12 research outputs found
BRAF V600E Status Sharply Differentiates Lymph Node Metastasis-associated Mortality Risk in Papillary Thyroid Cancer
[Context]: How lymph node metastasis (LNM)-associated mortality risk is affected by BRAF V600E in papillary thyroid cancer (PTC) remains undefined.
[Objective]: To study whether BRAF V600E affected LNM-associated mortality in PTC.
[Design, Setting, and Participants]: We retrospectively analyzed the effect of LNM on PTC-specific mortality with respect to BRAF status in 2638 patients (2015 females and 623 males) from 11 centers in 6 countries, with median age of 46 [interquartile range (IQR) 35-58] years and median follow-up time of 58 (IQR 26-107) months.
[Results]: Overall, LNM showed a modest mortality risk in wild-type BRAF patients but a strong one in BRAF V600E patients. In conventional PTC (CPTC), LNM showed no increased mortality risk in wild-type BRAF patients but a robustly increased one in BRAF V600E patients; mortality rates were 2/659 (0.3%) vs 4/321 (1.2%) in non-LNM vs LNM patients (P = 0.094) with wild-type BRAF, corresponding to a hazard ratio (HR) (95% CI) of 4.37 (0.80-23.89), which remained insignificant at 3.32 (0.52-21.14) after multivariate adjustment. In BRAF V600E CPTC, morality rates were 7/515 (1.4%) vs 28/363 (7.7%) in non-LNM vs LNM patients (P < 0.001), corresponding to an HR of 4.90 (2.12-11.29) or, after multivariate adjustment, 5.76 (2.19-15.11). Adjusted mortality HR of coexisting LNM and BRAF V600E vs absence of both was 27.39 (5.15-145.80), with Kaplan-Meier analyses showing a similar synergism.
[Conclusions]: LNM-associated mortality risk is sharply differentiated by the BRAF status in PTC; in CPTC, LNM showed no increased mortality risk with wild-type BRAF but a robust one with BRAF mutation. These results have strong clinical relevance.This work was supported partly by the following funding at the individual participating centers: Polish National Center of Research and Development MILESTONE Project—molecular diagnostics and imaging in individualized therapy for breast, thyroid and prostate cancer, grant No. STRATEGMED2/267398/4/ NCBR/2015 (Poland, AC, BJ); Grants No. PID2019-105303RB-I00 (AEI from MICINN), GCB14142311CRES (AECC Foundation), and B2017/BMD-3724 TIRONET2-CM (Spain; PS and GR-E); Grant No. AZV 16-32665A and MH CZ-DRO (Institute of Endocrinology-EU, 00023761) (Czech Republic; BB, VS); NIH/ National Institute on Aging Grant No. 5R03AG042334-02 (LY);
and grants from the Qingdao Science and Technology Project for People’s Livelihood No.13-1-3-58-nsh (China; FW) and the Innovative Platform Project of Qingdao No.12-1-2-15-jch (China; YW)
Overcoming the death of a close person in a hospice by the bereaved with or without faith
Ve svĂ© diplomovĂ© práci se zamýšlĂm nad tĂm, zda je rozdĂl se
vyrovnat s umĂránĂm a smrtĂ pro lidi bez vyznánĂ nebo s vyznánĂm a zda je
rozdĂl s vyrovnánĂm pro doprovázejĂcĂ bez vyznánĂ nebo s vyznánĂm, kteĹ™Ă
majà možnost náboženských rituálů.Katedra pedagogikyObhájenoIn my thesis I put and I try to answer the principal question whether there is the difference or not between people with and without religion facing up to death. I put the same question in case of the dying person and in case of the person accompanying someone to die
Molecular- genetic analysis of the Thyroid carcinomas
Introduction: Thyroid cancer represents more than 90% of endocrine tumors and its incidence, predominantly of papillary thyroid carcinoma (PTC), is still increasing in the Czech Republic. Several genetic changes are known, but thein impact to phenotype is still controversial. Aims: To study of the genetic causes (RET/PTC, BRAF and RAS alterations) and the role of RET polymorphisms in thyroid cancer (predominantly PTC), and to correlate genotype with phenotype. Subjects and Methods: Overall 234 PTC tissues, 8 poorly differentiated carcinomas, 3 anaplastic carcinomas, 23 medullary carcinomas, 6 follicular carcinomas and one follicular adenoma were analyzed. Samples of fresh frozen thyroid tissues, fine-needle aspiration biopsies and paraffin-embedded formalin-fixed tissue sections of patients with thyroid cancer and blood samples of healthy controls were used for analysis. The expression of RET/PTC rearrangements was detected on agarose gel. Five RET polymorphisms were analyzed using specific TaqMan probes. Detection of mutations in the BRAF gene and three RAS genes was performed by direct sequencing. Presence of alteration was correlated with clinicopathological parameters. Results: We found out that some RET polymophisms are associated with development of RET/PTC rearrangements in PTC and proved,...Ăšvod: Nadory štitne Ĺľlazy pĹ™edstavuji vice neĹľ 90% endokrinnich tumorĹŻ a jejich incidence, pĹ™edevšim papilarniho karcinomu, se v ÄŚeske republice neustale zvyšuje. Je znamo nÄ›kolik genetickych pĹ™iÄŤin, ale jejich vliv na fenotyp je stále kontroverzni. CĂle: Studium genetickych pĹ™iÄŤin (RET/PTC, BRAF a RAS alteraci) a polymorfismĹŻ v RET genu u nadorĹŻ štitne Ĺľlazy (pĹ™edevšim PTC) a korelace genotypu s fenotypem. Soubor a metody: Celkem bylo analyzovano 234 PTC tkani, 8 špatnÄ› diferencovanych karcinomĹŻ, 3 anaplasticke karcinomy, 23 medularnich karcinomĹŻ, 6 folikularnich karcinomĹŻ a jeden folikularni adenom. Pro analyzu byly pouĹľity vzorky zamraĹľenych ÄŤerstvych tkani, biopsii tenkou jehlou a parafinovych bloÄŤkĹŻ od pacientĹŻ s nadory štitne Ĺľlazy a vzorky krve od zdravych kontrol. Exprese RET/PTC pĹ™eskupeni byla detekovana na agarozovem gelu, RET polymorfismy byly analyzovany pomoci specifickych TaqMan sond. Detekce mutaci v BRAF genu a tĹ™ech RAS genech byla provedena pĹ™imou sekvenaci. ZjištÄ›ne alterace byly korelovany s klinicko-patologickymi parametry. VĂ˝sledky: Zjistili jsme, Ĺľe nÄ›ktere polymorfismy v RET genu asociuji se vznikem RET/PTC pĹ™eskupeni u PTC a prokazali jsme, Ĺľe BRAF mutace koreluje s vÄ›tši agresivitou tumoru. V RAS genech jsme nalezli nÄ›kolik genetickych zmÄ›n. ZávÄ›r: Studie pĹ™inesla...Department of Anthropology and Human GeneticsKatedra antropologie a genetiky ÄŤlovÄ›kaFaculty of SciencePĹ™ĂrodovÄ›decká fakult
Molecular-genetic analysis of papillary thyroid carcinoma
Katedra antropologie a genetiky ÄŤlovÄ›kaDepartment of Anthropology and Human GeneticsFaculty of SciencePĹ™ĂrodovÄ›decká fakult
Molecular- genetic analysis of the Thyroid carcinomas
to Ph.D. Thesis Molecular-genetic Analysis of Thyroid Carcinomas by V. Sýkorová Introduction: Thyroid cancer represents more than 90% of endocrine tumors and its incidence, predominantly of papillary thyroid carcinoma (PTC), is still increasing in the Czech Republic. Several genetic changes are known, but their impact to phenotype is still controversial. Aims: To study of the genetic causes (RET/PTC, BRAF and RAS alterations) and the role of RET polymorphisms in thyroid cancer (predominantly PTC), and to correlate genotype with phenotype. Subjects and Methods: Overall 234 PTC tissues, 8 poorly differentiated carcinomas, 3 anaplastic carcinomas, 23 medullary carcinomas, 6 follicular carcinomas and one follicular adenoma were analyzed. Samples of fresh frozen thyroid tissues, fine-needle aspiration biopsies and paraffin-embedded formalin-fixed tissue sections of patients with thyroid cancer and blood samples of healthy controls were used for analysis. The expression of RET/PTC rearrangements was detected on agarose gel. Five RET polymorphisms were analyzed using specific TaqMan probes. Detection of mutations in the BRAF gene and three RAS genes was performed by direct sequencing. Presence of alteration was correlated with clinicopathological parameters. Results: We found out that some RET..
Molecular-genetic analysis of papillary thyroid carcinoma
Katedra antropologie a genetiky ÄŤlovÄ›kaDepartment of Anthropology and Human GeneticsFaculty of SciencePĹ™ĂrodovÄ›decká fakult
Molecular- genetic analysis of the Thyroid carcinomas
Introduction: Thyroid cancer represents more than 90% of endocrine tumors and its incidence, predominantly of papillary thyroid carcinoma (PTC), is still increasing in the Czech Republic. Several genetic changes are known, but thein impact to phenotype is still controversial. Aims: To study of the genetic causes (RET/PTC, BRAF and RAS alterations) and the role of RET polymorphisms in thyroid cancer (predominantly PTC), and to correlate genotype with phenotype. Subjects and Methods: Overall 234 PTC tissues, 8 poorly differentiated carcinomas, 3 anaplastic carcinomas, 23 medullary carcinomas, 6 follicular carcinomas and one follicular adenoma were analyzed. Samples of fresh frozen thyroid tissues, fine-needle aspiration biopsies and paraffin-embedded formalin-fixed tissue sections of patients with thyroid cancer and blood samples of healthy controls were used for analysis. The expression of RET/PTC rearrangements was detected on agarose gel. Five RET polymorphisms were analyzed using specific TaqMan probes. Detection of mutations in the BRAF gene and three RAS genes was performed by direct sequencing. Presence of alteration was correlated with clinicopathological parameters. Results: We found out that some RET polymophisms are associated with development of RET/PTC rearrangements in PTC and proved,..
BRAF V600E Mutation-Assisted Risk Stratification of Solitary Intrathyroidal Papillary Thyroid Cancer for Precision Treatment
BACKGROUND:
Precise risk stratification-based treatment of solitary intrathyroidal papillary thyroid cancer (SI-PTC) that is larger than 1.0 cm and 4.0 cm or less is undefined.
METHODS:
A genetic-clinical risk study was performed on BRAF V600E in 955 patients (768 women and 187 men) with SI-PTC, with median age of 46 years and median clinical follow-up time of 64 months at 11 medical centers in six countries. The chi-square test or, for analyses with small numbers, Fisher's exact test was performed to compare recurrence rates. Recurrence-free probability was estimated by Kaplan-Meier (KM) analysis, and the independent effect of BRAF mutation on the recurrence was analyzed by Cox regression and Cox proportional hazard analyses. All statistical tests were two-sided.
RESULTS:
Recurrence of SI-PTC larger than 1.0 cm and 4.0 cm or less was 9.5% (21/221) vs 3.4% (11/319) in BRAF mutation vs wild-type BRAF patients, with a hazard ratio (HR) of 3.03 (95% confidence interval [CI] = 1.46 to 6.30) and a patient age- and sex-adjusted hazard ratio of 3.10 (95% CI = 1.49 to 6.45, P = .002). Recurrence rates of SI-PTC larger than 2.0 cm and 4.0 cm or less were 16.5% (13/79) vs 3.6% (5/139) in mutation vs wild-type patients (HR = 5.44, 95% CI = 1.93 to 15.34; and adjusted HR = 5.58, 95% CI = 1.96 to 15.85, P = .001). Recurrence rates of SI-PTC larger than 3.0 cm and 4 cm or less were 30.0% (6/20) vs 1.9% (1/54) in mutation vs wild-type patients (HR = 18.40, 95% CI = 2.21 to 152.98; and adjusted HR = 14.73, 95% CI = 1.74 to 124.80, P = .01). Recurrences of mutation-positive SI-PTC were comparable with those of counterpart invasive solitary PTC, around 20% to 30%, in tumors larger than 2.0 cm to 3.0 cm. BRAF mutation was associated with a statistically significant decrease in recurrence-free patient survival on KM analysis, particularly in SI-PTC larger than 2.0 cm and 4.0 cm or less. Similar results were obtained in conventional SI-PTC. The negative predictive values of BRAF mutation for recurrence were 97.8% (95% CI = 96.3% to 98.8%) for general SI-PTC and 98.2% (95% CI = 96.3% to 99.3%) for conventional SI-PTC.
CONCLUSIONS:
BRAF V600E identifies a subgroup of SI-PTC larger than 1.0 cm and 4.0 cm or less, particularly tumors larger than 2.0 cm and 4.0 cm or less, that has high risk for recurrence comparable with that of invasive solitary PTC, making more aggressive treatment reasonable
BRAF V600E mutation-assisted risk stratification of solitary intrathyroidal papillary thyroid cancer for precision treatment
[Background]: Precise risk stratification-based treatment of solitary intrathyroidal papillary thyroid cancer (SI-PTC) that is larger than 1.0 cm and 4.0 cm or less is undefined. [Methods]: A genetic-clinical risk study was performed on BRAF V600E in 955 patients (768 women and 187 men) with SI-PTC, with median age of 46 years and median clinical follow–up time of 64 months at 11 medical centers in six countries. The chi-square test or, for analyses with small numbers, Fisher’s exact test was performed to compare recurrence rates. Recurrence-free probability was estimated by Kaplan-Meier (KM) analysis, and the independent effect of BRAF mutation on the recurrence was analyzed by Cox regression and Cox proportional hazard analyses. All statistical tests were two-sided. [Results]: Recurrence of SI-PTC larger than 1.0 cm and 4.0 cm or less was 9.5% (21/221) vs 3.4% (11/319) in BRAF mutation vs wild-type BRAF patients, with a hazard ratio (HR) of 3.03 (95% confidence interval [CI] = 1.46 to 6.30) and a patient age- and sex-adjusted hazard ratio of 3.10 (95% CI = 1.49 to 6.45, P = .002). Recurrence rates of SI-PTC larger than 2.0 cm and 4.0 cm or less were 16.5% (13/79) vs 3.6% (5/139) in mutation vs wild-type patients (HR = 5.44, 95% CI = 1.93 to 15.34; and adjusted HR = 5.58, 95% CI = 1.96 to 15.85, P = .001). Recurrence rates of SI-PTC larger than 3.0 cm and 4 cm or less were 30.0% (6/20) vs 1.9% (1/54) in mutation vs wild-type patients (HR = 18.40, 95% CI = 2.21 to 152.98; and adjusted HR = 14.73, 95% CI = 1.74 to 124.80, P = .01). Recurrences of mutation-positive SI-PTC were comparable with those of counterpart invasive solitary PTC, around 20% to 30%, in tumors larger than 2.0 cm to 3.0 cm. BRAF mutation was associated with a statistically significant decrease in recurrence-free patient survival on KM analysis, particularly in SI-PTC larger than 2.0 cm and 4.0 cm or less. Similar results were obtained in conventional SI-PTC. The negative predictive values of BRAF mutation for recurrence were 97.8% (95% CI = 96.3% to 98.8%) for general SI-PTC and 98.2% (95% CI = 96.3% to 99.3%) for conventional SI-PTC. [Conclusions]: BRAF V600E identifies a subgroup of SI-PTC larger than 1.0 cm and 4.0 cm or less, particularly tumors larger than 2.0 cm and 4.0 cm or less, that has high risk for recurrence comparable with that of invasive solitary PTC, making more aggressive treatment reasonable.This work was partly supported by US National Institutes of Health (NIH) grants R01CA113507 and R01CA189224 to M. Xing and by the following additional funding at the individual participating centers: Polish National Center of Research and Development MILESTONE Project-molecular diagnostics and imaging in individualized therapy for breast, thyroid and prostate cancer, grant STRATEGMED2/267398/4/NCBR/2015 (Poland, AC, BJ); grants from Menzies Health Institute, Queensland and Queensland Smart State fellowship (Australia; AKL); grants SAF2013-44709-R (MINECO and FEDER), RD12/0036/0030, PI14/01980 (ISCIII), and GCB14142311CRES (AECC Foundation) (Spain; PS and GRE); grant IG 9338 from the Fondazione Cassa di Risparmio di Perugia and Associazione Italiana per la Ricerca sul Cancro (Italy) and the Beadle Family Foundation (San Antonio, TX; EP); grants AZV 16-32665A and MH CZ-DRO (Institute of Endocrinology-EU, 00023761) (Czech Republic; BB, VS); grants from the New South Wales Cancer Institute (CJO) and Cancer Council of New South Wales (Australia; RCB); NIH/National Institute on Aging grant 5R03AG042334-02 (LY); grants from the Ministero della Istruzione Universitaria e Ricerca Scientifica, the Associazione Italiana per la Ricerca sul Cancro, the Istituto Toscano Tumori, and the Ministero della Salute (Italy; DV, RE); and grants 81471324 from the Natural Science Foundation of China and SHDC12015127 (SQ).Peer Reviewe
Mouse 3T3-L1 cells were transfected with pGL4.10 (luc2/-500<i>CEBPa</i>) in triplicate.
<p>Following incubation with differentiation medium only, growth medium only, or differentiation medium with 1, 25(OH)<sub>2</sub>D<sub>3</sub> (100nM). Fire-fly and Renilla luciferase activity units were measured at 0, 12, 24 and 48 h. The firefly luciferase activity units were normalized to Renilla luciferase activity units. Data are normalized as fold activation relative to 0 h and shown as means ± SE (n = 3). Different letters represent treatment effects that were significantly different (<i>P</i> < 0.05) within each time-point.</p