Evaluation of dystrophin expression by immunohistochemistry as a prognostic factor in leiomyosarcomas (LMS).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e23525-e23525
Author(s):  
Raul Terés ◽  
Paula Cerdà ◽  
Ana Sebio ◽  
Pablo Gallardo ◽  
Aida Bujosa ◽  
...  
Keyword(s):  
Overall Survival ◽  
Soft Tissue Sarcomas ◽  
Suppressor Gene ◽  
Tumour Suppressor Gene ◽  
The Body ◽  
Semiquantitative Assessment ◽  
Dystrophin Expression ◽  
Grade 3 ◽  
Genetic Evaluations ◽  
Risk Of Relapse

e23525 Background: Leiomyosarcomas (LMS) are soft tissue sarcomas that derive from smooth muscle cells and can arise anywhere in the body (most frequently in extremities, uterus or retroperitoneum). The clinical prognostic factors are well established but molecular factors influencing prognostic are unknown. The DMD gene, which codifies for the dystrophin protein, has been proposed as tumour suppressor gene in LMS. The aim of our study is to evaluate dystrophin expression in LMS and its relation with the patient prognosis. Methods: A total of 103 patients (pts) with LMS were analysed. Clinical and pathological data were collected retrospectively from patients’ electronic board system. Dystrophin expression was analysed by immunohistochemistry (IHC) in paraffin embedded tissue LMS samples using the Novocastra NCL-DYS2 (Leica Biosystems). Semiquantitative assessment of the staining was classified from score 0 to 3 (0 = no dystrophin expression, 1 = low expression, 2 = moderate expression, 3 = high expression). Results: Of all 103 pts, 70 (68%) had localized disease and the majority of tumours were larger than 5 cm (75%). The most frequent locations of primary LMS were extremities (n = 31; 30.1%), uterus (n = 23; 23.2%) and retroperitoneum (n = 21; 20.4%). Most LMS were high grade (G): 7 pts G1 (6.8%), 35 pts G2 (34%) 2 and 53 pts G3 (51.5%). 50 of all grade LMS (48.6%) had loss of dystrophin expression (score 0), 17 (16.5%) had score 1, 23 (22.3%) score 2 and 10 (9.7%) score 3. Loss/low dystrophin expression measured as score 0 or 1, was more frequent in grade 3 LMS compared to grade 2 or grade 1 (77.4% vs. 57.1% vs. 16.7%; p = 0.005). There were no differences in dystrophin loss between localized or metastatic disease at diagnosis (64.2% vs. 72.2%; p > 0.05). In our series, loss or reduced dystrophin expression did not correlate with the risk of relapse in localized patients or overall survival in metastatic patients. Conclusions: Loss of dystrophin expression is a common event in LMS. Loss/low dystrophin expression is more frequent in grade 3 LMS compared to grade 2 and grade 1 LMS. Loss of dystrophin expression did not correlate with risk of relapse or overall survival in our series. Additional genetic evaluations to study DMD in LMS are underway.

scholarly journals Orbital Leiomyosarcoma After Bilateral Retinoblastoma Treated With Chemotherapy And Radiotherapy

2020 ◽  
Vol 2 (3) ◽  
Author(s):  
Aoife Smyth ◽  
Elizabeth M. McElnea ◽  
Penelope McKelvie ◽  
Alan McNab
Keyword(s):  
Healthcare Professionals ◽  
Genetic Defect ◽  
Soft Tissue Sarcomas ◽  
Suppressor Gene ◽  
Tumour Suppressor Gene ◽  
Secondary Malignancy ◽  
Bilateral Retinoblastoma ◽  
Increased Risk ◽  
One Year ◽  
Symptoms And Signs

A 23-year old man presented with a swelling medially in his left orbit. He had had bilateral retinoblastoma as an infant and was treated with bilateral enucleation, chemotherapy and radiotherapy. Histological examination confirmed the lesion to be leiomyosarcoma. A genetic defect in the RB1 tumour suppressor gene underlies the development of hereditary retinoblastoma and renders patients at substantially increased risk of developing subsequent non-ocular malignancies including soft tissue sarcomas. This risk is enhanced by radiotherapy particularly if administered before the age of one year. Awareness, by both patients and healthcare professionals, of this risk of secondary malignancy, is extremely important. Identification and aggressive investigation of new symptoms and signs may allow for the earlier detection of secondary malignancy which may, in turn, improve outcomes.

A phase II study of anlotinib with cediranib as a second-line treatment for patients with advanced biliary tract cancers (aBTCs).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e16712-e16712
Author(s):  
Ruihua Zhao ◽  
Hong Zong ◽  
Shuiling Jin ◽  
Qian Zhong ◽  
Miao Jiang ◽  
...  
Keyword(s):  
Overall Survival ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Objective Response ◽  
The Body ◽  
Line Treatment ◽  
Second Line ◽  
Intermittent Fever ◽  
Efficacy Evaluation ◽  
Grade 3

e16712 Background: Gemcitabine combined with cisplatin (GP) is currently used as a standard first-line chemotherapy regimen for aBTCs, However, the median overall survival (mOS) is only about 11.7 months, and there is no standard treatment option for patients who failed GP therapy. In this study, we aimed to investigate the efficacy and safety of anlotinib with cediranib as a second-line treatment for patients with aBTCs. Methods: A monocenter single-arm phase II study was conducted at the First Affiliated Hospital of Zhengzhou University. Patients with measurable aBTCs and progressed on GP were enrolled in this study. Patients received cediranib 200mg, on day1 + anlotinib 12mg on day1-14, Q3W until disease progression, intolerance of toxicity, investigator/patient decision to withdraw or other reasons specified in the protocol. Response (RECIST1.1) was assessed every 8 weeks. Plasma, stool and tumor tissues were collected for exploratory analyses. The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR) and drug safety. Results: We planned to include 20 patients. So far 9 patients were enrolled in this study, 66.7% (6/9) were men, 33.3% were women. The median age was 56y (43y-61y). The primary sites of the tumor were intrahepatic biliary (66.7%, 6/9) and gallbladder (33.3%, 3/9). At data cutoff (Dec 14, 2019), the median duration of follow-up was 2.5mos (range, 1.2 to 4) and all of the patients were still under treatment. 8 patients have undergone at least one efficacy evaluation, of which 2 (25%) PR, 5 SD (62.5%), DCR was 87.5% ((7/8). An SD patient had a long-term intermittent fever, which considered to be tumor fever, the body temperature returned to normal after 1 cycle of treatment. 1 patient was considered to be undefined because, at the first evaluation, the liver lesions were reduced however the lymph nodes in the retroperitoneum were enlarged. The median PFS and OS not yet reached. Grade 3-4 treatment-related adverse events (TRAEs) occurred in 11.1% (1/9) of patients. TRAEs led to discontinuation in 1 patient (grade 3 hypertension). TRAEs led to dose reduction of anlotinib in 2 patients. No TRAEs were fatal. Conclusions: The primary result showed that the combination of anlotinib and cediranib was well tolerated and demonstrates encouraging efficacy than historical control in second-line treatment for aBTC. Updated data, including safety, efficacy, and biomarkers will be presented. Clinical trial information: ChiCTR1900022003 .

Effect of adjuvant chemotherapy on survival in FNCLCC grade 3 soft tissue sarcomas: A multivariate analysis of the French Sarcoma Group database

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 10504-10504
Author(s):  
A. Italiano ◽  
F. Delva ◽  
V. Brouste ◽  
P. Terrier ◽  
M. Trassard ◽  
...  
Keyword(s):  
Overall Survival ◽  
Multivariate Analysis ◽  
Adjuvant Chemotherapy ◽  
Soft Tissue ◽  
Meta Analysis ◽  
Soft Tissue Sarcomas ◽  
Tumor Grade ◽  
Grade 3 ◽  
The Impact

10504 Background: The SMAC meta-analysis failed to demonstrate that adjuvant chemotherapy (AC) significantly improves overall survival (OS) in adult patients with localised resectable soft-tissue sarcoma (STS). We report here the analysis of the impact of AC in the population of STS patients included in the prospective database of the French Sarcoma Group. Methods: Between 1980 and 1999, 2,029 pts with STS were admitted to one of the 20 tertiary cancer centers of the GSF for the management of a first tumoral event and were included prospectively in a comprehensive database. 152 pts were excluded from the study because of metastatic disease at diagnosis. All the cases were reviewed by the pathology subcommittee of the GSF. Tumor grade was assessed according to the FNCLCC system based on tumor differentiation, mitotic count, and necrosis. Results: 283 pts (14.5%) had grade 1, 736 (39.5%) grade 2 and 858 (46%) grade 3 tumors. 1,102 pts (59%) had extremity tumors. The commonest pathological subtypes were MFH 22.5%, liposarcoma 18%, leiomyosarcoma 13%, and synovial sarcoma 10%. 1,122 pts (60%) received adjuvant radiotherapy. AC was delivered in 16 grade 1 pts (6%), 167 grade 2 pts (23%) and 323 grade 3 pts (38%). The majority of patients who received AC had tumors with a deep topography (91%) and/or > 5 cm (75%) and/or located in the limbs (61%). The median follow-up was 9 years. The 5 year-OS was 90% for grade 1 pts, 63% for grade 2 pts and 46% for grade 3 pts. On multivariate analysis ( table 1 ), AC was strongly associated with improved metastasis-free survival (MFS) (5 year MFS: 53% vs 47%, HR 0.7 [0.5–0.9], p=0.003) and overall survival (OS) (5 year OS: 56% vs 44%, HR 0.7 [0.5–0.8], p=0.004) in grade 3 pts. This association was not observed in grade 2 pts (5 year MFS: 73% vs 72%, HR 0.9 [0.6–1.4], p=0.9; 5 year OS: 73% vs 65%, HR 0.7 [0.5–1.1]). Conclusions: This large cohort-based analysis with long-term follow-up indicates that FNCLCC grade 3 pts are likely to benefit from AC. [Table: see text] [Table: see text]

Familial Erythrocytosis Associated with a Mutation in the HIF Prolyl Hydroxylase, PHD2.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 127-127
Author(s):  
Melanie J. Percy ◽  
Q. Zhao ◽  
A. Flores ◽  
C. N. Harrison ◽  
T. R.J. Lappin ◽  
...  
Keyword(s):  
Active Site ◽  
Target Genes ◽  
Elevated Serum ◽  
Proteasomal Degradation ◽  
Suppressor Gene ◽  
Tumour Suppressor Gene ◽  
Base Change ◽  
The Body ◽  
Molecular Defect ◽  
Prolyl Hydroxylases

Abstract Normal erythropoiesis is precisely regulated by a negative feedback mechanism based on the oxygen status of the body. Whenever a deficit in oxygen supply is detected erythropoietin (Epo) is rapidly synthesised to increase circulating red cells. This process is under the control of the HIF transcription complex, which is composed of one alpha and one beta subunit. Although the alpha subunit is constitutively synthesized, it is maintained at a low level by continual targeting to the proteasome. Prolines 402 and 564 in the oxygen dependent degradation (ODD) domain of HIF-1α are hydroxylated in the presence of oxygen by members of the PHD family of prolyl hydroxylases. Once hydroxylated HIF-1α is captured by the von Hippel Lindau tumour suppressor gene product (VHL), ubiquitylation follows and HIF-1α is then targeted for proteasomal degradation. Defects in the hypoxia response pathway appear to be the most common cause of erythrocytosis associated with inappropriately normal or elevated serum Epo. Several different mutations in the VHL gene have been detected in erythrocytosis individuals. Although these mutations explain a significant number of cases there remains a large cohort where the molecular defect is undefined. Thus we screened a group of such individuals for base changes in PHD 1–3. Two affected siblings and their deceased father were found to possess a heterozygous C to G change at base 950 in the coding sequence of PHD2, causing loss of proline at codon 317 and replacement with arginine. This base change was not present in their normal mother nor in 200 normal controls. Residue 317 is located in the enzyme’s active site and at a position two residues C-terminal to Asp315, which chelates the active site iron moiety. Functional analysis indicated that the Pro317Arg PHD2 variant bound to HIF-1α and HIF-2α more weakly and displayed substantially less HIF hydroxylase activity than the wild type protein. These results indicate that the Pro317Arg PHD2 mutant protein’s function will be impaired, less hydroxylation of HIF will occur, allowing more HIF to escape proteasomal degradation and to increase transcription of HIF target genes. Consequently, Epo gene expression will be elevated thereby allowing increased erythrocyte production and the development of erythrocytosis.

Role of Adjuvant Chemotherapy in the Treatment of Surgically Resected Pediatric Nonrhabdomyosarcomatous Soft Tissue Sarcomas: A Pediatric Oncology Group Study

1999 ◽  
Vol 17 (4) ◽  
pp. 1219-1219 ◽  
Author(s):  
Charles B. Pratt ◽  
Alberto S. Pappo ◽  
Peter Gieser ◽  
Jesse J. Jenkins ◽  
Arnold Salzberg,† ◽  
...  
Keyword(s):  
Overall Survival ◽  
Survival Rate ◽  
Adjuvant Chemotherapy ◽  
Soft Tissue ◽  
Soft Tissue Sarcomas ◽  
Tumor Grade ◽  
Event Free Survival ◽  
Free Survival ◽  
Pediatric Oncology Group ◽  
Grade 3

PURPOSE: To prospectively study the value of adjuvant chemotherapy in pediatric patients with surgically resected nonrhabdomyosarcomatous soft tissue sarcomas (NRSTS). PATIENTS AND METHODS: From June 1986 to May 1992, after complete surgical resection (±radiotherapy) of their NRSTS, 81 eligible patients either received adjuvant chemotherapy comprising vincristine, dactinomycin, cyclophosphamide, and doxorubicin or were observed. Only 30 patients accepted randomization, and 15 were assigned to each regimen. Of the remaining 51 patients, 19 elected adjuvant chemotherapy and 32 elected observation. RESULTS: Patients were predominantly male, and 69% of all patients were white. The median age at diagnosis was 12.3 years (range, 9.2 to 20.7 years). For the 81 eligible patients, the 5-year overall survival estimate was 84.5% ± 4.4% and event-free survival was 72.2% ± 5.4%. Among randomized patients, the 5-year estimated overall survival rate was 93.3% ± 7%, and the event-free survival rate was 86.7% ± 9.5% for the observation group, compared with 69.2% ± 13% and 40.7% ± 14%, respectively, for those who received chemotherapy. The significantly worse outcome of patients who received adjuvant chemotherapy disappeared when survival was stratified by tumor grade. Among all patients, a grade 3 lesion conferred a significant disadvantage with respect to event-free survival (P = .0001). CONCLUSION: The administration of adjuvant chemotherapy according to the schedule and dosages used in our trial did not improve the outcome of children with resected NRSTS. In this study, tumor grade was the most important predictor of clinical outcome in patients with resected NRSTS, and this factor should be incorporated into the stratification of patients in future trials.

scholarly journals Reduced-Intensity Versus Myeloablative Conditioning for Allogeneic Hematopoietic Cell Transplantation in Patients with Myelodysplastic Syndrome: A Systematic Review and Meta-Analysis of Randomized Clinical Trials & Cohort Studies

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 25-26
Author(s):  
Arshia Akbar ◽  
Zunairah Shah ◽  
Muhammad Ali Aziz ◽  
Muhammad Yasir Anwar ◽  
Saman Bahram ◽  
...  
Keyword(s):  
Overall Survival ◽  
Clinical Trials ◽  
Myelodysplastic Syndrome ◽  
Cohort Studies ◽  
Randomized Clinical Trials ◽  
Meta Analysis ◽  
Chronic Gvhd ◽  
P Value ◽  
Grade 3 ◽  
Risk Of Relapse

Background: Conditioning regimen given before allogeneic hematopoietic stem cell transplantation (allo-HSCT) contributes significantly to the outcomes following transplant for myelodysplastic syndrome (MDS). Myeloablative conditioning (MAC) regimens are often associated with a lower risk of relapse; however, their use is often limited by toxicity and a higher risk of non-relapse mortality (NRM). Reduced-intensity conditioning (RIC) regimens are associated with a higher risk of relapse, a lower NRM, a lower incidence of graft versus host disease (GVHD), and hence is feasible in patients with advanced age or comorbidities. This study highlights the importance of the difference between the two interventions used in allo-HSCT for myelodysplastic syndrome (MDS). Methods: We conducted a comprehensive literature search using PubMed, Clinicaltrial.gov, Embase, Cochrane, and Web of Science on 5th May 2020 with no restriction of language or period. Initial research revealed 1698 articles. After excluding review articles, duplicates, and non-relevant articles, we included two randomized clinical trials and three cohort studies, which reported overall survival (OS), relapse-free survival (RFS), relapse incidence (RI), and incidence of acute and chronic (GVHD). Based on inclusion criteria, two randomized clinical trials (BMT CTN 0901 Trial Scott et al. 2017 & EBMT RICMAC Trial Kroger et al. 2017) and three cohort studies (BBMT 55226 Park et al. 2018, BBMT Orozco et al. 2019, BMT Alatrash et al. 2019) were included. Results: Among combined MDS and acute myeloid leukemia (AML) patients (n=1188) enrolled in 5 studies, 651 patients had MDS. Patients underwent MAC (n=484) or RIC (n=692) followed by either a matched related donor (MRD), n=236, or matched unrelated donor (MUD), n=236, allo-HCT. The median age range at the time of transplant was 50-54 years The use of RIC causes statistically non-significant trend of improved overall survival (OS) (OR 1.11: 95% CI: 0.74-1.67, p-value= 0.61) along with more risk of relapse incidence (RI) (R 1.34: 95% CI: 0.56-3.18, p value= 0.51), and reduced relapse free survival (RFS) (OR 0.88, 95% CI: 0.55-1.44: p value= 0.59). Differences were found in terms of safety of both conditioning regimens. MAC allo-HCT have more acute GVHD, grade 3 and 4 (OR 0.66: 95% CI: 0.29-1.52, p value= 0.33) and chronic GVHD, grade 3 and 4 (OR 0.72: 95% CI: 0.41-1.27: p value= 0.26) and treatment-related mortality (TRM) (OR 0.83, 95% CI: 0.37-1.86, p value= 0.65). The meta-analysis results are shown in figure-1. Conclusion: In adult MDS patients undergoing allo-HSCT, RIC is associated with improved overall survival, but at the cost of reduced RFS, and a higher risk of relapse. MAC, on the other hand, is associated with more treatment-related mortality and GVHD. Results of our analysis point out these trends but these are not statistically significant Figure 1 Disclosures Anwer: Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.: Honoraria, Research Funding, Speakers Bureau.

tumour suppressor gene and the tobacco industry

The Lancet ◽  
2005 ◽  
Vol 365 (9464) ◽  
pp. 1026-1027
Author(s):  
A BITTON ◽  
M NEUMAN ◽  
J BARNOYA ◽  
S GLANTZ
Keyword(s):  
Tobacco Industry ◽  
Suppressor Gene ◽  
Tumour Suppressor Gene ◽  
Tumour Suppressor
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