Neoadjuvant intratumoral influenza vaccine treatment in patients with proficient mismatch repair colorectal cancer leads to increased tumor infiltration of CD8+ T cells and upregulation of PD-L1: a phase 1/2 clinical trial.

BACKGROUND: In colorectal cancer, the effects of immune checkpoint inhibitors are mostly limited to patients with deficient mismatch repair tumors, characterized by a high grade infiltration of CD8+T cells. Interventions aimed at increasing intratumoral CD8+T-cell infiltration in proficient mismatch repair tumors are lacking. METHODS: We conducted a proof of concept phase 1/2 clinical trial, where patients with non-metastasizing sigmoid or rectal cancer, scheduled for curative intended surgery, were treated with an endoscopic intratumorally administered neoadjuvant influenza vaccine. Blood and tumor samples were collected before the injection and at the time of surgery. The primary outcome was safety of the intervention. Evaluation of pathological tumor regression grade, immunohistochemistry, flow cytometry of blood, tissue bulk transcriptional analyses, and spatial protein profiling of tumor regions were all secondary outcomes. RESULTS: A total of 10 patients were included in the trial. Median patient age was 70 years (range 54-78), with 30% women. All patients had proficient mismatch repair Union of International Cancer Control stage I-III tumors. No endoscopic safety events occurred, with all patients undergoing curative surgery as scheduled (median 9 days after intervention). Increased CD8+T-cell tumor infiltration was evident after vaccination (median 73 vs 315 cells/mm2, p<0.05), along with significant downregulation of messenger RNA gene expression related to neutrophils and upregulation of transcripts encoding cytotoxic functions. Spatial protein analysis showed significant local upregulation of programmed death-ligand 1 (PD-L1) (adjusted p value<0.05) and downregulation of FOXP3 (adjusted p value<0.05). CONCLUSIONS: Neoadjuvant intratumoral influenza vaccine treatment in this cohort was demonstrated to be safe and feasible, and to induce CD8+T-cell infiltration and upregulation of PD-L1 proficient mismatch repair sigmoid and rectal tumors. Definitive conclusions regarding safety and efficacy can only be made in larger cohorts. TRIAL REGISTRATION NUMBER: NCT04591379.

First episode of uncomplicated diverticulitis does not increase the risk of colorectal cancer.

INTRODUCTION: Danish guidelines recommend colonoscopy after a case of acute diverticulitis to exclude colorectal cancer (CRC), but evidence in support this practice is limited. A series of studies has reported a low incidence of CRC in patients after they presented with acute diverticulitis, especially in uncomplicated cases. The purpose of this study was to investigate the incidence of CRC after acute diverticulitis detected during colonoscopy. METHODS: All patients seen between January 2010 and November 2017 with a first episode of acute diverticulitis and a subsequent computed tomography and colonoscopy were included. RESULTS: A total of 332 patients were included in the study. The incidence of CRC after a case of uncomplicated acute diverticulitis was 0.8%. The incidence of malignancy was 2.8% in the group of patients with complicated diverticulitis. CONCLUSIONS: This study showed a low risk of CRC after a case of acute diverticulitis and no cases of CRC in patients with uncomplicated diverticulitis without clinical symptoms of CRC. This indicates that revising guidelines in regards to follow-up after diverticulitis may be warranted. FUNDING: none. TRIAL REGISTRATION: not relevant.

Lumen-apposing metal stent for treatment of malignant biliary obstruction, placed through an uncovered duodenal self-expanding metal stent.

The development and refinement of endoscopic stenting techniques in recent years have made endoscopic treatment an important part of palliative care for irresectable malignant disease in the gastrointestinal tract. We present the case of a 82-year-old man with biliary obstruction and duodenal stenosis on the basis of disseminated pancreatic cancer. He was bothered by jaundice and reduced oral intake. This is typically alleviated using stents; however, the placement of a duodenal stent can limit the possibility of subsequent placement of a biliary stent. This therapeutic challenge was solved using a combination of lumen-apposing metal stents (LAMS) and self-expanding uncovered metal stents (SEMS). LAMS is a relatively novel type of stent intended for endoscopic ultrasonography-guided placement. First, we placed a SEMS in the duodenum, a LAMS was subsequently placed through the mesh of the duodenal SEMS, alleviating the biliary system. The patient was able to resume oral intake and his jaundice subsided.

[Lymphomas found by endoscopic screening for colorectal cancer].

While performing the screening programme for colorectal cancer in Denmark, some cases of adenomas have been found. By histological analysis they were shown to be lymphomas. In this case report, two such cases are described. Screening is the subject of much debate. These cases are relevant because they showthat malignant diseases, which the program was not designed to identify, were found. When debating screening it should be taken into consideration, that secondary diseases, with the potential for earlier diagnostics and potentially better prognosis may be detected.

Hepatic epitheloid haemangioendothelioma: a rare malignant tumour.

Our case concerns a 66-year-old man. After experiencing recurrent episodes of abdominal pain, an initial CT scan, ultrasound and gastroscopy was carried out. All of which showed normal findings.As a consequence of persisting symptoms, another CT scan was performed. This scan revealed a hypodense area in the right lobe of the liver. This was interpreted as a possible haemangioma. Subsequent MRI scans indicated an intrahepatic cholangiocarcinoma. A final ultrasound-guided liver biopsy was performed and histology demonstrated epitheloid haemangioendothelioma, which was locally advanced and inoperable.

[Colonoscopy following acute diverticulitis mandatory].

According to international guidelines, patients presenting with acute diverticulitis are offered lower endoscopy to rule out colorectal cancer. This practice is based on weak evidence. Recent studies have established that the incidence of colorectal cancer after acute diverticulitis is low. In case of complicated diverticulitis, with abscess or perforation, the incidence of colorectal cancer is higher. There is, thus, a lack of evidence supporting colonoscopy by uncomplicated diverticulitis, but if a patient presents with complicated diverticulitis, colonoscopy should be performed.

[Endoscopic full-thickness resection of adenoma in colon]. / Endoskopisk fuldvægsresektion af adenom i colon

A new technique allows endoscopic resection of lesions (< 2.5 cm) as full-thickness resection from the gastrointestinal tract, primarily the colon. The technique is called endoscopic full-thickness resection (eFTR). This case report demonstrates the first eFTR in Denmark using an over the scope clip system. The eFTR was performed in two different cases, one with adenoma relapse and the other with incomplete endoscopic mucosal resection, both with success. Both patients were discharged the following day after eFTR. The histology of the tissue samples from the eFTRs showed no residual neoplastic tissue at the surgical margins.

GLP-2 and mesenteric blood flow.

The 33 amino acid peptide hormone GLP-2 is produced by enteroendocrine L-cells, the density of which is highest in the ileum and the colon, in response to the presence of nutrients in the lumen. The biological effect of GLP-2 is mediated by activation of a G-protein-coupled 7-transmembrane receptor. GLP-2 receptors are expressed in the brainstem, lungs, stomach, small intestine and colon, but not in the heart. It has been shown in several animal studies that GLP-2 infusion increases intestinal blood flow and that this increase is confined to the small intestine. The aim of the three studies, on which the thesis is based, was to investigate basic physiological effects of GLP-2, in healthy volunteers and in SBS patients, with focus on the effects on mesenteric blood flow, blood flow at other vascular sites and effects on cardiac parameters. These parameters have been evaluated after both meal stimulation and GLP-2 administration. The studies showed the following results: Blood flow: In all three studies, blood flow changes in the SMA after GLP-2 administration were similar regarding changes over time and degree of change. Blood flow changes were similar to changes seen after a standard meal. Only RI changes were registered in all three studies, but the TAMV changes in study 2 and 3 had similar characteristics. Cardiovascular parameters: In all three studies no significant changes in blood pressure were registered in relation to GLP-2 administration. In study two and three, where cardiac parameters also were registered by impedance cardiography, increases in CO and SV were seen. Plasma GLP-2: There were, as expected, supraphysiological GLP-2 plasma levels after SC administration. All three studies have shown rapid changes in mesenteric blood flow after administration GLP-2. The changes have been the same both in regards to time to maximum changes (increase) and relatively close in regards to maximum extent of change. The changes in the SBS patients were less than in the healthy test subjects. The findings leave no doubt about that GLP-2 is a potent regulator of upper splanchnic blood flow. The study findings also support the notion that the observed increased mesenteric blood flow, isolated to the SMA, is secondary to the metabolic responses to GLP-2, and that these are likely due to a paracrine action by GLP-2 acting on GLP-2R bearing cells such as enteric neurons, probably expressing NO. In conclusion GLP-2 increases mesenteric blood flow in healthy subjects and in SBS patients, the increase is equivalent to a standard meal and dose dependent. The blood flow is not increased at other arterial vascular sites. GLP-2 does not acutely alter blood pressure, but increases, probably as compensation, pulse rate and cardiac output. GLP-2 induced vascular response in the superior mesenteric artery is related with the length of remaining intestine in SBS patients. The effect is therefore likely to reflect the metabolic activity in the tissue rather than direct effect on the vascular system.