Η σημασία της έκφρασης του προσδέτη της πρωτεΐνης 1 προγραμματισμένου κυτταρικού θανάτου (PD-L1) και των κυτταροτοξικών CD8 λεμφοκυττάρων σε χαμηλής διαφοροποίησης αδενοκαρκινώματα ενδομητρίου

Εισαγωγή: Η χρησιμοποίηση της ανοσοθεραπείας στη γυναικολογική ογκολογία κερδίζει σημαντικό έδαφος και είναι επιτακτική ανάγκη η αναγνώριση βιοδεικτών που θα συμβάλλουν στην αποτελεσματικότερη εφαρμογή της. Σκοπός της Μελέτης: Η αξιολόγηση της έκφρασης του PD-L1 και των CD8 λεμφοκυττάρων σε καρκινώματα ενδομητρίου χαμηλής διαφοροποίησης καθώς και η συσχέτιση των αποτελεσμάτων με κλινικοπαθολογοανατομικά χαρακτηριστικά. Μέθοδοι: Στη μελέτη συμπεριλήφθηκαν 101 ασθενείς με χαμηλής διαφοροποίησης ενδομητρικό καρκίνο που αντιμετωπίστηκε με πλήρη χειρουργική σταδιοποίηση. Η έκφραση των PD-L1 και CD8 εκτιμήθηκε με ανοσοϊστοχημεία. Αποτελέσματα: Το 46.5% αφορούσε σε ενδομητριοειδή, ενώ το 53.5% σε μη-ενδομητριοειδή καρκινώματα. Στα ενδομητριοειδή καρκινώματα παρατηρήθηκε σημαντικά υψηλότερη έκφραση τόσο του PD-L1 (p=0.042) όσο και των ενδοεπιθηλιακών CD8 κυττάρων (p=0.004) σε σχέση με τους άλλους ιστολογικούς τύπους. Δεν παρατηρήθηκαν στατιστικά σημαντικές σχέσεις μεταξύ των PD-L1 και CD8 και των υπόλοιπων υπό μελέτη κλινικοπαθολογικών χαρακτηριστικών. Η αυξημένη διήθηση με ενδο-ογκικά CD8 λεμφοκύτταρα συσχετίστηκε με μεγαλύτερη ελεύθερης νόσου επιβίωση, τόσο σε μονοπαραγοντική όσο και σε πολυπαραγοντική ανάλυση (p=0.001). Καρκινώματα αρνητικά για το PD-L1 και με αυξημένη διήθηση από CD8 λεμφοκύτταρα είχαν τη μεγαλύτερη ελεύθερης νόσου επιβίωση (p=0.032). Συμπεράσματα: Σε χαμηλής διαφοροποίησης καρκινώματα ενδομητρίου, ανεξαρτήτως του ιστολογικού τύπου, η αυξημένη διήθηση από ενδοεπιθηλιακά CD8 κύτταρα αποτελεί έναν ανεξάρτητο θετικό προγνωστικό δείκτη, και όταν συνδυάζεται με αρνητική έκφραση για το PD-L1 τότε προβλέπεται μεγαλύτερη επιβίωση ελεύθερη νόσου. Μεταστατικά καρκινώματα θετικά για το PD-L1 και με υψηλή διήθηση από CD8 λεμφοκύτταρα, τα οποία είναι κυρίως ενδομητριοειδούς ιστολογίας και εμφανίζουν μεγάλο φορτίο νέο-αντιγόνων, θα μπορούσαν να ωφεληθούν από την ανοσοθεραπεία.Background: To evaluate the expression of programmed cell death-ligand 1 (PD-L1) and CD8 in high-grade endometrial carcinomas and relate it to several clinicopathological parameters. Methods: One hundred and one (101) patients with high-grade endometrial carcinomas who were completely surgically staged were included in this study. PD-L1 and CD8 + expression was evaluated by immunohistochemistry. Results: In our cohort, 47 women (46.5%) had endometrioid carcinomas and 54 patients (53.5%) were diagnosed with nonendometrioid cancers. In endometrioid carcinomas, there was a significantly higher rate of positivity for PD-L1 expression (p = 0.042) and of intraepithelial CD8 + cell counts (p = 0.004) as opposed to non-endometrioid cancers. There were no significant relationships with any of the other clinicopathological features under study. Univariate and multivariate analysis revealed that only high intraepithelial CD8 + counts (p = 0.01) was associated with longer progression-free survival. Tumors positive for PD-L1 and high intraepithelial CD8 expression were mainly of endometrioid histology, whilst PD-L1-positive/ CD8 low and PD-L1-negative/CD8 low tumors were mostly non-endometrioid carcinomas (p = 0.01). PD-L1 negative/CD8 high tumors had the longest progression-free survival (p = 0.032). Conclusions: In grade 3 endometrial carcinomas, both of endometrioid and non-endometrioid type, high intraepithelial CD8 + counts represent an independent favorable prognostic factor and when related to PD-L1-negative tumors, a longer progression-free survival can be predicted. Immunotherapy could probably be considered for PD-L1-positive/CD8 + high tumors, which were mostly of endometrioid histology

The impact of programmed cell deathligand 1 (PD-L1) and CD8 expression in grade 3 endometrial carcinomas

Background: To evaluate the expression of programmed cell death-ligand 1 (PD-L1) and CD8 in high-grade endometrial carcinomas and relate it to several clinicopathological parameters. Methods: One hundred and one (101) patients with high-grade endometrial carcinomas who were completely surgically staged were included in this study. PDL1 and CD8 + expression was evaluated by immunohistochemistry. Results: In our cohort, 47 women (46.5%) had endometrioid carcinomas and 54 patients (53.5%) were diagnosed with nonendometrioid cancers. In endometrioid carcinomas, there was a significantly higher rate of positivity for PD-L1 expression (p = 0.042) and of intraepithelial CD8 + cell counts (p = 0.004) as opposed to nonendometrioid cancers. There were no significant relationships with any of the other clinicopathological features under study. Univariate and multivariate analysis revealed that only high intraepithelial CD8 + counts (p = 0.01) was associated with longer progression-free survival. Tumors positive for PD-L1 and high intraepithelial CD8 expression were mainly of endometrioid histology, whilst PD-L1-positive/ CD8 low and PD-L1-negative/CD8 low tumors were mostly non-endometrioid carcinomas (p = 0.01). PD-L1 negative/CD8 high tumors had the longest progression-free survival (p = 0.032). Conclusions: In grade 3 endometrial carcinomas, both of endometrioid and nonendometrioid type, high intraepithelial CD8 + counts represent an independent favorable prognostic factor and when related to PD-L1-negative tumors, a longer progression-free survival can be predicted. Immunotherapy could probably be considered for PD-L1-positive/CD8 + high tumors, which were mostly of endometrioid histology.Εισαγωγή: Η χρησιμοποίηση της ανοσοθεραπείας στη γυναικολογική ογκολογία κερδίζει σημαντικό έδαφος και είναι επιτακτική ανάγκη η αναγνώριση βιοδεικτών που θα συμβάλλουν στην αποτελεσματικότερη εφαρμογή της. Σκοπός της Μελέτης: Η αξιολόγηση της έκφρασης του PD-L1 και των CD8 λεμφοκυττάρων σε καρκινώματα ενδομητρίου χαμηλής διαφοροποίησης καθώς και η συσχέτιση των αποτελεσμάτων με κλινικοπαθολογοανατομικά χαρακτηριστικά. Μέθοδοι: Στη μελέτη συμπεριλήφθηκαν 101 ασθενείς με χαμηλής διαφοροποίησης ενδομητρικό καρκίνο που αντιμετωπίστηκε με πλήρη χειρουργική σταδιοποίηση. Η έκφραση των PD-L1 και CD8 εκτιμήθηκε με ανοσοϊστοχημεία. Αποτελέσματα: Το 46.5% αφορούσε σε ενδομητριοειδή, ενώ το 53.5% σε μη- ενδομητριοειδή καρκινώματα. Στα ενδομητριοειδή καρκινώματα παρατηρήθηκε σημαντικά υψηλότερη έκφραση τόσο του PD-L1 (p=0.042) όσο και των ενδοεπιθηλιακών CD8 κυττάρων (p=0.004) σε σχέση με τους άλλους ιστολογικούς τύπους. Δεν παρατηρήθηκαν στατιστικά σημαντικές σχέσεις μεταξύ των PD-L1 και CD8 και των υπόλοιπων υπό μελέτη κλινικοπαθολογικών χαρακτηριστικών. Η αυξημένη διήθηση με ενδο-ογκικά CD8 λεμφοκύτταρα συσχετίστηκε με μεγαλύτερη ελεύθερης νόσου επιβίωση, τόσο σε μονοπαραγοντική όσο και σε πολυπαραγοντική ανάλυση (p=0.001). Καρκινώματα αρνητικά για το PD-L1 και με αυξημένη διήθηση από CD8 λεμφοκύτταρα είχαν τη μεγαλύτερη ελεύθερης νόσου επιβίωση (p=0.032). Συμπεράσματα: Σε χαμηλής διαφοροποίησης καρκινώματα ενδομητρίου, ανεξαρτήτως του ιστολογικού τύπου, η αυξημένη διήθηση από ενδοεπιθηλιακά CD8 κύτταρα αποτελεί έναν ανεξάρτητο θετικό προγνωστικό δείκτη, και όταν συνδυάζεται με αρνητική έκφραση για το PD-L1 τότε προβλέπεται μεγαλύτερη επιβίωση ελεύθερη νόσου. Μεταστατικά καρκινώματα θετικά για το PD-L1 και με υψηλή διήθηση από CD8 λεμφοκύτταρα, τα οποία είναι κυρίως ενδομητριοειδούς ιστολογίας και εμφανίζουν μεγάλο φορτίο νέο-αντιγόνων, θα μπορούσαν να ωφεληθούν από την ανοσοθεραπεία

Association of preconception mixtures of phenol and phthalate metabolites with birthweight among subfertile couples.

Although parental preconception exposure to some phenols and phthalates have been associated with reduced birthweight, few studies have examined these chemicals as complex mixtures. We included 384 mothers and 211 fathers (203 couples) who gave birth to 384 singletons from a prospective cohort of couples seeking fertility evaluation. Urinary concentrations of bisphenol A (BPA), parabens, and 11 phthalate metabolites including those of di(2-ethylhexyl) phthalate (DEHP) were examined. Birthweight was abstracted from delivery records. We used principal component analysis and Bayesian Kernel Machine Regression (BKMR) to examine maternal and paternal preconception mixtures in relation to singleton birthweight. We also fit couple-based BKMR with hierarchical variable selection to assess couples' joint mixtures in relation to birthweight. PC scores of maternal and paternal preconception low molecular weight phthalates factor, and paternal preconception DEHP-BPA factor were associated with reduced birthweight. In BKMR models, we found that maternal preconception monoethyl phthalate and BPA concentrations, and paternal preconception mono-n-butyl phthalate concentrations were inversely associated with birthweight when the remaining mixture components were held at their median concentrations. In couple-based BKMR models, paternal preconception biomarkers contributed more to couples' joint effect on birthweight compared with maternal preconception biomarkers. A decreasing trend of birthweight was observed across quantiles of maternal, paternal, and couples' total preconception mixture concentrations, respectively. Results from this preconception cohort of subfertile couples suggest a complex interplay between paternal and maternal preconception exposure to mixtures of nonpersistent chemicals, with both parental windows of exposure jointly contributing to reduced birthweight

Toll-Like Receptors -2, -3, -4 and -7 Expression Patterns in the Liver of a CLP-Induced Sepsis Mouse Model

Objective: To investigate the expression of toll-like receptors (TLRs) in the liver of septic mouse model. Materials and methods: For this study seventy-two C57BL/6J mice were utilized. Sepsis was induced by cecal ligation and puncture (CLP) in the mice of the three septic (S) groups (euthanized at 24 hours, 48 hours and 72 hours). Sham (laparotomy)- operated mice constituted the control (C) groups (euthanized at 24, 48 and 72 hours). Blood samples were drawn and liver tissues were extracted and examined histologically. The expression of TLRs 2, 3, 4 and 7 was assessed via immunohistochemistry (IHC) and qrt-PCR (quantitative- Polymerase Chain Reaction). Results: Liver function tests were elevated in all S-groups in contrast to their time-equivalent control groups (S24 versus C24, S48 versus C48 and S72 versus C72) (p 0.05); whereas at 72 hours only TLR 4 levels were significantly elevated in the intestine (p < 0.05). Conclusion: TLRs seem to be expressed in significant levels in the livers of septic rodents, indicating that they have a possible role in the pathophysiology of liver damage in septic conditions

Clear cell “sugar tumor” of the lung: Diagnostic features of a rare pulmonary tumor

Clear cell tumor of the lung (CCTL) is an extremely rare neoplasm with about 50 cases reported in the literature so far. CCTL belongs to a family arising from putative perivascular epithelioid cells and is otherwise named as “sugar tumor” due to its high cellular glycogen concentration. Due to its rarity, diagnostic features of this entity are not widely known and this usually leads to misdiagnosis. Herein, we report a case of benign CCTL, which was primarily evaluated intraoperatively by FNA cytology and then by a pathological examination of the resected tumor. The cytologic preparations were moderately cellular and showed multiple large, irregular, cohesive clusters of ovoid or spindle tumor cells. Cells had clear cytoplasm, showing positivity with the periodic acid-Schiff (PAS) staining method owing to the glycogen (sugar) content. The rapid cytologic report excluded the possibility of malignancy and a middle lobectomy along with an anterior upper segmentectomy was performed. Immunochemistry revealed a diffuse positivity for HMB45, MART-1, SMA and focally for desmin, while specimen was negative for pancytokeratin cocktail AE1/AE3, cytokeratin7, cytokeratin20 and EMA. These findings confirmed the diagnosis of a benign CCTL. Due to its rarity and similarity with other clear cell tumors of the lung, awareness of this entity, recognition of the cytomorphologic features and familiarity with the associated clinical features can help clinicians avoid certain pitfalls in the diagnostic process. Considering its benign course, unnecessary extensive lung resections may also be avoided thus permitting conservative management of these patients. Keywords: Sugar tumor, Benign clear cell tumor, Case-report, PECom

Parental preconception exposure to phenol and phthalate mixtures and the risk of preterm birth.

Parental preconception exposure to select phenols and phthalates was previously associated with increased risk of preterm birth in single chemical analyses. However, the joint effect of phenol and phthalate mixtures on preterm birth is unknown. We included 384 female and 211 male (203 couples) participants seeking infertility treatment in the Environment and Reproductive Health (EARTH) Study who gave birth to 384 singleton infants between 2005 and 2018. Mean preconception urinary concentrations of bisphenol A (BPA), parabens, and eleven phthalate biomarkers, including di(2-ethylhexyl) phthalate (DEHP) metabolites, were examined. We used principal component analysis (PCA) with log-Poisson regression and Probit Bayesian Kernel Machine Regression (BKMR) with hierarchical variable selection to examine maternal and paternal phenol and phthalate mixtures in relation to preterm birth. Couple-based BKMR model was fit to assess couples' joint mixtures in relation to preterm birth. PCA identified the same four factors for maternal and paternal preconception mixtures. Each unit increase in PCA scores of maternal (adjusted Risk Ratio (aRR): 1.36, 95%CI: 1.00, 1.84) and paternal (aRR: 1.47, 95%CI: 0.90, 2.42) preconception DEHP-BPA factor was positively associated with preterm birth. Maternal and paternal BKMR models consistently presented the DEHP-BPA factor with the highest group Posterior Inclusion Probability (PIP). BKMR models further showed that maternal preconception BPA and mono(2-ethyl-5-hydroxyhexyl) phthalate, and paternal preconception mono(2-ethylhexyl) phthalate were positively associated with preterm birth when the remaining mixture components were held at their median concentrations. Couple-based BKMR models showed a similar relative contribution of paternal (PIP: 61%) and maternal (PIP: 77%) preconception mixtures on preterm birth. We found a positive joint effect on preterm birth across increasing quantiles of couples' total mixture concentrations. In this prospective cohort of subfertile couples, maternal BPA and DEHP, and paternal DEHP exposure before conception were positively associated with preterm birth. Both parental windows jointly contributed to the outcome. These results suggest that preterm birth may be a couple-based pregnancy outcome

The ChoCO-W prospective observational global study: Does COVID-19 increase gangrenous cholecystitis?

BACKGROUND: The incidence of the highly morbid and potentially lethal gangrenous cholecystitis was reportedly increased during the COVID-19 pandemic. The aim of the ChoCO-W study was to compare the clinical findings and outcomes of acute cholecystitis in patients who had COVID-19 disease with those who did not. METHODS: Data were prospectively collected over 6 months (October 1, 2020, to April 30, 2021) with 1-month follow-up. In October 2020, Delta variant of SARS CoV-2 was isolated for the first time. Demographic and clinical data were analyzed and reported according to the STROBE guidelines. Baseline characteristics and clinical outcomes of patients who had COVID-19 were compared with those who did not. RESULTS: A total of 2893 patients, from 42 countries, 218 centers, involved, with a median age of 61.3 (SD: 17.39) years were prospectively enrolled in this study; 1481 (51%) patients were males. One hundred and eighty (6.9%) patients were COVID-19 positive, while 2412 (93.1%) were negative. Concomitant preexisting diseases including cardiovascular diseases (p < 0.0001), diabetes (p < 0.0001), and severe chronic obstructive airway disease (p = 0.005) were significantly more frequent in the COVID-19 group. Markers of sepsis severity including ARDS (p < 0.0001), PIPAS score (p < 0.0001), WSES sepsis score (p < 0.0001), qSOFA (p < 0.0001), and Tokyo classification of severity of acute cholecystitis (p < 0.0001) were significantly higher in the COVID-19 group. The COVID-19 group had significantly higher postoperative complications (32.2% compared with 11.7%, p < 0.0001), longer mean hospital stay (13.21 compared with 6.51 days, p < 0.0001), and mortality rate (13.4% compared with 1.7%, p < 0.0001). The incidence of gangrenous cholecystitis was doubled in the COVID-19 group (40.7% compared with 22.3%). The mean wall thickness of the gallbladder was significantly higher in the COVID-19 group [6.32 (SD: 2.44) mm compared with 5.4 (SD: 3.45) mm; p < 0.0001]. CONCLUSIONS: The incidence of gangrenous cholecystitis is higher in COVID patients compared with non-COVID patients admitted to the emergency department with acute cholecystitis. Gangrenous cholecystitis in COVID patients is associated with high-grade Clavien-Dindo postoperative complications, longer hospital stay and higher mortality rate. The open cholecystectomy rate is higher in COVID compared with non -COVID patients. It is recommended to delay the surgical treatment in COVID patients, when it is possible, to decrease morbidity and mortality rates. COVID-19 infection and gangrenous cholecystistis are not absolute contraindications to perform laparoscopic cholecystectomy, in a case by case evaluation, in expert hands