25 research outputs found
Pathophysiological mechanisms of liver injury in COVID-19
The recent outbreak of coronavirus disease 2019 (COVIDâ19), caused by the Severe Acute Respiratory Syndrome Coronavirusâ2 (SARSâCoVâ2) has resulted in a worldâwide pandemic. Disseminated lung injury with the development of acute respiratory distress syndrome (ARDS) is the main cause of mortality in COVIDâ19. Although liver failure does not seem to occur in the absence of preâexisting liver disease, hepatic involvement in COVIDâ19 may correlate with overall disease severity and serve as a prognostic factor for the development of ARDS. The spectrum of liver injury in COVIDâ19 may range from direct infection by SARSâCoVâ2, indirect involvement by systemic inflammation, hypoxic changes, iatrogenic causes such as drugs and ventilation to exacerbation of underlying liver disease. This concise review discusses the potential pathophysiological mechanisms for SARSâCoVâ2 hepatic tropism as well as acute and possibly longâterm liver injury in COVIDâ19
Rapid response of metastatic cutaneous squamous cell carcinoma to pembrolizumab in a patient with xeroderma pigmentosum: Case report and review of the literature
A 48-year old patient with known xeroderma pigmentosum was referred to our skin cancer unit because of the recent development of histopathologically verified squamous cell carcinoma (SCC) lymph node metastasis on her left supraclavicular region. A whole body PET-CT showed additional abdominal and inguinal lymph node metastases. Her medical history included, in addition to several minimal surgeries of early forms of keratinocyte skin cancer, a poorly differentiated cutaneous SCC (cSCC) with invasion into the lymphatic vessels on her left tight, which was treated with wide surgical excision 5 years before
Reproducibility of lymphovascular space invasion (LVSI) assessment in endometrial cancer
Aims Lymphovascular space invasion (LVSI) in endometrial cancer (EC) is an important prognostic variable impacting on a patient's individual recurrence risk and adjuvant treatment recommendations. Recent work has shown that grading the extent of LVSI further improves its prognostic strength in patients with stage I endometrioid EC. Despite this, there is little information on the reproducibility of LVSI assessment in EC. Therefore, we designed a study to evaluate interobserver agreement in discriminating true LVSI from LVSI mimics (Phase I) and reproducibility of grading extent of LVSI (Phase II). Methods and results Scanned haematoxylin and eosin (H&E) slides of endometrioid EC (EEC) with a predefined possible LVSI focus were hosted on a website and assessed by a panel of six European gynaecological pathologists. In Phase I, 48 H&E slides were included for LVSI assessment and in Phase II, 42 H&E slides for LVSI grading. Each observer was instructed to apply the criteria for LVSI used in daily practice. The degree of agreement was measured using the two-way absolute agreement average-measures intraclass correlation coefficient (ICC). Reproducibility of LVSI assessment (ICC = 0.64, P < 0.001) and LVSI grading (ICC = 0.62, P < 0.001) in EEC was substantial among the observers. Conclusions Given the good reproducibility of LVSI, this study further supports the important role of LVSI in decision algorithms for adjuvant treatment
A combined computational and functional approach identifies IGF2BP2 as a driver of chemoresistance in a wide array of pre-clinical models of colorectal cancer
Aim Chemoresistance is a major cause of treatment failure in colorectal cancer (CRC) therapy. In this study, the
impact of the IGF2BP family of RNA-binding proteins on CRC chemoresistance was investigated using in silico, in vitro,
and in vivo approaches.
Methods Gene expression data from a well-characterized cohort and publicly available cross-linking immunoprecipiâ
tation sequencing (CLIP-Seq) data were collected. Resistance to chemotherapeutics was assessed in patient-derived
xenografts (PDXs) and patient-derived organoids (PDOs). Functional studies were performed in 2D and 3D cell culture
models, including proliferation, spheroid growth, and mitochondrial respiration analyses.
Results We identifed IGF2BP2 as the most abundant IGF2BP in primary and metastastatic CRC, correlating with
tumor stage in patient samples and tumor growth in PDXs. IGF2BP2 expression in primary tumor tissue was signifâ
cantly associated with resistance to selumetinib, geftinib, and regorafenib in PDOs and to 5-fuorouracil and oxaliplâ
atin in PDX in vivo. IGF2BP2 knockout (KO) HCT116 cells were more susceptible to regorafenib in 2D and to oxaliplatin,
selumitinib, and nintedanib in 3D cell culture. Further, a bioinformatic analysis using CLIP data suggested stabilizaâ
tion of target transcripts in primary and metastatic tumors. Measurement of oxygen consumption rate (OCR) and
extracellular acidifcation rate (ECAR) revealed a decreased basal OCR and an increase in glycolytic ATP production
rate in IGF2BP2 KO. In addition, real-time reverse transcriptase polymerase chain reaction (qPCR) analysis confrmed
decreased expression of genes of the respiratory chain complex I, complex IV, and the outer mitochondrial membrane
in IGF2BP2 KO cells. Conclusions IGF2BP2 correlates with CRC tumor growth in vivo and promotes chemoresistance by altering mitoâ
chondrial respiratory chain metabolism. As a druggable target, IGF2BP2 could be used in future CRC therapy to
overcome CRC chemoresistance
Third International Consensus Conference on lesions of uncertain malignant potential in the breast (B3 lesions)
The heterogeneous group of B3 lesions in the breast harbors lesions with different malignant potential and progression risk. As several studies about B3 lesions have been published since the last Consensus in 2018, the 3rd International Consensus Conference discussed the six most relevant B3 lesions (atypical ductal hyperplasia (ADH), flat epithelial atypia (FEA), classical lobular neoplasia (LN), radial scar (RS), papillary lesions (PL) without atypia, and phyllodes tumors (PT)) and made recommendations for diagnostic and therapeutic approaches. Following a presentation of current data of each B3 lesion, the international and interdisciplinary panel of 33 specialists and key opinion leaders voted on the recommendations for further management after core-needle biopsy (CNB) and vacuum-assisted biopsy (VAB). In case of B3 lesion diagnosis on CNB, OE was recommended in ADH and PT, whereas in the other B3 lesions, vacuum-assisted excision was considered an equivalent alternative to OE. In ADH, most panelists (76%) recommended an open excision (OE) after diagnosis on VAB, whereas observation after a complete VAB-removal on imaging was accepted by 34%. In LN, the majority of the panel (90%) preferred observation following complete VAB-removal. Results were similar in RS (82%), PL (100%), and FEA (100%). In benign PT, a slim majority (55%) also recommended an observation after a complete VAB-removal. VAB with subsequent active surveillance can replace an open surgical intervention for most B3 lesions (RS, FEA, PL, PT, and LN). Compared to previous recommendations, there is an increasing trend to a de-escalating strategy in classical LN. Due to the higher risk of upgrade into malignancy, OE remains the preferred approach after the diagnosis of ADH
Clinical Behavior and Molecular Landscape of Stage I p53-Abnormal Low-Grade Endometrioid Endometrial Carcinomas
PURPOSE: The clinical significance of the p53-abnormal (p53abn) molecular subtype in stage I low-grade endometrioid endometrial carcinoma (EEC) is debated. We aimed to review pathologic and molecular characteristics, and outcomes of stage I low-grade p53abn EEC in a large international cohort. EXPERIMENTAL DESIGN: Previously diagnosed stage I p53abn EC (POLE-wild-type, mismatch repair-proficient) low-grade EEC from Canadian retrospective cohorts and PORTEC-1&2 trials were included. Pathology review was performed by six expert gynecologic pathologists blinded to p53 status. IHC profiling, next-generation sequencing, and shallow whole-genome sequencing was performed. Kaplan-Meier method was used for survival analysis. RESULTS: We identified 55 stage I p53abn low-grade EEC among 3,387 cases (2.5%). On pathology review, 17 cases (31%) were not diagnosed as low-grade EEC by any pathologists, whereas 26 cases (47%) were diagnosed as low-grade EEC by at least three pathologists. The IHC and molecular profile of the latter cases were consistent with low-grade EEC morphology (ER/PR positivity, patchy p16 expression, PIK3CA and PTEN mutations) but they also showed features of p53abn EC (TP53 mutations, many copy-number alterations). These cases had a clinically relevant risk of disease recurrence (5-year recurrence-free survival 77%), with pelvic and/or distant recurrences observed in 12% of the patients. CONCLUSIONS: A subset of p53abn EC is morphologically low-grade EEC and exhibit genomic instability. Even for stage I disease, p53abn low-grade EEC are at substantial risk of disease recurrence. These findings highlight the clinical relevance of universal p53-testing, even in low-grade EEC, to identify women at increased risk of recurrence
Third International Consensus Conference on lesions of uncertain malignant potential in the breast (B3 lesions)
The heterogeneous group of B3 lesions in the breast harbors lesions with different malignant potential and progression risk. As several studies about B3 lesions have been published since the last Consensus in 2018, the 3rd International Consensus Conference discussed the six most relevant B3 lesions (atypical ductal hyperplasia (ADH), flat epithelial atypia (FEA), classical lobular neoplasia (LN), radial scar (RS), papillary lesions (PL) without atypia, and phyllodes tumors (PT)) and made recommendations for diagnostic and therapeutic approaches. Following a presentation of current data of each B3 lesion, the international and interdisciplinary panel of 33 specialists and key opinion leaders voted on the recommendations for further management after core-needle biopsy (CNB) and vacuum-assisted biopsy (VAB). In case of B3 lesion diagnosis on CNB, OE was recommended in ADH and PT, whereas in the other B3 lesions, vacuum-assisted excision was considered an equivalent alternative to OE. In ADH, most panelists (76%) recommended an open excision (OE) after diagnosis on VAB, whereas observation after a complete VAB-removal on imaging was accepted by 34%. In LN, the majority of the panel (90%) preferred observation following complete VAB-removal. Results were similar in RS (82%), PL (100%), and FEA (100%). In benign PT, a slim majority (55%) also recommended an observation after a complete VAB-removal. VAB with subsequent active surveillance can replace an open surgical intervention for most B3 lesions (RS, FEA, PL, PT, and LN). Compared to previous recommendations, there is an increasing trend to a de-escalating strategy in classical LN. Due to the higher risk of upgrade into malignancy, OE remains the preferred approach after the diagnosis of ADH
Can the classification of low-grade endometrial stromal tumors still be improved?
In this issue of Virchows Archiv, there is a comprehensive review article on the most recent advances in our understanding of the pathologic and molecular features of endometrial stromal tumors [1]. The review is written by a team and a senior author, with considerable experience in the field. The manuscript describes the changes made since the first classification based on the number of mitotic figures to the current approach based on the resemblance to normal endometrial stroma of the proliferative phase