scholarly journals Systematic molecular and clinical analysis of uterine leiomyomas from fertile-aged women undergoing myomectomy

2020 ◽  
Vol 35 (10) ◽  
pp. 2237-2244 ◽  
Author(s):  
A Äyräväinen ◽  
A Pasanen ◽  
T Ahvenainen ◽  
T Heikkinen ◽  
P Pakarinen ◽  
...  
Keyword(s):  
Conflicts Of Interest ◽  
Tumour Size ◽  
Fumarate Hydratase ◽  
Clinical Information ◽  
Molecular Data ◽  
Uterine Leiomyomas ◽  
Driver Mutations ◽  
Wild Type ◽  
Middle Aged ◽  
Aged Patients

Abstract STUDY QUESTION What are the distributions and associated clinical characteristics of mediator complex subunit 12 (MED12), high mobility group AT-hook 2 (HMGA2) and fumarate hydratase (FH) aberrations in uterine leiomyomas from fertile-aged myomectomy patients? SUMMARY ANSWER These driver mutations account for the majority (83%) of tumours in fertile-aged patients. WHAT IS KNOWN ALREADY Alterations affecting MED12, HMGA2 and FH account for 80–90% of uterine leiomyomas from middle-aged hysterectomy patients, while the molecular background of tumours from young myomectomy patients has not been systematically studied. STUDY DESIGN, SIZE, DURATION A retrospective series of 361 archival uterine leiomyoma samples from 234 women aged ≤45 years undergoing myomectomy in 2009–2014 was examined. Associations between the molecular data and detailed clinical information of the patients and tumours were analysed. PARTICIPANTS/MATERIALS, SETTING, METHODS DNA was extracted from formalin-fixed paraffin-embedded samples and MED12 exons 1 and 2 were sequenced to identify mutations. Level of HMGA2 expression was evaluated by immunohistochemistry. Biallelic FH inactivation was analysed with 2-succinylcysteine staining, which is an indirect method of assessing FH deficiency. All patients’ medical histories were reviewed, and clinical information of patients and tumours was combined with molecular data. MAIN RESULTS AND THE ROLE OF CHANCE The median age at operation was 34 years. The majority (58%) of patients were operated on for a single leiomyoma. Known driver mutations were identified in 83% of tumours (71% MED12; 9% HMGA2; 3% FH). In solitary leiomyomas, the MED12 mutation frequency was only 43%, and 29% were wild-type for all driver alterations. MED12 mutations were associated with multiple tumours, smaller tumour size and subserosal location. LIMITATIONS, REASONS FOR CAUTION Although comprehensive, the study is retrospective in nature and all samples have been collected for routine diagnostic purposes. The use of paraffin-embedded samples and immunohistochemistry may have led to an underestimation of mutations. Due to the limited sample size and rarity of especially FH-deficient leiomyomas, the data are partly descriptive. WIDER IMPLICATIONS OF THE FINDINGS The contribution of driver mutations in leiomyomas from young myomectomy patients is comparable to tumours obtained from hysterectomies of mostly middle-aged women. Our results support the earlier findings that MED12 mutations are associated with multiple tumours, smaller tumour size and subserosal location. The study emphasizes the distinct molecular background of solitary leiomyomas, and more research is needed to clarify the underlying causes of the notable proportion of wild-type leiomyomas. STUDY FUNDING/COMPETING INTEREST(S) The study was supported by the Academy of Finland (307773), the Sigrid Jusélius Foundation, the Cancer Foundation Finland and the iCAN Digital Precision Cancer Medicine Flagship. The authors declare no conflicts of interest. TRIAL REGISTRATION NUMBER N/A

scholarly journals Impact of TP53 Mutated Subclones in Acute Myeloid Leukemia

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1483-1483
Author(s):  
Gabriel Pabst ◽  
Katharina Prochazka ◽  
Gudrun Pregartner ◽  
Frank G. Rücker ◽  
Ellen Heitzer ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Cox Regression ◽  
Conflicts Of Interest ◽  
Negative Impact ◽  
Driver Mutations ◽  
Screening Methods ◽  
Wild Type ◽  
Tp53 Mutations ◽  
Acute Myeloid

Abstract Introduction Acute myeloid leukemia (AML) with "TP53 mutation, chromosomal aneuploidy or both" has recently been described as a distinct AML subgroup exhibiting an exceedingly adverse prognosis. Therefore, testing for TP53 mutations has become an essential part of the European LeukemiaNet 2017 recommendations for risk classification. However, the incidence and pathogenic role of subclonal TP53 mutations defined by a variant allele frequency (VAF) <20% has not been addressed in this disorder yet. Methods We evaluated the prognostic value of TP53 VAFs in a cohort of 1537 patients with newly diagnosed AML, prospectively treated within 3 trials of the "German-Austrian AML Study Group". Mutation testing was performed by targeted deep sequencing and patients with TP53 mutations were categorized into 3 groups defined by VAFs <20%, 20%-40% and >40%, respectively. Results A total of 108 TP53 mutations were identified in 98 patients (6.4%). Amongst those, 61 patients showed a VAF >40%, 19 a VAF between 20% and 40% and 18 a VAF <20%. In either group, the majority of mutations were missense substitutions (VAF >40%, 49/61 [80%]; 20%-40%, 17/19 [89%]; <20%, 17/18 [94%]) and were located in the DNA binding domain of the gene (VAF >40%, 49/61 [80%]; 20%-40%, 16/19 [84%]; <20%, 16/18 [89%]). Compared to AML with clonal TP53 mutations, those with subclonal ones showed significantly fewer complex karyotypes and chromosomal losses. The number of cooperating driver mutations was low with 0-5 per case and did not differ between the 3 TP53 mutated groups. The complete remission (CR) rate was significantly inferior in the TP53 mutated cohort (48.0% versus 84.9% for TP53 wild-type patients, P <0.001) but equally distributed among the VAF-based subgroups (TP53 VAF >40%, 42.6%; 20%-40%, 57.9%; <20%, 55.6%; P=0.424). The estimated median overall survival (OS) for all 1537 AML patients was 28.1 months (95% CI, 24.3-33.5) but differed substantially between TP53 wild-type and TP53 mutated patients (33.6 months [95%CI, 28.4-45.0] versus 6.5 months [95%CI, 5.0-8.2]). As depicted in Figure 1, OS rates were comparably low in all TP53 mutated subgroups (TP53 VAF >40%, 5.8 months; 20%-40%, 6.9 months; <20%, 6.9 months).The median estimated event-free survival (EFS) for all 1537 AML patients was 15.0 months (95% CI, 13.6-16.5) with that for TP53 wild-type patients being 16.5 months (95% CI, 15.0-18.2) and for TP53 mutated patients 5.7 months (95% CI, 4.3-7.4). Median EFS rates were comparably low in all TP53 mutated subgroups (TP53 VAF >40%, 5.2 months; 20%-40%, 6.9 months; <20%, 6.5 months). In Cox regression analyses adjusting for age, white blood cell count, cytogenetic risk and type of AML, the adverse prognostic effect of TP53 mutations remained significant, with subclonal mutations showing the strongest impact (hazard ratio, 3.71 [95% CI, 2.11-6.51] for OS). Conclusion In our study on a large cohort of AML patients, TP53 mutated subclones defined by VAF <20% account for ~18% of all TP53 mutated AML cases. We here provide evidence that subclonal TP53 mutations are associated with a comparable negative impact on prognosis as clonal TP53 mutations. These findings may have implications for TP53 screening methods and for future risk stratification in AML. Disclosures No relevant conflicts of interest to declare.

scholarly journals Haploinsufficiency of CALR Confers Hematopoietic Stem Cells (HSCs) with a Clonal Advantage over Wild-Type Cells, and, in Setting of Myeloproliferative Neoplasms, Compensates for the Functions of HSCs Impaired By the Calr Mutation

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 97-97 ◽  
Author(s):  
Kotaro Shide ◽  
Takuro Kameda ◽  
Ayako Kamiunten ◽  
Masaaki Sekine ◽  
Yoshinori Ozono ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Conflicts Of Interest ◽  
Myeloproliferative Neoplasms ◽  
Negative Influence ◽  
Driver Mutations ◽  
Spleen Weight ◽  
Wild Type ◽  
Hematopoietic Stem ◽  
Cell Counts ◽  
Calr Mutation

Abstract CALR exon9 frameshift mutations function as driver mutations in essential thrombocythemia (ET) and primary myelofibrosis patients with non-mutated JAK2 or MPL. The mutations augment signal transducer and activator of transcription activity in the presence of MPL, induce increased cell proliferation and growth factor independence in cell lines, and cause ET-like myeloproliferative neoplasms (MPN) in mice. In tumor cells bearing the CALR mutation, mutant CALR protein expression occurs while wild-type (WT) CALR expression is decreased by half. Although the biological activity of mutant CALR has been elucidated in detail, the significance of CALR haploinsufficiency is unclear. The purpose of this study was therefore to clarify the influence of CALR haploinsufficiency on hematopoiesis in normal and CALR-mutated MPN in mice. First, we analyzed the effect of CALR haploinsufficiency on hematopoiesis using CALR heterozygous knockout (CALR-hKO) mice (Tokuhiro et al. Sci Rep. 2015). Blood cell counts, liver and spleen weight, histology, cell fraction in bone marrow (BM) and spleen, and survival of CALR-hKO mice were all equivalent to that observed in WT mice. In the analysis of progenitor cells by fluorescence-activated cell sorting and colony formation assays, no difference was observed in the amount of progenitor cells and in colony replating capacity between WT mice and CALR-hKO mice. Interestingly, in competitive serial transplantation experiments using whole BM cells in primary and secondary transplanted mice, CALR-hKO cells showed higher levels of chimerism than WT cells. Next, the effect of CALR haploinsufficiency on hematopoiesis in mutant CALR-del52 overexpressing mice was analyzed. We compared three groups of mice, WT mice, CALR-del52 transgenic (TG) mice (Shide et al. Leukemia 2017) and CALR-del52 TG/CALR-hKO double-mutant (TG-hKO) mice. Both TG mice and TG-hKO mice developed ET-like MPN. Compared to WT mice, increases in megakaryocytes, platelets and hematopoietic progenitor cells (including HSCs) were observed in these mice. However, no differences were observed between TG mice and TG-hKO mice. Finally, 4000 LSK cells sorted from WT mice, TG mice, and TG-hKO mice (B6-Ly5.2) and B6-Ly5.1 competitor cells (1 × 106 WT BM cells) were mixed and injected into lethally irradiated B6-Ly5.1 recipient mice, and the percent chimerism of donor cells was followed for 1 year after transplantation. From 12 weeks after transplantation, the chimerism of TG cells was significantly lower than that of control WT cells, suggesting that the CALR mutation has a negative influence on clonal expansion of HSCs. The recipient mice transplanted with TG LSK cells showed very mild thrombocythemia. On the other hand, chimerism in TG-hKO cells was significantly higher than that in control WT cells up to 12 weeks after transplantation. Chimerism at 20 weeks after transplantation was equivalent to that in control WT cells, and the recipient mice transplanted with TG-hKO LSK cells showed severe thrombocythemia. These findings show that CALR haploinsufficiency compensates for HSCs functioning, which has been impaired by the CALR mutation, enhancing the ability of HSCs to develop ET. Mice experiments have showed that HSCs with the JAK2V617F mutation are fragile, and it is considered that mutations in DNMT3A or TET2 often occurred prior to mutations in JAK2 to compensate for the defect in self renewal capacity. Conversely, since the CALR mutation is not typically preceded by any mutations, it is considered that the CALR mutation may not require any preceding mutations. Our results showed that, like JAK2 V617F mutants, overexpression of the CALR-del52 mutant impairs HSC functioning. Furthermore, we found that CALR haploinsufficiency restores the functions of impaired HSCs to the same extent as that found in WT HSCs. When an HSC acquires the CALR mutation, "defect" and "recovery" states thus occur simultaneously in the cell. This finding may explain why mutant CALR clones expand without needing to undergo any preceding mutation. Disclosures No relevant conflicts of interest to declare.

Dyslipidemia and hyperglycemia predict coronary heart disease events in middle-aged patients with NIDDM

Diabetes ◽  
1997 ◽  
Vol 46 (8) ◽  
pp. 1354-1359 ◽  
Author(s):  
S. Lehto ◽  
T. Ronnemaa ◽  
S. M. Haffner ◽  
K. Pyorala ◽  
V. Kallio ◽  
...  
Keyword(s):  
Coronary Heart Disease ◽  
Heart Disease ◽  
Middle Aged ◽  
Aged Patients

Long Term Clinical and Echocardiographic Outcomes in Middle Aged Patients Undergoing the Ross Procedure

2019 ◽  
Vol 3 (sup1) ◽  
pp. 53-53
Author(s):  
Jamie Romeo ◽  
Grigorios Papageorgiou ◽  
Francisco da Costa ◽  
Hans Sievers ◽  
Ad Bogers ◽  
...  
Keyword(s):  
Ross Procedure ◽  
Middle Aged ◽  
Aged Patients

scholarly journals Morphology of the Undersurface of the Anterolateral Acromion and Its Relationship to Surrounding Structures

2021 ◽  
Vol 9 (1) ◽  
pp. 232596712097748
Author(s):  
Yusuke Ueda ◽  
Akimoto Nimura ◽  
Keisuke Matsuki ◽  
Kumiko Yamaguchi ◽  
Hiroyuki Sugaya ◽  
...  
Keyword(s):  
Deep Layer ◽  
Micro Computed Tomography ◽  
Middle Aged ◽  
Aged Patients ◽  
Coracoacromial Ligament ◽  
3 Dimensional ◽  
Bony Surface ◽  
Inferior Aspect ◽  
Histologic Evaluation ◽  
Arthroscopic Subacromial Decompression

Background: A better understanding of the morphology underneath the acromion is needed to prevent complications after arthroscopic subacromial decompression. The precise correlations between the morphologic features underneath the acromion and the surrounding structures including the attachment of the coracoacromial ligament (CAL) and the origin of the deltoid middle head have not yet been determined in the absence of artifacts on the bony surface caused by dissection techniques. Moreover, anatomic findings in previous studies using only older-aged cadavers or dried bones may not reflect the morphologic features of younger and healthy specimens. Purpose: To characterize the anterolateral structures morphologically in the inferior aspect of the acromion, assess the relationships of these structures with surrounding structures without dissection artifacts on the bony surface, and verify the cadaveric data in the asymptomatic shoulders of living middle-aged patients. Study Design: Descriptive laboratory study. Methods: We initially analyzed the relationship between the morphology of the anterolateral structures and surrounding structures in 18 cadaveric shoulders (mean age, 81.8 years), 15 of which were subjected to macroscopic investigation of the CAL attachment and 3-dimensional micro—computed tomography investigation with radiopaque markers and 3 of which were subjected to histologic examination. We also analyzed the morphology underneath the anterolateral acromion in 24 asymptomatic shoulders of middle-aged patients (mean age, 54.8 years) to verify the cadaveric data. In both the cadaveric shoulders and the asymptomatic shoulders of live patients, the long axis, width, and height of the anterolateral prominence were measured by use of 3-dimensional CT imaging. Results: In cadavers, the anterolateral prominence underneath the acromion corresponded to the attachment of the CAL. Histologic evaluation revealed that the CAL was continuous to the deep layer of the deltoid middle head in the lateral acromion. The study in asymptomatic shoulders of middle-aged patients revealed bony prominences similar to those observed in cadavers. Conclusion: The anterolateral prominence, which corresponds to the attachment of the CAL below the acromion, may be a native structure below the acromion. Moreover, the CAL is continuous to the deep layer of the deltoid middle head in the lateral acromion.

scholarly journals A Detailed Catalogue of Multi-Omics Methodologies for Identification of Putative Biomarkers and Causal Molecular Networks in Translational Cancer Research

2021 ◽  
Vol 22 (6) ◽  
pp. 2822
Author(s):  
Efstathios Iason Vlachavas ◽  
Jonas Bohn ◽  
Frank Ückert ◽  
Sylvia Nürnberg
Keyword(s):  
Cancer Research ◽  
Clinical Information ◽  
Disease Diagnosis ◽  
Molecular Data ◽  
Molecular Networks ◽  
Biological Knowledge ◽  
Omics Data ◽  
Translational Cancer Research ◽  
Using Data ◽  
Biological Entities

Recent advances in sequencing and biotechnological methodologies have led to the generation of large volumes of molecular data of different omics layers, such as genomics, transcriptomics, proteomics and metabolomics. Integration of these data with clinical information provides new opportunities to discover how perturbations in biological processes lead to disease. Using data-driven approaches for the integration and interpretation of multi-omics data could stably identify links between structural and functional information and propose causal molecular networks with potential impact on cancer pathophysiology. This knowledge can then be used to improve disease diagnosis, prognosis, prevention, and therapy. This review will summarize and categorize the most current computational methodologies and tools for integration of distinct molecular layers in the context of translational cancer research and personalized therapy. Additionally, the bioinformatics tools Multi-Omics Factor Analysis (MOFA) and netDX will be tested using omics data from public cancer resources, to assess their overall robustness, provide reproducible workflows for gaining biological knowledge from multi-omics data, and to comprehensively understand the significantly perturbed biological entities in distinct cancer types. We show that the performed supervised and unsupervised analyses result in meaningful and novel findings.

scholarly journals Clinical Outcomes of Hip Arthroscopy for Hip Labrum Calcification in Young and Middle‐Aged Patients

2021 ◽  
Author(s):  
Bai‐qing Zhang ◽  
Ming‐yang An ◽  
Feng Gao ◽  
Chun‐bao Li ◽  
Qi Wei ◽  
...  
Keyword(s):  
Clinical Outcomes ◽  
Hip Arthroscopy ◽  
Middle Aged ◽  
Aged Patients

Outcomes and Patient Satisfaction With Arthroscopic Partial Meniscectomy for Degenerative and Traumatic Tears in Middle-Aged Patients With No or Mild Osteoarthritis

2019 ◽  
Vol 47 (10) ◽  
pp. 2412-2419
Author(s):  
Alejandro Lizaur-Utrilla ◽  
Francisco A. Miralles-Muñoz ◽  
Santiago Gonzalez-Parreño ◽  
Fernando A. Lopez-Prats
Keyword(s):  
Patient Satisfaction ◽  
Functional Outcomes ◽  
Multivariate Regression ◽  
Partial Meniscectomy ◽  
Meniscal Tears ◽  
Middle Aged ◽  
Arthroscopic Partial Meniscectomy ◽  
Aged Patients ◽  
Female Sex

Background: There is controversy about the benefit of arthroscopic partial meniscectomy (APM) for degenerative lesions in middle-aged patients. Purpose: To compare satisfaction with APM between middle-aged patients with no or mild knee osteoarthritis (OA) and a degenerative meniscal tear and those with a traumatic tear. Study Design: Cohort study; Level of evidence, 2. Methods: A comparative prospective study at 5 years of middle-aged patients (45-60 years old) with no or mild OA undergoing APM for degenerative (n = 115) or traumatic (n = 143) tears was conducted. Patient satisfaction was measured by a 5-point Likert scale and functional outcomes by the Knee injury and Osteoarthritis Outcome Score (KOOS) and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). Univariate and multivariate regression analyses were used to identify factors correlating with patient-reported satisfaction at 5 years postoperatively. Results: Baseline patient characteristics were not different between groups. At the 5-year evaluation, the satisfaction rate in the traumatic and degenerative groups was 68.5% versus 71.3%, respectively ( P = .365). Patient satisfaction was significantly associated with functional outcomes ( r = 0.69; P = .024). In the degenerative group, 43 patients (37.4%) had OA progression to Kellgren-Lawrence (K-L) grade 2 or 3, but only 24 patients (20.8%) had a symptomatic knee at final follow-up. Multivariate regression analysis for patient dissatisfaction at 5-year follow-up showed the following significant independent factors: female sex (odds ratio [OR], 1.6 [95% CI, 1.1-2.3]; P = .018), body mass index >30 kg/m2 (OR, 2.6 [95% CI, 1.7-4.9]; P = .035), lateral meniscal tears (OR, 0.6 [95% CI, 0.1-0.9]; P = .039), and OA progression to K-L grade ≥2 at final follow-up (OR, 1.4 [95% CI, 1.2-2.6]; P = .014). At the final evaluation, there were no significant differences between groups in pain scores ( P = .648), WOMAC scores ( P = .083), or KOOS-4 scores ( P = .187). Likewise, there were no significant differences in the KOOS subscores for Pain ( P = .144), Symptoms ( P = .097), or Sports/Recreation ( P = .150). Although the degenerative group had significantly higher subscores for Activities of Daily Living ( P = .001) and Quality of Life ( P = .004), the differences were considered not clinically meaningful. Conclusion: There were no meaningful differences in patient satisfaction or clinical outcomes between patients with traumatic and degenerative tears and no or mild OA. Predictors of dissatisfaction with APM were female sex, obesity, and lateral meniscal tears. Our findings suggested that APM was an effective medium-term option to relieve pain and recover function in middle-aged patients with degenerative meniscal tears, without obvious OA, and with failed prior physical therapy.

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