Colorectal Adenomas Research Articles

Gut bacteria promote proliferation in benign S/RG/C2 colorectal tumour cells, and promote proliferation, migration and invasion in malignant HCT116 cells

Colorectal cancer (CRC) is a significant global health burden with a rising incidence worldwide. Distinct bacterial populations are associated with CRC development and progression, and it is thought that the relationship between CRC and associated gut bacteria changes during the progression from normal epithelium to benign adenoma and eventually malignant carcinoma and metastasis. This study compared the interaction of CRC-associated species Enterotoxigenic Bacteroides fragilis, Enterococcus faecalis and Fusobacterium nucleatum and one probiotic species, Escherichia coli Nissle 1917 with a colorectal adenoma (S/RG/C2) and a colorectal adenocarcinoma (HCT116) derived cell line. Gentamicin protection assays showed that all species displayed higher attachment to benign tumour monolayers when compared to malignant monolayers. However, invasion of 3/4 species was higher in the HCT116 cells than in the adenoma cells. All species were found to persist within tumour cell monolayers for a minimum of 48 h under standard aerobic cell culture conditions, with persistence significantly higher in HCT116 cells. Downstream assays were performed to analyse the behaviour of S/RG/C2 and HCT116 cells post-infection and revealed that all species increased the tumour cell yield of both cell lines. The migratory and invasive potential of HCT116 cells was increased after infection with F. nucleatum; however, no species significantly altered these characteristics in S/RG/C2 cells. These results add to the growing evidence for the involvement of microorganisms in CRC progression and suggest that these interactions may be dependent on tumour cell-specific characteristics.

Impact of a Time-Related Benchmark on the Adenoma Detection Rate in Surveillance Colonoscopy: A STROBE Statement-Oriented Cross-Sectional Cohort Study.

Colorectal adenomas are precursor lesions of globally increasing colorectal cancer. Hence, a high adenoma detection rate in colonoscopy is pivotal. We investigated the clinical impact of stratified colonoscopy observation time combined with observation time/intubation time ratio on the detection of colorectal adenomas. We conducted a single-center retrospective study including 369 consecutive patients who underwent colonoscopy following fecal immunochemical tests between May 2021 and April 2022. The primary outcome measure was the impact of the stratified observation time and observation time/ intubation time ratio (category 1: <6.0 minutes and <1.0, category 2: <6.0 minutes and ≥1.0, category 3: ≥6.0 minutes and <1.0, and category 4: ≥6.0 minutes and ≥1.0) on adenoma detection rate. Cecum intubation was obtained in 367 patients (99.5%). Adenomas were detected in 226 patients (61.2%). From the univariate analysis, age ≥53 years, habitual alcohol intake, colonoscopy attachment (+), and observation time with observation time/intubation time ratio categories 3 and 4 were determined as significant factors for adenoma detection rate. From the logistic regression analysis, age ≥ 53 years (odds ratio: 4.86, 95% CI: 2.25-10.52), habitual alcohol intake (odds ratio: 2.26, 95% CI: 1.33-3.82), category 3 (odds ratio: 3.66, 95% CI: 1.81-7.45), and category 4 (odds ratio: 5.60, 95% CI: 2.92-10.73) were significant factors for adenoma detection rate. We propose the observation time with observation time/intubation time ratio combined benchmark (with categories' thresholds based on observation time >6 minutes and scope withdrawal time exceeding intubation time [observation time/intubation time ratio > 1]) as a novel colonoscopy quality indicator. These findings represent an important educational message for endoscopists.

Strain-level detection of Fusobacterium nucleatum in colorectal cancer specimens by targeting the CRISPR-Cas region.

Fusobacterium nucleatum is associated with colorectal cancer (CRC), and identical F. nucleatum strains seemed to be detected in 75% of patients who exhibited the presence of F. nucleatum in both CRC and saliva samples in our previous study; however, the validation of strain identity and the development of a method for strain-level discrimination are required for etiological studies. We confirmed that F. nucleatum isolates obtained from CRC and saliva samples derived from patients with CRC originated from their identical strains using whole-genome sequencing. We evaluated the hypervariable region of the clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR-associated (CRISPR-Cas) system in F. nucleatum strains isolated from the CRC and saliva specimens of CRC patients to develop a method for genotyping this bacterium at the strain level. The developed method consisted of two simple PCR steps to amplify the different lengths and sequences of the CRISPR-Cas regions from F. nucleatum strains using specific but common primers. This method could successfully detect identical strains present in both cryopreserved CRC samples and saliva obtained from the same CRC patient. Dynamic monitoring of F. nucleatum strains in saliva obtained from patients with colorectal adenoma before and after oral care showed interindividual variability in F. nucleatum strains during oral care. This study provided a simple and rapid method for comprehensively identifying F. nucleatum at the strain level in clinical samples, leading to a paradigm shift in CRC research, such as the investigation of pathogenic F. nucleatum strains and monitoring of pathogenic strains in clinical trials for preventing CRC recurrence. (This study was registered in the UMIN Clinical Trials Registry under ID UMIN000016229.) IMPORTANCE Fusobacterium nucleatum is one of the predominant oral bacteria in humans. However, this bacterium is enriched in colorectal cancer (CRC) tissues and may be involved in CRC development. Our previous research suggested that F. nucleatum is present in CRC tissues originating from the oral cavity using a traditional strain-typing method [arbitrarily primed polymerase chain reaction (AP-PCR)]. First, using whole-genome sequencing, this study confirmed an exemplary similarity between the oral and tumoral strains derived from each patient with CRC. Second, we successfully developed a method to genotype this bacterium at the strain level, targeting the clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR-associated system, which is hypervariable (defined as F. nucleatum-strain genotyping PCR). This method can identify F. nucleatum strains in cryopreserved samples and is significantly superior to traditional AP-PCR, which can only be performed on isolates. The new methods have great potential for application in etiological studies of F. nucleatum in CRC.

Tubular Adenoma of the Breast: Radiologic-Pathologic Correlation.

Breast tubular adenomas (TAs) are rare, benign glandular epithelial tumors that arise from a proliferation of acini in the terminal duct lobular units. In the literature, 40 TA cases have previously been reported, and we describe 5 additional cases in this article. In the small number of reported cases, TAs present most often in women of reproductive age but may also occur in postmenopausal women. Mammographically and sonographically, TAs are almost indistinguishable from fibroadenomas (FAs), and they typically present on US as hypoechoic, oval, circumscribed, parallel masses with variable internal vascularity. TAs can also be seen on mammography as oval masses with microlobulated margins, or as grouped coarse, heterogeneous microcalcifications with or without associated mass or asymmetry. On MRI, TAs present as heterogeneously enhancing, T2-hyperintense oval masses with persistent kinetics. Histopathologically, TAs consist of closely packed round tubules with minimal stroma, in distinction to FAs, which have a prominent stromal component that surrounds and can distort the associated tubules. Because of their benign classification and excellent prognosis, patients with biopsy-confirmed TAs may resume routine screening. Complete surgical excision may be considered for cosmetic purposes or for TAs exhibiting associated suspicious calcifications or rapid growth.

The Diagnostic Yield of Genetic Testing in Patients With Multiple Colorectal Adenomas: A Specialist Center Cohort Study.

Adenoma multiplicity is associated with increased colorectal cancer (CRC) risk. The utility of genetic testing in patients with multiple colorectal adenomas (MCRA) remains uncertain. We evaluated the diagnostic yield of mutations in polyposis- and CRC-associated genes in patients with MCRA. We performed a cross-sectional review of adult patients with 10-99 cumulative adenomas from the prospective database at the St Mark's Hospital Polyposis Registry and Family Cancer Clinic between 1999 and 2021. Genetic testing was performed for adenomatous polyposis-associated genes, hamartomatous polyposis-associated genes, and nonpolyposis colorectal cancer-associated genes. Clinicopathological outcomes were extracted for multiple logistic regression analysis. Two hundred fifty-nine patients with MCRA (median age 61 [interquartile range 53-69] years) were identified. Sixty-six patients (25.5%) had a pathogenic variant or likely pathogenic variant, with APC and biallelic MUTYH mutations constituting the majority of identified pathogenic variant/likely pathogenic variants. Diagnostic yields were greater than 10% at any adenoma burden. In univariate analysis, higher adenoma burden and younger age were associated with higher yield (both P < 0.0001). In patients with MCRA with 10-19 adenomas without a relevant personal or family history of CRC, the diagnostic yield was nil. In multiple logistic regression analysis, higher adenoma burden, younger age, personal history of CRC, and first-degree familial history of CRC were associated with higher diagnostic yield. Diagnostic yield of >10% at any adenoma burden supports current guidance for constitutional genetic testing in patients with MCRA, although the low yield in people older than 60 years with 10-19 adenomas suggests that a stratified approach might be appropriate.

Association of tea and its extracts with colorectal adenomas: meta-analysis and systematic review.

There are many studies on the association of tea and its extracts with colorectal adenomas, but the results have varied. The study aims to investigate the effect of tea and its extracts on colorectal adenomas using meta analysis and systematic review. Literature was obtained through PubMed, Cochrane Library, Embase and Chinese BioMedical Literature Service System since the establishment of the database until April 31, 2023. Search terms include adenomas, polyps, colorectal, rectal, rectum, tea, epigallocatechin, drinking and beverages. Meta-regression analysis was used to infer the source of heterogeneity. Heterogeneity was assessed using I2 statistics and Q test. The effect measures were odds ratio (OR) and 95% confidence interval (95% CI). Stata17.0 software was used for data processing. The findings indicated that study design (t = 0.78, P = 0.454), types of tea intake (t = 1.35, P = 0.205), occurrences (t = -0.19, P = 0.852), regions (t = 1.13, P = 0.281) and grades of adenomas (t = 0.06, P = 0.952) were statistical homogeneity. Tea and its extracts were negatively correlated with the risk of colorectal adenomas (OR = 0.81, 95% CI: 0.66-0.98). No publication bias was found in this study (t = -0.22, P = 0.828) and the results are robust. This study suggests that tea and its extracts have a certain protective effect on colorectal adenomas, which provides scientific evidence for preventive strategies for colorectal adenomas. As for the causal relationship between tea and its extracts on colorectal adenomas, further prospective studies are needed.

Colibactin mutational signatures in NTHL1 tumor syndrome and MUTYH associated polyposis patients.

Polyketide synthase (pks) island harboring Escherichia coli are, under the right circumstances, able to produce the genotoxin colibactin. Colibactin is a risk factor for the development of colorectal cancer and associated with mutational signatures SBS88 and ID18. This study explores colibactin-associated mutational signatures in biallelic NTHL1 and MUTYH patients. Targeted Next Generation Sequencing (NGS) was performed on colorectal adenomas and carcinomas of one biallelic NTHL and 12 biallelic MUTYH patients. Additional fecal metagenomics and genome sequencing followed by mutational signature analysis was conducted for the NTHL1 patient. Targeted NGS of the NTHL1 patient showed somatic APC variants fitting SBS88 which was confirmed using WGS. Furthermore, fecal metagenomics revealed pks genes. Also, in 1 out of 11 MUTYH patient a somatic variant was detected fitting SBS88. This report shows that colibactin may influence development of colorectal neoplasms in predisposed patients.

SAT509 The Clinical Significance of Cribriform Morular Thyroid Carcinoma

Abstract Disclosure: G. Soh: None. K. Sek: None. S. Yang: None. M. Nga: None. S. Mok: None. We present two young (aged below 30) female patients who were diagnosed with the rare cribriform morular thyroid carcinoma. Both patients presented with neck swellings and underwent total thyroidectomy for the thyroid malignancies. The histological diagnosis prompted subsequent genetic evaluation. Both patients demonstrated genotypic and phenotypic evidence of familial adenomatosis polyposis (FAP) syndrome. One of the patients had a mutation which resulted in a premature translational stop signal in the adenomatous polyposis coli (APC) gene. She was eventually diagnosed with adenocarcinoma in 2 colonic polyps and underwent a curative pan-proctocolectomy. The other patient was diagnosed clinically with FAP as she had multiple (30-40) colonic polyps which were tubular adenomas. She had a variant of unknown significance in the APC gene. She declined surgery and remained on colonoscopic surveillance. Both patients’ thyroid cancers are in clinical remission. While uncommon, diagnosing cribriform-morular thyroid carcinoma is significant as 25 to 30% of patients harbour genetic mutations in the APC gene on chromosome 5q21. This is associated with FAP syndrome, an autosomal dominant genetic syndrome characterized by young-onset colonic polyposis, usually of malignant potential. Additionally, these patients may exhibit features of Gardner’s syndrome, a subset of FAP syndrome in which patients can develop extra-colonic manifestations such as osteomas of the mandible and supernumerary teeth. Histologically, cribriform morular thyroid carcinoma are well circumscribed and show a variable combination of follicular, cribriform, papillary, trabecular, solid and morular patterns. There is nuclear and cytoplasmic staining for beta catenin, as the inactivating APC mutation causes a loss of beta catenin destruction complex, impeding beta catenin degradation and increasing its nuclear translocation. This is a key event in thyroid tumorigenesis. The diagnosis of cribriform morular thyroid carcinoma should alert the clinician about the possibility of FAP with consideration for further clinical and genetic evaluation to confirm the diagnosis. References1)Cameselle-Teijeiro, J. M., Peteiro-González, D., Caneiro-Gómez, J., Sánchez-Ares, M., Abdulkader, I., Eloy, C., Melo, M., Amendoeira, I., Soares, P., &amp; Sobrinho-Simões, M. (2018). Cribriform-morular variant of thyroid carcinoma: A neoplasm with distinctive phenotype associated with the activation of the Wnt/β-catenin pathway. Modern Pathology, 31(8), 1168–1179. https://doi.org/10.1038/s41379-018-0070-2 2)Peiling Yang, S., &amp; Ngeow, J. (2016). Familial non-medullary thyroid cancer: Unraveling the Genetic Maze. Endocrine-Related Cancer, 23(12). https://doi.org/10.1530/erc-16-0067 Presentation Date: Saturday, June 17, 2023

Prospective study of diagnostic yields of flexible spectral imaging color enhancement installed in colon capsule endoscopy for colorectal polyps and tumors

Background and AimsWe prospectively aimed to determine the efficacy of flexible spectral imaging color enhancement (FICE) at second-generation colon capsule endoscopy (CCE) for colorectal polyps and tumors (CRTs). MethodsThis study included optical colonoscopy within four months after CCE. Two colonoscopists independently reviewed white light images (CCE-WL) and FICE images (CCE-FICE), respectively. Based on colonoscopic findings as the gold standard, the diagnostic accuracy for CRTs was compared between CCE-WL and CCE-FICE. ResultsOf 89 enrolled patients (65 men and 24 women; 75 with CRTs including 36 with serrated lesions, 63 with adenomas, and 9 with adenocarcinomas), the per-patient detectability of CCE-FICE for the representative CRT was significantly higher than that of CCE-WL: overall CRTs (CCE-WL,79%; CCE-FICE,88%, P=0.0001), 6-9 mm CRTs (63%; 94%, P=0.0055), ≥6mm CRTs (78%; 93%, P=0.0159), respectively. The per-lesion sensitivity of CCE-FICE was significantly higher than that of CCE-WL for CRTs: overall (61%; 79%, P<0.0001), <6 mm (53%; 69%, P<0.0001) and 6-9 mm CRTs (65%; 93%, P=0.0007), slightly elevated CRTs (53%; 75 %, P<0.0001), tubular adenomas (61%; 79%, P<0.0001), and serrated polyps (57%; 74%, P=0.0022), respectively. Both modes detected all adenocarcinomas. There were no significant differences of the per-lesion sensitivity for ≥10 mm or protruding CRTs between CCE-WL and CCE-FICE (81%; 94%, P=0.1138, 77%; 86%, P=0.0614, respectively). Kappa coefficients for overall CRTs at CCE-WL and CCE-FICE were 0.66 and 0.64, respectively, which indicated substantial agreement. ConclusionsCCE-FICE improved the detection rates for all CRTs except adenocarcinomas, ≥10 mm and protruding polyps, when compared to CCE-WL (UMIN 000021125).

Screening and identifying of biomarkers in early colorectal cancer and adenoma based on genome-wide methylation profiles

BackgroundColorectal cancer is one of the most common malignant tumors worldwide with high morbidity and mortality. This study aimed to identify different methylation sites as new methylation markers in CRC and colorectal adenoma through tissue detection.MethodsDNA extraction and bisulfite modification as well as Infinium 450K methylation microarray detection were performed in 46 samples of sporadic colorectal cancer tissue, nine samples of colorectal adenoma, and 20 normal samples, and bioinformatic analysis was conducted involving genes enrichments of GO and KEGG. Pyrosequencing methylation detection was further performed in 68 sporadic colorectal cancer tissues, 31 samples of colorectal adenoma, and 49 normal colorectal mucosae adjacent to carcinoma to investigate the differentially methylated genes obtained from methylation microarray.ResultsThere were 65,535 differential methylation marker probes, among which 25,464 were hypermethylated markers and 40,071 were hypomethylated markers in the adenoma compared with the normal group, and 395,571 were differentially methylated markers in patients with sporadic colorectal cancer compared with the normal group, including 21,710 hypermethylated markers and 17,861 hypomethylated markers. Five hypermethylated genes including ZNF471, SND1, SPOCK1, FBLIM1, and OTX1 were detected and confirmed in 68 cases of colorectal cancer, 31 cases of adenoma, and 49 cases of normal control group.ConclusionsHypermethylated genes of ZNF471, SND1, SPOCK1, FBLIM1, and OTX1 were obtained from methylation chip detection and further confirm analysis in colorectal cancer and adenoma compared with normal tissue, which may be promising diagnostic markers of colorectal cancer and colorectal adenoma.

Value of faecal exfoliated cells in colorectal tumour screening using SDC2 methylation test

Background This study aimed to evaluate the diagnostic value of a non-invasive methylation gene test in clinical colorectal tumour screening. Method The quantitative methylation-specific PCR technique was used to detect faecal methylated syndecan-2 (mSDC2) in patients who received the screening of colorectal cancer (CRC). To evaluate the positive predictive value (PPV) of mSDC2 in patients with colorectal cancer, advanced adenoma (AA), and colorectal tumor (CRN) in risk factor stratification. Results The PPV of CRC, CRC + AA and CRN in male patients were 28.03%, 43.55% and 56.24%, respectively, which were higher than female patients. The positive detection rate of mSDC2 and the PPV of CRC gradually increased with age; The PPV in patients aged over 80 years was up to 78.05%, which was more significant than in younger patients with CRC. The PPV of CRC, AA and CRN were 37.10%, 11.80% and 63.37%, respectively. mSDC2 has a high detection rate of 85–100% in AA with intramucosal carcinoma alone or in combination with severe atypical hyperplasia or villous adenoma. Conclusion The mSDC2 test has a higher PPV in patients with colorectal cancer and colorectal adenoma (AD), especially in high-risk groups over 50 years of age, and may help in the early diagnosis of colorectal tumours in the future.

Usefulness of AI-Equipped Endoscopy for Detecting Colorectal Adenoma during Colonoscopy Screening: Confirm That Colon Neoplasm Finely Can Be Identified by AI without Overlooking Study (Confidential Study).

In the present prospective case series study, we investigated the lesion-detection ability of an AI-equipped colonoscopy as an addition to colonoscopy (CS) screening. Participants were 100 patients aged ≥20 years who had not undergone CS at the study site in the last 3 years and passed the exclusion criteria. CS procedures were conducted using conventional white light imaging and computer-aided detection (CADe). Adenoma detection rate (ADR; number of individuals with at least one adenoma detected) was compared between the conventional group and the CADe group. Of the 170 lesions identified, the ADR of the CADe group was significantly higher than the ADR of the conventional group (69% vs. 61%, p = 0.008). For the expert endoscopists, although ADR did not differ significantly, the mean number of detected adenomas per procedure (MAP) was significantly higher in the CADe group than in the conventional group (1.7 vs. 1.45, p = 0.034). For non-expert endoscopists, ADR and MAP were significantly higher in the CADe group than in the conventional group (ADR 69.5% vs. 56.6%, p = 0.016; MAP 1.66 vs. 1.11, p < 0.001). These results indicate that the CADe function in CS screening has a positive effect on adenoma detection, especially for non-experts.

Metachronous Colorectal Adenomas Occur Close to the Index Lesion.

The aim of this study is to assess the spatial relationship between index and metachronous colorectal adenoma location. After the complete excision of a human sporadic colorectal adenoma, patients are at elevated risk of developing a further metachronous adenoma. Data regarding the occurrence site of a metachronous colorectal adenoma relative to the index adenoma are scarce. Prospectively maintained databases were interrogated to identify all colonoscopies and adenoma excisions performed over a 10-year period at a single university teaching hospital. Data for the colonic segments at which adenoma removal were reported at index and all subsequent colonoscopies were extracted and 2 allied data sets merged. A total of 15,121 colonoscopies and 4759 polyp events were recorded. Four hundred fifty-two patients [296 male, 156 female, median (range) age 75 (32 to 100) y] developed at least 1 metachronous adenoma at follow-up colonoscopy. When single index events only are considered (ie, synchronous adenoma cases excluded), over 61% of metachronous adenomas were recorded in the same or an adjacent colonic segment. When the full span of the colon is considered, metachronous adenomas were more likely to occur in a section of the colon proximal to that of the index adenoma (41%±5%) than the same (39%±5%) or distal segment (20%±5%; P=0.006; 1-way χ2 test). A metachronous human sporadic colorectal adenoma is more likely to be found in the same colonic segment to that of the index adenoma or 1 immediately adjacent. These data suggest a shared origin of metachronous adenoma with preceding lesions, supporting the existence of precancerous fields.

S248 Association Between Dietary Fiber Intake and Colorectal Adenoma: A Systematic Review and Meta-Analysis

S248 Association Between Dietary Fiber Intake and Colorectal Adenoma: A Systematic Review and Meta-Analysis

S374 Folate Receptor Is a Marker of Colorectal Adenoma in a Prospective Cohort of Matched Colorectal Adenoma and Normal Colon Organoids

S374 Folate Receptor Is a Marker of Colorectal Adenoma in a Prospective Cohort of Matched Colorectal Adenoma and Normal Colon Organoids

S3343 McKittrick-Wheelock Syndrome: Chronic Diarrhea Due to a Giant Tubulovillous Adenoma With Endoscopic Management

S3343 McKittrick-Wheelock Syndrome: Chronic Diarrhea Due to a Giant Tubulovillous Adenoma With Endoscopic Management

S2471 Incidental Focal FDG Uptake on PET-CT Scan Resulting in Diagnosis of a Large Tubulovillous Adenoma

S2471 Incidental Focal FDG Uptake on PET-CT Scan Resulting in Diagnosis of a Large Tubulovillous Adenoma

140P Colorectal adenoma subtypes exhibit distinct molecular profiles- implications to early detection

140P Colorectal adenoma subtypes exhibit distinct molecular profiles- implications to early detection

S440 Impact of Artificial Intelligence on Colorectal Adenoma Detection in High-Risk Colonoscopy: Initial Experience at a Safety-Net Hospital

S440 Impact of Artificial Intelligence on Colorectal Adenoma Detection in High-Risk Colonoscopy: Initial Experience at a Safety-Net Hospital

Benign urinary bladder masses: rare entities

BackgroundThis study aimed to present the characteristics and outcomes of benign urinary bladder masses, as well as the characteristics of the patients diagnosed with such lesions.MethodsA single-center, cross-sectional, retrospective study was conducted. The study involved patients who underwent transurethral resection of the primary bladder tumor over a four-year period (May 2017–2021) and were subsequently diagnosed with a benign bladder lesion.ResultsOut of 478 patients who underwent transurethral resection of the primary bladder tumor, 26 (5.4%) were diagnosed with a benign bladder lesion. The most common benign bladder lesion was urothelial papilloma (50%, 13 patients). The majority of patients with urothelial papilloma were men (76.9%) and had a history of smoking (61.5%). The mean age was 62 years. Most were diagnosed accidentally (69.2%), while others presented with hematuria (23.1%) or dysuria (7.7%). Most urothelial papillomas had a macroscopic polypoid appearance (61.5%), and most of them were solitary (84.6%), with a mean size amounting to 1 cm. Only one patient experienced a recurrence and developed papillary urothelial neoplasm of low malignant potential (PUNLMP). Cystitis cystica/glandularis and polypoid cystitis were the second most commonly diagnosed benign bladder lesion, each identified in 3 patients. Singular cases of leiomyoma, inflammatory myofibroblastic tumor, chondroma, paraganglioma, villous adenoma, eosinophilic cystitis (pseudotumor), and ectopic prostatic tissue are described.ConclusionBenign bladder lesions constitute a group of various rare entities that can clinically and radiologically mimic urothelial carcinoma, but mostly show a good prognosis and a low incidence of recurrence.