Methylation of SDC2/TFPI2 and Its Diagnostic Value in Colorectal Tumorous Lesions

Background:SDC2 methylation is a feasible biomarker for colorectal cancer detection. Its specificity for colorectal cancer is higher than 90%, but the sensitivity is normally lower than 90%. This study aims to improve the sensitivity of SDC2 detection through finding a high positive target from the false-negative samples of SDC2 detection based on analysis of the bowel subsite difference in methylation.Methods: Hypermethylated TFPI2 was identified in SDC2 hypomethylated colorectal cancer samples retrieved from TCGA database with the methylation level lower than 0.2. The methylation-specific PCR assay was developed and then evaluated using tissue samples (184 cancer and 54 healthy control samples) and stool samples (289 cancer, 190 adenoma, and 217 healthy control samples).Results:TFPI2 was hypermethylated in most SDC2 hypomethylated colorectal cancer samples. When the SDC2/TFPI2-combined PCR assay was performed in stool specimens, the AUC value of cancer vs. control was 0.98, with the specificity of 96.40% and sensitivity of 96.60%, and the AUC value of adenoma vs. control was 0.87, with the specificity of 95.70% and the sensitivity of 80.00%. The improvement in sensitivity was the most momentous in the left colon. As the detection index, the Ct value was better in improving the sensitivity of detection than the methylation level based on the 2−ΔΔCt value.Conclusion:TFPI2 can improve the sensitivity of SDC2 methylation–specific detection of colorectal tumorous lesions while maintaining high specificity, in particular reducing the missed detection of left colon cancer and adenoma.

First-In-Human Results on the Biodistribution, Pharmacokinetics, and Dosimetry of [177Lu]Lu-DOTA.SA.FAPi and [177Lu]Lu-DOTAGA.(SA.FAPi)2

Recently, great interest has been gained regarding fibroblast activation protein (FAP) as an excellent target for theranostics. Several FAP inhibitor molecules such as [68Ga]Ga-labelled FAPI-02, 04, 46, and DOTA.SA.FAPi have been introduced and are highly promising molecular targets from the imaging point of view. FAP inhibitors introduced via bifunctional DOTA and DOTAGA chelators offer the possibility to complex Lutetium-177 due to an additional coordination site, and are suitable for theranostic applications owing to the increased tumor accumulation and prolonged tumor retention time. However, for therapeutic applications, very little has been accomplished, mainly due to residence times of the compounds. In an attempt to develop a promising therapeutic radiopharmaceutical, the present study aimed to evaluate and compare the biodistribution, pharmacokinetics, and dosimetry of [177Lu]Lu-DOTA.SA.FAPi, and [177Lu]Lu-DOTAGA.(SA.FAPi)2 in patients with various cancers. The FAPi agents, [177Lu]Lu-DOTA.SA.FAPi and [177Lu]Lu-DOTAGA.(SA.FAPi)2, were administered in two different groups of patients. Three patients (mean age—50 years) were treated with a median cumulative activity of 2.96 GBq (IQR: 2.2–3 GBq) [177Lu]Lu-DOTA.SA.FAPi and seven (mean age—51 years) were treated with 1.48 GBq (IQR: 0.6–1.5) of [177Lu]Lu-DOTAGA.(SA.FAPi)2. Patients in both the groups underwent serial imaging whole-body planar and SPECT/CT scans that were acquired between 1 h and 168 h post-injection (p.i.). The residence time and absorbed dose estimate in the source organs and tumor were calculated using OLINDA/EXM 2.2 software. Time versus activity graphs were plotted to determine the effective half-life (Te) in the whole body and lesions for both the radiotracers. Physiological uptake of [177Lu]Lu-DOTA.SA.FAPi was observed in the kidneys, colon, pancreas, liver, gall bladder, oral mucosa, lacrimal glands, and urinary bladder contents. Physiological biodistribution of [177Lu]Lu-DOTAGA.(SA.FAPi)2 involved liver, gall bladder, colon, pancreas, kidneys, and urinary bladder contents, lacrimal glands, oral mucosa, and salivary glands. In the [177Lu]Lu-DOTA.SA.FAPi group, the highest absorbed doses were noted in the kidneys (0.618 ± 0.015 Gy/GBq), followed by the colon (right colon: 0.472 Gy/GBq and left colon: 0.430 Gy/GBq). In the [177Lu]Lu-DOTAGA.(SA.FAPi)2 group, the colon received the highest absorbed dose (right colon: 1.160 Gy/GBq and left colon: 2.870 Gy/GBq), and demonstrated a significantly higher mean absorbed dose than [177Lu]Lu-DOTA.SA.FAPi (p < 0.011). [177Lu]Lu-DOTAGA.(SA.FAPi)2 had significantly longer median whole-body Te compared to that of [177Lu]Lu-DOTA.SA.FAPi [46.2 h (IQR: 38.5–70.1) vs. 23.1 h (IQR: 17.8–31.5); p-0.0167]. The Te of tumor lesions was significantly higher for [177Lu]Lu-DOTAGA.(SA.FAPi)2 compared to [177Lu]Lu-DOTA.SA.FAPi [86.6 h (IQR: 34.3–94.6) vs. 14 h (IQR: 12.8–15.5); p-0.0004]. The median absorbed doses to the lesions were 0.603 (IQR: 0.230–1.810) Gy/GBq and 6.70 (IQR: 3.40–49) Gy/GBq dose per cycle in the [177Lu]Lu-DOTA.SA.FAPi, and [177Lu]Lu-DOTAGA.(SA.FAPi)2 groups, respectively. The first clinical dosimetry study demonstrated significantly higher tumor absorbed doses with [177Lu]Lu-DOTAGA.(SA.FAPi)2 compared to [177Lu]Lu-DOTA.SA.FAPi. [177Lu]Lu-DOTAGA.(SA.FAPi)2 is safe and unveiled new frontiers to treat various end-stage cancer patients with a theranostic approach.

A pilot randomized controlled trial comparing THUNDERBEAT to the Maryland LigaSure energy device in laparoscopic left colon surgery

Background The THUNDERBEAT is a multi-functional energy device which delivers both ultrasonic and bipolar energy, but there are no randomized trials which can provide more rigorous evaluation of the clinical performance of THUNDERBEAT compared to other energy-based devices in colorectal surgery. The aim of this study was to compare the clinical performance of THUNDERBEAT energy device to Maryland LigaSure in patients undergoing left laparoscopic colectomy. Methods Prospective randomized trial with two groups: Group 1 THUNDERBEAT and Group 2 LigaSure in a single university hospital. 60 Subjects, male and female, of age 18 years and above undergoing left colectomy for cancer or diverticulitis were included. The primary outcome was dissection time to specimen removal (DTSR) measured in minutes from the start of colon mobilization to specimen removal from the abdominal cavity. Versatility (composite of five variables) was measured by a score system from 1 to 5 (1 being worst and 5 the best), and adjusted/weighted by coefficient of importance with distribution of the importance as follow: hemostasis 0.275, sealing 0.275, cutting 0.2, dissection 0.15, and tissue manipulation 0.1. Other variables were: dryness of surgical field, intraoperative and postoperative complications, and mortality. Follow-up time was 30 days. Results 60 Patients completed surgery, 31 in Group 1 and 29 in Group 2. There was no difference in the DTSR between the groups, 91 min vs. 77 min (p = 0.214). THUNDERBEAT showed significantly higher score in dissecting and tissue manipulation in segment 3 (omental dissection), and in overall versatility score (p = 0.007) as well as versatility score in Segment 2 (retroperitoneal dissection p = 0.040) and Segment 3 (p = 0.040). No other differences were noted between the groups. Conclusions Both energy devices can be employed effectively and safely in dividing soft tissue and sealing mesenteric blood vessels during laparoscopic left colon surgery, with THUNDERBEAT demonstrating some advantages over LigaSure during omental dissection and tissue manipulation. ClinicalTrial.gov # NCT02628093.

Can the simplified magnetic resonance index of activity be used to evaluate the degree of activity in Crohn's disease?

Background and aims A simplified magnetic resonance index of activity (MaRIAs) was recently proposed. Our aim was to verify whether MaRIAs can accurately assess the activity degree of CD. Methods We retrospectively analyzed the MRI, ileocolonoscopy, fecal calprotectin (FC), erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) data of 93 CD patients. With the SES-CD as the gold standard, MaRIAs’ accuracy, the correlation of MaRIAs and SES-CD, FC, ESR, CRP, and interevaluator reliability were assessed. Results MaRIAs ≥ 1 detected segments with active CD with 90.80% specificity and 81.37% sensitivity (area under the curve was 0.91, 95% confidence interval 0.87–0.94). MaRIAs score of 2 or more detected severe lesions with 88.89% specificity and 95.12% sensitivity (AUC was 0.96, 95% confidence interval was 0.94–0.98). The MaRIAs score showed a high correlation with the SES-CD in the terminal ileum, transverse colon, right colon, and left colon (r = 0.85, 0.91, 0.88, 0.86, P < 0.001) and a moderate correlation with the SES-CD in the rectum (r = 0.74, P < 0.001). The global MaRIAs score was highly correlated with the global SES-CD (r = 0.90, P < 0.001). The global MaRIAs score was positively correlated with the fecal calprotectin (FC), erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) (r = 0.77, r = 0.64, and r = 0.68). The intragroup correlation coefficient (ICC) of the two physicians was nice in the terminal ileum, the right colon, the transverse colon, the left colon and was moderately good in the rectum. Conclusion MaRIAs can accurately evaluate the disease activity level of CD and are highly correlated with SES-CD and biomarkers. The interrater reliability of the two physicians was moderately good to nice.

EP.TU.634Role of Colonoscopy in left colon diverticulitis

Aim Methods Result Conclusions

Experimental Study of the Quantification of Indocyanine Green Fluorescence in Ischemic and Non-Ischemic Anastomoses, Using the Sergreen Software Program

Background: Tissue ischemia is a key risk factor for anastomotic leakage (AL). Indocyanine green (ICG) is widely used in colorectal surgery to define the segments with the best vascularization. In an experimental model, we present a new system for quantifying ICG saturation, SERGREEN software.Methods: This was a controlled experimental study with eight pigs. In the initial control stage, ICG saturation was analyzed at the level of two anastomoses in the right and left colon. Control images of the two segments were taken after ICG administration. The images were processed with the SERGREEN program. Then, in the experimental ischemia stage, the inferior mesenteric artery was sectioned at the level of the anastomosis of the left colon. Fifteen minutes after the section, sequential images of the two anastomoses were taken every 30’ for the following 2 h.Results: At the control stage, the mean scores were 134.2 (95% CI: 116.3-152.2) for the right colon and 147 (95% CI: 134.7-159.3) for the left colon (p = 0.174). The right colon remained stable throughout the experiment. In the left colon, saturation fell by 47.9 points with respect to the preischemia value (p <0.01). After the first postischemia determination, the values of the ischemic left colon remained stable throughout the experiment. The relative decrease in ICG saturation of the ischemic left colon was 32.6%.Conclusions: The SERGREEN program quantifies ICG saturation in normal and ischemic situations and detects differences between them. A reduction in ICG saturation of 32.6% or more was correlated with complete tissue ischemia.

First-In-Human Results On The Biodistribution, Pharmacokinetics, And Dosimetry of [177Lu]Lu-DOTA.SA.FAPi and [177Lu]Lu-DOTAGA.(SA.FAPi)2 in Patients with Various End-stage Cancers

Purpose: The present study aimed to evaluate and compare the biodistribution, pharmacokinetics, dosimetry of [177Lu]Lu-DOTA.SA.FAPi, and [177Lu]Lu-DOTAGA.(SA.FAPi)2 in patients with various cancers.Methods: The FAPi agents, [177Lu]Lu-DOTA.SA.FAPi and [177Lu]Lu-DOTAGA.(SA.FAPi)2 were administered in two different groups of patients. Three patients (mean age; 50 years) were treated with a median cumulative activity of 2.96 GBq (IQR: 2.2 – 3 GBq) [177Lu]Lu-DOTA.SA.FAPi and seven (mean age; 51 years) were treated with 1.48 GBq (IQR: 0.6 – 1.5) of [177Lu]Lu-DOTAGA.(SA.FAPi)2. Patients in both the groups underwent serial imaging whole-body planar and SPECT/CT scans that were acquired between 1 hour and 168 hours post-injection (p.i.)The residence time and absorbed dose estimate in the source organs and tumor were calculated using OLINDA/EXM 2.2 software. Time versus activity graphs were plotted to determine the effective half-life (Te) in the whole body and lesions for both the radiotracers. Results: Physiological uptake of [177Lu]Lu-DOTA.SA.FAPi was observed in the kidneys, colon, pancreas, liver, gall bladder, oral mucosa, lacrimal glands, and urinary bladder contents. Physiological biodistribution of [177Lu]Lu-DOTAGA.(SA.FAPi)2 involved liver, gall bladder, colon, pancreas, kidneys, and urinary bladder contents, lacrimal glands, oral mucosa, and salivary glands. The whole body effective dose for [177Lu]Lu-DOTAGA.(SA.FAPi)2 was significantly higher than [177Lu]Lu-DOTA.SA.FAPi [2.26E-01 ± 1.24E-01; vs. 6.22E-02 ± 9.96E-03 mSv/MBq, P-0.058). In the [177Lu]Lu-DOTA.SA.FAPi group, the highest absorbed dose were noted in the Kidneys (0.618 ± 0.015 Gy/GBq), followed by a colon (right colon: 0.472 Gy/GBq and left colon: 0.43 Gy/GBq). In the [177Lu]Lu-DOTAGA.(SA.FAPi)2 group, the colon received the highest absorbed dose (right colon: 1.16 Gy/GBq and left colon: 2.87 Gy/GBq), and demonstrated a significantly higher mean absorbed dose than [177Lu]Lu-DOTA.SA.FAPi (P < 0.011). [177Lu]Lu-DOTAGA.(SA.FAPi)2 had significantly longer median whole-body Te compared to that of [177Lu]Lu-DOTA.SA.FAPi [46.2 h (IQR: 38.5 – 70.1) vs. 23.1 h (IQR: 17.8 – 31.5); P-0.0167]. The median absorbed doses to the lesions were 6.03E-01(IQR: 2.30E-01 - 1.81E+00) Gy/GBq and 6.70E+00 (IQR: 3.40E+00 - 4.9E+01) Gy/GBq dose per cycle in the [177Lu]Lu-DOTA.SA.FAPi, and [177Lu]Lu-DOTAGA.(SA.FAPi)2 groups, respectively. Conclusion: The first clinical dosimetry study demonstrated significantly higher tumor absorbed doses with [177Lu]Lu-DOTAGA.(SA.FAPi)2 compared to [177Lu]Lu-DOTA.SA.FAPi. [177Lu]Lu-DOTAGA.(SA.FAPi)2 is safe and unveiled new frontiers to treat various end-stage cancer patients with a theranostic approach.

Quality of life after extended lymph node dissection for colon cancer

Aim: to evaluate the effect of the lymphadenectomy (LD) level on the quality of life (QoL) in patients who underwent laparoscopic colon resection for colon cancer.Patients and methods: the study included 86 patients who underwent surgery for colon cancer from January 2018 to August 2020. The patients were randomized in 2 groups: the main group — with D3 lymphadenectomy — 41 patients and the control group — with D2 — 45 patients. Two validated QoL questionnaires (QLQ-C30 v. 3.0, QLQ-CR29 v. 2.1) of the European Organization for Research and Treatment of Cancer (EORTC) were applied by the patients on the day before the surgery and on the 30th day after the surgery and were used for the further analysis.Results: there were no significant differences between the groups in gender, age, weight, height, BMI, assessment of functional and physical status according to the ASA and ECOG scales, incidence of comorbidities, tumor site, type and volume surgical of procedures. Regardless of the level of lymphadenectomy, the significant improvement in QoL after surgery was obtained (pQoLD3 = 0.005, pQoLD2 = 0.023) in both groups. The significant increase in the incidence of diarrhea by 2.65 times was detected after laparoscopic right hemicolectomies with extended lymphadenectomy (p = 0.042). Also, there was a significant 2.45 fold increase in the risk of developing erectile dysfunction (ED) after D3 lymphadenectomy in the patients who underwent laparoscopic resections of the left colon in the early postoperative period (p = 0.031).Conclusion: the analysis of physical, social functioning and symptomatic scales has established that in patients who underwent colon resection for cancer of the left colon erectile dysfunction occurred to a greater extent after D3 LD, whereas diarrhea was more likely to develop after resection of the right colon with D3 LD than with D2 LD.