriminatory ability was found when combining elastographic modalities. Conclusions: In pediatric liver disease, USe, TE and MRe had a good discriminatory ability for assessment of advanced liver fibrosis, although TE and MRe performed best. In most children with pediatric liver disease, TE is a reliable and easily applicable measure.

Extensive extraintestinal manifestations of ulcerative colitis in a patient initially suspected to have disseminated malignancy.

A 44-year-old patient with known ulcerative colitis presented with abdominal pain and an abdominal mass. CT revealed cecal stranding, a mass at the left colonic flexure involving the pancreas and multiple lesions in the lungs, retroperitoneum and liver. The patient had also developed a scalp rash as well as impaired hearing. Biopsies from the abdominal mass and lungs revealed necrotic inflammation, and the clinical suspicion of malignancy could not be ruled out. After further examination, the patient was treated with high-dose steroids, which rapidly reduced the extraintestinal manifestations. Due to a persistent abscess formation at the left colonic flexure and pancreas, the patient was referred to our hospital for a total colectomy. Histology showed acute and chronic inflammation with cryptitis, indicating ulcerative colitis. Our case is a rare presentation of extensive extraintestinal disease in organs such as the lungs and liver, as well as necrotic mass formation at the colon site which mimicked malignancy.