A Comprehensive Approach to the Thyroid Bethesda Category III (AUS) in the Transition Zone Between 2nd Edition and 3rd Edition of The Bethesda System for Reporting Thyroid Cytopathology: Subcategorization, Nuclear Scoring, and More.

Significant interobserver variabilities exist for Bethesda category III: atypia of undetermined significance (AUS) of The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC). Thus, subcategorization of AUS including AUS "nuclear" and AUS "other" is proposed in the recent 3rd edition of TBSRTC. This study investigated the impact of the nuclear features/architectural features/nuclear score (NS) (3-tiered)/subcategories and subgroups on risk of malignancy (ROM) in thyroid fine-needle aspirations (FNA). 6940 FNAs were evaluated. 1224 (17.6%) cases diagnosed as AUS were reviewed, and 240 patients (initial FNAs of 260 nodules and 240 thyroidectomies) were included. Subcategories and subgroups were defined according to TBSRTC 2nd and 3rd editions. Histological diagnostic groups included nonneoplastic disease, benign neoplasm, low-risk neoplasm, and malignant neoplasm. Overall, ROM was 30.7%. ROM was significantly higher in FNAs with nuclear overlapping (35.5%), nuclear molding (56.9%), irregular contours (42.1%), nuclear grooves (74.1%), chromatin clearing (49.4%), and chromatin margination (57.7%), and these features were independent significant predictors for malignancy. FNAs with NS3 had significantly higher ROM (64.2%). Three-dimensional groups were significantly more frequent in malignant neoplasms (35.7%). ROM was significantly higher in AUS-nuclear subcategory (48.2%) and in AUS-nuclear and architectural subcategory (38.3%). The highest ROM was detected in AUS-nuclear1 subgroup (65.2%). ROM was significantly higher in the group including AUS-nuclear and AUS-nuclear and architectural subcategories, namely "high-risk group" than the group including other subcategories, namely "low-risk group" (42.0%vs 13.9%). In conclusion, subcategorization may not be the end point, and nuclear scoring and evaluation of architectural patterns according to strict criteria may provide data for remodeling of TBSRTC categories.

Effects of hypoxia versus ischaemia on vascular functions of isolated rat thoracic aorta: revisiting the in vitro vascular ischaemia/reperfusion model.

Introduction: The in vitro rat vascular ischaemia and reperfusion model is used to evaluate the molecular and functional effects of potential agents against ischaemia and reperfusion injury of autologous graft veins. However, there is no consensus on whether hypoxia, rather than ischaemia, is sufficient to induce vascular dysfunction. Aim: To compare the effects of hypoxia and ischaemia, with or without reperfusion, on the vascular functions of isolated thoracic aortic rings of rats. Material and methods: Thoracic aortas of 12 male Sprague-Dawley rats (350-500 g, 18-24 months old) were isolated and divided into rings that were randomly allocated to control, ischaemia, hypoxia, ischaemia-reperfusion, and hypoxia-reperfusion groups. Aortic rings other than those of the control group were stored at 4°C for 24 h in saline. For ischaemia, saline was gassed with nitrogen. After 24 h, aortic rings in the ischaemia-reperfusion and hypoxia-reperfusion groups were incubated with 200 µM sodium hypochlorite for 30 min. Vascular and endothelial functions were tested in an organ bath set-up. Results: Vascular response to potassium chloride (80 mM) decreased in all experimental groups compared to the control group (p = 0.007), but phenylephrine-induced contraction (10-5 M) increased only in the ischaemia-reperfusion group (p < 0.0001). Acetylcholine (10-11-10-5 M)-induced endothelium-dependent vasorelaxations were impaired in all groups - particularly in the ischaemia-reperfusion group (p = 0.0011). Sodium nitroprusside (10-12-10-7 M)-induced endothelium-independent vasorelaxations were similar across all groups (p = 0.1258). Conclusions: Ischaemia followed by reperfusion should be implanted to achieve maximum endothelial and contractile dysfunction in vitro, and to replicate ischaemia and reperfusion injury of autologous graft veins.

18F-FDG PET/CT texture analysis of anthracotic lymph nodes detected with EBUS and comparison with cytological findings.

OBJECTIVE: Lymph node metastasis is the most important factor both in the selection of treatment since many alternatives have been created in recent years, and in the evaluation of prognosis in lung cancer. The most unpredictable cause of lymph node false positivity in fluorine-18-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) is anthracosis. The aim of this study is to compare 18F-FDG PET/CT texture information of anthracotic (ALN) and metastatic (MLN) lymph nodes, after re-evaluation of the cytological samples obtained from anthracotic lymph nodes by EBUS-TBNA. SUBJECTS AND METHODS: Ninety nine patients, 78 of whom had primary lung cancer were included in the study. Two hundred and three lymph nodes from 99 patients sampled by EBUS-TBNA and diagnosed cytologically as ALN or MLN were evaluated retrospectively. All ALN were classified as grades 1, 2 and 3 cytologically. Volume of interest (VOI) of 203 lymph nodes was re-drawn and maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV) and total lesion glycolysis (TLG) values were recorded. RESULTS: There was a statistically significant difference in MTV and TLG values in MLN and all ALN grades. However, only grade 1-2 ALNs could be differentiated from MLNs with SUVmax, and no statistically significant difference was found in grade 3 ALN and MLN. Metabolic tumor volume and TLG values over 4.10cm3 and 26.57 showed 60% and 59% sensitivity and 83% and 94 specificity respectively for the identification of MLN. CONCLUSION: The contribution of MTV and TLG values of 18F-FDG PET/CT to the differential diagnosis of ALN is much more valuable than SUVmax values, especially for grade 3 anthracosis. It was thought that cytological reporting of only grade 3 ALN could make a better contribution to the 18F-FDG PET/CT evaluation analysis.

Fibroadenoma of Axillary Ectopic Breast Tissue.

Teaching point: Ectopic breast fibroadenoma is a rare benign neoplasm that may mimic pathological lymph node clinically and on imaging.

Dienogest reduces endometrioma volume and endometriosis-related pain symptoms.

This study aimed to evaluate the efficacy and adverse effects of dienogest for the treatment of endometriomas. Dienogest (2 mg/day) was administered to patients with endometrioma continuously through the 6-month study period. The patients were prospectively examined on the efficacy and side effects at baseline, at third months, and sixth months of the treatment. Twenty-four out of 30 patients were able to complete the study. The mean volume of the endometrioma decreased significantly from 112.63 ± 161.31 cm³ at baseline to 65.47 ± 95.69 cm³ at a 6-month follow-up (-41%) (p = .005). The VAS score for pelvic pain decreased significantly from 7.50 to 3.00 (p < .001) at the sixth months of treatment. The most common side effects were menstrual irregularities. Laboratory parameters did not change during the study. Dienogest considered being effective for 6 months of use in decreasing the size of endometrioma, reducing endometriosis-associated pain with a favourable safety and tolerability profile.Impact statementWhat is already known on this subject? Laparoscopic excisional surgery for endometrioma is currently the most valid approach in the treatment of endometriomas. However, there are concerns about ovarian reserve damage during surgery.What do the results of this study add? Dienogest considered being effective in decreasing the size of endometrioma, reducing endometriosis-associated pain with a favourable safety and tolerability profile. Long-term use of dienogest in younger patients with endometriomas who are yet to give birth may reduce the possibility of surgery by reducing the size of the endometriomas and may preserve ovarian reserve.What are the implications of these findings for clinical practice and/or further research? Dienogest may reduce the incidence of infectious complications such as pelvic abscess after oocyte retrieval and the surgical procedures in infertile patients with endometrioma.

Recurrent mutations at estrogen receptor binding sites alter chromatin topology and distal gene expression in breast cancer.

BACKGROUND: The mutational processes underlying non-coding cancer mutations and their biological significance in tumor evolution are poorly understood. To get better insights into the biological mechanisms of mutational processes in breast cancer, we integrate whole-genome level somatic mutations from breast cancer patients with chromatin states and transcription factor binding events. RESULTS: We discover that a large fraction of non-coding somatic mutations in estrogen receptor (ER)-positive breast cancers are confined to ER binding sites. Notably, the highly mutated estrogen receptor binding sites are associated with more frequent chromatin loop contacts and the associated distal genes are expressed at higher level. To elucidate the functional significance of these non-coding mutations, we focus on two of the recurrently mutated estrogen receptor binding sites. Our bioinformatics and biochemical analysis suggest loss of DNA-protein interactions due to the recurrent mutations. Through CRISPR interference, we find that the recurrently mutated regulatory element at the LRRC3C-GSDMA locus impacts the expression of multiple distal genes. Using a CRISPR base editor, we show that the recurrent C→T conversion at the ZNF143 locus results in decreased TF binding, increased chromatin loop formation, and increased expression of multiple distal genes. This single point mutation mediates reduced response to estradiol-induced cell proliferation but increased resistance to tamoxifen-induced growth inhibition. CONCLUSIONS: Our data suggest that ER binding is associated with localized accumulation of somatic mutations, some of which affect chromatin architecture, distal gene expression, and cellular phenotypes in ER-positive breast cancer.