Unselected Cases Research Articles

Conversion of Total Wrist Arthrodesis to a Total Wrist Arthroplasty: Twelve Patients Followed for 7 (2–16) Years

Total wrist arthroplasty has become a viable alternative to arthrodesis. Wrist arthrodesis is not necessarily the final surgery for many of the patients because some patients never accept the residual pain and reduced function that accompanies a stiff wrist. The purpose of this study was to evaluate the clinical performance (pain, function, and satisfaction) of rearticulation, as well as the complications and reoperations of the procedure in a prospective unselected case series of patients. Twelve (7 men) patients with a mean age of 53 (42-67) years were converted to a total wrist arthroplasty at a mean of 8 (3-17) years after wrist arthrodesis. The patients had undergone 53 wrist surgeries prior to rearticulation. One wrist with a periprosthetic fracture of the ulna and a loose distal radioulnar joint arthroplasty that had been removed during the conversion was finally fused a second time. At follow-up 7 (2-16) years after conversion, increased wrist active range of motion (0°-98°), supination (75°-85°), reduced Patient-Rated Wrist Evaluation score (56-30), and reduced visual analog scale pain scores were found. All arthroplasties were radiologically stable, well-fixed and osseointegrated. None regretted the surgery knowing the outcome. Conversion from total wrist arthrodesis to a modern wrist arthroplasty is feasible, yielding good functional results, significant pain relief, and stable implants. Therapeutic IV.

Extended panel testing in ovarian cancer reveals BRIP1 as the third most important predisposition gene

PurposeThe prevalence of germline pathogenic variants (PVs) in homologous recombination repair (HRR) and Lynch syndrome (LS) genes in ovarian cancer (OC) is uncertain. MethodsAn observational study reporting the detection rate of germline PVs in HRR and LS genes in all OC cases tested in the North West Genomic Laboratory Hub between September 1996 and May 2024. Effect sizes are reported using odds ratios (ORs) and 95% confidence intervals (95% CI) for unselected cases tested between April 2021 and May 2024 versus 50,703 controls from the Breast Cancer Risk after Diagnostic Gene Sequencing study. Results2934 women were tested for BRCA1/2 and 433 (14.8%) had a PV. In up to 1572 women tested for PVs in non-BRCA1/2 HRR genes, detection rates were PALB2 = 0.8%, BRIP1 = 1.1%, RAD51C = 0.4% and RAD51D = 0.4%. In 940 unselected cases, BRIP1 (OR = 8.7, 95% CI 4.6-15.8) was the third most common OC predisposition gene followed by RAD51C (OR = 8.3, 95% CI 3.1-23.1), RAD51D (OR = 6.5, 95% CI 2.1-19.7), and PALB2 (OR = 3.9, 95% CI 1.5-10.3). No PVs in LS genes were detected in unselected cases. ConclusionPanel testing in OC resulted in a detection rate of 2% to 3% for germline PVs in non-BRCA1/2 HRR genes, with the largest contributor being BRIP1. Screening for LS in unselected cases of OC is unnecessary.

Germline pathogenic variants of cancer predisposition genes in a multicentre Italian cohort of pancreatic cancer patients.

Background and aimGermline BRCA1–2 test is routinely recommended in Pancreatic Cancer (PC) patients, due to its clinical-epidemiological relevance. Data on the prevalence of germline pathogenic variants (gPV) in other cancer predisposition and DNA Damage Repair (DDR) system-related genes in unselected PC cases are sparce in Italy. We assessed this prevalence in a multicentre cohort, to derive recommendations for PC patients. MethodsClinical data of 1200 consecutive PC patients, of any age and stage, tested with a multigene germline panel were collected. A descriptive analysis of gPV frequency and clinical variables was performed both in 1092 patients tested for an 18 genes core-panel (CP-18 cohort) and in 869 patients screened only for CDKN2A. Results11.5 % (126/1092) of CP-18 cohort patients harbored a gPV in ≥ 1 gene. Highest gPV frequencies were detected in ATM (3.1 %), BRCA2 (2.9 %), BRCA1 (1.6 %), CHEK2 (1.1 %). Patients harboring any CP-18 gene and BRCA1–2 gPV were younger and with a higher rate of personal (PH) or family history (FH) of cancer when compared to no gPV patients. The risk of having a gPV was ≥ 7 % in all subgroups of patients, including those aged > 73, with tumor stage I-III and negative FH/PH. CDKN2A gPV were detected in 2.6 % (23/869) of patients. ConclusionsA remarkable prevalence of gPV in cancer predisposition and DDR genes is reported in this large multicentre cohort of consecutive and unselected PC patients. Therefore, we recommend multigene germline testing (at least including BRCA1–2, ATM, CDKN2A, PALB2) for all PC patients, irrespective of age, stage, PH/FH.

HGG-16. PEDIATRIC-TYPE DIFFUSE HIGH-GRADE GLIOMA OF METHYLATION-BASED RTK2A AND RTK2B SUBCLASSES PRESENT DISTINCT RADIOLOGICAL AND HISTOMOLECULAR FEATURES

Abstract BACKGROUND Diffuse pediatric-type high-grade gliomas (pedHGG), H3-wildtype and IDH-wildtype, encompass three main methylome-based subclasses: pedHGG-MYCN, -RTK1A/B/C, and -RTK2A/B. Since their first description in 2017, tumors of pedHGG-RTK2A/B have not been further characterized and their clinical significance is unknown. METHODS A not yet published cases series on pedHGG with a gliomatosis cerebri (GC) growth pattern showed an increased incidence of pedHGG-RTK2A/B (n=18/40). We assembled a cohort of 14 additional methylation-based pedHGG-RTK2A/B tumors and pooled them with the GC tumors providing centrally reviewed radiological, histological, and molecular characterization. RESULTS Our cohort of 32 pedHGG-RTK2A/B tumors consisted of 25 RTK2A (78%) and seven RTK2B (22%) cases. The median age was 11.6 years (4-17) with an overall survival of 15.9 months (interquartile range 12.1-25.8). Of the additional unselected cases with available imaging (10 of 14), seven showed a GC phenotype at diagnosis or follow-up. In addition, pedHGG-RTK2B tumors exhibited bithalamic involvement (6/7, 86%). Histopathology confirmed a diffuse glial neoplasm in all cases with prominent angiocentric features in both subclasses. Most tumors (24/29, 83%) diffusely expressed EGFR, notably with a focal perivascular enhancement. Cells of pedHGG-RTK2A lacked Olig2 expression, whereas 43% (3/7) of pedHGG-RTK2B expressed Olig2. Loss of ATRX expression occurred in four pedHGG-RTK2B samples (57%). In sequencing analyses (RTK2A: n=18, RTK2B: n=5), EGFR alterations (n=15/23, 65%; predominantly point mutations) were commonly found in both subclasses. Mutations in BCOR (n=14/18, 78%), SETD2 (n=7/18, 39%), and TERT promoter (n=6/18, 33%) occurred exclusively in pedHGG-RTK2A tumors, while pedHGG-RTK2B tumors were enriched for TP53 mutations (4/5, 80%). CONCLUSIONS In conclusion, genotype-phenotype correlations in a multicenter series of pedHGG-RTK2A/B tumors revealed a highly diffuse-infiltrating tumor frequently exhibiting a GC phenotype. The two subclasses share particular histomolecular features (EGFR alterations, angiocentric pattern), whereas they differ in specific characteristics (pedHGG-RTK2A: Olig2 negativity, BCOR and SETD2 mutations; pedHGG-RTK2B: ATRX and TP53 alterations).

Test performance and clinical utility of expanded non-invasive prenatal test: Experience on 71,883 unselected routine cases from one single center.

The balance between benefits and risks of discordant outcomes makes the Genome-Wide Non-Invasive Prenatal Test (GW-NIPT) controversial. This study aims to evaluate performance and clinical utility in a wide cohort of unselected clinical cases from a single center when a standardized protocol is applied and integrated with a secondary algorithm for data interpretation. In 2years, over 70,000 pregnant patients underwent GW-NIPT for fetal common trisomies, sex chromosome aneuploidies, rare autosomal aneuploidies, segmental abnormalities (CNVs≥7Mb) and microdeletions (CNVs<7Mb). All samples were uniformly processed with Veriseq NIPT Solution v2 and analyzed using all data metrics along with a home-made algorithm for sequencing data analysis. Results were retrospectively reviewed for clinical outcomes. Among 71,883 eligible cases including twin pregnancies, 1011 (1.4%) received a positive result and 781 were confirmed by invasive prenatal diagnosis. Clinical sensitivity ranged from 99.65% for common trisomy (T21, T18, T13) to 83.33% for microdeletions, while specificity remained high (99.98%) for each class of fetal abnormalities detected. Integrating a standardized protocol with an internal algorithm allowed discordant results to be reduced, yielding high accuracy. Observed reliability in detecting genome-wide chromosomal conditions reinforced the expanded NIPT utility in clinical practice.

Telomere-lengthening germline variants predispose to a syndromic papillary thyroid cancer subtype

Papillary thyroid cancer (PTC) is the most common endocrine malignancy. 10% to 15% of individuals show familial clustering with three or more affected members, but the factors underlying this risk are unknown. In a group of recently studied individuals with POT1 pathogenic variants and ultra-long telomere length, PTC was the second most common solid tumor. We tested whether variants in POT1 and four other telomere-maintenance genes associated with familial cancer underlie PTC susceptibility. Among 470 individuals, we identified pathogenic or likely pathogenic variants in three genes encoding telomere-binding proteins: POT1, TINF2, and ACD. They were found in 4.5% and 1.5% of familial and unselected cases, respectively. Individuals harboring these variants had ultra-long telomere length, and 15 of 18 (83%) developed other cancers, of which melanoma, lymphoma, and sarcoma were most common. Among individuals with PTC and melanoma, 22% carried a deleterious germline variant, suggesting that a long telomere syndrome might be clinically recognizable. Successive generations had longer telomere length than their parents and, at times, developed more cancers at younger ages. Tumor sequencing identified a single oncogenic driver, BRAF p.Val600Glu, in 10 of 10 tumors studied, but no telomere-maintenance mechanism, including at the TERT promoter. These data identify a syndromic subset of PTCs with locusheterogeneity and telomere lengthening as a convergent mechanism. They suggest these germline variants lower the threshold to cancer by obviating the need for an acquired telomere-maintenance mechanism in addition to sustaining the longevity of oncogenic mutations.

Germline pathogenic variants associated with triple-negative breast cancer in US Hispanic and Guatemalan women using hospital and community-based recruitment strategies

PurposeRecruit and sequence breast cancer subjects in Guatemalan and US Hispanic populations. Identify optimum strategies to recruit Latin American and Hispanic women into genetic studies of breast cancer.MethodsWe used targeted gene sequencing to identify pathogenic variants in 19 familial breast cancer susceptibility genes in DNA from unselected Hispanic breast cancer cases in the US and Guatemala.Recruitment across the US was achieved through community-based strategies. In addition, we obtained patients receiving cancer treatment at major hospitals in Texas and Guatemala.ResultsWe recruited 287 Hispanic US women, 38 (13%) from community-based and 249 (87%) from hospital-based strategies. In addition, we ascertained 801 Guatemalan women using hospital-based recruitment. In our experience, a hospital-based approach was more efficient than community-based recruitment. In this study, we sequenced 103 US and 137 Guatemalan women and found 11 and 10 pathogenic variants, respectively. The most frequently mutated genes were BRCA1, BRCA2, CHEK2, and ATM. In addition, an analysis of 287 US Hispanic patients with pathology reports showed a significantly higher percentage of triple-negative disease in patients with pathogenic variants (41% vs. 15%). Finally, an analysis of mammography usage in 801 Guatemalan patients found reduced screening in women with a lower socioeconomic status (p < 0.001).ConclusionGuatemalan and US Hispanic women have rates of hereditary breast cancer pathogenic variants similar to other populations and are more likely to have early age at diagnosis, a family history, and a more aggressive disease. Patient recruitment was higher using hospital-based versus community enrollment. This data supports genetic testing in breast cancer patients to reduce breast cancer mortality in Hispanic women.

Specialized Laparoscopic Devices in the Treatment of Hydatic Hepatic Cysts: A Retrospective Analysis and Review of the Literature.

Background and objective While hydatid disease is associated with a high prevalence only in certain endemic areas, it can be encountered in any geographical region. The characteristics of this parasitic disease, and its implications during development, such as the risk of seeding, and the complications caused by cyst rupture, means that its therapeutic management should adhere to strict principles and may sometimes require approaches specially tailed for this type of pathology. In this study, we aimed to provide a comparative analysis of conventional laparoscopic techniques vs. treatment withspecialized instrumentation in these patients. Methods Our study involveda retrospective evaluationof a cohort comprising 41 patients diagnosed with hepatic hydatid cysts, who underwent procedures with both conventional laparoscopic techniques and specialized instrumentation tailored for this particular pathology. Furthermore, we conducted a comprehensive review of the literature examining alternative types of laparoscopic instrumentation specifically crafted for the management of hydatid cysts. This review employed an extensive search utilizing PubMed and Google Scholar databases. Results The examination of cases within our study revealed a high prevalence of hydatid disease among male patients (63.41%) and a predominance of instances originating from rural regions necessitating emergent admissions (p<0.05). Notably, in 58.54% of cases, surgical interventions employed specialized instrumentation, with a notable discrepancy in conversion rates to open surgery favoring the standard approach: 12.2% vs. 2.44% (p=0.025). Additionally, the laparoscopic approach was associated with prolonged surgical durations compared to the dedicated technique (p=0.002), besides a higher incidence of postoperative complications (12.2% vs 7.32%). Furthermore, patients undergoing laparoscopic procedures with standard instrumentation experienced lengthier hospital stays (p=0.002). Our comprehensive review of the literature identified six distinct surgical methodologies utilizing specifically tailored instrumentation for addressing hydatid cysts. Analysis of these findings underscored a preference for single localizations and selective cases. Postoperative complication rates ranged from 6.66% to 22.22%, with conversion rates to open surgery reaching up to 23.33%, and recurrence rates observed to be as high as 7.81%. Conclusions The patented approach, which uses special trocars that provide stable anchorage and allow a safe puncture-aspiration, reaspiration, and fragmentation processes, has superior characteristics compared to the laparoscopic approach with standard instrumentation. Comparative analysis with other similar procedures described in the literature has shown similar results regarding the frequency of complications, with our technique being superior in terms of approaching multiple cysts and recurrence rate. It has been successfully applied even in unselected cases.

P491 Clinical application of ICCE criteria for suspected Crohn’s disease undergoing small bowel capsule endoscopy

Abstract Background Small-bowel capsule endoscopy (SBCE) is the primary diagnostic modality for exploring the small bowel (SB) in patients with suspected Crohn’s disease (CD) and inconclusive ileocolonoscopy findings, provided there are no obstructive symptoms or known bowel strictures. In 2005, the International Conference on Capsule Endoscopy (ICCE) established preselection criteria for these patients (Figure 1). SBCE is indicated if one criterion from group A is met, along with any other from the remaining groups (B/C/D). The aim of this study is to evaluate the diagnostic accuracy of ICCE criteria in unselected cases of suspected small bowel CD (SBCD) explored with SBCE. Methods An observational, single-center, retrospective study was conducted, including all SBCE performed in patients with suspected CD between January 2020 and August 2023. Demographic and clinical data, inflammatory markers, SBCE findings, confirmed CD diagnosis and indication to therapy were analyzed. Results A total of 46 patients were included (67.4% females, median age 43 years, IQR 32-60). SBCE identified lesions suggestive of CD based on Mow's criteria in 23.9% of patients (n=11). These findings led to a CD diagnosis in all cases, with subsequent initiation of immunomodulators or biologic therapy. In the study population, 35 (71.4%) patients had 2 ICCE criteria (A+B/C/D). The percentage of patients with ≥2 criteria did not differ significantly between those with and without CD (90.9% vs. 71.4%, p=0.18). However, overall ungrouped ICCE criteria showed a significant correlation with confirmed CD (OR 1.56, 95%CI 1.03-2.36). The creation of a model using 4 ungrouped ICCE criteria significantly improved CD prediction accuracy (area under the ROC curve 0.77, sensitivity 91%, specificity 51.4%). Patients with 4 ungrouped ICCE criteria had a higher likelihood of having confirmed CD (90 vs 48%, p=0.02). Conclusion In our patient cohort, the existing ICCE criteria seem insufficient for effectively identifying patients with a higher probability of SBCD. Our findings suggest that adopting a cut-off of 4 ungrouped ICCE criteria would increase the diagnostic accuracy of SBCE for SBCD.

BRAFV600E immunohistochemistry can reliably substitute BRAF molecular testing in the Lynch syndrome screening algorithm in colorectal cancer.

The Lynch syndrome (LS) screening algorithm requires BRAF testing as a fundamental step to distinguish sporadic from LS-associated colorectal carcinomas (CRC). BRAF testing by immunohistochemistry (IHC) has shown variable results in the literature. Our aim was to analyse concordance between BRAFV600E IHC and BRAF molecular analysis in a large, mono-institutional CRC whole-slide, case series with laboratory validation. MisMatch repair (MMR) protein (hMLH1, hPMS2, hMSH2, and hMSH6) and BRAFV600E IHC were performed on all unselected cases of surgically resected CRCs (2018-2023). An in-house validation study for BRAFV600E IHC was performed in order to obtain optimal IHC stains. BRAFVV600E IHC was considered negative (score 0), positive (scores 2-3), and equivocal (score 1). Interobserver differences in BRAFV600E IHC scoring were noted in the first 150 cases prospectively collected. Nine-hundred and ninety CRCs cases (830 proficient (p)MMR/160 deficient (d)MMR) were included and all cases performed BRAFV600E IHC (BRAFV600E IHC-positive 13.5% of all series; 66.3% dMMR cases; 3.4% pMMR cases), while 333 also went to BRAF mutation analysis. Optimal agreement in IHC scoring between pathologists (P < 0.0001) was seen; concordance between BRAFV600E IHC and BRAF molecular analysis was extremely high (sensitivity 99.1%, specificity 99.5%; PPV 99.1%, and NPV 99.5%). Discordant cases were reevaluated; 1 score 3 + IHC/wildtype case was an interpretation error and one score 0 IHC/mutated case was related to heterogenous BRAFV600E IHC expression. Among the 12 IHC-equivocal score 1+ cases (which require BRAF molecular analysis), three were BRAF-mutated and nine BRAF-wildtype. BRAFV600E IHC can be used as a reliable surrogate of molecular testing after stringent in-house validation.

Endometrial Pipelle Biopsy Computer-Aided Diagnosis: A Feasibility Study

Endometrial biopsies are important in the diagnostic workup of women who present with abnormal uterine bleeding or hereditary risk of endometrial cancer. In general, approximately 10% of all endometrial biopsies demonstrate endometrial (pre)malignancy that requires specific treatment. As the diagnostic evaluation of mostly benign cases results in a substantial workload for pathologists, artificial intelligence (AI)-assisted preselection of biopsies could optimize the workflow. This study aimed to assess the feasibility of AI-assisted diagnosis for endometrial biopsies (endometrial Pipelle biopsy computer-aided diagnosis), trained on daily-practice whole-slide images instead of highly selected images. Endometrial biopsies were classified into 6 clinically relevant categories defined as follows: nonrepresentative, normal, nonneoplastic, hyperplasia without atypia, hyperplasia with atypia, and malignant. The agreement among 15 pathologists, within these classifications, was evaluated in 91 endometrial biopsies. Next, an algorithm (trained on a total of 2819 endometrial biopsies) rated the same 91 cases, and we compared its performance using the pathologist’s classification as the reference standard. The interrater reliability among pathologists was moderate with a mean Cohen’s kappa of 0.51, whereas for a binary classification into benign vs (pre)malignant, the agreement was substantial with a mean Cohen’s kappa of 0.66. The AI algorithm performed slightly worse for the 6 categories with a moderate Cohen’s kappa of 0.43 but was comparable for the binary classification with a substantial Cohen’s kappa of 0.65. AI-assisted diagnosis of endometrial biopsies was demonstrated to be feasible in discriminating between benign and (pre)malignant endometrial tissues, even when trained on unselected cases. Endometrial premalignancies remain challenging for both pathologists and AI algorithms. Future steps to improve reliability of the diagnosis are needed to achieve a more refined AI-assisted diagnostic solution for endometrial biopsies that covers both premalignant and malignant diagnoses.

Automated Cytomorphological Analysis of Bone Marrow Samples: A Proof-of-Principle Study for AI-Based Classification on a Real-Life Data Set of 979 Unselected Cases

BACKGROUND: Cytomorphological analysis of bone marrow (BM) samples is a cornerstone of hematological diagnostics. It requires microscopical cell counting by a human specialist, resulting in a differential cell count and a morphological description/diagnosis. The process is susceptible to interobserver variability and may be limited by the areas examined. AIM: Clinical implementation of AI-based recognition of pathological patterns in BM smears to support cytomorphological diagnostics. METHODS: We evaluated unselected BM samples over a three-week period (n= 979), including cases with various hematological diseases. We analyzed both shipped unstained slides (n=522, 53%) and smears prepared in-house from BM aspirates (n=457, 47%) with variable shipping time (0-10d, median = 1d), reflecting diagnostic reality in an international reference laboratory. After conventional cytomorphological assessment, each sample was further analyzed by immunophenotyping, cytogenetics, FISH or molecular genetics, according to diagnostic guidelines. BM slides were then scanned using a Metasystems Metafer System (Altlussheim, GER), yielding up to 52 fields of view (FOVs) (2048x1496px each). Cells were automatically identified, segmented, and imaged resulting in 2636 cells per case on average (range = 0 - 10,072, SD = 2164), which were classified into 24 distinct cell classes using an AI-classifier based on the ResNext-architecture. After eliminating 107 samples (10.9%) due to insufficient scanning/sample quality or low cell counts (&amp;lt;100), 872 samples were further analyzed. We defined 7 relevant pathological patterns extractable from human differential counts which served as ground truth for comparison with AI-based classifications: elevated blast fraction (three-tiered, ≥5%, ≥10%, ≥20%), eosinophilia (≥ 20%), plasmacytosis (≥10%), lymphocytosis (≥20%) and monocytosis (≥5%). For each case, we calculated the median prediction probability (MPP) for each pathological pattern, based on the sum of single cell predictions for pattern-specific cell type and cell fraction (Figure 1). RESULTS: Out of 872 analyzed cases, 341 cases showed one pathological pattern (39.1%), 85 cases showed two patterns (9.7%), and 8 showed three patterns (0.9%) as ground truth. MPP for the pathological patterns were: 0.60 for blasts ≥20% (indicating acute leukemia), 0.52 for blasts ≥10% (e.g. suggesting MDS-IB2), 0.61 for blasts ≥5% (e.g. suggesting MDS-IB1), 0.90 for Eosinophilia (suggesting ML-Eo, HES), 0.87 for plasmacytosis (suggesting plasma cell myeloma), 0.87 for lymphocytosis (suggesting lymphoma) and 0.79 for monocytosis (suggesting MDS or CMML). In cases presenting a blast fraction ≥20% (ground truth) and an MPP for blasts below the median of 0.61, MPP for lymphocytosis and monocytosis was substantially higher (0.81 and 0.71 respectively). This points to the known challenge of differentiating these 3 cell types in AI-supported as well as in human cell classification. Of note, pathological patterns of high clinical relevance (i.e. elevated blast fractions) had consistently low MPP in true negative cases (0.03 for blasts ≥20%, 0.07 for blasts ≥10%, 0.15 for blasts ≥5%). CONCLUSION: We successfully implemented automated scanning and AI-based recognition of pathological patterns in a high-throughput routine workflow on unselected BM smears with variable pathologies, preanalytical parameters and quality. AI detected 7 relevant pathological patterns extracted from human differentials at acceptable prediction probability, even if present concurrently. Confusion of mononuclear cells was noted and requires further optimization of image acquisition and AI-based quality control (e.g., upstream binary classifiers or pre-selection of FOVs) to enhance robustness. This preliminary study proves the technical feasibility of AI-based recognition of pathological BM patterns, to support human investigators in decision making for further diagnostic processes.

Untutored training pathway to achieve competence in esophagogastric endoscopic submucosal dissection in a Western center

Background and AimsEndoscopic submucosal dissection (ESD) has a long learning curve. We aimed to assess the efficacy of an ESD unsupervised training model for experienced endoscopists. MethodsStepwise training included visit to high-volume center, unsupervised training on an ex-vivo porcine model and in-vivo human upper GI cases with anatomical progression. Performance measures: en-bloc resection, R0 resection, complication rates and operative time. ResultsFollowing observation of 30 esophago-gastric ESDs and 15 un-tutored ex-vivo ESDs, five human cases of distal gastric ESDs were performed, followed by 55 unselected esophago-gastric cases. En-bloc and R0 resection rates were 93.0% and 80.7%, respectively. Operative time was 14.0 min/cm2 in stomach and 25.1 min/cm2 in esophagus, with evidence of learning curve for esophageal ESDs (first block 30.26 vs second block 14.81 min/cm2, p=0.01). ConclusionsUn-tutored training for esophago-gastric ESD is feasible and allows endoscopists, experienced in therapeutic endoscopy, to achieve the required standards towards competency.

Detection Rate and Spectrum of Pathogenic Variations in a Cohort of 83 Patients with Suspected Hereditary Risk of Kidney Cancer.

Hereditary predisposition to cancer affects about 3-5% of renal cancers. Testing criteria have been proposed in France for genetic testing of non-syndromic renal cancer. Our study explores the detection rates associated with our testing criteria. Using a comprehensive gene panel including 8 genes related to renal cancer and 50 genes related to hereditary predisposition to other cancers, we evaluated the detection rate of pathogenic variants in a cohort of 83 patients with suspected renal cancer predisposition. The detection rate was 7.2% for the renal cancer genes, which was 2.41-fold higher than the estimated 3% proportion of unselected kidney cases with inherited risk. Pathogenic variants in renal cancer genes were observed in 44.5% of syndromic cases, and in 2.7% of non-syndromic cases. Incidental findings were observed in CHEK2, MSH2, MUTYH and WRN. CHEK2 was associated with renal cancer (OR at 7.14; 95% CI 1.74-29.6; p < 0.003) in our study in comparison to the gnomAD control population. The detection rate in renal cancer genes was low in non-syndromic cases. Additional causal mechanisms are probably involved, and further research is required to find them. A study of the management of renal cancer risk for CHEK2 pathogenic variant carriers is needed.

Clinicopathologic features and prognostic significance of mixed (Low and high-grade) papillary urothelial carcinoma comparison with low and high-grade papillary urothelial carcinoma.

The World Health Organization/International Society of Urological Pathology (2022 WHO/ISUP) classification categorizes noninvasive carcinomas based on the highest grade observed in a pathology sample. According to this classification, a lesion is classified as mixed-grade (MG) if the highest-grade component comprises less than 5% high-grade (HG) carcinoma [14]. This study included 160 cases of low-grade papillary urothelial carcinoma (LGUC) and 160 cases of HG papillary urothelial carcinoma (HGUC), selected randomly. In addition, 160 consecutive and unselected cases of MG papillary urothelial carcinoma (MGUC) were obtained from all bladder transurethral resection specimens diagnosed with papillary urothelial carcinoma between January 2007 and January 2021. The results of the multivariate analysis showed that histologic grade, invasion of the lamina propria, and the presence of carcinoma in situ at presentation were independent prognostic parameters regarding recurrence-free survival (p = 0.002; hazard ratio (HR) = 1.44, 95% confidence interval (CI) = 1.059-1.956, p = 0.02; and HR = 1.76, 95% CI = 1.159-2.684, p = 0.008, respectively). Histologic grade was the only independent prognostic parameter of disease-specific survival (DSS) (p < 0.001). Comparisons between non-muscle invasive (NMI) MGUC and NMI LGUC, as well as between NMI MGUC and NMI HGUC, revealed statistically significant differences in terms of DSS (HR = 0.07, 95% CI = 0.024-0.252,p< 0.001 and HR = 1.59, 95% CI = 1.023-2.460, p = 0.039, respectively). Our study findings demonstrate statistically significant differences regarding DSS between NMI MGUC and NMI HGUC, as well as between NMI MGUC and NMI LGUC. Therefore, we suggested that considering the presence of less than 5% MGUC as a separate category may be appropriate. However, it is important to validate our results in larger cohorts with longer follow-up periods to establish the clinical significance of MGUC and provide guidance for patient management.

Exome sequencing identified rare recurrent copy number variants and hereditary breast cancer susceptibility.

Copy number variants (CNVs) are a major source of genetic variation and can disrupt genes or affect gene dosage. They are known to be causal or underlie predisposition to various diseases. However, the role of CNVs in inherited breast cancer susceptibility has not been thoroughly investigated. To address this, we performed whole-exome sequencing based analysis of rare CNVs in 98 high-risk Northern Finnish breast cancer cases. After filtering, selected candidate alleles were validated and characterized with a combination of orthogonal methods, including PCR-based approaches, optical genome mapping and long-read sequencing. This revealed three recurrent alterations: a 31 kb deletion co-occurring with a retrotransposon insertion (delins) in RAD52, a 13.4 kb deletion in HSD17B14 and a 64 kb partial duplication of RAD51C. Notably, all these genes encode proteins involved in pathways previously identified as essential for breast cancer development. Variants were genotyped in geographically matched cases and controls (altogether 278 hereditary and 1983 unselected breast cancer cases, and 1229 controls). The RAD52 delins and HSD17B14 deletion both showed significant enrichment among cases with indications of hereditary disease susceptibility. RAD52 delins was identified in 7/278 cases (2.5%, P = 0.034, OR = 2.86, 95% CI = 1.10-7.45) and HSD17B14 deletion in 8/278 cases (2.9%, P = 0.014, OR = 3.28, 95% CI = 1.31-8.23), the frequency of both variants in the controls being 11/1229 (0.9%). This suggests a role for RAD52 and HSD17B14 in hereditary breast cancer susceptibility. The RAD51C duplication was very rare, identified only in 2/278 of hereditary cases and 2/1229 controls (P = 0.157, OR = 4.45, 95% CI = 0.62-31.70). The identification of recurrent CNVs in these genes, and especially the relatively high frequency of RAD52 and HSD17B14 alterations in the Finnish population, highlights the importance of studying CNVs alongside single nucleotide variants when searching for genetic factors underlying hereditary disease predisposition.

Diagnostic Yield and Benefits of Whole Exome Sequencing in CAKUT Patients Diagnosed in the First Thousand Days of Life

Congenital anomalies of the kidney and urinary tract (CAKUT) are the predominant cause of chronic kidney disease (CKD) and the need for kidney replacement therapy (KRT) in children. Although more than 60 genes are known to cause CAKUT if mutated, genetic etiology is detected, on average, in only 16% of unselected CAKUT cases, making genetic testing unproductive. Whole exome sequencing (WES) was performed in 100 patients with CAKUT diagnosed in the first 1000 days of life with CKD stages 1 to 5D/T. Variants in 58 established CAKUT-associated genes were extracted, classified according to the American College of Medical Genetics and Genomics guidelines, and their translational value was assessed. In 25% of these mostly sporadic patients with CAKUT, a rare likely pathogenic or pathogenic variant was identified in 1 or 2 of 15 CAKUT-associated genes, including GATA3, HNF1B, LIFR, PAX2, SALL1, and TBC1D1. Of the 27 variants detected, 52% were loss-of-function and 18.5% de novo variants. The diagnostic yield was significantly higher in patients requiring KRT before 3 years of age (43%, odds ratio 2.95) and in patients with extrarenal features (41%, odds ratio 3.5) compared with patients lacking these criteria. Considering that all affected genes were previously associated with extrarenal complications, including treatable conditions, such as diabetes, hyperuricemia, hypomagnesemia, and hypoparathyroidism, the genetic diagnosis allowed preventive measures and/or early treatment in 25% of patients. WES offers significant advantages for the diagnosis and management of patients with CAKUT diagnosed before 3 years of age, especially in patients who require KRT or have extrarenal anomalies.

The APOBEC3B c.783delG Truncating Mutation Is Not Associated with an Increased Risk of Breast Cancer in the Polish Population.

The APOBEC3B gene belongs to a cluster of DNA-editing enzymes on chromosome 22 and encodes an activation-induced cytidine deaminase. A large deletion of APOBEC3B was associated with increased breast cancer risk, but the evidence is inconclusive. To investigate whether or not APOBEC3B is a breast cancer susceptibility gene, we sequenced this gene in 617 Polish patients with hereditary breast cancer. We detected a single recurrent truncating mutation (c.783delG, p.Val262Phefs) in four of the 617 (0.65%) hereditary cases by sequencing. We then genotyped an additional 12,484 women with unselected breast cancer and 3740 cancer-free women for the c.783delG mutation. The APOBEC3B c.783delG allele was detected in 60 (0.48%) unselected cases and 19 (0.51%) controls (OR = 0.95, 95% CI 0.56-1.59, p = 0.94). The allele was present in 8 of 1968 (0.41%) familial breast cancer patients from unselected cases (OR = 0.80, 95% CI 0.35-1.83, p = 0.74). Clinical characteristics of breast tumors in carriers of the APOBEC3B mutation and non-carriers were similar. No cancer type was more frequent in the relatives of mutation carriers than in those of non-carriers. We conclude the APOBEC3B deleterious mutation p.Val262Phefs does not confer breast cancer risk. These data do not support the hypothesis that APOBEC3B is a breast cancer susceptibility gene.

Abstract 1938: Germline mutations in breast cancer genes are associated with early age of diagnosis and triple negative disease in Guatemalan and US Hispanic women

Abstract Abstract Background: Mutations in hereditary breast cancer genes play an essential role in cancer risk. Little is known of the type and frequency of mutations in Hispanic populations in the United States and Central American countries, including Guatemala. Methods: We used exome sequencing to identify mutations in blood DNA from unselected Hispanic breast cancer cases from community recruitment and from two hospitals each in Texas and Guatemala. Data from a structured questionnaire was used to compare mutation carriers of medium and high penetrance genes. Variants were annotated with ClinVar and VarSome. Results: We recruited 262 Hispanic US women, 37 (14%) from community-based recruitment and 225 (86%) from hospitals in Texas. In addition, we ascertained 633 patients from two hospitals in Guatemala City. A total of 91 out of 895 subjects (10%) had a variant classified as pathogenic in a gene with known high or medium penetrance for inherited breast cancer. The most frequently mutated genes were the high penetrance BRCA1 (44/895, 4.9%) followed by BRCA2 (23/895, 2.6%), PALB2 (5/895, 0.6%), CHEK2 (5/895 0.6%), ATM (6/895, 0.7%) and TP53 (6/895, 0.7%). Pathogenic variants were also detected in the moderate penetrance genes BARD1 and MSH6, and rare pathogenic variants detected in the low penetrance genes AXIN2, FH, MLH1, MSH2, MUTYH, NF1, and SDHB. The high ratio of BRCA1/BRCA2 mutations is due to the presence of two potential founder mutations, BRCA1 c.212+1G&amp;gt;A splice mutation (18 cases) and BRCA1 c.799delT (9 cases) in Guatemala. Compared to all others, cases with pathogenic mutations had a significantly earlier age at diagnosis (45 vs. 52 years, P&amp;lt;0.001) and were more likely to have a diagnosis before menopause. A higher percentage of mutation carriers had a relative with any cancer (51% vs. 37%, P=0.038) or breast cancer (33% vs. 15%, P&amp;lt;0.001). Patients with pathogenic mutations had a significantly higher percentage of triple-negative disease (60% vs. 13%, P=0.00046). Finally, mammography usage was less frequent in women with a lower socioeconomic status, indicating that this group is less likely to be screened for breast cancer (P&amp;lt;0.001). Conclusions: Guatemalan women have rates of hereditary breast cancer mutations like other populations, and these women are more likely to have early age at diagnosis, triple-negative disease, and family history. Patient recruitment was higher using hospital-based versus community enrollment. This data supports genetic testing in breast cancer patients and those at high risk as part of a strategy to reduce breast cancer mortality in Hispanic women. Citation Format: Jesica Godinez Paredes, Isabel Rodriguez, Megan Ren, Anali Orozco, Jeremy Ortiz, Anaseidy Albanez, Catherine Jones, Zeina Nahleh, Lilian Barreda, Lisa Garland, Dongjing Wu, Jiahui Wang, Victor Argueta, Roberto Orozco, Eduardo Gharzouzi, Michael Dean. Germline mutations in breast cancer genes are associated with early age of diagnosis and triple negative disease in Guatemalan and US Hispanic women [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1938.

A Swedish Familial Genome-Wide Haplotype Analysis Identified Five Novel Breast Cancer Susceptibility Loci on 9p24.3, 11q22.3, 15q11.2, 16q24.1 and Xq21.31

Most breast cancer heritability is unexplained. We hypothesized that analysis of unrelated familial cases in a GWAS context could enable the identification of novel susceptibility loci. In order to examine the association of a haplotype with breast cancer risk, we performed a genome-wide haplotype association study using a sliding window analysis of window sizes 1-25 SNPs in 650 familial invasive breast cancer cases and 5021 controls. We identified five novel risk loci on 9p24.3 (OR 3.4; p 4.9 × 10-11), 11q22.3 (OR 2.4; p 5.2 × 10-9), 15q11.2 (OR 3.6; p 2.3 × 10-8), 16q24.1 (OR 3; p 3 × 10-8) and Xq21.31 (OR 3.3; p 1.7 × 10-8) and confirmed three well-known loci on 10q25.13, 11q13.3, and 16q12.1. In total, 1593 significant risk haplotypes and 39 risk SNPs were distributed on the eight loci. In comparison with unselected breast cancer cases from a previous study, the OR was increased in the familial analysis in all eight loci. Analyzing familial cancer cases and controls enabled the identification of novel breast cancer susceptibility loci.