Benjamin Weixler

Gut microbiota modulate T cell trafficking into human colorectal cancer

Objective Tumour-infiltrating lymphocytes (TILs) favour survival in human colorectal cancer (CRC). Chemotactic factors underlying their recruitment remain undefined. We investigated chemokines attracting T cells into human CRCs, their cellular sources and microenvironmental triggers. Design Expression of genes encoding immune cell markers, chemokines and bacterial 16S ribosomal RNA (16SrRNA) was assessed by quantitative reverse transcription-PCR in fresh CRC samples and corresponding tumour-free tissues. Chemokine receptor expression on TILs was evaluated by flow cytometry on cell suspensions from digested tissues. Chemokine production by CRC cells was evaluated in vitro and in vivo, on generation of intraperitoneal or intracecal tumour xenografts in immune-deficient mice. T cell trafficking was assessed on adoptive transfer of human TILs into tumour-bearing mice. Gut flora composition was analysed by 16SrRNA sequencing. Results CRC infiltration by distinct T cell subsets was associated with defined chemokine gene signatures, including CCL5, CXCL9 and CXCL10 for cytotoxic T lymphocytes and T-helper (Th)1 cells; CCL17, CCL22 and CXCL12 for Th1 and regulatory T cells; CXCL13 for follicular Th cells; and CCL20 and CCL17 for interleukin (IL)-17-producing Th cells. These chemokines were expressed by tumour cells on exposure to gut bacteria in vitro and in vivo. Their expression was significantly higher in intracecal than in intraperitoneal xenografts and was dramatically reduced by antibiotic treatment of tumour-bearing mice. In clinical samples, abundance of defined bacteria correlated with high chemokine expression, enhanced T cell infiltration and improved survival. Conclusions Gut microbiota stimulate chemokine production by CRC cells, thus favouring recruitment of beneficial T cells into tumour tissues.

Presence of bone marrow micro‐metastases in stage I‐III colon cancer patients is associated with worse disease‐free and overall survival

The prognostic significance of bone marrow micro‐metastases (BMM) in colon cancer patients remains unclear. We conducted a prospective cohort study with long‐term follow‐up to evaluate the relevance of BMM as a prognostic factor for disease free (DFS) and overall survival (OS) in stage I‐III colon cancer patients. In this prospective multicenter cohort study 144 stage I‐III colon cancer patients underwent bone marrow aspiration from both iliac crests prior to open oncologic resection. The bone marrow aspirates were stained with the pancytokeratin antibody A45‐B/B3 and analyzed for the presence of epithelial tumor cells. DFS and OS were analyzed using a Cox proportional hazard model and robust standard errors to account for clustering in the multicenter setting. Median overall follow‐up was 6.2 years with no losses to follow‐up, and 7.3 years in patients who survived. BMM were found in 55 (38%) patients. In total, 30 (21%) patients had disease recurrence and 56 (39%) patients died. After adjusting for known prognostic factors, BMM positive patients had a significantly worse DFS (hazard ratio [HR] 1.33; 95% confidence interval [95% CI]: 1.02‐1.73; P = 0.037) and OS (HR 1.30; 95% CI: 1.09‐1.55; P = 0.003) compared to BMM negative patients. Bone marrow micro‐metastases occur in over one third of stage I‐III colon cancer patients and are a significant, independent negative prognostic factor for DFS and OS. Future trials should evaluate whether node‐negative colon cancer patients with BMM benefit from adjuvant chemotherapy.

Comparative Analysis of Tumor Cell Dissemination to the Sentinel Lymph Nodes and to the Bone Marrow in Patients With Nonmetastasized Colon Cancer: A Prospective Multicenter Study

Importance Small nodal tumor infiltrates (SNTI; isolated tumor cells and micrometastases) in sentinel lymph nodes and bone marrow micrometastases (BMM) were independently described as prognostic factors in patients with colon cancer. Objective To examine the association between the occurrence of SNTI and BMM as well as their prognostic relevance. Design, Setting, and Participants This prospective study was conducted at 3 university-affiliated institutions in Switzerland between May 2000 and December 2006. Statistical analyses were performed in October 2016. A total of 122 patients with stage I to III colon cancer were included. Follow-up time exceeded 6 years, with no patients lost to follow-up. Interventions Bone marrow aspiration from the iliac crests and in vivo sentinel lymph node mapping were performed during open standard oncological resection. Bone marrow aspirates were stained with the pancytokeratin marker A45-B/B3. All sentinel lymph nodes underwent multilevel sectioning and were stained with hematoxylin-eosin and the pancytokeratin marker AE1/AE3. Main Outcomes and Measures Association of SNTI in sentinel lymph nodes and BMM in patients with stage I to III colon cancer and the prognostic effect on disease-free survival (DFS) and overall survival (OS). Results Of the 122 patients, 63 (51.6%) were female, with a mean (SD) age of 71.2 (11.7) years. Small nodal tumor infiltrates and BMM were found in a total of 21 patients (17.2%) and 46 patients (37.7%), respectively. The occurrence of BMM was not associated with the presence of SNTI by standard correlation (&kgr;, −0.07; 95% CI, −0.29 to 0.14; P = .49) nor by univariate logistic regression analysis (odds ratio, 0.64; 95% CI, 0.22-1.67; P = .37) or multivariate logistic regression analysis (odds ratio, 1.09; 95% CI, 0.34-3.28; P = .88). The presence of SNTI was an independent negative prognostic factor for DFS (hazard ratio [HR], 2.93; 95% CI, 1.24-6.93; P = .02) and OS (HR, 4.04; 95% CI, 1.56-10.45; P = .005), as was BMM (HR, 2.07; 95% CI, 1.06-4.06; P = .04; and HR, 2.68; 95% CI, 1.26-5.70; P = .01; respectively). The combined detection of BMM and SNTI demonstrated the poorest DFS (HR, 6.73; 95% CI, 2.29-19.76; P = .006) and OS (HR, 5.96; 95% CI, 1.66-21.49; P = .03). Conclusions and Relevance This study demonstrates no association between the occurrence of SNTI and BMM in patients with stage I to III colon cancer. However, both SNTI and BMM are independent negative prognostic factors regarding DFS and OS, and the occurrence of both is associated with significantly worse prognosis compared with either one of them. Trial Registration clinicaltrials.gov Identifier: NCT00826579

Cancer‐associated retinopathy as the leading symptom in colon cancer

Cancer‐associated retinopathy (CAR) is a rare paraneoplastic visual syndrome. Its early detection may lead to the diagnosis of the causative malignancy. As many different types of malignancies are known to be associated with CAR, it is important that clinicians are aware of the phenomenon of CAR.

Megaduodenum in a 59-year-old man: a very late postoperative complication after duodenal atresia

Intestinal malformations are common defects of the newborn, treated in experienced centres. Reports on long-term follow-up and associated complications are scarce, possibly leading to misinterpretation of clinical signs and symptoms in adulthood. To prevent treatment errors, it is important that physicians are aware of long-term complications of intestinal malformations.