High Prevalence of Genital Human Papillomavirus Infection in Patients With Primary Immunodeficiencies

BackgroundGenital human papillomavirus (HPV)-infections are common in the general population and are responsible for relevant numbers of epithelial malignancies. Much data on the HPV-prevalence is available for secondary immunodeficiencies, especially for patients with human immunodeficiency virus (HIV)-infection. Little is known about the genital HPV-prevalence in patients with primary immunodeficiencies (PIDs).MethodsWe performed a cross-sectional study of patients with PIDs and took genital swabs from male and female patients, which were analyzed with polymerase chain reaction for the presence of HPV-DNA. Clinical and laboratory data was collected to identify risk factors.Results28 PID patients were included in this study. 10 of 28 (35.7%) had HPV-DNA in their genital swabs. 6 patients had high-risk HPV-types (21.4%). Most patients had asymptomatic HPV-infections, as genital warts were rare (2 of 28 patients) and HPV-associated malignancy was absent. Differences in the HPV-positivity regarding clinical PID-diagnosis, duration of PID, age, sex, immunosuppression, immunoglobulin replacement, or circumcision in males were not present. HPV-positive PID patients had higher numbers of T cells (CD3+), of cytotoxic T cells (CD3+/CD8+), of transitional B cells (CD19+/CD38++/CD10+/IgD+), and of plasmablasts (CD19+/CD38+/CD27++/IgD-) compared to HPV-negative.ConclusionPID patients exhibit a high rate of genital HPV-infections with a high rate of high-risk HPV-types. Regular screening for symptomatic genital HPV-infection and HPV-associated malignancy in PID patients seems recommendable.

LBX2-AS1 as a Novel Diagnostic Biomarker and Therapeutic Target Facilitates Multiple Myeloma Progression by Enhancing mRNA Stability of LBX2

Objective: Multiple myeloma (MM) represents a common age-associated malignancy globally. The function and underlying mechanism of antisense lncRNA LBX2-AS1 remain ambiguous in multiple myeloma (MM). Herein, we aimed to observe the biological implication of this lncRNA in MM.Methods: RT-qPCR was employed to examine circulating LBX2-AS1 and LBX2 in 60 paired MM and healthy subjects. Correlation between the two was analyzed by Pearson test. Under transfection with shLBX2-AS1, proliferation and apoptosis were evaluated in MM cells through CCK-8, colony formation and flow cytometry. LBX2 expression was examined in MM cells with shLBX2-AS1 or pcDNA3.1-LBX2 transfection. Following treatment with cycloheximide or actinomycin D, LBX2 expression was examined in pcDNA3.1-LBX2-transfected MM cells at different time points. Rescue assays were then presented. Finally, xenograft tumor models were established.Results: Circulating LBX2-AS1 was up-regulated in MM patients and positively correlated to LBX2 expression. Area under the curve (AUC) of LBX2-AS1 expression was 0.7525. Its up-regulation was also found in MM cells and primarily distributed in cytoplasm. LBX2-AS1 knockdown distinctly weakened proliferative ability and induced apoptosis in MM cells. Overexpressing LBX2-AS1 markedly strengthened LBX2 expression by increasing its mRNA stability. Rescue assays showed that silencing LBX2-AS1 distinctly weakened the pcDNA3.1-LBX2-induced increase in proliferation and decrease in apoptosis for MM cells. Silencing LBX2-AS1 markedly weakened tumor growth.Conclusion: Our data demonstrated that circulating LBX2-AS1 could be an underlying diagnostic marker in MM. Targeting LBX2-AS1 suppressed tumor progression by affecting mRNA stability of LBX2 in MM. Hence, LBX2-AS1 could be a novel therapeutic marker against MM.

619 Is the Subdivision of Thy3 Nodules Needed? An Audit Reviewing the Management of Thy3 Nodules, and the Associated Malignancy Rates

Introduction Following the 2014 update to the BAETS thyroid nodule cytology guidance, the management of Thy3 lesions was modified by subdivision into Thy3a and Thy3f categories. Both lesions remain indeterminate but are proposed to have differing risks of malignancy when counselling patents: these risks have been called into question by subsequent data. Aim This Audit aimed to review the management of Thy3 (Thy3a and Thy3f) cytological diagnoses, within an NHS Trust, and compare this to the BAET Guidance 2014. Further, malignancy rates for Thy3a and Thy3f cytology were made over the calculated over the time period. Method A retrospective Audit looking at 118 patients with a Thy3 cytology identified between 2014 and 2019. Data separated into data pre-2015 and 2015 onwards. Results In 2014, 29% of Thy3a nodules were managed in line with 2014 BAETS guidance. This improved to 34% from 2015. Meanwhile, Thy3f diagnoses were managed mostly in favour of the BAETS guidelines – 83% in 2014 and 92% 2015 onwards. The malignancy rates found, amongst all 118 patients, were 17.2% and 14.8% for Thy3f and Thy3a nodules respectively. Conclusions At this institution, Thy3 cytological diagnoses, regardless of classification into Thy3a or Thy3f, were largely treated in the same way (by a diagnostic hemi-thyroidectomy). The management of the nodules may reflect a variety of factors, including how comfortable patients and surgeons are when handling uncertainty. With malignancy rates for both Thy3a and Thy3f nodules being much the same, it is not surprising that they are managed in a similar way.

Familiarity Breeds Strategy: In Silico Untangling of the Molecular Complexity on Course of Autoimmune Liver Disease-to-Hepatocellular Carcinoma Transition Predicts Novel Transcriptional Signatures

Autoimmune liver diseases (AILD) often lead to transformation of the liver tissues into hepatocellular carcinoma (HCC). Considering the drawbacks of surgical procedures in such cases, need of successful non-invasive therapeutic strategies and treatment modalities for AILD-associated-HCC still exists. Due to the lack of clear, sufficient knowledge about factors mediating AILD-to-HCC transition, an in silico approach was adopted to delineate the underlying molecular deterministic factors. Parallel enrichment analyses on two different public microarray datasets (GSE159676 and GSE62232) pinpointed the core transcriptional regulators as key players. Correlation between the expression kinetics of these transcriptional modules in AILD and HCC was found to be positive primarily with the advancement of hepatic fibrosis. Most of the regulatory interactions were operative during early (F0–F1) and intermediate fibrotic stages (F2–F3), while the extent of activity in the regulatory network considerably diminished at late stage of fibrosis/cirrhosis (F4). Additionally, most of the transcriptional targets with higher degrees of connectivity in the regulatory network (namely DCAF11, PKM2, DGAT2 and BCAT1) may be considered as potential candidates for biomarkers or clinical targets compared to their low-connectivity counterparts. In summary, this study uncovers new possibilities in the designing of novel prognostic and therapeutic regimen for autoimmunity-associated malignancy of liver in a disease progression-dependent fashion.

When to Consider Lynch Syndrome in Non-Colon and Non-Endometrial Malignancies

Lynch syndrome (LS) is a common genetic syndrome characterized by pathogenic mutations of DNA mismatch repair genes resulting in a hereditary predisposition to cancer. While typically associated with colonic and endometrial cancer, LS additionally influences the development of many other malignancies. The Amsterdam II and Revised Bethesda Guidelines are the established clinical criteria for diagnosing LS. These guidelines are based on the most general characteristics of LS and do not address specific characteristics of the less commonly LS-associated malignancies. For individuals that present initially with a non-colon and non-endometrial malignancy, recommendations and guidelines on when to consider screening for LS are limited. Therefore, it is essential that clinicians are familiar with distinct LS-associated patient- and tumor-specific characteristics, especially of the less common LS-associated cancers, so that LS’s diagnosis is not missed. In this review article, we focus on extra-colonic and extra-endometrial LS-associated cancers, paying particular attention to any established or currently investigated cancer features that help raise suspicion for LS and potentially lead to its earlier diagnosis. This review will also discuss current guidelines specific to each LS-associated malignancy.

106 A Retrospective Study Comparing Histopathology Proformas For Anterior Resections Against the Royal College of Pathology (RCPath) Guidelines

Introduction Royal College of Pathologists (RCPath) published guidance on clinical information needed on histopathology forms accompanying colorectal cancer specimens. Inadequate information can significantly impact the ability of histopathologists to accurately interpret specimens; in turn correctly diagnose and stage cancers. The primary aim of our audit was to evaluate local compliance with the RCPath guidelines. Method Histopathology request forms of 50 patients undergoing anterior resections between January 2018-19 were retrospectively evaluated against the RCPath guidelines, ‘Standards and datasets for reporting cancers’ published in December 2017. Results Of the 50 patients, the site and type of tumour resection were documented in 94% and 56% of cases, respectively. 48% of cases specified whether the surgery was open or laparoscopic. However only 4% mentioned the preoperative tumour stage, and only 10% recorded whether any pre-operative therapy had been given. Furthermore, no cases reported whether there was a family history of bowel cancer or inflammatory bowel disease. Conclusions Information on colorectal histopathology forms is failing to meet RCPath guidelines. Significant information regarding preoperative treatment, associated malignancy risk factors and resection type is absent in over half of cases. This will have detrimental effects on the ability of histopathologists to accurately assess and interpret cancer specimens.

Von Meyenburg Complexes and Malignancy: A Systematic Review

Von Meyenburg Complexes (VMC) are benign lesions secondary to ductal plate malformations. These are relatively rare in adults and are often asymptomatic, with many lesions being diagnosed on imaging. Despite these benign characteristics, VMC have the potential to undergo malignant changes leading to conditions such as cholangiocarcinoma and other cancers. The objective of the review is to report and analyze the cases of biliary hamartomas which were associated with malignancy. We performed a structured systematic review of literature and identified 31 cases of biliary duct hamartomas associated with malignancy. The mean age at onset was 61 years +/- 13 (min 19 to max 88) with the majority of the patients being male (64.5%). Of all cases, 41.9% reported symptoms (13/31 cases) with the most common symptom being abdominal pain (32.3%). Biopsies reported malignancy in 77.4% of cases (24/31 cases) with the most common reported associated malignancy being cholangiocarcinoma 54.8% (17/31). 93.3% of the cases underwent surgical intervention (28/30 cases). VMC are an important entity with malignancy potential which is under-reported. Presence of red flag symptoms such as weight loss and obstructive jaundice in patients with diagnosed biliary hamartomas should prompt an evaluation for malignancy. Key-words: Von meyenburg complexes; cholangiocarcinoma; malignancy; biliary hamartomas

Paget’s disease of the breast – observational retrospective study of the past 20 years

Introduction: Paget‘s disease of the breast (PD) is a rare type of carcinoma that affects the skin of the nipple-areolar complex. Unresolved issues exist regarding its diagnosis and therapy. The aim of the study was to gather data on how the therapy of the disease is approached in clinical practice, and to formulate current diagnostic and therapeutic recommendations. Methods: Retrospective evaluation of data from medical records of patients with PD who underwent surgery at our department between 2001 and 2020. The data was evaluated using basic statistical methods. Results: Sixty four female patients with the mean age of 62.5 years. In 58 women, PD was confirmed before surgery, with the median of 20 weeks from initial symptoms to diagnosis. Forty seven of the patients were operated for presumed isolated PD; in 38 cases, histopathological evaluation of the specimen revealed an associated malignancy in the mammary gland. Primary breast-conserving surgery (BCS) was performed in 46 patients; surgical revision was indicated in 17 cases. In 6 patients with PD associated with non-invasive breast cancer treated by BCS without radiotherapy (RT), a local recurrence appeared in 3 cases, which is significantly more compared to the group of patients undergoing total mastectomies (p=0.032). No local recurrence appeared in 9 cases of isolated PD treated by BCS, including 6 patients without RT. The tumors associated with PD were mostly ER-negative (44/57) and HER2-positive (22/25). Conclusion: In cases where PD is suspected, careful clinical examination and the use of available diagnostic imaging techniques including MRI are appropriate. BCS without RT is not an adequate oncological therapy where an associated malignancy of the breast is found.