scholarly journals Paired comparisons of mutational profiles before and after brachytherapy in asian uveal melanoma patients

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Woo Seung Lee ◽  
Junwon Lee ◽  
Jun Jeong Choi ◽  
Hyun Goo Kang ◽  
Sung Chul Lee ◽  
...  
Keyword(s):  
Uveal Melanoma ◽  
Statistical Significance ◽  
Paired Comparisons ◽  
Copy Number Alterations ◽  
Primary Tumors ◽  
Molecular Features ◽  
Whole Exome ◽  
Before And After ◽  
Melanoma Patients ◽  
First Time

AbstractUveal melanoma(UM) is the most common primary intraocular malignancy in adults. However, the incidence of UM in Asia is 10 to 20 times less than in Western populations. Therefore, for the first time, we report our whole exome sequencing (WES) data analysis to discover differences in the molecular features of Asian and Western UM, and to determine the disparities between the primary tumor before brachytherapy and enucleated samples after brachytherapy. WES of 19 samples (13 primary tumors, 5 enucleation samples after brachytherapy, and 1 liver metastasis) from 13 patients diagnosed with UM and treated between 2007 and 2019 at the Yonsei University Health System (YUHS) were analyzed using bioinformatics pipelines. We identified significantly altered genes in Asian UM and changes in mutational profiles before and after brachytherapy using various algorithms. GNAQ, BAP1, GNA11, SF3B1 and CYSLTR2 were significantly mutated in Asian UM, which is similar that reported frequently in previous Western-based UM studies. There were also similar copy number alterations (M3, 1p loss, 6p gain, 8q gain) in both groups. In paired comparisons of the same patients, DICER1 and LRP1B were distinctly mutated only in tumor samples obtained after brachytherapy using rare-variant association tests (P = 0.01, 0.01, respectively). The mutational profiles of Asian UM were generally similar to the data from previous Western-based studies. DICER1 and LRP1B were newly mutated genes with statistical significance in the regrowth samples after brachytherapy compared to the primary tumors, which may be related to resistance to brachytherapy.

scholarly journals Mutations and Copy Number Alterations in IDH Wild-Type Glioblastomas Are Shaped by Different Oncogenic Mechanisms

Biomedicines ◽  
2020 ◽  
Vol 8 (12) ◽  
pp. 574
Author(s):  
Ege Ülgen ◽  
Sıla Karacan ◽  
Umut Gerlevik ◽  
Özge Can ◽  
Kaya Bilguvar ◽  
...  
Keyword(s):  
Copy Number ◽  
Copy Number Alteration ◽  
Age At Diagnosis ◽  
Copy Number Alterations ◽  
Primary Tumors ◽  
Double Minutes ◽  
Molecular Features ◽  
Genetic Landscape ◽  
Underlying Mechanisms ◽  
Mutational Processes

Little is known about the mutational processes that shape the genetic landscape of gliomas. Numerous mutational processes leave marks on the genome in the form of mutations, copy number alterations, rearrangements or their combinations. To explore gliomagenesis, we hypothesized that gliomas with different underlying oncogenic mechanisms would have differences in the burden of various forms of these genomic alterations. This was an analysis on adult diffuse gliomas, but IDH-mutant gliomas as well as diffuse midline gliomas H3-K27M were excluded to search for the possible presence of new entities among the very heterogenous group of IDH-WT glioblastomas. The cohort was divided into two molecular subsets: (1) Molecularly-defined GBM (mGBM) as those that carried molecular features of glioblastomas (including TERT promoter mutations, 7/10 pattern, or EGFR-amplification), and (2) those who did not (others). Whole exome sequencing was performed for 37 primary tumors and matched blood samples as well as 8 recurrences. Single nucleotide variations (SNV), short insertion or deletions (indels) and copy number alterations (CNA) were quantified using 5 quantitative metrics (SNV burden, indel burden, copy number alteration frequency-wGII, chromosomal arm event ratio-CAER, copy number amplitude) as well as 4 parameters that explored underlying oncogenic mechanisms (chromothripsis, double minutes, microsatellite instability and mutational signatures). Findings were validated in the TCGA pan-glioma cohort. mGBM and “Others” differed significantly in their SNV (only in the TCGA cohort) and CNA metrics but not indel burden. SNV burden increased with increasing age at diagnosis and at recurrences and was driven by mismatch repair deficiency. On the contrary, indel and CNA metrics remained stable over increasing age at diagnosis and with recurrences. Copy number alteration frequency (wGII) correlated significantly with chromothripsis while CAER and CN amplitude correlated significantly with the presence of double minutes, suggesting separate underlying mechanisms for different forms of CNA.

A randomized phase II study of adjuvant sunitinib or valproic acid in high-risk patients with uveal melanoma.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e22059-e22059
Author(s):  
Takami Sato ◽  
Marlana M. Orloff ◽  
Matias Emanuel Valsecchi ◽  
Ayako Shimada ◽  
Inna Chervoneva ◽  
...  
Keyword(s):  
Valproic Acid ◽  
High Risk ◽  
Uveal Melanoma ◽  
Adjuvant Treatment ◽  
Survival Rates ◽  
Distant Metastases ◽  
Toxicity Assessment ◽  
Primary Tumors ◽  
Systemic Metastasis ◽  
Melanoma Patients

e22059 Background: Uveal melanoma is the most common primary intraocular cancer in adults. Despite successful treatment of primary tumors, up to 50% of patients later die of distant metastases. Currently, no effective adjuvant treatment is available. Presence of both monosomy 3 and 8q amplification (M3 + 8q amp) or DecisionDx-UM Class 2 in the primary uveal melanoma characterizes a group of patients with high metastatic death rates with reported 2-year survival rates ranging from 50% to 78%. This study aims to decrease or delay the death from metastatic uveal melanoma. Methods: Uveal melanoma patients with high risk for systemic metastasis defined as any of the following were eligible: A) M3 + 8q amp; B) Class 2. Patients must show no evidence of systemic metastasis and they need to be enrolled within 6 months of initial treatment of primary uveal melanoma. Patients were randomized to receive either sunitinib 25 mg daily or valproic acid (VPA) 750 mg daily as adjuvant treatment for 6 consecutive months. Improvement of 2-year overall survival (OS) rate from historical reference (70%) to 85% was the primary endpoint. The secondary endpoints included 1) systemic relapse-free survival (RFS) rate at 18 months, 2) ability to complete adjuvant treatment and, 3) toxicity assessment. The study was not powered to compare the efficacy between each arm. Results: A total of 90 patients were enrolled in this study. Two patients were excluded from the study including one in the sunitinib arm (did not start treatment after randomization) and one in the VPA arm (refused to stop VPA at 6 months). Nine of 45 patients in the sunitinib arm and 4 of 43 patients in the VPA arm could not complete the 6-month treatment due to toxicity (sunitinib n = 6, VPA n = 2) or systemic progression (sunitinib n = 3, VPA n = 2). The rest of patients completed the 6-month course of study treatments and all patients were followed at least for 2 years. With a median follow-up of 40.2 months, the 2-year OS rates of the sunitinib and VPA group were 95.6% (90% CI 86.5-98.6) and 90.7% (90% CI 80.1 - 95.8), respectively. The 18-month RFS rates of the sunitinib and VPA group were 75.6% (90% CI 63.1 - 84.3) and 62.8% (90% CI 49.4 - 73.5), respectively. Conclusions: Although the study is still ongoing, adjuvant sunitinib and VPA were considered to be safe and tolerable treatments for high-risk uveal melanoma. Sunitinib showed a tendency for a better outcome, thus a Cohort 2 was created to investigate the safety and potential improvement of 18-month RFS rate with 12 months of treatment with sunitinib. Clinical trial information: NCT02068586.

Adjuvant sunitinib in high-risk patients with uveal melanoma: A pilot study.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 8560-8560
Author(s):  
Matias Emanuel Valsecchi ◽  
Nancy Shockley ◽  
Deborah Summers ◽  
Carol L Shields ◽  
Jerry A Shields ◽  
...  
Keyword(s):  
Pilot Study ◽  
High Risk ◽  
Uveal Melanoma ◽  
Death Rate ◽  
Large Tumor ◽  
Primary Tumors ◽  
High Risk Patients ◽  
Monosomy 3 ◽  
Risk Patients ◽  
Melanoma Patients

8560 Background: Uveal melanoma is the most common primary intraocular cancer in adults. Despite the successful treatments for primary tumors, up to 50% of the patients later die of distant metastases. Currently no effective adjuvant treatment is available for these patients. Our group previously reported that sunitinib stabilized systemic metastases in 65% of uveal melanoma patients who failed prior treatments. In this pilot study, we tested sunitinib in an adjuvant setting in high-risk patients with primary uveal melanoma. Methods: Patients with estimated metastatic death rate ≥ 50% based on the following criteria were eligible: (1) monosomy 3 and 8q amplification; (2) large tumor (≥ 15 mm in diameter and ≥7 mm in thickness); (3) monosomy 3 and other risk factors (large tumor, epithelioid dominant cell type, local recurrence, or extra-scleral extension). Sunitinib was given at 25 mg PO daily for at least 6 months. Primary endpoint was disease-free survival (DFS) and overall survival (OS), estimated with Kaplan-Meier analysis (SPSS 17.0). Secondary endpoint was safety. Results: A total of 23 Caucasian patients (median, 54 years; range: 25 – 77) were enrolled. All patients received sunitinib for at least 6 months (range: 6 – 12). Eighteen patients had confirmed monosomy 3, from whom 13 (72%) also showed 8q amplification. The median follow-up was 24 months (range 12 – 54 months). Only one patient died of unknown cause (OS: 30.4 months). A total of seven patients (30%) developed systemic metastases, all of which were liver metastases. The DFS and OS rates at 2 years were 70% (95% CI: 47 – 86%) and 100%, respectively. The OS rate at 2 years was better than historical control with monosomy 3 patients (51%, 95% CI: 31 – 71%) (Invest Ophthalmol Vis Sci 2003; 44:1008). In those patients who relapsed, the median time to progression after finishing sunitinib was 2 months (range: 0 – 8). The most common adverse events were: diarrhea (47%), fatigue (39%), dermatitis (30%), stomatitis (13%), leucopenia (8%), and nausea (4%). Most were grade 1 or 2 (88%) and only one was considered grade 4 (diarrhea). Conclusions: In high-risk uveal melanoma patients with estimated metastatic death rate of ≥ 50%, adjuvant sunitinib showed promising results and deserves further investigation.

The genomic and evolutionary landscape of osteosarcoma progression and lung metastasis.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 11029-11029 ◽  
Author(s):  
Jin Wang ◽  
Hua Bao ◽  
Huaiyuan Xu ◽  
Tony WH Shek ◽  
Xue Wu ◽  
...  
Keyword(s):  
Copy Number ◽  
Lung Metastases ◽  
Early Stage ◽  
Phylogenetic Analyses ◽  
Parallel Evolution ◽  
Genetic Alterations ◽  
Base Substitution ◽  
Primary Tumors ◽  
Whole Exome ◽  
First Time

11029 Background: Osteosarcoma (OS) is a primary malignant bone tumor that has a high potential to metastasize to lungs. Recent studies have characterized somatic mutations of primary OS tumors. Nevertheless, lung metastases of OS are poorly studied, and whether they harbor distinct genetic alterations beyond those observed in primary tumors is largely unknown. Methods: We performed whole-exome sequencing (WES) of matched primary tumors and lung metastases in a cohort of 15 OS patients. Somatic single nucleotide variations (SNV) and copy number alterations (CNA) were analyzed to characterize the genomic and evolutionary landscape of metastatic OS. Results: Compared to matched primary tumors, lung metastases exhibited higher transversion rate for base substitution, and poor overlap ( < 10%) of genetic alterations was observed between primary and metastasis tumors. Multiple novel significantly mutated genes were identified, including ZNF717 in lung metastases, SPDYE1 in primary tumors, and CRIPAK in both. Copy number analysis indicated recurrent CNAs, including NEURL1B deletion and FLG amplifications in lung metastases, GSTT1 deletion in primary tumors, and CEACAM gene family deletion in both. Furthermore, phylogenetic analyses revealed that paired primary tumors and metastases underwent parallel evolution with few ubiquitous clonal mutations, suggesting that OS metastases are likely to be derived from primary tumors at a very early stage of their evolution. Conclusions: This study for the first time provides important evidence that OS metastases harbor distinct genetic alterations compared with primary tumors. Our findings strongly support a parallel evolution model of primary and metastatic tumors. Moreover, several novel CNAs and significantly mutated genes that are specifically associated with lung metastases may provide future therapeutic insight for OS.

71 Whole exome sequencing of individuals presenting extreme phenotypes of high and low-risk of developing tobacco-induced lung adenocarcinoma: relevance of immune and DNA-repair related pathways

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A77-A77
Author(s):  
Jose Perez-Gracia ◽  
Mapi Andueza ◽  
Ana Patiño-Garcia ◽  
Alfonso Gurpide
Keyword(s):  
Dna Repair ◽  
Lung Adenocarcinoma ◽  
Genetic Background ◽  
Statistical Significance ◽  
Tobacco Consumption ◽  
Pathway Database ◽  
Database Analysis ◽  
Whole Exome ◽  
Extreme Phenotypes ◽  
First Time

BackgroundIndividual susceptibility to carcinogens may depend on genetic background. We performed for the first-time Whole Exome Sequencing (WES) of germline DNA from individuals presenting phenotypes of extreme sensitivity and resistance to developing tobacco-induced lung adenocarcinoma, in order to characterize the genetic background associated with these relevant phenotypes.MethodsWe performed WES of germline DNA from heavy smokers (≥15 pack-years) who either developed lung adenocarcinoma at an early age (≤55 years, extreme cases, n=50) or did not present lung adenocarcinoma or other tumors at an advanced age (≥72 years, extreme controls, n=50). We selected non-synonymous variants (missense and non-sense) located in the coding regions and consensus splice sites of the genes showing significantly different allelic frequencies between both cohorts. We validated our results in germline data from 52 additional extreme cases selected from TCGA using the same criteria (diagnosis of lung adenocarcinoma at ≤55 years, tobacco consumption ≥15 pack-years).ResultsThe mean age for the extreme cases and controls was respectively 49.7 and 77.5 years. Mean tobacco consumption was 43.5 and 54.4 pack-years. We identified 619 significantly different variants between both cohorts, and we validated 107 of these in 52 extreme cases selected from TCGA (mean age 49.3 years, mean tobacco consumption 37 pack-years). Nine validated variants, located in relevant cancer related genes, such as PARP4 (DNA repair), HLA-A (antigen presentation) or NQO1 (detoxification) among others, achieved statistical significance in the False Discovery Rate test (FDR) (table 1). The most significant validated variant (p=4.48 × 10-5) was located in the tumor-suppressor gene ALPK2. The Reactome Pathway Database analysis showed that the genes harboring the most significant validated variants were significantly related to antigen processing and presentation, interferon and cytokine signaling and immune regulation, also achieving statistical significance in the FDR test (table 2).Abstract 71 Table 1Most significant validated variants.Abstract 71 Table 2Reactome pathway database analysis of pathways related to the genes that harbor the validated variantsConclusionsWe describe for the first time genetic variants associated with extreme phenotypes of high and low-risk for the development of tobacco-induced lung adenocarcinoma, assessed with WES. The most significant validated variants were related with antigen presentation, immune regulation and DNA repair. Our results and our strategy warrant further development to characterize these clinically relevant phenotypes.Ethics ApprovalThe study was approved by the Investigational Review Board of Clinica Universidad de Navarra, approval number 021/2009.

scholarly journals Prognostic Factor Utility of BAP1 Immunohistochemistry in Uveal Melanoma: A Single Center Study in Spain

Cancers ◽  
2021 ◽  
Vol 13 (21) ◽  
pp. 5347
Author(s):  
Laura Tabuenca Del Barrio ◽  
Luiz Miguel Nova-Camacho ◽  
Alicia Zubicoa Enériz ◽  
Iñigo Martínez de Espronceda Ezquerro ◽  
Alicia Córdoba Iturriagagoitia ◽  
...  
Keyword(s):  
Uveal Melanoma ◽  
Tumor Infiltrating Lymphocytes ◽  
Pathological Examination ◽  
Basal Diameter ◽  
Single Center Study ◽  
Melanoma Patients ◽  
Infiltrating Lymphocytes ◽  
First Time

Even today, the mortality rate for uveal melanoma (UM) remains very high. In our research, we sought to determine which pathological and clinical features were correlated with the prognosis of UM. BAP1 (BRCA1-Associated Protein 1) gene mutation has been analyzed as one of the strongest predictors for metastasis in UM. The BAP1 gene codifies the BAP1 protein which has a tumor suppressor function. The presence of this protein can be determined by BAP1 immunohistochemical staining. Eighty-four uveal melanoma patients and forty enucleated eyeballs were examined. Metastasis was present in 24 patients. Nuclear BAP1 staining was low in 23 patients. The presence of a higher large basal diameter tumor (p < 0.001), tumor infiltrating lymphocytes (p = 0.020), and a lack of nuclear BAP1 immunostaining (p = 0.001) ocurred significantly more often in the metastatic group. Metastasis-free survival was lower in patients with low nuclear BAP1 staining (p = 0.003). In conclusion, to the best of our knowledge, this is the first time that BAP1 staining has been studied in uveal melanoma in a Spanish community. We believe that this technique should become routine in the pathological examination of uveal melanoma in order to allow adequate classification of patients and to establish an individual follow-up plan.

Untersuchungen zur Quantifizierung der Änderung der Skelettmuskeldurchblutung nach Gefäßrevaskularisationen mit einem 99mTechnetiummarkierten Tracer

1990 ◽  
Vol 29 (05) ◽  
pp. 215-220 ◽  
Author(s):  
R. Benning ◽  
K. Nagel ◽  
M. Jugenheimer ◽  
S. Fischer ◽  
S. Worthmann ◽  
...  
Keyword(s):  
Transluminal Angioplasty ◽  
Lower Limbs ◽  
Surgical Patients ◽  
Treadmill Test ◽  
Negative Results ◽  
Clinical Observations ◽  
Before And After ◽  
Comparative Results ◽  
First Time ◽  
Percutaneous Transluminal

A new 99mTc-labelled tracer (99mTc-Sestanriibi) was used for the first time to demonstrate the perfusion of the skeletal muscle. In 16 patients with obstructive atherosclerosis of the lower limbs the change of perfusion of thigh and lower leg was studied with SPECT before and after vascular surgery (n = 11) or percutaneous transluminal angioplasty (n = 5). Comparative results of scintigraphic measurements and clinical observations (ancle-arm pressure, treadmill test) in 10 surgical patients (14 operated legs) showed correct positive or negative results in 86% (12/14).

Trombodynamics Method in the Assessment of Coagulation Parameters in Psychopharmacotherapy of Endogenous Mental Disorders

Psychiatry ◽  
2020 ◽  
Vol 18 (4) ◽  
pp. 16-25
Author(s):  
N. S. Karpova ◽  
O. S. Brusov ◽  
I. V. Oleichik ◽  
M. I. Faktor ◽  
N. S. Levchenko ◽  
...  
Keyword(s):  
Mental Disorders ◽  
Response To Therapy ◽  
Procoagulant Activity ◽  
Coagulation Activity ◽  
Continuous Type ◽  
Chronic Neuroinflammation ◽  
Psychopharmacological Treatment ◽  
Before And After ◽  
First Time ◽  
Schizotypal Disorder

Background: currently, it has been proven that the pathogenesis of endogenous mental disorders is associated with the process of neuroinflammation in the brain of patients. It is also known that chronic neuroinflammation, accompanied by a violation the permeability of the blood-brain barrier. It is accompanied by the activation of platelets that generate procoagulant microparticles, which leads to a disturbance of the hemostasis system, causing an increase in blood clotting in patients. Objective: to investigate the dynamics of procoagulant activity of blood in patients with endogenous mental disorders before and after psychopharmacotherapy.Patients and methods: the study included 185 patients aged 16 to 64 years with the following mental disorders: schizophrenia with attack-like/attack-progressive/continuous type of course (F20.00–2), affective disease (F31.1–5; F32.0–3; F33.0–3), schizotypal disorder with affective fluctuations (F21.3–4). The thrombodynamic test (TD) was performed on T-2 Trombodynamis device according to the manufacturer’s instructions (Hemacore LLC, Moscow, Russia). All patients received standard pharmacotherapy according to their condition.Results: a significant decrease of procoagulant activity of spontaneous clots in the patients’ blood after psychopharmacological treatment is observed. Our data on the positive dynamics of changes in the values of TD test’s indicators in most of the examined patients suggest that a decrease in the coagulation activity of the patients’ blood as a result of treatment may be associated with the anti- inflammatory effect of antipsychotics and antidepressants.Conclusion: for the first time, it was shown that there is a positive dynamic in changing the values of the main parameters of the TD test in most patients with endogenous mental diseases. The results of TD tests can be the basis for monitoring the response to therapy.

STUDY CLINICAL FEATURE AND RESULT OF TREATMENT PHACOMORPHIC GLAUCOMA

2015 ◽  
pp. 71-75
Author(s):  
Van Nam Phan ◽  
Ba Ken Tran
Keyword(s):  
Visual Acuity ◽  
Intraocular Pressure ◽  
Statistical Significance ◽  
Corneal Edema ◽  
Clinical Feature ◽  
Anterior Chamber Angle ◽  
Male Population ◽  
Significant Difference ◽  
Operative Complications ◽  
Before And After

Purpose: Study clinical feature of phacomorphic glaucoma. To evaluate the result of treatment phacomorphic glaucoma. Method: The retrospective, interventional study on 36 cases with phacomorphic glaucoma who underwent treated at Hue Central Hospital from 6/2010 to 6/2011. Standard of research: visual, IOP, before and after surgery, accompanying lesions and post-operative complications. The surgery is considered successful when postoperative IOP less than 21 mmHg. Results: Age 50-59 presented 30.5 percent, ≥ 60 presented 91.7 percent. There was a slight female preponderance (66.7%) compared to the male population (33.3%) which implies a statistically marginally significant difference. However there was no statistical significance difference when compared by the two subgroups. Patient in country presented 61,1% and city presented 38,9%. The duration between the onset of pain and surgery from 0 to < 5 days (77.8%), from 6 to 10 (16.7%) and >10 days presented 5.5%. The preoperative intraocular pressure 35 to 45mmHg (47.2%), 46-55 (30.6%), 56-65 (13.9%) and more than 65 presented 8.3%. The visual acuity preoperation less than 1metre count finger (94.5%), less than 3 metre count finger presented 5.5%. Close anterior chamber angle presented 80.6% and shallow was presented 19.4%. Corneal edema presented 100%, iritis presented 94.4%, dilated pupil larger 5mm presented 83.3%, Synchynea iris and cataract presented 72.2%. ECCE, implantation IOL combined trabeculectomy presented 11.1%, Phaco, implantation IOL combined trabeculectomy presented 69,5%, ECCE implantation IOL presented 5.6%, Phaco, implantation IOL presented 13.8%. Postoperative visual acuity from 1/10 to 5/10 presented 72.2%, no case have VA larger than 5/10. Postoperative 3 months VA 1/10 to 5/10 presented 72.2%, larger VA 5/10 presented 8.3%. Postoperative 3 months intraocular pressure ≤ 21mmHg presented 91.7%, 22 to 24mmHg presented 8.3%, no case have IOP ≥25mmHg. Postoperative edema presented 58.3%, iritis presented 58.3%. Key words: phacomorphic Glaucoma

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