Luís Gustavo Capochin Romagnolo

Abstract Incidence rates of colorectal cancer vary geographically and have changed over time 1 . Notably, in the past two decades, the incidence of early-onset colorectal cancer, which affects individuals below 50 years of age, has doubled in many countries 2–5 . The reasons for this increase are unknown. Here we investigate whether mutational processes contribute to geographic and age-related differences by examining 981 colorectal cancer genomes from 11 countries. No major differences were found in microsatellite-unstable cancers, but variations in mutation burden and signatures were observed in the 802 microsatellite-stable cases. Multiple signatures, most with unknown aetiologies, exhibited varying prevalence in Argentina, Brazil, Colombia, Russia and Thailand, indicating geographically diverse levels of mutagenic exposure. Signatures SBS88 and ID18, caused by the bacteria-produced mutagen colibactin 6,7 , had higher mutation loads in countries with higher colorectal cancer incidence rates. SBS88 and ID18 were also enriched in early-onset colorectal cancers, being 3.3 times more common in individuals who were diagnosed before 40 years of age than in those over 70 years of age, and were imprinted early during colorectal cancer development. Colibactin exposure was further linked to APC driver mutations, with ID18 being responsible for about 25% of APC driver indels in colibactin-positive cases. This study reveals geographic and age-related variations in colorectal cancer mutational processes, and suggests that mutagenic exposure to colibactin-producing bacteria in early life may contribute to the increasing incidence of early-onset colorectal cancer.

BACKGROUND: Genetic counselling and testing for Lynch syndrome (LS) have recently been introduced in several Latin America countries. We aimed to characterize the clinical, molecular and mismatch repair (MMR) variants spectrum of patients with suspected LS in Latin America. METHODS: Eleven LS hereditary cancer registries and 34 published LS databases were used to identify unrelated families that fulfilled the Amsterdam II (AMSII) criteria and/or the Bethesda guidelines or suggestive of a dominant colorectal (CRC) inheritance syndrome. RESULTS: We performed a thorough investigation of 15 countries and identified 6 countries where germline genetic testing for LS is available and 3 countries where tumor testing is used in the LS diagnosis. The spectrum of pathogenic MMR variants included MLH1 up to 54%, MSH2 up to 43%, MSH6 up to 10%, PMS2 up to 3% and EPCAM up to 0.8%. The Latin America MMR spectrum is broad with a total of 220 different variants which 80% were private and 20% were recurrent. Frequent regions included exons 11 of MLH1 (15%), exon 3 and 7 of MSH2 (17 and 15%, respectively), exon 4 of MSH6 (65%), exons 11 and 13 of PMS2 (31% and 23%, respectively). Sixteen international founder variants in MLH1, MSH2 and MSH6 were identified and 41 (19%) variants have not previously been reported, thus representing novel genetic variants in the MMR genes. The AMSII criteria was the most used clinical criteria to identify pathogenic MMR carriers although microsatellite instability, immunohistochemistry and family history are still the primary methods in several countries where no genetic testing for LS is available yet. CONCLUSION: The Latin America LS pathogenic MMR variants spectrum included new variants, frequently altered genetic regions and potential founder effects, emphasizing the relevance implementing Lynch syndrome genetic testing and counseling in all of Latin America countries.

INTRODUCTION: Technical difficulty and unfamiliar surgical anatomy are the main challenges in transanal total mesorectal excision. Precise 3-dimensional real-time image guidance may facilitate the safety, accuracy, and efficiency of transanal total mesorectal excision. TECHNIQUE: A preoperative CT was obtained with 10 skin fiducials and further processed to emphasize the border of the anatomical structure by 3-dimensional modeling and pelvic organ segmentation. A forced sacral tilt by placing a 10-degree wedge under the patient's sacrum was induced to minimize pelvic organ movement caused by lithotomy position. An optical navigation system with cranial software was used. Preoperative CT images were loaded into the navigation system, and patient tracker was mounted onto the iliac bone. Once the patient-to-image paired point registration using skin fiducials was completed, the laparoscopic instrument mounted with instrument tracker was calibrated for instrument tracking. After validating the experimental setup and process of registration by navigating laparoscopic anterior resection, stereotactic navigation for transanal total mesorectal excision was performed in the low rectal neuroendocrine tumor. RESULTS: The fiducial registration error was 1.7 mm. The accuracy of target positioning was sufficient at less than 3 mm (1.8 ± 0.9 mm). Qualitative assessment using a Likert scale was well matched between the 2 observers. Of the 20 scores, 19 were judged as 4 (very good) or 5 (excellent). There was no statistical difference between mean Likert scales of the abdominal or transanal landmarks (4.4 ± 0.5 vs 4.3 ± 1.0, p = 0.965). CONCLUSIONS: Application of an existing navigation system to transanal total mesorectal excision for a low rectal tumor is feasible. The acceptable accuracy of target positioning justifies its clinical use. Further research is needed to prove the clinical need for the procedure and its impact on clinical outcomes.

BACKGROUND: Long-term morbidity after multimodal treatment for rectal cancer is suggested to be mainly made up by nerve-injury-related dysfunctions. Stereotactic navigation for rectal surgery was shown to be feasible and will be facilitated by highlighting structures at risk of iatrogenic damage. The aim of this study was to investigate the ability to make a 3D map of the pelvic nerves with magnetic resonance imaging (MRI). METHODS: A systematic review was performed to identify a main positional reference for each pelvic nerve and plexus. The nerves were manually delineated in 20 volunteers who were scanned with a 3-T MRI. The nerve identifiability rate and the likelihood of nerve identification correctness were determined. RESULTS: The analysis included 61 studies on pelvic nerve anatomy. A main positional reference was defined for each nerve. On MRI, the sacral nerves, the lumbosacral plexus, and the obturator nerve could be identified bilaterally in all volunteers. The sympathetic trunk could be identified in 19 of 20 volunteers bilaterally (95%). The superior hypogastric plexus, the hypogastric nerve, and the inferior hypogastric plexus could be identified bilaterally in 14 (70%), 16 (80%), and 14 (70%) of the 20 volunteers, respectively. The pudendal nerve could be identified in 17 (85%) volunteers on the right side and in 13 (65%) volunteers on the left side. The levator ani nerve could be identified in only a few volunteers. Except for the levator ani nerve, the radiologist and the anatomist agreed that the delineated nerve depicted the correct nerve in 100% of the cases. CONCLUSION: Pelvic nerves at risk of injury are usually visible on high-resolution MRI with dedicated scanning protocols. A specific knowledge of their course and its application in stereotactic navigation is suggested to improve quality of life by decreasing the likelihood of nerve injury.