Development and external validation of nomograms to predict sarcoma-specific death and disease progression after surgical resection of localized high-grade conventional primary central chondrosarcoma and dedifferentiated chondrosarcoma

Aims Our aim was to develop and validate nomograms that would predict the cumulative incidence of sarcoma-specific death (CISSD) and disease progression (CIDP) in patients with localized high-grade primary central and dedifferentiated chondrosarcoma. Methods The study population consisted of 391 patients from two international sarcoma centres (development cohort) who had undergone definitive surgery for a localized high-grade (histological grade II or III) conventional primary central chondrosarcoma or dedifferentiated chondrosarcoma. Disease progression captured the first event of either metastasis or local recurrence. An independent cohort of 221 patients from three additional hospitals was used for external validation. Two nomograms were internally and externally validated for discrimination (c-index) and calibration plot. Results In the development cohort, the CISSD at ten years was 32.9% (95% confidence interval (CI) 19.8% to 38.4%). Age at diagnosis, grade, and surgical margin were found to have significant effects on CISSD and CIDP in multivariate analyses. Maximum tumour diameter was also significantly associated with CISSD. In the development cohort, the c-indices for CISSD and CIDP at five years were 0.743 (95% CI 0.700 to 0.819) and 0.761 (95% CI 0.713 to 0.800), respectively. When applied to the validation cohort, the c-indices for CISSD and CIDP at five years were 0.839 (95% CI 0.763 to 0.916) and 0.749 (95% CI 0.672 to 0.825), respectively. The calibration plots for these two nomograms demonstrated good fit. Conclusion Our nomograms performed well on internal and external validation and can be used to predict CISSD and CIDP after resection of localized high-grade conventional primary central and dedifferentiated chondrosarcomas. They provide a new tool with which clinicians can assess and advise individual patients about their prognosis. Cite this article: Bone Joint J 2020;102-B(12):1752–1759.

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High-grade meningiomas: biology and implications

Neurosurgical FOCUS ◽

10.3171/2017.12.focus17756 ◽

2018 ◽

Vol 44 (4) ◽

pp. E2 ◽

Cited By ~ 10

Author(s):

Wenya Linda Bi ◽

Vikram C. Prabhu ◽

Ian F. Dunn

Keyword(s):

Clear Cell ◽

Histological Grade ◽

Methylation Profile ◽

High Grade ◽

Copy Number Alterations ◽

Surgical Disease ◽

Mutation Burden ◽

Genomic Analyses ◽

Grade Ii ◽

Gains And Losses

The epochal developments in the treatment of meningioma—microsurgery, skull base techniques, and radiation therapy—will be appended to include the rational application of targeted and immune therapeutics, previously ill-fitting concepts for a tumor that has traditionally been a regarded as a surgical disease. The genomic and immunological architecture of these tumors continues to be defined in ever-greater detail. Grade I meningiomas are driven by NF2 alterations or mutations in AKT1, SMO, TRAF7, PIK3CA, KLF4, POLR2A, SUFU, and SMARCB1. Higher-grade tumors, however, are driven nearly exclusively by NF2/chr22 loss and are marked by infrequent targetable mutations, although they may harbor a greater mutation burden overall. TERT mutations may be more common in tumors that progress in histological grade; SMARCE1 alteration has become a signature of the clear cell subtype; and BAP1 in rhabdoid variants may confer sensitivity to pharmacological inhibition. Compared with grade I meningiomas, the most prominent alteration in grade II and III meningiomas is a significant increase in chromosomal gains and losses, or copy number alterations, which may have behavioral implications. Furthermore, integrated genomic analyses suggest phenotypic subgrouping by methylation profile and a specific role for PRC2 complex activation. Lastly, there exists a complex phylogenetic relationship among recurrent high-grade tumors, which continues to underscore a role for the most traditional therapy in our arsenal: surgery.

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Secondary chondrosarcoma arising from osteochondroma

The Bone & Joint Journal ◽

10.1302/0301-620x.101b9.bjj-2019-0190.r1 ◽

2019 ◽

Vol 101-B (10) ◽

pp. 1313-1320 ◽

Cited By ~ 4

Author(s):

Yusuke Tsuda ◽

Jonathan J. Gregory ◽

Tomohiro Fujiwara ◽

Seggy Abudu

Keyword(s):

Local Recurrence ◽

Histological Grade ◽

Radical Resection ◽

Resection Margins ◽

Free Survival ◽

Secondary Chondrosarcoma ◽

Grade Ii ◽

Definitive Surgery ◽

Local Recurrence Free Survival

Aims The aim of this study was to report the outcomes of patients who underwent definitive surgery for secondary chondrosarcomas arising from osteochondromas. Patients and Methods A total of 51 patients with secondary chondrosarcomas occurring from osteochondromas were reviewed. Median age was 36 years (interquartile range (IQR) 15 to 82). Median follow-up was 6.9 years (IQR 2.8 to 10.6). The pelvis was the most commonly affected site (59%). Histological grades were grade I in 35 (69%), grade II in 13 (25%), and grade III in three patients (6%). Results Preoperative biopsy histology correctly predicted the final histological grade in 27% of patients. The ten-year disease-specific survival (DSS) for all patients was 89.4%. Local recurrence occurred in 15 patients (29%), more commonly in pelvic tumours (37%) compared with limb tumours (19%). Four patients with pelvic tumours died from progression of local recurrence. No patient with limb tumours died of disease. Wide/radical margin was associated with improved local recurrence-free survival (p = 0.032) and local recurrence was associated with worse DSS (p = 0.005). Conclusion We recommend that a secondary chondrosarcoma arising from osteochondroma of the pelvis is resected with wide/radical resection margins. The balance between the morbidity of surgery and risk of local recurrence needs to be considered in patients with limb secondary chondrosarcomas. Cite this article: Bone Joint J 2019;101-B:1313–1320

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Evaluation of Akt and RICTOR Expression Levels in Astrocytomas of All Grades

Journal of Histochemistry & Cytochemistry ◽

10.1369/0022155416675850 ◽

2016 ◽

Vol 65 (2) ◽

pp. 93-103 ◽

Cited By ~ 11

Author(s):

Arthur William Alvarenga ◽

Luis Eduardo Machado ◽

Bruna Roz Rodrigues ◽

Fernanda Cristina Sulla Lupinacci ◽

Paulo Sanemastu ◽

...

Keyword(s):

Histological Grade ◽

Mammalian Target Of Rapamycin ◽

Experimental Models ◽

High Grade ◽

Ki 67 ◽

Protein Partners ◽

Phosphorylated Akt ◽

Grade Ii ◽

Human Astrocytomas

The mammalian target of rapamycin (mTOR) binds to several protein partners and forms two complexes, termed mTOR complexes 1 and 2 (mTORC1/2), that differ in components, substrates, and regulation. mTORC2 contains the protein Rapamycin-insensitive companion of mTOR (RICTOR); phosphorylates kinases of the AGC family, such as Akt; and controls the cytoskeleton. Even though the regulation of mTORC2 activity remains poorly understood, the hyperactivation of this signaling pathway has been shown to contribute to the oncogenic properties of gliomas in experimental models. In this work, we evaluated expression and phosphorylation of Akt, and expression of RICTOR and Ki-67 in 195 human astrocytomas of different grades (38 cases of grade I, 49 grade II, 15 grade III, and 93 grade IV) and 30 normal brains. Expression and phosphorylation of Akt increased with histological grade and correlated with a worse overall survival in glioblastomas (GBMs). RICTOR was overexpressed in grade I and II astrocytomas and demonstrated a shift to nuclear localization in GBMs. Nuclear RICTOR was associated to increased proliferation in GBMs. Our results point to an increase in total and phosphorylated Akt in high-grade gliomas and to a possible role of RICTOR in proliferations of high-grade GBM cells.

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Value of p53 and estrogen receptors immunohistochemical staining in endometrial carcinoma

International Journal of Reproduction Contraception Obstetrics and Gynecology ◽

10.18203/2320-1770.ijrcog20195339 ◽

2019 ◽

Vol 8 (12) ◽

pp. 4885

Author(s):

Dejan Opric ◽

Amer Suskic ◽

Sanela Halilovic Suskic ◽

Gorana Nikolic ◽

Isidora Filipovic

Keyword(s):

Estrogen Receptors ◽

Endometrial Carcinoma ◽

Diagnostic Value ◽

Public Hospitals ◽

Lower Grade ◽

High Grade ◽

P53 Expression ◽

Study Population ◽

Grade Ii ◽

Endometrial Carcinomas

Background: Since there are many articles dealing with estimating prognostic and diagnostic value of ER and p53, using different, usually complex ICH interpretation methods, we wanted to evaluate significance of p53 and ER ICH positivity in endometrial carcinoma, using easily applicable criteria that would help pathologists and clinicians to be sure in ICH findings noted in the report.Methods: This paper deals with data of the patients treated for endometrial carcinoma in Public Hospitals in Travnik, gynecological department in the period from 1st January 2013 to 1st January 2019. The study included 97 women with endometrial carcinoma, with ages ranging from 42 to 90 years (mean of 64 years). Sample consisted of 72 cases (74.2%) of endometrioid and 25 cases (25.8%) of non-endometrioid carcinoma.Results: p53 expression was observed in 13.8% carcinomas of the endometrioid type and in 68% carcinomas of non-endometrioid type, while estrogen receptors were more frequently observed in tumors of the endometrioid type (61%) in contrast to non-endometrioid type (28%). Among 72 cases, those with grade I expressed estrogen receptors (26 out of 34 cases - 72%) more frequently than those with grades II and III. Frequency of p53 positivity was significantly higher at higher grades (grade I - 5.8%, grade II - 11.5%, grade III - 71.4%). Stage I carcinomas showed p53 staining less frequently (22.2%) that carcinomas diagnosed at later stages (31.5%).Conclusions: Using 80% nuclei stained as threshold for p53 positivity, we concluded that p53 is marker of high-grade endometrial carcinomas: high grade endometrioid and non-endometrioid carcinomas. Using 1% of cells as threshold for ER positivity, we confirmed that ER are common in endometrioid type carcinoma, in contrast to non-endometrioid type. Although observed, higher frequency of ER in tumors with lower grade and stage was not statistically confirmed in our study population.

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Stereology in Grading and Prognosis of Canine Cutaneous Mast Cell Tumors

Veterinary Pathology ◽

10.1177/0300985820985138 ◽

2021 ◽

pp. 030098582098513

Author(s):

Mafalda Casanova ◽

Sandra Branco ◽

Inês Berenguer Veiga ◽

André Barros ◽

Pedro Faísca

Keyword(s):

Mast Cell ◽

Clinical Outcome ◽

Prognostic Value ◽

Histological Grade ◽

Intraobserver Variability ◽

Low Grade ◽

High Grade ◽

Mast Cell Tumors ◽

Cutaneous Mast Cell ◽

Grade Iii

Canine cutaneous mast cell tumors (ccMCTs) are currently graded according to Patnaik and Kiupel grading schemes. The qualitative and semiquantitative parameters applied in these schemes may lead to inter- and intraobserver variability. This study investigates the prognostic value of volume-weighted mean nuclear volume ([Formula: see text]), a stereological estimation that provides information about nuclear size and its variability. [Formula: see text] of 55 ccMCTs was estimated using the “point-sampled intercept” method and compared with histological grade and clinical outcome. The clinical history of dogs treated with surgical excision alone was available for 30 ccMCTs. Statistical differences in [Formula: see text] were found between grade II ([Formula: see text]= 115 ± 29 µm3) and grade III ccMCTs ([Formula: see text]= 197 ± 63 µm3), as well as between low-grade ([Formula: see text]= 113 ± 28 µm3) and high-grade ccMCTs ([Formula: see text]= 184 ± 63 µm3). An optimal cutoff value of [Formula: see text] ≥ 150 µm3 and [Formula: see text] ≥ 140 µm3 was determined for grade III and high-grade ccMCTs, respectively. In terms of prognosis, [Formula: see text] was not able to predict the clinical outcome in 42% of the cases; however, cases with [Formula: see text]<125 µm3 had a favorable outcome. These results indicate that, despite having limited prognostic value when used as a solitary parameter, [Formula: see text] is highly reproducible and is associated with histological grade as well as with benign behavior.

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Pancreatic Cancers with High Grade Tumor Budding Exhibit Hallmarks of Diminished Anti-Tumor Immunity

Cancers ◽

10.3390/cancers13051090 ◽

2021 ◽

Vol 13 (5) ◽

pp. 1090

Author(s):

Hassan Sadozai ◽

Animesh Acharjee ◽

Thomas Gruber ◽

Beat Gloor ◽

Eva Karamitopoulou

Keyword(s):

Gene Expression ◽

Pancreatic Cancer ◽

Disease Progression ◽

Immune Escape ◽

Epithelial Mesenchymal Transition ◽

Tumor Budding ◽

Ductal Adenocarcinoma ◽

Low Grade ◽

High Grade ◽

Mesenchymal Transition

Tumor budding is associated with epithelial-mesenchymal transition and diminished survival in a number of cancer types including pancreatic ductal adenocarcinoma (PDAC). In this study, we dissect the immune landscapes of patients with high grade versus low grade tumor budding to determine the features associated with immune escape and disease progression in pancreatic cancer. We performed immunohistochemistry-based quantification of tumor-infiltrating leukocytes and tumor bud assessment in a cohort of n = 111 PDAC patients in a tissue microarray (TMA) format. Patients were divided based on the ITBCC categories of tumor budding as Low Grade (LG: categories 1 and 2) and High Grade (HG: category 3). Tumor budding numbers and tumor budding grade demonstrated a significant association with diminished overall survival (OS). HG cases exhibit notably reduced densities of stromal (S) and intratumoral (IT) T cells. HG cases also display lower M1 macrophages (S) and increased M2 macrophages (IT). These findings were validated using gene expression data from TCGA. A published tumor budding gene signature demonstrated a significant association with diminished survival in PDAC patients in TCGA. Immune-related gene expression revealed an immunosuppressive TME in PDAC cases with high expression of the budding signature. Our findings highlight a number of immune features that permit an improved understanding of disease progression and EMT in pancreatic cancer.

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Radiomic nomogram based on MRI to predict grade of branching type intraductal papillary mucinous neoplasms of the pancreas: a multicenter study

Cancer Imaging ◽

10.1186/s40644-021-00395-6 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Sijia Cui ◽

Tianyu Tang ◽

Qiuming Su ◽

Yajie Wang ◽

Zhenyu Shu ◽

...

Keyword(s):

Calibration Curve ◽

Main Pancreatic Duct ◽

Validation Cohort ◽

External Validation ◽

High Grade ◽

Intraductal Papillary Mucinous Neoplasms ◽

Training Cohort ◽

Independent Validation ◽

Medical Centers ◽

Mucinous Neoplasms

Abstract Background Accurate diagnosis of high-grade branching type intraductal papillary mucinous neoplasms (BD-IPMNs) is challenging in clinical setting. We aimed to construct and validate a nomogram combining clinical characteristics and radiomic features for the preoperative prediction of low and high-grade in BD-IPMNs. Methods Two hundred and two patients from three medical centers were enrolled. The high-grade BD-IPMN group comprised patients with high-grade dysplasia and invasive carcinoma in BD-IPMN (n = 50). The training cohort comprised patients from the first medical center (n = 103), and the external independent validation cohorts comprised patients from the second and third medical centers (n = 48 and 51). Within 3 months prior to surgery, all patients were subjected to magnetic resonance examination. The volume of interest was delineated on T1-weighted (T1-w) imaging, T2-weighted (T2-w) imaging, and contrast-enhanced T1-weighted (CET1-w) imaging, respectively, on each tumor slice. Quantitative image features were extracted using MITK software (G.E.). The Mann-Whitney U test or independent-sample t-test, and LASSO regression, were applied for data dimension reduction, after which a radiomic signature was constructed for grade assessment. Based on the training cohort, we developed a combined nomogram model incorporating clinical variables and the radiomic signature. Decision curve analysis (DCA), a receiver operating characteristic curve (ROC), a calibration curve, and the area under the ROC curve (AUC) were used to evaluate the utility of the constructed model based on the external independent validation cohorts. Results To predict tumor grade, we developed a nine-feature-combined radiomic signature. For the radiomic signature, the AUC values of high-grade disease were 0.836 in the training cohort, 0.811 in external validation cohort 1, and 0.822 in external validation cohort 2. The CA19–9 level and main pancreatic duct size were identified as independent parameters of high-grade of BD-IPMNs using multivariate logistic regression analysis. The CA19–9 level and main pancreatic duct size were then used to construct the radiomic nomogram. Using the radiomic nomogram, the high-grade disease-associated AUC values were 0.903 (training cohort), 0.884 (external validation cohort 1), and 0.876 (external validation cohort 2). The clinical utility of the developed nomogram was verified using the calibration curve and DCA. Conclusions The developed radiomic nomogram model could effectively distinguish high-grade patients with BD-IPMNs preoperatively. This preoperative identification might improve treatment methods and promote personalized therapy in patients with BD-IPMNs.

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Improving Student Creativity Activeness And Implementation Approach In Cbsa On Civics Lesson Grade Ii Sd Negeri 39 Lengayang Gompong.Kec Markets Academic Year 2016/2017

Jurnal Ilmiah Pendidikan Scholastic ◽

10.36057/jips.v1i2.251 ◽

2018 ◽

Vol 1 (2) ◽

pp. 89-96

Author(s):

Darleli Darleli

Keyword(s):

Civic Education ◽

Evaluation Study ◽

Class Action ◽

Peer Tutors ◽

Implementation Approach ◽

Before And After ◽

Study Population ◽

Grade Ii ◽

The Subject ◽

Academic Year

The purpose of this study is to prove that the use of the environment around the school can improve students' understanding of the subject Civic Education in Elementary School student 39 Class II Gompong Market. This study uses a class action approach. The study population was taken of all students in grade II , the data collection techniques used artificial teacher learning achievement test. Actions performed a total of two cycles. Data analysis techniques used analysis of the percentage of change in the results of the evaluation study before and after tutoring services with peer tutors. Thus there is an increase in students' mastery of the first cycle and the second cycle. Based on the above, it can be made a conclusion as follows: " Improving Student Creativity activeness And Implementation Approach In CBSA On Civics Lesson Grade II SD Negeri 39 Lengayang Gompong.Kec Markets Academic Year 2016/2017 " .

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