Individualized therapy in endometrial cancer, the most common gynaecologic cancer in the developed world, focuses on identifying specific molecular subtypes. Mutations in the exonuclease domain of ...the DNA polymerase epsilon (POLE) gene define one such subtype, which causes an ultra-mutated tumour phenotype. These tumours may have an improved progression-free survival and may be receptive to specific therapies. However, the clinical phenotype of these tumours is unknown. The objective of this study was to evaluate the clinical and genetic features of POLE-mutated tumours from a large cohort of women whose cases are characterized by: (1) the availability of detailed clinical and lifestyle data; (2) mutation analysis; and (3) long-term follow-up.
A total of 604 patients with endometrial cancer were included in the study. Data from a detailed questionnaire, including lifestyle and family history information, provided extensive pertinent information on the patients. Sequencing of exons 9-14 of the POLE gene was performed. Follow-up data were gathered and analysed.
Hotspot pathogenic POLE mutations were identified in N = 38/599 patients (6.3%). Patients with a POLE-mutated tumour were significantly younger, were more often nulliparous, and had a history of smoking. POLE-mutated tumours were more frequently aneuploid. Prognosis for patients with hotspot POLE-mutated tumours was significantly better in comparison with patients with non-mutated tumours; however careful selection of pathogenic mutations is essential to the definition of this prognostically favourable group.
This study demonstrates that POLE-mutated endometrial cancer is significantly associated with previously unknown clinicopathologic characteristics. Outcome in POLE-mutated tumours was excellent in cases with hotspot mutations. Our results suggest that prediction of excellent outcome in cases of POLE-mutated EMCA should be restricted to cases of EMCA with hotspot mutations until further data are available on the rising number of mutations with unknown significance.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The emergence of novel immunomodulatory cancer therapies over the last decade, above all immune checkpoint blockade, has significantly advanced tumor treatment. For colorectal cancer (CRC), a novel ...scoring system based on the immune cell infiltration in tumors has greatly improved disease prognostic evaluation and guidance to more specific therapy. These findings underline the relevance of tumor immunology in the future handling and therapeutic approach of malignant disease. Inflammation can either promote or suppress CRC pathogenesis and inflammatory mediators, mainly cytokines, critically determine the pro- or anti-tumorigenic signals within the tumor environment. Here, we review the current knowledge on the cytokines known to be critically involved in CRC development and illustrate their mechanisms of action. We also highlight similarities and differences between CRC patients and murine models of CRC and point out cytokines with an ambivalent role for intestinal cancer. We also identify some of the future challenges in the field that should be addressed for the development of more effective immunomodulatory therapies.
Several pathogenic roles attributed over the past two decades to either T helper (Th)1 or Th2 cells are increasingly becoming associated with interleukin (IL)-17 and most recently IL-9 signalling. ...However, the implication of IL-9 in IBD has not been addressed so far.
We investigated the expression of IL-9 and IL-9R by using peripheral blood, biopsies and surgical samples. We addressed the functional role of IL-9 signalling by analysis of downstream effector proteins. Using Caco-2 cell monolayers we followed the effect of IL-9 on wound healing.
IL-9 mRNA expression was significantly increased in inflamed samples from patients with UC as compared with controls. CD3(+) T cells were major IL-9-expressing cells and some polymorphonuclear leucocytes (PMN) also expressed IL-9. IL-9 was co-localised with the key Th9 transcription factors interferon regulatory factor 4 and PU.1. Systemically, IL-9 was abundantly produced by activated peripheral blood lymphocytes, whereas its receptor was overexpressed on gut resident and circulating PMN. IL-9 stimulation of the latter induced IL-8 production in a dose-dependent manner and rendered PMN resistant to apoptosis suggesting a functional role for IL-9R signalling in the propagation of gut inflammation. Furthermore, IL-9R was overexpressed on gut epithelial cells and IL-9 induced STAT5 activation in these cells. Moreover, IL-9 inhibited the growth of Caco-2 epithelial cell monolayers in wound healing experiments.
Our results provide evidence that IL-9 is predominantly involved in the pathogenesis of UC suggesting that targeting IL-9 might become a therapeutic option for patients with UC.
Gastrointestinal (GI) neoplasms with rhabdoid features have been reported since 1989 under diverse names (giant cell carcinoma, pleomorphic carcinoma, malignant rhabdoid tumor, adenocarcinoma with ...rhabdoid features/phenotype, anaplastic carcinoma, etc.), but their clinicopathologic spectrum, SMARCB1 (INI1) status and relationship to common GI carcinomas have not been clarified yet. We describe 2 carcinomas from the stomach and the cecum with exclusive rhabdoid morphology. The patients died of disease at 6 and 10 months, respectively. The tumors coexpressed vimentin, pancytokeratin, and EMA. Both showed complete loss of nuclear SMARCB1/INI1. Molecular analysis (KRAS, EGFR, BRAF, PIK3CA, and microsatellite studies) revealed a CpG-island methylator phenotype in the cecal tumor (CIMP/MLH1/BRAF/MSI-H), confirming epithelial origin. The gastric tumor showed poorly differentiated adenocarcinoma in regional nodes, again confirming epithelial derivation. Other genes tested were wild type in both cases. Review of reported cases (total39) revealed a glandular component in 33%. Affected sites arestomach (13), colon (11), small bowel (10), and distal esophagus (5). Of the 34 patients with follow-up ≥12 months, 29 (85%) died within 1 year (mean4 mo). Molecular tests were performed in 8/39 cases. A CIMP/BRAF/MLH1 phenotype was found in 3/4 right colon tumors. Loss of nuclear SMARCB1 protein was noted in 3/6 cases tested. This study highlights the heterogeneity of rhabdoid GI neoplasms and supports their epithelial derivation. Rhabdoid phenotype likely represents a common pathway of dedifferentiation with frequent loss of SMARCB1 and highly aggressive course. The CIMP phenotype represents a novel subset of rhabdoid GI carcinomas. This rare variant should be distinguished from proximal-type epithelioid sarcoma and other SMARCB1-deficient mimics.
The Helicobacter pylori (Hp) type IV secretion system (T4SS) forms needle-like pili, whose binding to the integrin-β1 receptor results in injection of the CagA oncoprotein. However, the apical ...surface of epithelial cells is exposed to Hp, whereas integrins are basolateral receptors. Hence, the mechanism of CagA delivery into polarized gastric epithelial cells remains enigmatic. Here, we demonstrate that T4SS pilus formation during infection of polarized cells occurs predominantly at basolateral membranes, and not at apical sites. Hp accomplishes this by secreting another bacterial protein, the serine protease HtrA, which opens cell-to-cell junctions through cleaving epithelial junctional proteins including occludin, claudin-8, and E-cadherin. Using a genetic system expressing a peptide inhibitor, we demonstrate that HtrA activity is necessary for paracellular transmigration of Hp across polarized cell monolayers to reach basolateral membranes and inject CagA. The contribution of this unique signaling cascade to Hp pathogenesis is discussed.
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•T4SS pilus formation during H. pylori (Hp) infection occurs at basolateral membranes•Hp secretes HtrA, a serine protease that cleaves epithelial junctional proteins•HtrA and opening of cell junctions are required for Hp paracellular transmigration•The T4SS pilus is activated at basolateral membranes and injects CagA
The type IV secretion system of Helicobacter pylori requires basolateral integrin receptors for its function. Tegtmeyer et al. unravel that secreted serine protease HtrA opens cell-to-cell junctions by cleaving occludin, claudin-8, and E-cadherin. This allows bacterial transmigration across polarized epithelial cells to reach integrins for injecting CagA at basolateral membranes.
Tumor budding is a robust prognostic parameter in several tumor entities but is rarely investigated in endometrial carcinoma. We applied the recently standardized counting method from the ...International Tumor Budding Consensus Conference for colorectal cancer (ITBCC) on a cohort of 255 endometrial carcinomas with known molecular profiles according to The Cancer Genome Atlas (TCGA) subgroups. Our investigation aims to clarify the potential prognostic role of tumor budding in endometrial carcinoma in contrast to other known prognostic factors, including molecular factors. In addition, the microcystic elongated and fragmented (MELF) pattern and tumor budding were compared with respect to their potential as markers for epithelial–mesenchymal transition (EMT). Tumor budding was found in n = 67 (26.3%) tumors, with a very low mean of 0.7 buds per ×20 HE field. Tumor budding was significantly associated with depth of invasion, nodal status, lymphatic invasion (each p < 0.001), grading (p = 0.004), and vascular invasion (p = 0.01). Tumor budding showed moderate inter-observer-variability with prognostic stratification irrespective of the observer (κ-value = 0.448). In multivariate analysis, tumor budding served as a significant independent prognosticator for worse outcomes in overall and recurrence-free survival (HR 2.376 and 2.736, p < 0.001), but not when the TCGA subgroups entered into the analysis. In consequence, dependency had to be clarified in the subgroup analysis for Polymerase E mutated (POLEmut), mismatch repair deficient (MMRdef), nonspecific mutation profile (NSMP), and P53 aberrant (P53abn) endometrial carcinomas. A particular impact was identified in the intermediate prognostic groups of NSMP and MMRdef carcinomas. Tumor budding outperformed the MELF pattern in single and combined prognostic information. In conclusion, the presence of tumor budding alone is a promising, robust, and easy-to-apply prognostic parameter in endometrial carcinoma. In a morpho-molecular approach, it exerts its prognostic potential in the most clinically relevant subgroups of endometrial carcinoma and serves as a good biomarker for EMT.
As antibodies to tumor necrosis factor (TNF) suppress immune responses in Crohn's disease by binding to membrane-bound TNF (mTNF), we created a fluorescent antibody for molecular mTNF imaging in this ...disease. Topical antibody administration in 25 patients with Crohn's disease led to detection of intestinal mTNF(+) immune cells during confocal laser endomicroscopy. Patients with high numbers of mTNF(+) cells showed significantly higher short-term response rates (92%) at week 12 upon subsequent anti-TNF therapy as compared to patients with low amounts of mTNF(+) cells (15%). This clinical response in the former patients was sustained over a follow-up period of 1 year and was associated with mucosal healing observed in follow-up endoscopy. These data indicate that molecular imaging with fluorescent antibodies has the potential to predict therapeutic responses to biological treatment and can be used for personalized medicine in Crohn's disease and autoimmune or inflammatory disorders.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
In 2021, a joint ESGO/ESTRO/ESP committee updated their evidence-based guidelines for endometrial cancer, recommending a new risk grouping incorporating both clinicopathologic and molecular ...parameters. We applied the new risk grouping and compared the results to those of the prior 2016 clinicopathologic system.
We classified molecularly a cohort of 604 women diagnosed with endometrial cancer using immunohistochemistry for TP53 and MMR proteins on a tissue microarray, as well as Sanger sequencing for POLE mutations. These results, combined with clinicopathologic data, allowed the patients to be risk grouped using both the new 2021 molecular/clinicopathologic parameters and the prior 2016 clinicopathologic system.
The application of the 2021 molecular markers shows Kaplan-Meier curves with a significant difference between the groups for all survival. Molecular classification under the 2021 guidelines revealed a total of 39 patients (39/594, 7%) with a change in risk group in relation to the 2016 classification system: the shift was alone due to either P53abn or POLEmut molecular marker. In order to ensure correct 2021 molecular risk classification, not all patients with endometrial cancer need a molecular diagnostic: 433 (72.9%) cases would need to be analyzed by TP53 IHC, only 46 (7.7%) by MMR IHC and 286 (48.1%) POLE sequencing reactions.
Application of the 2021 molecular risk groups is feasible and shows significant differences in survival. IHC for TP53 and MMR and applying POLE sequencing is only needed in selected cases and leads to shifting risk groups both upward and downward for a sizeable number of patients. It is possible to significantly reduce the number of analyses required to implement the classification if resources are limited.
•Application of the 2021 ESGO/ESTRO/ESP molecular risk groups is feasible and shows significant differences in survival.•Immunochemistry for TP53 and MMR and applying POLE sequencing is only needed in selected cases.•The shift in the risk groups are done by P53and and POLEmut classifications in a sizeable number of patients.
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