A comprehensive characterization of the spectrum of MUTYH germline pathogenic variants in Latin America.

MUTYH-Associated Polyposis (MAP) is caused by biallelic pathogenic germline variants in the MUTYH gene. However, individuals harboring monoallelic MUTYH pathogenic variants in the presence of a positive family history have been reported to have a twofold increased risk of colorectal cancer (CRC) and extra colonic cancers. Our aim was to characterize the spectrum of monoallelic and biallelic germline MUTYH pathogenic variants in Latin American patients and to describe their clinical and genetic characteristics. Patients were identified from eight high-risk genetic cancer centers of five Latin American countries. Statistical analysis was performed using the two-sided P test using the Vassarstats statistical tools. Statistical significance was set at a p value ≤ 0.05. Of the 105 unrelated patients with cancer or colorectal polyposis, 84.8% and 15.2% carried pathogenic monoallelic and biallelic MUTYH variants, respectively. The most common pathogenic variants were p.Gly396Asp and p.Tyr179Cys (55% and 23%, respectively). The mean age at first diagnosis was 48.29 years (range 31-71) and 49.90 years (range 27-87) in biallelic and monoallelic MUTYH patients, respectively. CRC was the only cancer diagnosed in patients with biallelic MUTYH pathogenic variants (75%), while breast cancer (46.1%) was more common than CRC (24.7%) in individuals with monoallelic MUTYH pathogenic variants. We reported a high frequency of European founder variants in our diverse population. Some phenotypic differences from current studies were identified, such as a higher breast cancer burden in monoallelic carriers and a complete absence of extra-colon tumors in biallelic patients.

International Validation of the Immunoscore Biopsy in Patients With Rectal Cancer Managed by a Watch-and-Wait Strategy.

PURPOSE: No biomarker capable of improving selection and monitoring of patients with rectal cancer managed by watch-and-wait (W&W) strategy is currently available. Prognostic performance of the Immunoscore biopsy (ISB) was recently suggested in a preliminary study. METHODS: This international validation study included 249 patients with clinical complete response (cCR) managed by W&W strategy. Intratumoral CD3+ and CD8+ T cells were quantified on pretreatment rectal biopsies by digital pathology and converted to ISB. The primary end point was time to recurrence (TTR; the time from the end of neoadjuvant treatment to the date of local regrowth or distant metastasis). Associations between ISB and outcomes were analyzed by stratified Cox regression adjusted for confounders. Immune status of tumor-draining lymph nodes (n = 161) of 17 additional patients treated by neoadjuvant chemoradiotherapy and surgery was investigated by 3'RNA-Seq and immunofluorescence. RESULTS: Recurrence-free rates at 5 years were 91.3% (82.4%-100.0%), 62.5% (53.2%-73.3%), and 53.1% (42.4%-66.5%) with ISB High, ISB Intermediate, and ISB Low, respectively (hazard ratio [HR; Low v High], 6.51; 95% CI, 1.99 to 21.28; log-rank P = .0004). ISB was also significantly associated with disease-free survival (log-rank P = .0002), and predicted both local regrowth and distant metastasis. In multivariate analysis, ISB was independent of patient age, sex, tumor location, cT stage (T, primary tumor; c, clinical), cN stage (N, regional lymph node; c, clinical), and was the strongest predictor for TTR (HR [ISB High v Low], 6.93; 95% CI, 2.08 to 23.15; P = .0017). The addition of ISB to a clinical-based model significantly improved the prediction of recurrence. Finally, B-cell proliferation and memory in draining lymph nodes was evidenced in the draining lymph nodes of patients with cCR. CONCLUSION: The ISB is validated as a biomarker to predict both local regrowth and distant metastasis, with a gradual scaling of the risk of pejorative outcome.

Dominantly inherited micro-satellite instable cancer - the four Lynch syndromes - an EHTG, PLSD position statement.

The recognition of dominantly inherited micro-satellite instable (MSI) cancers caused by pathogenic variants in one of the four mismatch repair (MMR) genes MSH2, MLH1, MSH6 and PMS2 has modified our understanding of carcinogenesis. Inherited loss of function variants in each of these MMR genes cause four dominantly inherited cancer syndromes with different penetrance and expressivities: the four Lynch syndromes. No person has an "average sex "or a pathogenic variant in an "average Lynch syndrome gene" and results that are not stratified by gene and sex will be valid for no one. Carcinogenesis may be a linear process from increased cellular division to localized cancer to metastasis. In addition, in the Lynch syndromes (LS) we now recognize a dynamic balance between two stochastic processes: MSI producing abnormal cells, and the host's adaptive immune system's ability to remove them. The latter may explain why colonoscopy surveillance does not reduce the incidence of colorectal cancer in LS, while it may improve the prognosis. Most early onset colon, endometrial and ovarian cancers in LS are now cured and most cancer related deaths are after subsequent cancers in other organs. Aspirin reduces the incidence of colorectal and other cancers in LS. Immunotherapy increases the host immune system's capability to destroy MSI cancers. Colonoscopy surveillance, aspirin prevention and immunotherapy represent major steps forward in personalized precision medicine to prevent and cure inherited MSI cancer.

Variaciones anatómicas en la vascularización del colon derecho y su implicancia en la escisión completa del mesocolon con linfadenectomía D3. Estudio de corte transversal / Anatomical variations in right colon vascularization: its implication in complete mesocolic excision with D3 lymphadenectomy. A cross-sectional study

Introducción: La escisión completa del mesocolon con linfadenectomía D3 (CME-D3) mejora los resultados de los pacientes operados por cáncer del colon. Reconocer adecuadamente la anatomía vascular es fundamental para evitar complicaciones. Objetivo: El objetivo primario fue determinar la prevalencia de las variaciones anatómicas de la arteria mesentérica superior (AMS) y sus ramas en relación a la vena mesentérica superior (VMS). El objetivo secundario fue evaluar la asociación entre las distintas variantes anatómicas y el sexo y la etnia de lo pacientes. Diseño: Estudio de corte transversal. Material y métodos: Se incluyeron 225 pacientes con cáncer del colon derecho diagnosticados entre enero 2017 y diciembre de 2020. Dos radiólogos independientes describieron la anatomía vascular observada en las tomografías computadas. Según la relación de las ramas de la AMS con la VMS, la población fue dividida en 2 grupos y subdividida en 6 (1a-c, 2a-c). Resultados: La arteria ileocólica fue constante, transcurriendo en el 58,7% de los casos por la cara posterior de la VMS. La arteria cólica derecha, presente en el 39,6% de los pacientes, cruzó la VMS por su cara anterior en el 95,5% de los casos. La variante de subgrupo más frecuente fue la 2a seguida por la 1a (36,4 y 24%, respectivamente). No se encontró asociación entre las variantes anatómicas y el sexo u origen étnico. Conclusión: Las variaciones anatómicas de la AMS y sus ramas son frecuentes y no presentan un patrón predominante. No hubo asociación entre las mismas y el sexo u origen étnico en nuestra cohorte. El reconocimiento preoperatorio de estas variantes mediante angiotomografía resulta útil para evitar lesiones vasculares durante la CME-D3. (AU)

Background: Complete mesocolic excision with D3 lymphadenectomy (CME-D3) improves the outcomes of patients operated on for colon cancer. Proper recognition of vascular anatomy is essential to avoid complications. Aim: Primary outcome was to determine the prevalence of anatomical variations of the superior mesenteric artery (SMA) and its branches in relation to the superior mesenteric vein (SMV). Secondary outcome was to evaluate the association between these anatomical variations and sex and ethnicity of the patients. Design: Cross-sectional study. Material and methods: Two hundred twenty-fivepatients with right colon cancer diagnosed between January 2017 and December 2020 were included. Two independent radiologists described the vascular anatomy of computed tomography scans. The population was divided into 2 groups and subdivided into 6 groups (1a-c, 2a-c), according to the relationship of the SMA and its branches with the SMV. Results: The ileocolic artery was constant, crossing the SMV posteriorly in 58.7% of the cases. The right colic artery, present in 39.6% of the patients, crossed the SMV on its anterior aspect in 95.5% of the cases. The most frequent subgroup variant was 2a followed by 1a (36.4 and 24%, respectively). No association was found between anatomical variants and gender or ethnic origin. Conclusions: The anatomical variations of the SMA and its branches are common, with no predominant pattern. There was no association between anatomical variations and gender or ethnic origin in our cohort. Preoperative evaluation of these variations by computed tomography angi-ography is useful to avoid vascular injuries during CME-D3. (AU)

Mortality by age, gene and gender in carriers of pathogenic mismatch repair gene variants receiving surveillance for early cancer diagnosis and treatment: a report from the prospective Lynch syndrome database.

Background: The Prospective Lynch Syndrome Database (PLSD) collates information on carriers of pathogenic or likely pathogenic MMR variants (path_MMR) who are receiving medical follow-up, including colonoscopy surveillance, which aims to the achieve early diagnosis and treatment of cancers. Here we use the most recent PLSD cohort that is larger and has wider geographical representation than previous versions, allowing us to present mortality as an outcome, and median ages at cancer diagnoses for the first time. Methods: The PLSD is a prospective observational study without a control group that was designed in 2012 and updated up to October 2022. Data for 8500 carriers of path_MMR variants from 25 countries were included, providing 71,713 years of follow up. Cumulative cancer incidences at 65 years of age were combined with 10-year crude survival following cancer, to derive estimates of mortality up to 75 years of age by organ, gene, and gender. Findings: Gynaecological cancers were more frequent than colorectal cancers in path_MSH2, path_MSH6 and path_PMS2 carriers [cumulative incidence: 53.3%, 49.6% and 23.3% at 75 years, respectively]. Endometrial, colon and ovarian cancer had low mortality [8%, 13% and 15%, respectively] and prostate cancers were frequent in male path_MSH2 carriers [cumulative incidence: 39.7% at 75 years]. Pancreatic, brain, biliary tract and ureter and kidney and urinary bladder cancers were associated with high mortality [83%, 66%, 58%, 27%, and 29%, respectively]. Among path_MMR carriers undergoing colonoscopy surveillance, particularly path_MSH2 carriers, more deaths followed non-colorectal Lynch syndrome cancers than colorectal cancers. Interpretation: In path_MMR carriers undergoing colonoscopy surveillance, non-colorectal Lynch syndrome cancers were associated with more deaths than were colorectal cancers. Reducing deaths from non-colorectal cancers presents a key challenge in contemporary medical care in Lynch syndrome. Funding: We acknowledge funding from the Norwegian Cancer Society, contract 194751-2017.

Long-term outcomes and risk factors for diverticulitis recurrence after a successful laparoscopic peritoneal lavage in Hinchey III peritonitis.

PURPOSE: Recently, treatment of Hinchey III diverticulitis by laparoscopic peritoneal lavage has been questioned. Moreover, long-term outcomes have been scarcely reported. Primary outcome was to determine the recurrence rate of diverticulitis after a successful laparoscopic peritoneal lavage in Hinchey III diverticulitis. Secondary outcomes were identification of associated risk factors for recurrence and elective sigmoidectomy rate. METHODS: A retrospective cohort study in a tertiary referral center was performed. Patients with Hinchey III diverticulitis who underwent a successful laparoscopic peritoneal lavage between June 2006 and December 2019 were eligible. Diverticulitis recurrence was analyzed according to the Kaplan-Meier and log-rank test, censoring for death, loss of follow-up, or elective sigmoid resection in the absence of recurrence. Risk factors for recurrence were identified using Cox regression analysis. RESULTS: Sixty-nine patients had a successful laparoscopic peritoneal lavage (mean age: 63 years; 53.6% women). Four patients had an elective sigmoid resection without recurrences. Recurrence rate was 42% (n = 29) after a median follow-up of 63 months. The cumulative global recurrence at 1, 3, and 5 years was 30% (95% CI, 20-43%), 37.5% (95% CI, 27-51%), and 48.9% (95% CI, 36-64%), respectively. Smoking (HR, 2.87; 95% CI, 1.22-6.5; p = 0.016) and episodes of diverticulitis prior to laparoscopic peritoneal lavage (HR, 5.2; 95% CI, 2.11-12.81; p < 0.001) were independently associated with an increased risk of recurrence. CONCLUSIONS: Diverticulitis recurrence after a successful laparoscopic peritoneal lavage is high, decreasing after the first year of follow-up. Smoking and previous episodes of acute diverticulitis independently increase the risk of new episodes of diverticulitis.

Mono- and biallelic germline variants of DNA glycosylase genes in colon adenomatous polyposis families from two continents.

Recently, biallelic germline variants of the DNA glycosylase genes MUTYH and NTHL1 were linked to polyposis susceptibility. Significant fractions remain without a molecular explanation, warranting searches for underlying causes. We used exome sequencing to investigate clinically well-defined adenomatous polyposis cases and families from Finland (N=34), Chile (N=21), and Argentina (N=12), all with known susceptibility genes excluded. Nine index cases (13%) revealed germline variants with proven or possible pathogenicity in the DNA glycosylase genes, involving NEIL1 (mono- or biallelic) in 3 cases, MUTYH (monoallelic) in 3 cases, NTHL1 (biallelic) in 1 case, and OGG1 (monoallelic) in 2 cases. NTHL1 was affected with the well-established, pathogenic c.268C>T, p.(Gln90Ter) variant. A recurrent heterozygous NEIL1 c.506G>A, p.(Gly169Asp) variant was observed in two families. In a Finnish family, the variant occurred in trans with a truncating NEIL1 variant (c.821delT). In an Argentine family, the variant co-occurred with a genomic deletion of exons 2 - 11 of PMS2. Mutational signatures in tumor tissues complied with biological functions reported for NEIL1. Our results suggest that germline variants in DNA glycosylase genes may occur in a non-negligible proportion of unexplained colon polyposis cases and may predispose to tumor development.

Colorectal cancer incidences in Lynch syndrome: a comparison of results from the prospective lynch syndrome database and the international mismatch repair consortium.

OBJECTIVE: To compare colorectal cancer (CRC) incidences in carriers of pathogenic variants of the MMR genes in the PLSD and IMRC cohorts, of which only the former included mandatory colonoscopy surveillance for all participants. METHODS: CRC incidences were calculated in an intervention group comprising a cohort of confirmed carriers of pathogenic or likely pathogenic variants in mismatch repair genes (path_MMR) followed prospectively by the Prospective Lynch Syndrome Database (PLSD). All had colonoscopy surveillance, with polypectomy when polyps were identified. Comparison was made with a retrospective cohort reported by the International Mismatch Repair Consortium (IMRC). This comprised confirmed and inferred path_MMR carriers who were first- or second-degree relatives of Lynch syndrome probands. RESULTS: In the PLSD, 8,153 subjects had follow-up colonoscopy surveillance for a total of 67,604 years and 578 carriers had CRC diagnosed. Average cumulative incidences of CRC in path_MLH1 carriers at 70 years of age were 52% in males and 41% in females; for path_MSH2 50% and 39%; for path_MSH6 13% and 17% and for path_PMS2 11% and 8%. In contrast, in the IMRC cohort, corresponding cumulative incidences were 40% and 27%; 34% and 23%; 16% and 8% and 7% and 6%. Comparing just the European carriers in the two series gave similar findings. Numbers in the PLSD series did not allow comparisons of carriers from other continents separately. Cumulative incidences at 25 years were < 1% in all retrospective groups. CONCLUSIONS: Prospectively observed CRC incidences (PLSD) in path_MLH1 and path_MSH2 carriers undergoing colonoscopy surveillance and polypectomy were higher than in the retrospective (IMRC) series, and were not reduced in path_MSH6 carriers. These findings were the opposite to those expected. CRC point incidence before 50 years of age was reduced in path_PMS2 carriers subjected to colonoscopy, but not significantly so.

Benchmarks in colorectal surgery: multinational study to define quality thresholds in high and low anterior resection.

BACKGROUND: Benchmark comparisons in surgery allow identification of gaps in the quality of care provided. The aim of this study was to determine quality thresholds for high (HAR) and low (LAR) anterior resections in colorectal cancer surgery by applying the concept of benchmarking. METHODS: This 5-year multinational retrospective study included patients who underwent anterior resection for cancer in 19 high-volume centres on five continents. Benchmarks were defined for 11 relevant postoperative variables at discharge, 3 months, and 6 months (for LAR). Benchmarks were calculated for two separate cohorts: patients without (ideal) and those with (non-ideal) outcome-relevant co-morbidities. Benchmark cut-offs were defined as the 75th percentile of each centre's median value. RESULTS: A total of 3903 patients who underwent HAR and 3726 who had LAR for cancer were analysed. After 3 months' follow-up, the mortality benchmark in HAR for ideal and non-ideal patients was 0.0 versus 3.0 per cent, and in LAR it was 0.0 versus 2.2 per cent. Benchmark results for anastomotic leakage were 5.0 versus 6.9 per cent for HAR, and 13.6 versus 11.8 per cent for LAR. The overall morbidity benchmark in HAR was a Comprehensive Complication Index (CCI®) score of 8.6 versus 14.7, and that for LAR was CCI® score 11.9 versus 18.3. CONCLUSION: Regular comparison of individual-surgeon or -unit outcome data against benchmark thresholds may identify gaps in care quality that can improve patient outcome.

[Hand-assisted Laparoscopic Surgery: experience with an original technique]. / Cirugía colorrectal laparoscópica mano asistida: experiencia con una técnica original.

Introduction: Hand-assisted laparoscopic colorectal surgery (HALS) is an alternative to straight laparoscopic approach (SL) that requires the use of a specific device to maintain the pneumoperitoneum. Our group has described an original double glove technique to replace it. Our purpose was to compare perioperative outcomes of patients undergoing HALS using this original technique vs SL. Methods: Retrospective review of a prospective database including patients who underwent elective laparoscopic colorectal resections between 2004 to 2020 at the Hospital Italiano, Argentina. Logistic regression analysis, propensity score matching, and inverse probability weighting were used to estimate adjusted treatment effects for perioperative outcomes. Results: HALS (n=458) and SL (n=1692) cases were demographically similar. HALS was associated with a shorter operative time (170.3 vs 206.9 minutes, p<0.001). Such difference was even more pronounced in obese (44.1 min), large patients (37.5 min), complex procedures (33.8 min) and surgeries carried out by non-trained surgeons (57,6 vs 31,6 minutes, p<0.001). Hand-assisted was associated with a lower conversion rate (5% vs 9.9%, p<0.001) with an adjusted odds ratio of 0.45 (95%CI 0.28-0.73). No difference in hospital stay, morbidity, and readmission rates was found. Conclusions: HALS with double-glove technique is comparable to SL in terms of postoperative outcomes keeping reduced operative time and conversion rates, especially in obese patients undergoing complex procedures.

Introducción: La cirugía colorrectal laparoscópica mano asistida (CLMA) es un abordaje alternativo a la laparoscopia directa (LD) que requiere de un dispositivo específico para mantener el neumoperitoneo. Nuestro grupo describió una técnica original de doble guante como alternativa a este dispositivo. El objetivo del presente trabajo fue analizar los resultados de esta técnica comparándola con la técnica de LD. Métodos: Se analizó una serie consecutiva de pacientes sometidos a cirugías colorrectales laparoscópicas entre 2004 y 2020 en el Hospital Italiano de Bs, As, Argentina. Se realizó un modelo de regresión múltiple de selección progresiva y apareamiento por puntaje de propensión para analizar los resultados perioperatorios. Resultados: Los casos de CLMA (n=458) y LD (n=1692) fueron demográficamente similares. CLMA se asoció a un menor tiempo operatorio (170,3 vs 206,9 minutos, p<0.001). Dicha reducción fue más marcada en obesos (44.1 min), pacientes grandes (37.5 min), cirugías complejas (33.8 min) y en procedimientos realizados por cirujanos no entrenados (57,6 vs 31,6 minutos, p<0.001). CLMA resultó tener menor índice de conversión (5% vs 9.9%, p<0.001) con una razón de probabilidades ajustada de 0,45. No se hallaron diferencias en cuanto a estadía hospitalaria, morbimortalidad y readmisión. Conclusión: CLMA con doble guante es comparable a la LD manteniendo un tiempo operatorio reducido y bajo índice de conversión, particularmente en pacientes obesos sometidos a procedimientos complejos.

No Difference in Penetrance between Truncating and Missense/Aberrant Splicing Pathogenic Variants in MLH1 and MSH2: A Prospective Lynch Syndrome Database Study.

BACKGROUND: Lynch syndrome is the most common genetic predisposition for hereditary cancer. Carriers of pathogenic changes in mismatch repair (MMR) genes have an increased risk of developing colorectal (CRC), endometrial, ovarian, urinary tract, prostate, and other cancers, depending on which gene is malfunctioning. In Lynch syndrome, differences in cancer incidence (penetrance) according to the gene involved have led to the stratification of cancer surveillance. By contrast, any differences in penetrance determined by the type of pathogenic variant remain unknown. OBJECTIVE: To determine cumulative incidences of cancer in carriers of truncating and missense or aberrant splicing pathogenic variants of the MLH1 and MSH2 genes. METHODS: Carriers of pathogenic variants of MLH1 (path_MLH1) and MSH2 (path_MSH2) genes filed in the Prospective Lynch Syndrome Database (PLSD) were categorized as truncating or missense/aberrant splicing according to the InSiGHT criteria for pathogenicity. RESULTS: Among 5199 carriers, 1045 had missense or aberrant splicing variants, and 3930 had truncating variants. Prospective observation years for the two groups were 8205 and 34,141 years, respectively, after which there were no significant differences in incidences for cancer overall or for colorectal cancer or endometrial cancers separately. CONCLUSION: Truncating and missense or aberrant splicing pathogenic variants were associated with similar average cumulative incidences of cancer in carriers of path MLH1 and path_MSH2.

Uptake of hysterectomy and bilateral salpingo-oophorectomy in carriers of pathogenic mismatch repair variants: a Prospective Lynch Syndrome Database report.

PURPOSE: This study aimed to report the uptake of hysterectomy and/or bilateral salpingo-oophorectomy (BSO) to prevent gynaecological cancers (risk-reducing surgery [RRS]) in carriers of pathogenic MMR (path_MMR) variants. METHODS: The Prospective Lynch Syndrome Database (PLSD) was used to investigate RRS by a cross-sectional study in 2292 female path_MMR carriers aged 30-69 years. RESULTS: Overall, 144, 79, and 517 carriers underwent risk-reducing hysterectomy, BSO, or both combined, respectively. Two-thirds of procedures before 50 years of age were combined hysterectomy and BSO, and 81% of all procedures included BSO. Risk-reducing hysterectomy was performed before age 50 years in 28%, 25%, 15%, and 9%, and BSO in 26%, 25%, 14% and 13% of path_MLH1, path_MSH2, path_MSH6, and path_PMS2 carriers, respectively. Before 50 years of age, 107 of 188 (57%) BSO and 126 of 204 (62%) hysterectomies were performed in women without any prior cancer, and only 5% (20/392) were performed simultaneously with colorectal cancer (CRC) surgery. CONCLUSION: Uptake of RRS before 50 years of age was low, and RRS was rarely undertaken in association with surgical treatment of CRC. Uptake of RRS aligned poorly with gene- and age-associated risk estimates for endometrial or ovarian cancer that were published recently from PLSD and did not correspond well with current clinical guidelines. The reasons should be clarified. Decision-making on opting for or against RRS and its timing should be better aligned with predicted risk and mortality for endometrial and ovarian cancer in Lynch syndrome to improve outcomes.

Maternal ancestry and hematological cancer risk: case-control study in an Argentinean population.

Aim: We investigated the role of maternal ancestry in neoplastic hematological malignancies (HMs) risk in a population from Central Argentina. Materials & methods: We analyzed 125 cases with HMs and 310 controls from a public hospital, and a set of 202 colorectal, breast, lung, and hematologic cancer patients from a private hospital. Results: A decreased risk for HMs was associated with the Native American haplogroup B2 (odds ratio = 0.49; 95% CI: 0.25-0.92; p = 0.02). The sub-Saharan African parahaplogroup L was associated with higher susceptibility for disease (odds ratio = 3.10; 95% CI: 1.04-9.31; p = 0.043). Although the mean ancestral proportions in the total studied population was as published (61.7% Native American, 34.6% European and 3.7% African), an unequal distribution was observed between hospitals. Conclusion: We confirmed the tri-hybrid nature of the Argentinean population, with proportions varying within the country. Our finding supports the notion that associated haplogroup is population and cancer specific.

The colorectal cancer-associated faecal microbiome of developing countries resembles that of developed countries.

BACKGROUND: The incidence of colorectal cancer (CRC) is increasing in developing countries, yet limited research on the CRC- associated microbiota has been conducted in these areas, in part due to scarce resources, facilities, and the difficulty of fresh or frozen stool storage/transport. Here, we aimed (1) to establish a broad representation of diverse developing countries (Argentina, Chile, India, and Vietnam); (2) to validate a 'resource-light' sample-collection protocol translatable in these settings using guaiac faecal occult blood test (gFOBT) cards stored and, importantly, shipped internationally at room temperature; (3) to perform initial profiling of the collective CRC-associated microbiome of these developing countries; and (4) to compare this quantitatively with established CRC biomarkers from developed countries. METHODS: We assessed the effect of international storage and transport at room temperature by replicating gFOBT from five UK volunteers, storing two in the UK, and sending replicates to institutes in the four countries. Next, to determine the effect of prolonged UK storage, DNA extraction replicates for a subset of samples were performed up to 252 days apart. To profile the CRC-associated microbiome of developing countries, gFOBT were collected from 41 treatment-naïve CRC patients and 40 non-CRC controls from across the four institutes, and V4 16S rRNA gene sequencing was performed. Finally, we constructed a random forest (RF) model that was trained and tested against existing datasets from developed countries. RESULTS: The microbiome was stably assayed when samples were stored/transported at room temperature and after prolonged UK storage. Large-scale microbiome structure was separated by country and continent, with a smaller effect from CRC. Importantly, the RF model performed similarly to models trained using external datasets and identified similar taxa of importance (Parvimonas, Peptostreptococcus, Fusobacterium, Alistipes, and Escherichia). CONCLUSIONS: This study demonstrates that gFOBT, stored and transported at room temperature, represents a suitable method of faecal sample collection for amplicon-based microbiome biomarkers in developing countries and suggests a CRC-faecal microbiome association that is consistent between developed and developing countries.

Fluoroscopy and endoscopy-guided transanastomotic rendezvous: a novel technique for recanalization of a completely obstructed colorectal anastomosis.

BACKGROUND: Colorectal anastomotic stricture is a frequent complication that may affect up to 30% of patients. However, a complete obstruction is rare. Endoscopic balloon dilation is the first-line therapy, but it invariably requires being able to cross the stricture with the dilation device. When this is not possible, surgical revision is the alternative, but it is associated with higher morbidity. CASE PRESENTATION: A 76-year-old male patient underwent an urgent high anterior resection with transverse loop colostomy for an occlusive high rectal tumor. On postoperative day 8, he presented with anastomotic leakage and abscess formation, requiring percutaneous drainage. Ten months after surgery, a colonoscopy revealed a complete stricture of the anastomosis, refractory to negotiation of a guide wire, thus precluding balloon dilation. Hence, a modified rendezvous technique was planned. Simultaneously, a flexible endoscope and a rigid rectoscope were progressed through the distal loop colostomy, and the anus, respectively. A needle device was introduced through the rectoscope and used to pierce the colonic stump. A guide wire was progressed, and the stricture was dilated with a controlled radial expansion balloon catheter. Finally, a 12-Fr Foley catheter was left through the anastomosis. A total of three endoscopic balloon dilation sessions were completed, and successful colostomy reversal was carried out 10 days after the last session. CONCLUSION: Fluoroscopy-endoscopy-guided recanalization is an effective and safe treatment option for complete colorectal anastomotic stricture.

Risk-reducing hysterectomy and bilateral salpingo-oophorectomy in female heterozygotes of pathogenic mismatch repair variants: a Prospective Lynch Syndrome Database report.

PURPOSE: To determine impact of risk-reducing hysterectomy and bilateral salpingo-oophorectomy (BSO) on gynecological cancer incidence and death in heterozygotes of pathogenic MMR (path_MMR) variants. METHODS: The Prospective Lynch Syndrome Database was used to investigate the effects of gynecological risk-reducing surgery (RRS) at different ages. RESULTS: Risk-reducing hysterectomy at 25 years of age prevents endometrial cancer before 50 years in 15%, 18%, 13%, and 0% of path_MLH1, path_MSH2, path_MSH6, and path_PMS2 heterozygotes and death in 2%, 2%, 1%, and 0%, respectively. Risk-reducing BSO at 25 years of age prevents ovarian cancer before 50 years in 6%, 11%, 2%, and 0% and death in 1%, 2%, 0%, and 0%, respectively. Risk-reducing hysterectomy at 40 years prevents endometrial cancer by 50 years in 13%, 16%, 11%, and 0% and death in 1%, 2%, 1%, and 0%, respectively. BSO at 40 years prevents ovarian cancer before 50 years in 4%, 8%, 0%, and 0%, and death in 1%, 1%, 0%, and 0%, respectively. CONCLUSION: Little benefit is gained by performing RRS before 40 years of age and premenopausal BSO in path_MSH6 and path_PMS2 heterozygotes has no measurable benefit for mortality. These findings may aid decision making for women with LS who are considering RRS.