Gynaecological cancer surveillance for women with Lynch syndrome: systematic review and cost-effectiveness evaluation.

Background: Lynch syndrome is an inherited condition which leads to an increased risk of colorectal, endometrial and ovarian cancer. Risk-reducing surgery is generally recommended to manage the risk of gynaecological cancer once childbearing is completed. The value of gynaecological colonoscopic surveillance as an interim measure or instead of risk-reducing surgery is uncertain. We aimed to determine whether gynaecological surveillance was effective and cost-effective in Lynch syndrome. Methods: We conducted systematic reviews of the effectiveness and cost-effectiveness of gynaecological cancer surveillance in Lynch syndrome, as well as a systematic review of health utility values relating to cancer and gynaecological risk reduction. Study identification included bibliographic database searching and citation chasing (searches updated 3 August 2021). Screening and assessment of eligibility for inclusion were conducted by independent researchers. Outcomes were prespecified and were informed by clinical experts and patient involvement. Data extraction and quality appraisal were conducted and results were synthesised narratively. We also developed a whole-disease economic model for Lynch syndrome using discrete event simulation methodology, including natural history components for colorectal, endometrial and ovarian cancer, and we used this model to conduct a cost-utility analysis of gynaecological risk management strategies, including surveillance, risk-reducing surgery and doing nothing. Results: We found 30 studies in the review of clinical effectiveness, of which 20 were non-comparative (single-arm) studies. There were no high-quality studies providing precise outcome estimates at low risk of bias. There is some evidence that mortality rate is higher for surveillance than for risk-reducing surgery but mortality is also higher for no surveillance than for surveillance. Some asymptomatic cancers were detected through surveillance but some cancers were also missed. There was a wide range of pain experiences, including some individuals feeling no pain and some feeling severe pain. The use of pain relief (e.g. ibuprofen) was common, and some women underwent general anaesthetic for surveillance. Existing economic evaluations clearly found that risk-reducing surgery leads to the best lifetime health (measured using quality-adjusted life-years) and is cost-effective, while surveillance is not cost-effective in comparison. Our economic evaluation found that a strategy of surveillance alone or offering surveillance and risk-reducing surgery was cost-effective, except for path_PMS2 Lynch syndrome. Offering only risk-reducing surgery was less effective than offering surveillance with or without surgery. Limitations: Firm conclusions about clinical effectiveness could not be reached because of the lack of high-quality research. We did not assume that women would immediately take up risk-reducing surgery if offered, and it is possible that risk-reducing surgery would be more effective and cost-effective if it was taken up when offered. Conclusions: There is insufficient evidence to recommend for or against gynaecological cancer surveillance in Lynch syndrome on clinical grounds, but modelling suggests that surveillance could be cost-effective. Further research is needed but it must be rigorously designed and well reported to be of benefit. Study registration: This study is registered as PROSPERO CRD42020171098. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: NIHR129713) and is published in full in Health Technology Assessment; Vol. 28, No. 41. See the NIHR Funding and Awards website for further award information.

Lynch syndrome is an inherited condition which puts people at a higher risk of getting bowel cancer, womb cancer and ovarian cancer. Although people with Lynch syndrome are more likely to get these cancers, they are more likely to survive cancer if they get it. People diagnosed with Lynch syndrome get regular testing (surveillance) using a camera to check for bowel cancer or polyps. For womb and ovarian cancer, surveillance may also be an option, but it is less well studied in these cancers. This means that many women are not offered surveillance. Women with Lynch syndrome are recommended to have risk-reducing surgery when their risk starts rising, if they do not want any more children. We wanted to find out whether surveillance for womb and ovarian cancer would work and would be good value for money. Doctors and patients have said that these are important research questions. We searched for published research on this subject and found a lot of studies, but these studies were often small or not well designed, so they could only tell us a limited amount. Studies did not always measure the things that patients want to know. There was some evidence that people having surveillance might live longer than people not having surveillance, but there was also some evidence that risk-reducing surgery is better than surveillance. Surveillance has detected some cancers which had no symptoms, but there are also cancers diagnosed soon after a surveillance visit where nothing was found. People often find surveillance painful, but experiences vary. Our work shows that surveillance and surgery could be good value for money for many women with Lynch syndrome. We need better research to help patients and doctors decide whether surveillance is right for them.

The Role of Endoscopic Ultrasound in Ampullary Lesion Management.

Ampullary lesions, neoplasms originating in the papilla of Vater, represent a rare yet clinically significant group of tumors with diverse etiologies and management challenges. This comprehensive review aims to elucidate the pivotal role of endoscopic ultrasound (EUS) in the diagnosis, staging, and management of ampullary lesions. This review begins by providing an overview of ampullary lesions, their epidemiology, and associated risk factors. We delve into their clinical presentation, emphasizing the importance of early and accurate diagnosis. Furthermore, we explore the limitations of traditional diagnostic modalities and highlight the growing relevance of EUS in ampullary lesion evaluation. We discuss the superior spatial resolution of EUS in comparison with other imaging methods, and we present an in-depth analysis of EUS-guided sampling and its pivotal role in obtaining histological samples for accurate diagnosis. In addition to diagnosis, we examine the indispensable role of EUS in ampullary lesion staging and its clinical implications. Furthermore, we discuss the potential of EUS in the surveillance and follow-up of ampullary lesions, ensuring timely detection of recurrence and monitoring treatment response in sporadic cases and in the context of familial syndromes, such as familial adenomatous polyposis (FAP). In conclusion, this review underscores the indispensable role of endoscopic ultrasound in the multifaceted approach to ampullary lesion evaluation. EUS not only enhances diagnostic accuracy but also informs treatment decisions and minimally invasive therapeutic interventions. As our understanding of ampullary lesions continues to evolve, EUS remains an invaluable tool for the improvement of patient outcomes and quality of life.

Quantitative characterization of eosinophilia in nasal polyps with AI-based single cell classification.

KEY POINTS: Eosinophilic granulocytes have characteristic morphological features. This makes them prime candidates for utilization of a single cell binary classification network. Single cell binary classification networks can reliably help quantify eosinophils in nasal polyps.

Real-world outcomes on quality-of-life improvement in patients with nasal polyposis treated with mepolizumab. RINOSUR study.

Chronic rhinosinusitis with nasal polyps (CRSwNP) is characterized by nasal obstruction, reduced sense of smell, rhinorrhea, and facial pain for more than 12 weeks, significantly affecting quality of life (QoL), especially in patients with NSAID-exacerbated respiratory disease (NERD). Initial treatment includes intranasal corticosteroids and nasal irrigations, followed by systemic corticosteroids (SC) in severe cases, as well as endoscopic sinus surgery (ESS) and biological agents. Mepolizumab, a monoclonal antibody against IL-5, has been shown to reduce eosinophilic inflammation in CRSwNP. This study evaluates the improvement in quality of life of patients with CRSwNP treated with mepolizumab before December 2023, recorded by the RINOSUR group. A retrospective observational multicenter cohort study is presented in adult patients with severe asthma and concomitant CRSwNP, treated with mepolizumab 100 mg. Variables such as sex, asthma, allergies, NERD, corticosteroid dependence, and serum eosinophil count were recorded. All patients underwent nasal endoscopy and completed the SNOT22 questionnaire. Therapeutic response was evaluated at 12 months. Out of 143 patients recruited, only 28.6% had the necessary data. 61% were women with a mean age of 55 years. All were corticosteroid-dependent and had required at least one ESS. A 22% reduction in SC cycles was observed, and no patient required revision surgery in the 12 months following treatment. The SNOT22 score was reduced by 53 points, and serum eosinophilia also showed a significant decrease. Mepolizumab is effective in treating severe uncontrolled CRSwNP, improving QoL and reducing dependence on systemic corticosteroids. Its activity is monitored by peripheral blood eosinophilia. Consistency in data collection is crucial to evaluate efficacy and manage the disease.

Endoscopic and Pharmacologic Treatment of Obesity in Patients With Hereditary Polyposis Syndromes.

Patients with hereditary polyposis syndromes (HPS) are among the highest risk of multiple types of cancer. This risk is further magnified by comorbid obesity; however, HPS present unique risks for bariatric surgery. The advent of endoscopic bariatric and metabolic therapies along with advancements in the realm of antiobesity medications provides potential weight loss alternatives in this vulnerable population. We present 2 cases of patients with obesity and HPS successfully treated with intragastric balloons in combination with antiobesity medications.

Adrenal tumours in patients with pathogenic APC mutations: a retrospective study.

BACKGROUND: Adrenal tumours are associated with familial adenomatous polyposis (FAP). In the literature, most studies use the clinical definition of FAP (more than 100 adenomatous polyps found in endoscopic studies). However, not all patients that meet clinical criteria for FAP carry pathogenic mutations in the adenomatous polyposis coli (APC) gene, as there is genetic heterogeneity responsible for FAP with the polyposis sometimes explained by genetic and environmental factors other than pathogenic APC mutations. Reciprocally, not all the patients with pathogenic APC variants will fulfil the classic criteria of FAP. OBJECTIVE: This study aims to investigate the characteristics of adrenal tumours in patients with pathogenic or likely pathogenic APC variants and explore the hormonal function of these patients. METHOD: This is a retrospective cohort study. Patients with pathogenic or likely pathogenic APC variants were recruited and their radiological assessments were reviewed. Patient demographic data, APC variants, adrenal mass characteristics and hormonal testing results were collected. RESULT: The prevalence of adrenal mass was 26.7% (24/90) among patients with pathogenic or likely pathogenic APC variants. Using the classic definition, the prevalence was 32.4% (22/68). Four patients had adrenal hormone testing, two of which had Conn's syndrome and two had nonspecific subclinical results. CONCLUSION: In our cohort, the prevalence of adrenal tumours among patients with pathogenic and likely pathogenic APC mutations is at least twice to three times higher than the general population prevalence reported from international population-based studies. The hormonal functions of patients with pathogenic APC variants and adrenal tumours can be investigated with routine testing in further research.

Desmoplastic fibroma of the mandible in a 5-year-old child as an early oral manifestation of familial adenomatous polyposis.

Desmoplastic fibroma (DF) is a benign yet locally aggressive intraosseous tumour rarely encountered in the mandible. It often mimics other oral lesions. Familial adenomatous polyposis (FAP) is a condition in which individuals tend to develop multiple colorectal polyps, which may convert to colorectal cancer unless treated. FAP has various colonic and extra-colonic manifestations, including oral manifestations. A case of DF of the mandible in a 5-year-old child is presented here. The patient remained free of recurrence 4 years after segmental resection and immediate reconstruction with a fibula free flap. Subsequent genetic testing revealed FAP, implicating DF as an early oral manifestation. A review of the existing literature emphasizes the challenges in diagnosing DF and its association with FAP, stressing the importance of comprehensive assessment and genetic screening in suspected cases.

Ileoanal Pouch Salvage Rates with Endoluminal Vacuum Therapy for Early vs. Late Anastomotic Leaks.

BACKGROUND: Anastomotic leaks post-ileoanal pouch-anal anastomosis (IPAA) significantly compromise patient outcomes and increase healthcare resource utilization. The aim of this study was to evaluate outcomes of Endoluminal Vacuum Therapy (EndoVac) for pouch leaks. We hypothesized that EndoVac for early compared with late leaks was associated with a higher pouch survival rate. METHODS: We retrospectively reviewed consecutive pouch anastomotic leaks treated with EndoVac therapy at our institution between 2013-2023. Patients were stratified into early (≤30 days) and late (>30 days) leaks. Anastomotic healing was defined as complete closure of the leak site and resolution of symptoms. Pouch failure was defined as a permanent ileostomy or pouch excision. The probability of pouch survival was estimated using the Kaplan-Meier method. RESULTS: A total of 14 IPAA patients were included: median age 34 years, 71% were male, and median body mass index 23.46kg/m2. DIAGNOSES: ulcerative colitis (n=12) and familial adenomatous polyposis (n=2). The median (IQR) time from pouch construction to leak was 44.5 (12-192) days; of these, 6 (43%) early and 8 (57%) late. All (100%) leaks were at the anastomosis; all (100%) were diverted at the time of EndoVac therapy: 10 (71%) still diverted and 4 (29%) re-diverted. Patients underwent a median of 5.5 EndoVac changes (3-7) over a duration of 13.5 (6-21) days from initiation of treatment to cessation of therapy. After EndoVac therapy, healing was observed in 10 (71%) patients, 2 of whom required a minor handsewn anastomotic revision but healed completely, and 4 did not heal: 3 had pouch excision and 1 underwent redo pouch surgery. Anastomotic healing (66.7% vs. 75%, p=0.7) and pouch survival (83.3% vs. 75%, p=0.73) were not significantly different between the early and late leak groups. The overall pouch salvage rate was 78.5%. CONCLUSIONS: EndoVac therapy was effective in achieving high rates of pouch salvage and anastomotic healing in patients with ileoanal pouch leaks, irrespective of the timing of intervention postoperatively. This supports the use of EndoVac as a viable treatment option for both early and late anastomotic leaks.

Familial adenomatous polyposis: a case report.

BACKGROUND: Familial adenomatous polyposis is characterized by the presence of multiple colorectal adenomatous polyps and caused by germline mutations in the tumor suppressor gene and adenomatous polyposis coli, located on chromosome 5q21-q22. Familial adenomatous polyposis occurs in approximately 1/10,000 to 1/30,000 live births, and accounts for less than 1% of all colorectal cancers in the USA. It affects both sexes equally and has a worldwide distribution. The incidence of colon cancer in low- and middle-income countries is rising. In addition to the increasing incidence, lack of early detection and impeded access to optimal multidisciplinary treatment may worsen survival outcomes. Developing quality diagnostic services in the proper health context is crucial for early diagnosis and successful therapy of patients with colorectal cancer, and applying a resource-sensitive approach to prioritize essential treatments on the basis of effectiveness and cost-effectiveness is key to overcoming barriers in low- and middle-income countries. We report a case of familial adenomatous polyposis presenting as adenocarcinoma with multiple colorectal adenomatous polyps. The diagnosis of familial adenomatous polyposis was made by the presence of numerous colorectal adenomatous polyps and family history of colonic adenocarcinoma. Due to its rarity, we decided to report it. CASE PRESENTATION: A 22-year-old Ethiopian female patient presented to Addis Ababa University College of Health science, Addis Ababa, Ethiopia with rectal bleeding. Abdominopelvic computed tomography scan was done and showed distal rectal asymmetric anterior wall thickening in keeping with rectal tumor. Colonoscopy was done and she was diagnosed to have familial adenomatous polyposis with severe dysplasia. In the meantime, colonoscopy guided biopsy was taken and the diagnosis of adenocarcinoma with familial adenomatous polyposis was rendered. For this, total proctocolectomy was carried out. On laparotomy there was also incidental finding of left ovarian deposition for which left salpingo-oophorectomy was done, and 4 weeks after surgical resection, the patient was started on oxaliplatin, leucovorin, fluorouracil chemotherapy regimen. CONCLUSION: In the clinical evaluation of a patient with rectal bleeding, familial adenomatous polyposis must be considered as a differential diagnosis in subjects having family history of colonic adenocarcinoma for early diagnostic workup, management, family genetic counseling, and testing.

Outcomes of Endoscopic Sinus Surgery for Chronic Rhinosinusitis With Nasal Polyposis and Risk Factors of Recurrence in a Tertiary Care Teaching Hospital.

Background: Endoscopic sinus surgery (ESS) has become the gold standard for treating patients with chronic rhinosinusitis (CRS) refractory to medical therapy. It is considered a relatively safe and effective procedure in all age groups, with overall success rates ranging from 76% to 97.5%. However, failure of primary endoscopic sinus surgery (PESS) occurs at a rate ranging from 2% to 24%. Patients who are still symptomatic after PESS and optimal medical therapy are candidates for revision endoscopic sinus surgery (RESS). Objectives: to study the outcomes of ESS and assess the risk factors of recurrence of nasal polyps, as well as to compare the outcomes of PESS and RESS at a tertiary care teaching hospital. Design: A retrospective cross-sectional study. Methods: This study is conducted on patients with CRS with nasal polyps (CRSwNP) who underwent ESS at King Saud University Medical City (KSUMC) between May 2015 and December 2021. During this period, ESS was performed 470 times for CRSwNP. The Sinonasal Outcome Test 22 (SNOT-22) questionnaire, the Lund-Kennedy (LK) score, the Lund-MacKay (LM) score, and the polyp grading system were used to evaluate subjective and objective outcomes. They were scored preoperatively and from 6 to 12 months postoperatively. Results: Out of the 470 endoscopic sinus surgeries, 321 (68.3%) were PESS and 149 (31.7%) were RESS. Asthma, aspirin sensitivity, and Samter's triad were observed more in the RESS group. The LK and LM scores were significantly different between primary and revision sinus surgeries, revealing that PESS patients had better postoperative LK and LM scores. The RESS patients had significantly worse postoperative SNOT-22 scores compared to PESS patients. Conclusion: Lund-MacKay, Lund-Kennedy, and SNOT-22 scores improved after ESS for both primary and revision ESS patients, with better outcomes observed after PESS compared to RESS. The presence of asthma, aspirin sensitivity, Samter's Triad, high-grade nasal polyps, and older age were identified as risk factors for CRSwNP recurrence, which may require RESS.

Gastric polyposis and risk of gastric cancer in patients with familial adenomatous polyposis.

BACKGROUND: Gastric polyposis is common in familial adenomatous polyposis (FAP) syndrome. However, the incidence and risk factors for gastric cancer (GC) are unclear. We aimed to evaluate the incidence of GC and associated risk factors in a large FAP population. METHODS: Retrospective review of patients with FAP undergoing upper endoscopy at Mayo Clinic from 1989 to 2023. Cumulative incidence of GC (95% CIs) were calculated using Kaplan-Meier survival approaches. Associations of clinical characteristics with development of GC were examined using Cox proportional hazards regression. RESULTS: A total of 337 patients underwent 2502 endoscopies with a median of 10.4 years (IQR, 3.9-17.2) of endoscopic surveillance. At any time during surveillance, 294 patients (87%) had gastric polyps; 200 (59%), fundic gland polyps; 116 (34%), low-grade dysplasia (LGD); and 11 (3.3%), high-grade dysplasia (HGD). Among these, only 6 patients (2%) developed GC-5 with HGD (3 [50%] on previous endoscopy and 2 [33%] at the time of cancer diagnosis) and 1 (16%) with LGD on previous endoscopy. The 10-year cumulative incidence of GC is 0% with no polyps, 1% with polyps, 6% with LGD, 11% with polyps ≥2 cm, and 20% with HGD. Both HGD and polyps ≥2 cm had a strong association with the development of GC (P < .001). CONCLUSION: Although the overall risk of GC in FAP is low, outcomes remain poor. GC can be predicted by endoscopic findings and specific GC surveillance guidelines are imperative to improve detection rates and guide timely intervention.

A Descriptive Analysis of Nasal Polyposis in HIV Positive Versus HIV Negative Patients.

Nasal polyposis (NP) represents a benign proliferation of soft tissue tumors within the nasal cavity and paranasal sinuses, characterized by chronic inflammation of the sinonasal mucosa. This phenomenon, attributed to various environmental and physiological factors, presents clinically as semi-transparent masses with variable morphology, often obstructing nasal passages and causing respiratory compromise, olfactory dysfunction, and recurrent infections. Predominantly associated with chronic rhinosinusitis (CRS), NP poses significant challenges in diagnosis and management, particularly in the context of comorbid conditions such as human immunodeficiency virus (HIV) infection. HIV infection, known for its debilitating effects on the immune system, is theorized to exacerbate NP development and manifestation through mechanisms involving CD4 cell depletion and dysregulation of immune responses. Despite extensive research, elucidating potential pathways linking HIV infection to NP, comprehensive understanding remains elusive. This study aims to address this knowledge gap by conducting a retrospective chart review of patients presenting with NP at Charlotte Maxeke Johannesburg Academic Hospital between January 2016 and December 2020. The primary objective is to investigate the influence of HIV status on the clinical, radiological, and histological features of NP. Data collection, encompassing patient demographics, HIV status, clinical presentations, radiological findings, and histopathological characteristics, will be conducted between March 2021 and August 2022. Preliminary analysis of collected data reveals a cohort of 41 patients meeting inclusion criteria, with notable exclusions based on undisclosed HIV status and incomplete documentation. Initial findings suggest a nuanced interplay between genetic predisposition, environmental factors, and HIV status in NP pathogenesis, underscoring the need for further research to validate these observations. In conclusion, this study underscores the importance of elucidating the complex relationship between HIV infection and NP to optimize diagnostic and therapeutic approaches, particularly in regions with a high HIV prevalence such as South Africa. By comprehensively assessing the clinical, radiological, and histological features of NP in HIV-positive and HIV-negative populations, this research endeavours to enhance our understanding of NP pathophysiology and improve patient outcomes.

Outcome of Post Functional Endoscopic Sinus Surgery Nasal Irrigation with Normal Saline Versus Normal Saline with Budesonide in Patients with Sinonasal Polyposis: A Randomized Control Trial.

Chronic rhinosinusitis(CRS) is a condition characterized by inflammation of the lining of nose and sinuses lasting for 12 weeks or more. CRS with nasal polyp nasal polyp(CRSwNP) is seen in 0.5-4% of the population and is present in about 20% of patients with CRS. Functional endoscopic sinus surgery aids in restoring the ventilation and drainage of paranasal sinuses. Postoperatively, various solutions are used to irrigate the sinus cavity for pharmaceutical and mechanical lavage. Hence, it is imperative to compare different solutions to choose the best to give a favorable outcome. A total of 24 postoperative CRSwNP patients were randomly divided into two groups. Group A received routine post-FESS medication as per the institute guidelines. Group B received budesonide nasal irrigation in addition to regular care. Both groups were evaluated endoscopically at 1, 4, and 12 weeks after the surgery. Pre and postoperative quality of life were compared. Endoscopic Lund-Kennedy scoring (objective measurement) and Sino-Nasal Outcome Test 22 score were used to compare the two groups. The mean preoperative Sino Nasal Outcomes Test 22 score(SNOT-22) was 46.58 ± 6.18 in group A and 50.5 ± 5.7 in group B. It was reduced to 15.00 ± 2.00 and 9.75 ± 1.95 postoperatively in both groups respectively at the end of 3 months. Postoperatively, the mean endoscopic score was 2.36 ± 0.80 in group A and 1.18 ± 0.40 in group B at the end of 3 months. In conclusion, saline plus budesonide nasal irrigation is a better option when compared to saline only irrigation in terms of efficacy and therapeutic effect in patients undergoing FESS for CRSwNP, hence, it should be advocated in regular clinical practice.

A Solitary Peutz-Jeghers Hamartomatous Polyp in the Gastric Body: A Case Report.

Peutz-Jeghers syndrome (PJS) is a rare autosomal dominant genetic condition characterized by the development of hamartoma-type intestinal polyposis and areas of skin pigmentation, among other signs. Additionally, the occurrence of solitary Peutz-Jeghers polyps is exceedingly rare. We present the case of a 50-year-old female with a medical history of hypothyroidism, chronic gastritis, and dyslipidemia, who presented with dyspeptic symptoms and occasional rectal bleeding. Endoscopic examination revealed a solitary hamartomatous polyp in the gastric body and other gastrointestinal abnormalities. The patient underwent treatment and is being monitored with regular endoscopic studies and evaluations for other potential neoplasms. This case underscores the importance of considering the syndrome as a potential differential diagnosis. It emphasizes the necessity of a multidisciplinary approach to managing and monitoring such cases, particularly the early detection of possible neoplasms.

Effect of genetic profiling on surgical decisions at hereditary colorectal cancer syndromes.

Hereditary colorectal cancer syndromes, such as Lynch syndrome and familial adenomatous polyposis (FAP), present significant clinical challenges due to the heightened cancer risks associated with these genetic conditions. This review explores genetic profiling impact on surgical decisions for hereditary colorectal cancer (HCRC), assessing options, timing, and outcomes. Genotypes of different HCRCs are discussed, revealing a connection between genetic profiles, disease severity, and outcomes. For Lynch syndrome, mutations in the MLH1, MSH2, MSH6, and PMS2 genes guide the choice of surgery. Subtotal colectomy is recommended for patients with mutations in MLH1 and MSH2, while segmental colectomy is preferred for those with MSH6 and PMS2 mutations. In cases of metachronous colon cancer after segmental colectomy, subtotal colectomy with ileorectal anastomosis is advised for all mutations. Surgical strategies for primary rectal cancer include anterior resection or abdominoperineal resection (APR), irrespective of the specific mutation. For rectal cancer occurring after a previous segmental colectomy, proctocolectomy with ileal pouch-anal anastomosis (IPAA) or APR with a permanent ileostomy is recommended. In FAP, surgical decisions are based on genotype-phenotype correlations. The risk of desmoid tumors post-surgery supports a single-stage approach, particularly for certain APC gene variants. Juvenile Polyposis Syndrome (JPS) surgical decisions involve genetic testing, polyp characteristics with attention to vascular lesions in SMAD4 mutation carriers. However, genetic profiling does not directly dictate the specific surgical approach for JPS. In conclusion this review highlights the critical role of personalized surgical plans based on genetic profiles to optimize patient outcomes and reduce cancer risk. Further research is needed to refine these strategies and enhance clinical guidelines.

In Silico Deciphering of the Potential Impact of Variants of Uncertain Significance in Hereditary Colorectal Cancer Syndromes.

Colorectal cancer (CRC) ranks third in terms of cancer incidence worldwide and is responsible for 8% of all deaths globally. Approximately 10% of CRC cases are caused by inherited pathogenic mutations in driver genes involved in pathways that are crucial for CRC tumorigenesis and progression. These hereditary mutations significantly increase the risk of initial benign polyps or adenomas developing into cancer. In recent years, the rapid and accurate sequencing of CRC-specific multigene panels by next-generation sequencing (NGS) technologies has enabled the identification of several recurrent pathogenic variants with established functional consequences. In parallel, rare genetic variants that are not characterized and are, therefore, called variants of uncertain significance (VUSs) have also been detected. The classification of VUSs is a challenging task because each amino acid has specific biochemical properties and uniquely contributes to the structural stability and functional activity of proteins. In this scenario, the ability to computationally predict the effect of a VUS is crucial. In particular, in silico prediction methods can provide useful insights to assess the potential impact of a VUS and support additional clinical evaluation. This approach can further benefit from recent advances in artificial intelligence-based technologies. In this review, we describe the main in silico prediction tools that can be used to evaluate the structural and functional impact of VUSs and provide examples of their application in the analysis of gene variants involved in hereditary CRC syndromes.

Hereditary Colorectal Cancer and Polyposis Syndromes Caused by Variants in Uncommon Genes.

A substantial number of hereditary colorectal cancer (CRC) and colonic polyposis cannot be explained by alteration in confirmed predisposition genes, such as mismatch repair (MMR) genes, APC and MUTYH. Recently, a certain number of potential predisposition genes have been suggested, involving each a small number of cases reported so far. Here, we describe the detection of rare variants in the NTLH1, AXIN2, RNF43, BUB1, and TP53 genes in nine unrelated patients who were suspected for inherited CRC and/or colonic polyposis. Seven of them were classified as pathogenic or likely pathogenic variants (PV/LPV). Clinical manifestations of carriers were largely consistent with reported cases with, nevertheless, distinct characteristics. PV/LPV in these uncommon gene can be responsible for up to 2.7% of inherited CRC or colonic polyposis syndromes. Our findings provide supporting evidence for the role of these genes in cancer predisposition, and contribute to the determination of related cancer spectrum and cancer risk for carriers, allowing for the establishment of appropriate screening strategy and genetic counseling in affected families.

Cowden Syndrome: A Rare Cause of Intestinal Polyposis.

Cowden syndrome (CS) is a rare autosomal dominant genodermatosis disorder. This disease is characterized by the development of several hamartomata lesions in a variety of tissues from all three embryonic layers. The most well-known hamartomata are those of the gastrointestinal system, which represent one of the major criteria for the diagnosis of CS. Yet, the most frequent initial presenting symptom of the disease is thought to be mucocutaneous symptoms such as trichilemmomas, acral keratosis, and oral papilloma. Early diagnosis and management are essential to improving the quality of life for patients with CS as this disorder predisposes them to cancers such as thyroid, breast, gastrointestinal, and endometrial cancers. This report presents a rare case of CS in a Bahraini child who presented with macrocephaly and had numerous intestinal polyposis. Genetic testing using whole exome sequencing confirmed the diagnosis, identifying a pathogenic de novo phosphatase and tensin homolog gene (PTEN) variant (Chr10 NM_000314.8: c.17_18del p.(Lys6Argfs*4)) in a heterozygous state. This variant has been confirmed by Sanger sequencing.

Exploring Familial Adenomatous Polyposis Through Radiology: A Case Series and Literature Review.

Familial adenomatous polyposis (FAP) is a dominantly inherited, autosomal form of hereditary condition caused by a germline mutation in the adenomatous polyposis coli (APC) gene. The early development of adenomatous polyps in the colon and rectum predisposes to rampant proliferation, which usually leads to colorectal cancer. Hence, this condition demands intensive surveillance and aggressive intervention. This case report epitomizes the convergence of advanced imaging with genetic diagnosis and, in essence, points toward a complete multidisciplinary approach as critical for proper management of FAP. The detailed evaluation of two siblings presenting with similar gut symptoms from this article focused on the individualization that this condition needs when managed, although underpinning the critical role coordinated care plays in changing disease outcomes.