Fusions involving NTRK1, NTRK2, and NTRK3 are oncogenic drivers occurring in a spectrum of mesenchymal neoplasms ranging from benign to highly malignant tumors. To gain further insights into the ...staining profile with the pan-TRK assay, we analyzed a large number of soft tissue sarcomas and correlated our findings with molecular testing. Additionally, we expand the spectrum of NTRK-fusion tumors by reporting a mesenchymal lesion in the lung as well as a mesenchymal skin lesion in the spectrum of benign fibrous histiocytoma with NTRK—fusion. We retrospectively reviewed soft tissue sarcomas diagnosed at the Diagnostic and Research Institute of Pathology, Medical University of Graz, between 1999 and 2019, and cases from the consultation files of one of the authors (BLA). In total, 494 cases were analyzed immunohistochemically with pan-TRK antibody (clone EPR17341, RTU, Roche/Ventana) and positive cases (defined as any cytoplasmic/nuclear staining in more than 1% of tumor cells) underwent next-generation sequencing (NGS). Immunohistochemical staining was observed in 16 (3.2%) cases. Eleven cases with focal weak and moderate cytoplasmic/membranous or focal moderate to strong nuclear staining did not harbor an NTRK-fusion (three synovial sarcomas, three leiomyosarcomas, two extraskeletal myxoid chondrosarcomas, and one each: dedifferentiated liposarcoma, pleomorphic liposarcoma, and myxofibrosarcoma). Four cases showed strong diffuse nuclear and/or cytoplasmatic staining, and one case showed diffuse, but weak cytoplasmic staining. All these cases demonstrated an NTRK-fusion (LMNA-NTRK1, IRF2BP2-NTRK1, TMB3-NTRK1, ETV6-NTRK3, RBPMS-NTRK3). Pan-TRK assay (clone EPR17341, RTU, Roche, Ventana) immunohistochemistry serves as a reliable diagnostic marker that can also be expressed in non-NTRK-rearranged mesenchymal neoplasms. It can be used as a surrogate marker for identification of NTRK fusion, nevertheless, an RNA-based NGS for detection of the specific fusion should be performed to confirm the rearrangement, if patients are undergoing targeted therapy. Additionally, we identified NTRK-fusion-positive, primary mesenchymal tumors of the lung and the skin.
Tertiary lymphoid structures (TLS) are associated with favorable outcome in non-metastatic colorectal carcinoma (nmCRC), but the dynamics of TLS maturation and its association with effective ...anti-tumor immune surveillance in nmCRC are unclear. Here, we hypothesized that not only the number of TLS but also their composition harbors information on recurrence risk in nmCRC. In a comprehensive molecular, tissue, laboratory, and clinical analysis of 109 patients with stage II/III nmCRC, we assessed TLS numbers and degree of maturation in surgical specimens by multi-parameter immunofluorescence of follicular dendritic cell (FDC) and germinal center (GC) markers. TLS formed in most tumors and were significantly more prevalent in highly-microsatellite-instable (MSI-H) and/or BRAF-mutant nmCRC. We could distinguish three sequential TLS maturation stages which were characterized by increasing prevalence of FDCs and mature B-cells: 1 Early TLS, composed of dense lymphocytic aggregates without FDCs, 2 Primary follicle-like TLS, having FDCs but no GC reaction, and 3 Secondary follicle-like TLS, having an active GC reaction. A simple integrated TLS immunoscore reflecting these parameters identified a large subgroup of nmCRC patients with a very low risk of recurrence independently of clinical co-variables such as ECOG performance status, age, stage, and adjuvant chemotherapy. We conclude that (1) mismatch repair and BRAF mutation status are associated with the formation of TLS in nmCRC, (2) TLS formation in nmCRC follows sequential maturation steps, culminating in germinal center formation, and (3) this maturation process harbors important prognostic information on the risk of disease recurrence.
Abstract Background Recent evidence indicates that tumor progression involves factors of systemic inflammation, such as platelets and lymphocytes. In this study, we investigated the prognostic ...relevance of the preoperative platelet to lymphocyte (P/L) ratio on time to recurrence (TTR) and overall survival (OS) in patients with stage II and III colon cancer (CC) who underwent curative resection. Methods In this retrospective study, 372 CC patients were included. Kaplan–Meier curves and multivariate Cox proportional models were calculated for TTR and OS. Results In univariate analysis, the elevated P/L ratio was significantly associated with decreased TTR (HR = 1.60, 95% CI = 1.02 to 2.51, P = .040) and remained significant in multivariate analysis (HR = 1.65, 95% CI = 1.05 to 2.58, P = .030), where HR and CI represent Hazard ratio and confidence interval, respectively. Patients with elevated P/L ratio showed a median TTR of 116 months. In contrast, patients with low P/L ratio had a median TTR of 132 months. In OS analysis, the elevated P/L ratio showed a trend toward decreased OS in univariate analysis (HR = 1.54, 95% CI = .95 to 2.48, P = .079). Conclusion In this study, we identified the preoperative P/L ratio as a prognostic marker for TTR in stage II and III CC patients.
Background
Unplanned excisions (UE) of soft tissue sarcomas (STS) carry a high risk for local recurrence (LR) due to marginal/intralesional resections. However, there are reports about improved ...prognosis for UE patients who have re-resection compared with patients who undergo planned surgery. The present multicentre study was designed to define characteristics of UE patients and to investigate the impact of UE on subsequent therapy and patient outcomes.
Methods
A total of 728 STS patients (376 males, 352 females; mean age: 58 years) who underwent definite surgery at one of three tumour centres were retrospectively included. Time-to-event analyses were calculated with log-rank and Gray’s tests, excluding patients with primary metastasis (
n
= 59). A propensity-score (PS) of being in the UE group was estimated, based on differences at baseline between the UE group and non-UE group. An inverse-probability-of-UE weight (IPUEW) was generated and time-to-event analyses calculated after IPUEW weighting.
Results
Before referral, 38.6% of patients (
n
= 281) had undergone UE. Unplanned excision patients were younger (
p
= 0.036), rather male (
p
= 0.05), and had smaller (
p
< 0.005), superficially located tumours (
p
< 0.005). Plastic reconstructions (
p
< 0.005) and adjuvant radiotherapy (
p
= 0.041) more often were needed at re-resection. In univariable analysis, re-resected patients had improved overall survival (OS;
p
= 0.027) and lower risk of distant metastasis (DM;
p
= 0.002) than primarily resected patients, whereas risk of LR was similar (
p
= 0.359). After weighting for the IPUEW, however, differences in terms of OS (
p
= 0.459) and risk of DM (
p
= 0.405) disappeared.
Conclusions
The present study does not support prior findings of improved outcome for UE patients. Unplanned excisions have a major impact on subsequent therapy, yet they do not seem to affect negatively the long-term oncology outcome.
Soft tissue sarcomas (STS) constitute a rare tumour entity comprising over 50 histological subtypes. MicroRNAs (miRNAs) are short non-protein coding RNA molecules that regulate gene expression by ...targeting the 3'-untranslated region of messenger RNAs. They are involved in a variety of human diseases, including malignancies, such as endometrial cancer, osteosarcoma, bronchial carcinoma and breast cancer. In STS, various miRNAs are differentially expressed, thus contributing to development, progression and invasion. Therefore, the aim of the present review is to summarise current knowledge on the role of miRNAs in STS. Furthermore, the potential role of miRNAs as diagnostic, prognostic and predictive biomarkers is discussed.
Cellular myxoma is a benign soft tissue tumor frequently associated with
mutation that may morphologically resemble low-grade myxofibrosarcoma. This study aimed to identify the undescribed ...methylation profile of cellular myxoma and compare it to myxofibrosarcoma. We performed molecular analysis on twenty cellular myxomas and nine myxofibrosarcomas and analyzed the results using the methylation-based DKFZ sarcoma classifier. A total of 90% of the cellular myxomas had
mutations (four loci had not been previously described). Copy number variations were found in all myxofibrosarcomas but in none of the cellular myxomas. In the classifier, none of the cellular myxomas reached the 0.9 threshold. Unsupervised t-SNE analysis demonstrated that cellular myxomas form their own clusters, distinct from myxofibrosarcomas. Our study shows the diagnostic potential and the limitations of molecular analysis in cases where morphology and immunohistochemistry are not sufficient to distinguish cellular myxoma from myxofibrosarcoma, particularly regarding
wild-type tumors. The DKFZ sarcoma classifier only provided a valid prediction for one myxofibrosarcoma case; this limitation could be improved by training the tool with a more considerable number of cases. Additionally, the classifier should be introduced to a broader spectrum of mesenchymal neoplasms, including benign tumors like cellular myxoma, whose distinct methylation pattern we demonstrated.
Abstract Background Inflammation plays an important role in tumor proliferation and survival in cancer patients. The aim of this study was to investigate the prognostic impact of the ...pre-operative–derived neutrophil/lymphocyte ratio (dNLR) in a large cohort of soft tissue sarcoma (STS) patients after curative surgical resection. Methods The impact of preoperative dNLR on disease-free survival (DFS) and overall survival (OS) in retrospectively evaluated 340 STS patients was assessed using Kaplan–Meier curves and Cox proportional models. Results Applying receiver operating curve analysis, we determined a cut-off value of 2.39 for the dNLR to be optimal for discrimination of patients' survival in the whole cohort. Kaplan–Meier curves revealed a dNLR greater than or equal to 2.39 as a marker for decreased DFS ( P = .031) and OS ( P = .007, log-rank test) in STS patients. In multivariate analysis, increased dNLR was significantly associated with poor OS (hazard ratio 1.60, 95% confidence interval 1.07 to 2.40, P = .022). Conclusions This study demonstrates that preoperative dNLR might represent a well-correlated surrogate marker for the widely validated NLR. The dNLR is easily obtainable and can provide important information for individual risk assessment in clinical trials.
Hedgehog signaling pathway in ovarian cancer Szkandera, Joanna; Kiesslich, Tobias; Haybaeck, Johannes ...
International Journal of Molecular Sciences,
01/2013, Letnik:
14, Številka:
1
Journal Article, Book Review
Recenzirano
Odprti dostop
Despite advances in surgical and chemotherapeutic treatment options, less than 50% of patients with advanced-stage ovarian cancer survive five years after initial diagnosis. In this regard, novel ...treatment approaches are warranted utilizing molecularly targeted therapies directed against particular components of specific signaling pathways which are required for tumor development and progression. One molecular pathway of interest is the hedgehog (Hh) signaling pathway. Activation of the Hh pathway has been observed in several cancer types, including ovarian cancer. This review highlights the crucial role of Hh signaling in the development and progression of ovarian cancer and might lead to a better understanding of the Hh signaling in ovarian tumorigenesis, thus encouraging the investigation of novel targeted therapies.
In the last decade, new tumor entities have been described, including
-rearranged neoplasms of different biologic behavior. To gain further insights into the behavior of these tumors, we analyzed a ...spectrum of
-rearranged neoplasms and discuss their key diagnostic and molecular features in relation to their prognosis. We report five patients with
-rearranged neoplasms, including one simple bone cyst (SBC), two complex cystic bone lesions lacking morphological characteristics of SBC, and two sarcomas. In three cases, fluorescence in situ hybridization (FISH) and in all cases copy number variation (CNV) profiling and fusion analyses were performed. All patients were male, three cystic lesions occurred in children (aged 10, 14, and 17 years), and two sarcomas in adults (69 and 39 years). Fusion analysis revealed two
rearrangements in two cystic lesions and three
rearrangements in one complex cystic lesion and two sarcomas.
FISH revealed tumor cells with break-apart signal without amplification in one complex cystic lesion and
amplification in both sarcomas was documented. CNV analysis showed simple karyotypes in all cystic lesions, while more complex karyotypes were found in
-rearranged sarcomas. Our study supports and expands previously reported molecular findings of
-rearranged neoplasms. The study highlights the importance of combining radiology and morphologic features with molecular aberrations. The use of additional molecular methods, such as CNV and FISH in the routine diagnostic workup, can be crucial in providing a correct diagnosis and avoiding overtreatment.
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