Adenomatous Polyposis Research Articles

An update of the variant spectrum of the APC gene in Iranian familial adenomatous polyposis patients

Familial adenomatous polyposis (FAP) is an autosomal dominant colorectal cancer syndrome that is characterized by the development of multiple adenomas in the colon and rectum with high penetrance rates. This disease has specific features like the occurrence of pathogenic variations in the APC gene and diverse FAP phenotypes due to the occurrence region. In this study we aimed to evaluate pathogenic variants in exons of the APC gene in Iranian patients with FAP. A total of 35 FAP individuals were referred to the gastroenterology ward of Taleghani Hospital. As the aim of the study was to study the germline variations in the participants, the peripheral blood was collected and after the DNA extraction, PCR, and Sanger sequencing processes for the APC gene, the results were evaluated by the ACMG classification guidelines to report their pathogenicity. Accordingly, out of eight specific detected variants, three of them were novel, and the rest were reported previously. These eight variants were all truncating protein and pathogenic, and they were limited to 849–1378 codons. Overall, detected variants revealed discrepancies and parallels with previous reported cases in terms of quantity, occurrence region, and association with demographic and clinicopathological characteristics of patients. The spectrum of detected variants and the patient’s phenotype showed distinct characteristics, such as occurrence in specific regions and the absence of extracolonic symptoms like Congenital hypertrophy of the retinal pigment epithelium (CHRPE). These findings open the path to comprehending the typical symptoms, their rarity, and their occurrence in the Iranian population and also due to the facts, we found that the studying of the APC gene alone for diagnosing FAP disease is not sufficient, and considering other genes are completely rational in the case of sequencing and studying the variants.

Case Series of Men with the Germline APC I1307K variant and Treatment-Emergent Neuroendocrine Prostate Cancer

Introduction: Somatic mutations in the Wnt signaling gene Adenomatous Polyposis Coli (APC) promote metastatic prostate cancer (PCa) progression. Less is known regarding the impact of germline APC mutations on PCa outcomes. We sought to investigate the prevalence of aggressive variant PCa (AVPC) and treatment-emergent neuroendocrine PCa (t-NEPC) in patients with the germline APC I1307K variant, an alteration found in 7% of Ashkenazi Jewish men. Materials and MethodsWe report a retrospective cohort study comparing patients with PCa and either APC I1307K germline mutation, APC somatic mutations, or unselected patients. Proportions of patients with AVPC among all the cases were estimated along with 95% Clopper-Pearson exact confidence intervals (CI). Odds ratios with 95% CI were provided for the prevalence of t-NEPC and AVPC in patients with germline APC I1307K compared to patients with frameshift alterations in APC. ResultsFrom 2016-2022, 18 patients with PCa at 3 institutions with the germline APC (I1307K) mutation were identified. Clinically-defined AVPC was found in 8 of the 15 cases with metastatic disease (53%; 95% CI: 26%-79%). Combined somatic alterations in two or more of RB1, TP53 or PTEN (molecularly-defined AVPC) were found in 5/18 cases (28%; 95% CI: 10%-54%). When compared to 20 patients with APC somatic frameshift mutations, patients with the germline APC I1307K variant had a significantly increased risk of AVPC (OR 7.2; 95% CI 1.27, 40.68). ConclusionPCa that develops in the presence of the germline APC I1307K mutation appear to be enriched for clinically-defined and molecularly-defined AVPC and in particular, for t-NEPC.

Apoptosis of Kinetin Riboside in Colorectal Cancer Cells Occurs by Promoting β-Catenin Degradation.

Kinetin riboside is a naturally produced cytokinin that displays strong antiproliferative activity in various human cancer cells. However, the mechanism of chemoprevention in colorectal cancer cells has not been elucidated. We used a cell-based reporter system to identify kinetin riboside as an antagonist of the Wnt/β-catenin pathway, which is aberrantly upregulated in colorectal cancer. Kinetin riboside suppressed β-catenin response transcription (CRT) by accelerating the degradation of intracellular β-catenin via a proteasomal degradation pathway. Pharmacological inhibition of glycogen synthase kinase-3β did not affect CRT downregulation. Kinetin riboside decreased the intracellular β-catenin levels in colorectal cancer cells with mutations in adenomatous polyposis coli (APC) and β-catenin. Consistently, kinetin riboside repressed expression of c-Myc and cyclin D1, β-catenin/T-cell factor (TCF)-dependent genes, and inhibited the proliferation of colorectal cancer cells. In addition, kinetin riboside stimulated apoptosis, as measured by an increase in annexin V-FITC-stained cells. These findings suggest that kinetin riboside exerts its anti-cancer activity by promoting β-catenin degradation and has significant potential as a chemopreventive agent for colorectal cancer cells.

Structural basis of the interaction between BCL9-Pygo and LDB-SSBP complexes in assembling the Wnt enhanceosome

The Wnt enhanceosome is responsible for transactivation of Wnt-responsive genes and a promising therapeutic target for treatment of numerous cancers with Adenomatous Polyposis Coli (APC) or β-catenin mutations. How the Wnt enhanceosome is assembled remains poorly understood. Here we show that B-cell lymphoma 9 protein (BCL9), Pygopus (Pygo), LIM domain-binding protein 1 (LDB1) and single-stranded DNA-binding protein (SSBP) form a stable core complex within the Wnt enhanceosome. Their mutual interactions rely on a highly conserved N-terminal asparagine proline phenylalanine (NPF) motif of Pygo, through which the BCL9-Pygo complex binds to the LDB-SSBP core complex. Our crystal structure of a ternary complex comprising the N-terminus of human Pygo2, LDB1 and SSBP2 reveals a single LDB1-SSBP2 complex binding simultaneously to two Pygo2 molecules via their NPF motifs. These interactions critically depend on the NPF motifs which bind to a deep groove formed between LDB1 and SSBP2, potentially constituting a binding site for drugs blocking Wnt/β-catenin signaling. Analysis of human cell lines lacking LDB or Pygo supports the functional relevance of the Pygo-LDB1-SSBP2 interaction for Wnt/β-catenin-dependent transcription.

Future directions in imaging pouches.

The sections of this special issue on the ileal pouch demonstrate that in the nearly 45 years since the ileal pouch has been utilized to treat patients with colitis and familial adenomatous polyposis, a substantial number of patients experience both short- and long-term morbidity and that imaging plays an important role in their management. Further, referral centers are encountering an increasing number of patients with pouch and peri-pouch complications and dysfunction. Many of these patients have had their pouches for years, and many have experienced a reduced quality of life as a result of their symptoms.As we look to the future, what are the specific questions that arise from this compilation of experience from institutions that see large numbers of patients with an ileal pouch? In what areas are we deficient? In what areas are we using the wrong methods? What should we be doing differently?

Robotic-assisted colectomyin children: a comparative study with laparoscopic surgery.

The aim of this study was to compare outcomes of laparoscopic and robotic-assisted colectomy in children. All children who underwent a colectomy with a laparoscopic (LapC) or robotic-assisted (RobC) approach in our institution (January 2010-March 2023) were included. Demographics, surgical data, and post-operative outcomes within 30days were collected. Additional cost related to the robotic approach was calculated. Comparisons were performed using Fisher tests for categorical variables and Mann-Whitney tests for continuous variables. A total of 55 colectomies were performed: 31 LapC and 24 RobC (median age: 14.9years). Main indications included: inflammatory bowel disease (n = 36, 65%), familial adenomatous polyposis (n = 6, 11%), sigmoid volvulus (n = 5, 9%), chronic intestinal pseudo-obstruction (n = 3, 5%). LapC included 22 right, 4 left, and 5 total colectomies. RobC included 15 right, 4 left, and 5 total colectomies. Robotic-assisted surgery was associated with increased operative time (3h vs 2.5h, p = 0.02), with a median increase in operative time of 36min. There were no conversions. Post-operative complications occurred in 35% of LapC and 38% of RobC (p = 0.99). Complications requiring treatment under general anesthesia (Clavien-Dindo 3) occurred in similar rates (23% in LapC vs 13% in RobC, p = 0.49). Length of hospitalization was 10days in LapC and 8.5days in RobC (p = 0.39). The robotic approach was associated with a median additional cost of 2156€ per surgery. Robotic-assisted colectomy is as safe and feasible as laparoscopic colectomy in children, with similar complication rates but increased operative times and cost.

A case of attenuated familial adenomatous polyposis in which genetic testing revealed that the children were asymptomatic gene carriers.

Attenuated familial adenomatous polyposis, which accounts for ~10% of familial adenomatous polyposis, is difficult to diagnose because of its milder course and later onset. In both familial adenomatous polyposis and attenuated familial adenomatous polyposis, duodenal cancer is usually recognized 10-20years after the diagnosis of colonic polyposis. We present herein a 66-year-old man who received pancreaticoduodenectomy due to ampullary carcinoma 17years before onset of colonic polyposis. He then received extended right hemicolectoy for ascending colon cancer and ⁓100 polyps located from ceacum to splenic flexure of colon 2years ago. The patient received Adenomatous polyposis coli (APC) genetic testing and detected a germline pathogenic frameshift variant in the APC gene (NM_000038.6:c.4875delA, ClinVar variant ID (127299)). The variant is classified as likely pathogenic according to the American College of Medical Genetics and Genomics guidelines. APC genetic testing was subsequently performed on his younger children (30 and 26year old) and they found a same frameshift variant as his father. They were not detected any colonic polyposis by colonoscopy. This is a rare case report of attenuated familial adenomatous polyposis that diagnosed with gastric and colon polyposis >10years after the diagnosis of ampullary carcinoma and the first report of genetic diagnosis of an attenuated familial adenomatous polyposis variant in young relatives before the onset of the disease.

Laparoscopic pancreas-preserving near total duodenectomy for large villous adenoma in patients with total colectomy for familial adenomatous polyposis

Most familial adenomatous polyposis (FAP) patients undergo total colectomy, but duodenal polyposis develops in up to 90% of patients with FAP and a 4% to 18% risk of duodenal and ampullary cancer remains. Laparoscopic pancreas-preserving near total duodenectomy is thought to be a potential option and can be an effective approach to preserve the pancreas. A 48-year-old male patient, who underwent laparoscopic total colectomy with end ileostomy because of FAP with colorectal cancer, was diagnosed with a 20 mm-sized duodenal adenoma in the second to the third portion. The operation was performed on December 27, 2021. Near total duodenectomy was done and type II Billroth gastrojejunostomy was done. Laparoscopic pancreas-sparing duodenectomy is shown to be safe, with favorable short-term oncologic outcome compared to laparoscopic pancreatoduodenectomy in terms of less blood loss, faster recovery time, and much less total cost.

Feasibility of underwater endoscopic mucosal resection for endoscopic management of gastric neoplasms in patients with familial adenomatous polyposis.

Underwater endoscopic mucosal resection (UEMR) has been developed as an effective endoscopic intervention for colon, rectum, and duodenum neoplasms. However, there are no comprehensive reports regarding the stomach, and its safety and efficacy are unknown. We aimed to examine the feasibility of UEMR for gastric neoplasms in patients with familial adenomatous polyposis (FAP). We retrospectively extracted data of patients with FAP who underwent endoscopic resection (ER) for gastric neoplasms at Osaka International Cancer Institute from February 2009 to December 2018. Elevated gastric neoplasms of ≤ 20mm in diameter were extracted, and conventional endoscopic mucosal resection (CEMR) and UEMR were compared. Furthermore, outcomes after ER until March 2020 were examined. 91 endoscopically resected gastric neoplasms were extracted from 31 patients with 26 pedigrees, and 12 neoplasms underwent CEMR and 25 neoplasms underwent UEMR was compared. The procedure time was shorter for UEMR than for CEMR. There was no significant difference between en bloc resection and R0 resection rates by EMR methods. CEMR and UEMR showed postoperative hemorrhage rates of 8% and 0%, respectively. Residual/local recurrent neoplasms were identified in four lesions (4%), but additional endoscopic intervention (three UEMR and one cauterization) resulted in a local cure. UEMR was feasible in gastric neoplasms of FAP patients, especially in elevated lesions and those of ≤ 20mm in diameter.

Preclinical Evaluation of a Microwave-Based Accessory Device for Colonoscopy in an In Vivo Porcine Model with Colorectal Polyps

Background and Aims: Colonoscopy is currently the most effective way of detecting colorectal cancer and removing polyps, but it has some drawbacks and can miss up to 22% of polyps. Microwave imaging has the potential to provide a 360° view of the colon and addresses some of the limitations of conventional colonoscopy. This study evaluates the feasibility of a microwave-based colonoscopy in an in vivo porcine model. Methods: A prototype device with microwave antennas attached to a conventional endoscope was tested on four healthy pigs and three gene-targeted pigs with mutations in the adenomatous polyposis coli gene. The first four animals were used to evaluate safety and maneuverability and compatibility with endoscopic tools. The ability to detect polyps was tested in a series of three gene-targeted pigs. Results: the microwave-based device did not affect endoscopic vision or cause any adverse events such as deep mural injuries. The microwave system was stable during the procedures, and the detection algorithm showed a maximum detection signal for adenomas compared with healthy mucosa. Conclusions: Microwave-based colonoscopy is feasible and safe in a preclinical model, and it has the potential to improve polyp detection. Further investigations are required to assess the device’s efficacy in humans.

Clinical significance of SPOP and APC gene alterations in colorectal cancer in Indian population.

Speckle-Type Poz Protein (SPOP) involved in the regulation of proteasome-mediated degradation of several oncoproteins, resulting in cancer initiation and progression. Mutations in Adenomatous Polyposis Coli (APC) gene is reported in most sporadic and hereditary colorectal cancer (CRC). Identifying the cellular changes involved in carcinogenesis when APC is mutated is an important issue that needs attention. The tumor suppressive function of SPOP and APC has long been a major focus in the research field of colorectal cancer. However, the clinical significance of SPOP and APC gene alteration in CRC has not been established to date. Mutational analysis was performed by single-strand conformational polymorphism followed by Sanger sequencing, methylation status by methylation-specific PCR, and protein expression by immunohistochemistry on 142 tumor tissues along with their adjacent non-cancerous specimens. The overall survival (OS) and recurrence free survival (RFS) were estimated by Kaplan-Meier Curve. Mutation rates of APC and SPOP gene were 2.8% and 11.9% while that of promoter hypermethylation were 37% and 47%, respectively. The grade of differentiation and Lymph node metastasis were significantly correlated with APC methylation pattern (p ≤ 0.05). The down regulation of APC was more often seen in colonic cancer compared to rectal cancer (p = 0.07) and more commonly in T3-4 depth of invasion (p = 0.07) and in patients without lymphovascular and perineural invasion (p = 0.007, p = 0.08 respectively). The median overall survival and recurrence free survival (RFS) was 67 & 36months while 3-yr and 5-yr OS and RFS were 61.1% & 56.4% and 49.2% & 44.8%, respectively. APC promoter methylation had a better overall survival (p = 0.035) while loss of SPOP expression had a worse survival (p = 0.09). Our findings reveal high percentage of SPOP gene mutations in CRC. A significant link is found between promoter hyper methylationand protein expression in all mutant cases of APC and SPOP, suggesting that both genes may be associated in the development of colorectal cancer in people of Indian decent. Hypermethylation of APC gene and loss of SPOP expression have shown an association with disease prognosis and could be further studied looking at its potential role in planning adjuvant treatment in CRC patients.

Azithromycin induces read-through of the nonsense Apc allele and prevents intestinal tumorigenesis in C3B6F1 ApcMin/+ mice

Therapeutic strategies that promote read-through of a mutant gene have proved effective for certain non-neoplastic diseases. However, the efficacy of this approach is unproven regarding neoplastic diseases with germline nonsense mutations, including familial adenomatous polyposis. Here we examined the cancer-preventive efficacy of the macrolide antibiotic azithromycin, with a reported read-through effect, on intestinal tumorigenesis in C3B6F1 ApcMin/+ mice harboring a nonsense Apc mutation resulting in a truncated Apc protein. Mice were given drinking water lacking azithromycin or containing 0.0125–0.2 mg/mL azithromycin from 3 weeks of age. The small intestine and cecum were analyzed for pathological changes and alterations of intestinal flora. Azithromycin suppressed the number of tumors and the proportion of adenocarcinomas, with the most effective drinking-water concentration being 0.0125 mg/mL. Furthermore, azithromycin recovered the cellular level of full-length Apc, resulting in downregulation of β-catenin and cyclin D1. Conversely, the effect of azithromycin on the diversity of the intestinal microbiota depended on the drinking-water concentration. These results suggest that the balance between azithromycin-mediate read-through of mutant Apc mRNA and antibacterial effects influences intestinal tumorigenesis. Thus, azithromycin is a potential anticancer agent for familial adenomatous polyposis patients harboring nonsense mutations.

Descripción de 4 casos: tumor desmoide de la mama, diagnóstico y manejo de un tumor infrecuente

IntroductionThe desmoid tumor (DT) of the breast is a rare lesion consisting of proliferation of fibroblastic cells. It can be located intra- or extra-abdominally and the mammary location is exceptional. Although it is a benign lesion, it has a locally aggressive behavior without lymph node or distant metastasis. Its etiology is unknown and 10–20% of cases are related to familial adenomatous polyposis. It presents as a new, painless solid nodule. The treatment has traditionally been surgical resection, with high rates of recurrence despite free margins. Other therapies are being studied. Our objective is to review the management of DT of the breast through the analysis of the casuistry in our center in the last 10 years and the review of the available evidence. MethodsRetrospective descriptive analysis. The cases were identified using the hospital information exploitation system. A narrative review of the literature was performed. ResultsOur series consists of 4 cases, women between 36 and 66 years old. Three of them consulted for a palpable nodule. The CNB presented findings compatible with DT. The cases were presented to a multidisciplinary committee and a wide surgical resection was proposed. The AP confirmed the diagnosis and in one of the cases reported affected margins. During follow-up, recurrence was observed in this case. ConclusionsDTs are infrequent tumors, with clinical repercussions and variable response to treatment. This must include the expectant option and, in any case, be individualized and agreed upon within a multidisciplinary perspective.

Programmed cell death ligand-1 (PD-L1) expression in desmoid tumors: a retrospective study.

Desmoid tumor is a rare benign but locally aggressive monoclonal and fibroblastic proliferation. It lacks metastatic potential but is associated with a high local recurrence after surgery. It is either characterized by the Beta-catenin gene (CTNNB1) or the adenomatous polyposis coli gene (APC) mutation. The most appropriate treatment approach is watchful waiting with periodic follow-ups for asymptomatic patients. However, symptomatic patients who are not good candidates for surgery due to high morbidity risk may benefit from medical therapy. The new drugs targeting programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) display promising results in many cancer types. This study assessed the PD-L1 status of desmoid tumors in 18 patients.Biopsy and resection materials of 18 patients diagnosed with desmoid tumors between April 2016 and April 2021 were retrieved and assessed for PD-L1 expression. The prepared slides were immunohistochemically stained with PD-L1 antibody using Leica Bond® automated immunohistochemistry stainer.No positive PD-L1 staining of the desmoid tumor cells was detected in any specimens. Intratumoral lymphocytes were present in all specimens. However, five of them were positively stained for PD-L1.Based on the results of our study, anti-PD-1/PD-L1 therapy may not be a valuable option in desmoid tumor treatment due to the lack of expression of PD-L1 by desmoid tumor cells. Nevertheless, the presence of positively stained intratumoral lymphocytes may warrant further studies.

Lorpucitinib (JNJ-64251330) in patients with familial adenomatous polyposis (FAP): Results from a phase 1b study.

10514 Background: FAP is the most common hereditary adenomatous polyposis syndrome and, if left untreated, will lead to colorectal cancer development in nearly all patients. Chronic inflammation, driven in part by the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway, may promote polyp formation. Enteric-selective inhibition of the JAK/STAT pathway may provide a treatment for FAP. Lorpucitinib is an oral, small molecule, potent pan-JAK inhibitor with favorable enteric-selective properties. Here, we report the efficacy, safety, and pharmacokinetic (PK) results from a phase 1b study of lorpucitinib in patients with FAP (NCT05014360). Methods: Patients aged ≥18 years with ≥6 polyps ≥2 mm in diameter in the rectum or colon with FAP ( APC germline mutation or obligate carrier) received lorpucitinib 75 mg twice daily for 24 weeks. The primary objective was to evaluate the effect of lorpucitinib on colorectal polyp burden at Week 24, assessed by endoscopy at baseline and Week 24. Secondary objectives were safety, PK, and biomarker assessments of lorpucitinib activity. Results: Overall, 42 (23 pre-colectomy; 19 post-colectomy) patients with FAP were enrolled, with a median age of 33 (range, 19-61) years. No clear effect on polyp burden was observed at Week 24. Gut mucosal and polyp concentrations of lorpucitinib were much higher than plasma concentrations, indicating an enteric-selective distribution. Mean sigmoid colon, rectum, and polyp concentrations of lorpucitinib at Week 8 were 112-, 473-, and 108-fold higher, respectively, than the observed maximum plasma concentration at Week 8 (1 hour). At Week 8, lorpucitinib achieved JAK tyrosine kinase inhibition in mucosal biopsies as evidenced by a median 37% reduction in normalized pSTAT-3 levels. Lorpucitinib reduced serum-based inflammatory biomarkers such as C-reactive protein and serum amyloid A by Week 16 of therapy. Some patients reported an improvement of clinical symptoms such as less frequent bowel movements and less blood in the stool. The most common adverse events (AEs) were abdominal pain (16%), bilirubin increased (13%), headache (13%), lipase increased (13%), and diarrhea (13%). There were no treatment-related serious AEs, grade 3 treatment-emergent AEs, serious infections, or venous thromboembolisms. Conclusions: These results show that lorpucitinib had no clear effect on polyp burden. The study found that lorpucitinib is safe and exhibits an enteric-selective distribution in FAP patients. Inhibition of JAK tyrosine kinase signaling was associated with reduced STAT-3 phosphorylation in mucosal biopsies from FAP patients. While reductions observed in polyp burden were not clinically significant, lorpucitinib treatment lowered levels of several serum inflammatory biomarkers. Treatment with lorpucitinib was safe and well tolerated, and may improve clinical symptoms associated with FAP. Clinical trial information: NCT05014360 .

Serial ctDNA monitoring to predict response in mCRC patients treated with anlotinib in combination with oxaliplatin and capecitabine (CAPEOX) as the first-line therapy.

e15581 Background: Circulating tumour DNA (ctDNA) sequencing offers a non-invasive approach to monitor therapeutic efficacy in colorectal cancer. However, the mutational landscape of ctDNA during treatment and its impact on clinical outcomes remain unknown. This study aimed to investigate the value of ctDNA in predicting treatment response and PFS in mCRC patients treated with anlotinib plus CAPEOX as first-line therapy. Methods: We conducted a multicenter, single-arm, phase II, exploratory study of patients with RAS/BRAF wild-type unresectable metastatic colorectal cancer (mCRC) who underwent Anlotinib in combination with CAPEOX as the first-line therapy (NCT04080843). Plasma samples from 26 patients were collected at three timepoints: 1 week before treatment (baseline), close to the time of optimal remission (C1) and the time of the last blood collection or the time of disease progression (C2). The maximum somatic allele frequency (MSAF) was calculated for each case and used to provide an estimate of the ctDNA fraction in the blood. Results: 77 plasma samples from the 26 enrolled mCRC patients were sequenced by NGS based on a panel comprising 202 genes. 90 variations were detected in baseline plasma, with a positive rate of 96.2% (25/26). Adenomatous polyposis coli ( APC), was the most mutated gene (84.6%, 22/26). Other mutated genes were TP53 (80.8%, 21/26), FBXW7 (19.2%, 5/26), KRAS (11.5%, 3/26), PIK3CA (11.5%, 3/26) and ROS1 (11.5%, 3/26). The median MSAF of baseline ctDNA was significantly higher in patients who had only liver metastases. Compared with baseline, the ctDNA MSAF level at C1 timepoint was decreased among the whole 26 patients (p < 0.001). By comparing ctDNA positive group (ctDNA MSAF > 0) and ctDNA negative group (ctDNA MSAF = 0) at C1 timepoint, CR cases were mainly in ctDNA negative group, while PD cases accounted for a high proportion in the ctDNA positive group. The median progression-free survival (mPFS) of the whole patients was 11.27 months (95%CI 7.33m to 14.52m). The mPFS was 14.52 months (95% CI 14.4 to NR) of patients with ctDNA negative at C1, which was longer than 9.17 months (95% CI 7.16 to 14.06) of patients with ctDNA positive at C1 (p = 0.012). For 25 patients who had plasma samples of three timepoints, we divided the patients into Non-PD group and PD group according to the clinical outcome at C2 timepoint. Compared with C1 timepoint, the ctDNA MSAF level at C2 timepoint was increased in both Non-PD group and PD group. However, the increment of ctDNA MSAF level in PD group was higher than that in non-PD group (p = 0.000069 vs p = 0.024). Conclusions: This ctDNA profiling study revealed the utility of ctDNA in predicting clinical outcomes in mCRC patients under first-line treatment. Serial ctDNA monitoring might become useful in an active surveillance strategy for the management of mCRC. Clinical trial information: NCT04080843 .

A scalable approach to democratizing cancer risk stratification: One healthcare system’s approach using a patient-facing digital platform.

10622 Background: Access to genetic testing and risk stratification is primarily gated by referrals from non-genetics providers for patients who meet testing criteria. The majority of Americans seek care at community hospitals that are closer to home; community hospitals are faced with the challenge of how to democratize access to precision oncology and cancer prevention. Research has shown that the establishment of such protocols is challenging, requiring organizational buy-in, capital, resources, and the involvement of multiple levels of clinical and nonclinical stakeholders. Here we highlight Sarah Cannon, the Cancer Institute of HCA Healthcare, and their programmatic approach to risk stratification using a digital platform offered universally to all patients undergoing screening mammography. Methods: From February to November in 2022, fourteen sites were assessed to have appropriate provider and facility capabilities to support the implement the CARE program. The web-based risk-stratification tool is sent to individuals before standard ambulatory appointments to assess their lifetime risk for breast cancer based on the Tyrer-Cuzick (version 8.0) risk algorithm and National Comprehensive Cancer Network (NCCN) genetic testing criteria. Testing criteria included hereditary breast, ovarian, pancreatic, and prostate cancers, Lynch syndrome, and familial adenomatous polyposis (FAP). Retrospective data was pulled from patients seen between February 2022 through January 2023. The outcome measures included percentage of individuals who completed the risk-assessment, met genetic testing criteria, pursued germline genetic testing, received a positive germline result, and/or had a breast cancer risk ≥20%. Results: During the 10 months at the 14 community hospitals a total of 25,671 individuals were invited for risk assessment through the CARE program; 19,277 (75.1%) individuals completed assessment. Overall, 5,070 (26.3%) met genetic testing criteria and 1,536 individuals had a ≥20% lifetime risk of breast cancer, for a total of 34% of patients identified as elevated risk. 23.4% (1,187) of those meeting criteria opted to proceed with germline genetic testing. An additional 126 individuals who did not meet criteria pursued genetic testing. Of the 1,313 completed genetic tests, 96 (7%) had positive genetic test results. Fifty-four of 96 (56%) positive results had an impact on medical management and cancer prevention. Conclusions: Sarah Cannon and HCA Healthcare have successfully begun implementing a comprehensive, digital risk stratification program in the community hospital setting to provide standardized access to genomic testing and risk stratification. By identifying patients with an elevated risk for cancer, the potential for increased early cancer detection and precision oncology can be observed in a scalable and sustainable program.

P-108 An interplay between immune cells and microbiota drives the spontaneous regression of colorectal polyps in familial adenomatous polyposis pig model

P-108 An interplay between immune cells and microbiota drives the spontaneous regression of colorectal polyps in familial adenomatous polyposis pig model

Radical surgery for non-neoplastic colonic diseases

Aim. To improve the results of surgical treatment for patients with non-neoplastic colonic diseases by optimizing the choice of radical surgery extent. Materials and methods. The study material was the analysis of radical surgical interventions performed in 87 patients with non-neoplastic colonic diseases: ulcerative colitis, Crohn’s disease, familial adenomatous polyposis, chronic colonic and coloproctogenic stasis, diverticular colon disease. The age of the operated patients was 20–72 years. There were 49 (56.3 %) men and 38 (43.7 %) women. The criteria for choosing the radical surgery extent for these diseases were defined and substantiated. Results. There were 3 postoperative mortalities (3.4 %) among patients operated on absolute indications for acute complications of ulcerative colitis and Crohn’s disease. Recurrences of ulcerative colitis, Crohn’s disease and familial adenomatous polyposis occurred in 16 (18.4 %) operated patients in the area of the retained rectal stump and terminal ileum. Malignant transformation of the rectal stump occurred in 5 (5.7 %) patients with these recurrences. The extent of radical surgery in non-neoplastic colonic diseases depended on the diagnosis of the underlying disease, the presence of complications, the depth of wall lesions and the extent of the pathological process, the risk of recurrence in the anatomical parts of the small and large intestine. Conclusions. Deciding on the extent of the radical stage of surgical intervention depended on the diagnosis, features of the clinical course of non-neoplastic colorectal diseases, recurrences, the general condition of a patient, the pathological process extent and severity. Performing the optimal extent of radical surgery for non-neoplastic colonic diseases helped reduce the number of recurrences in the terminal part of the small intestine to 4 (4.6 %), in the area of the rectal stump to 7 (8.1 %), improved functional outcomes and quality of life in 76 (87.3 %) operated patients.

Cribriform Morular Thyroid Carcinoma - Ultimobranchial Pouch-Related? Deep Molecular Insights of a Unique Case.

A 44-year-old female patient with a familial adenomatous polyposis (FAP) was diagnosed with a cribriform morular thyroid carcinoma (CMTC). We observed within the very necrotic tumor a small but distinct poorly differentiated carcinomatous component. As expected, next generation sequencing of both components revealed a homozygous APC mutation and in addition, a TERT promoter mutation. A TP53 mutation was found exclusively in the CMTC part, while the poorly differentiated component showed a clonal evolution, harboring an activating PIK3CA mutation and copy number gains of BRCA2, FGF23, FGFR1, and PIK3CB-alterations which are typically seen in squamous cell carcinoma. The mutational burden in both components was low, and there was no evidence for microsatellite instability. No mutations involving the mitogen-activated protein kinase (MAPK) pathway, typically seen in papillary thyroid carcinomas, were detected. Immunohistochemically, all tumor parts were negative for thyroglobulin, providing further evidence that this entity does not belong to the follicular epithelial cell-derived thyroid carcinoma group. CD5 was negative in the poorly differentiated component, making a relation to intrathyroidal thymic carcinoma rather unlikely. However, since this marker was seen in the morules, a loss in the poorly differentiated component and a relation to the ultimobranchial body cannot be excluded either. After total thyroidectomy and radioiodine ablation, the patient was disease-free with no residual tumor burden on 2-year follow-up.