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1.
Hum Mutat ; 2021 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-33600035

RESUMO

BAP1 germline pathogenic sequence variants (PSVs) underlie a unique tumor predisposition syndrome (BAP1 - TPDS) associated with increased lifetime risk for developing primarily pleural and peritoneal mesothelioma and uveal and cutaneous melanoma. Overwhelmingly, BAP1 PSVs are unique, family specific inactivating variants. We identified seven families, 6 of Jewish Iraqi origin, harboring an identical BAP1 splice variant (c.783+2T>C), currently assigned a "likely pathogenic" status. Given a non-classical BAP1-TPDS tumor type clustering, and low penetrance in these families, the pathogenicity of this variant was re-evaluated by a combined approach including literature analysis, revised bioinformatics analysis, allelic loss, effect on transcript, and tumor protein expression patterns. None of three available tumors showed allelic loss, there was no discernable effect on alternative splicing based on reverse transcription PCR, and there was no decrease or loss of somatic protein expression in 2/3 analyzed tumors. This led to assigning a Benign Strong (BS) criteria, BS4, supporting BS3 criteria, and to weakening the Pathogenic Supporting (PP) criteria PP5. Combined, these data suggest that this sequence variant should be re-classified as a variant of unknown significance by ACMG criteria. This article is protected by copyright. All rights reserved.

2.
Breast J ; 2021 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-33576117

RESUMO

Female BRCA1/BRCA2 mutation carriers may elect bilateral risk-reducing mastectomy. There is a paucity of data on yield of imaging surveillance after risk-reducing mastectomy. This retrospective study focused on female BRCA1/BRCA2 mutation carriers who underwent bilateral mastectomy either as primary preventative, or as secondary preventative, after breast cancer diagnosis. All participants underwent breast imaging at 6- to 12-month intervals after mastectomy. Data on subsequent breast cancer diagnosis and timing were collected and compared between the groups. Overall, 184 female mutation carriers (134 BRCA1, 45 BRCA2, 5 both BRCA genes) underwent bilateral mastectomy after initial breast cancer diagnosis, between April 1, 2009 and August 31, 2018. During a mean follow-up of 6.2 ± 4.2 years, 13 (7.06%) were diagnosed with breast cancer; 12 ipsilateral (range: 0.4-28.8 years) and 1 contralateral breast cancer, 15.9 years after surgery. On the contrary, among asymptomatic BRCA1 (n = 40) and BRCA2 (n = 13) mutation carriers who underwent primary risk-reducing mastectomy (mean age at surgery 39.5 ± 8.4 years); none has developed breast cancer after a mean follow-up of 5.4 ± 3.4 years. BRCA1/BRCA2 mutation carriers with prior disease who underwent risk-reducing mastectomy after breast cancer diagnosis are still prone for developing ipsi or contralateral breast cancer, and therefore may benefit from continues clinical and imaging surveillance, unlike BRCA1/BRCA2 mutation carriers who undergo primary preventative bilateral mastectomy.

3.
Eur J Cancer ; 146: 30-47, 2021 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-33578357

RESUMO

BRCA1 and BRCA2 gene pathogenic variants account for most hereditary breast cancer and are increasingly used to determine eligibility for PARP inhibitor (PARPi) therapy of BRCA-related cancer. Because issues of BRCA testing in clinical practice now overlap with both preventive and therapeutic management, updated and comprehensive practice guidelines for BRCA genotyping are needed. The integrative recommendations for BRCA testing presented here aim to (1) identify individuals who may benefit from genetic counselling and risk-reducing strategies; (2) update germline and tumour-testing indications for PARPi-approved therapies; (3) provide testing recommendations for personalised management of early and metastatic breast cancer; and (4) address the issues of rapid process and tumour analysis. An international group of experts, including geneticists, medical and surgical oncologists, pathologists, ethicists and patient representatives, was commissioned by the French Society of Predictive and Personalised Medicine (SFMPP). The group followed a methodology based on specific formal guidelines development, including (1) evaluating the likelihood of BRCAm from a combined systematic review of the literature, risk assessment models and expert quotations, and (2) therapeutic values of BRCAm status for PARPi therapy in BRCA-related cancer and for management of early and advanced breast cancer. These international guidelines may help clinicians comprehensively update and standardise BRCA testing practices.

4.
Artigo em Inglês | MEDLINE | ID: mdl-33449224

RESUMO

PURPOSE: The co-occurrence or double heterozygosity of pathogenic/likely pathogenic sequence variants (P/LPSVs) in major cancer susceptibility genes has rarely been reported. Such co-occurrence raises the issues of accurate genetic counseling, preferred recommended surveillance scheme, and the use of preimplantation genetic diagnosis (PGD). METHODS: A clinical report of an Ashkenazi Jewish (AJ) family with co occurrence of two PSVs in BRCA1 and TP53 and a literature search. RESULTS: In an AJ family with a substantial history of cancer limited to the maternal side, two siblings co-harbored TP53 (c.733C>A; p.G245S) and the predominant 5266dup BRCA1 mutation, originating from the mother and the father, respectively. PGD is ongoing. Four families were thus far reported as double heterozygotes for both BRCA1/BRCA2 and TP53. Based on the limited available data, it seems that the phenotype in double PSV heterozygotes is not more severe than in single PSV carrier in either gene. CONCLUSIONS: This family highlights the need to genotype both parents, especially in populations with founder mutations, when a BRCA1 mutation is detected in an offspring, regardless of family history. The combination of mutations in these two genes presents a challenge for PGD since both genes are located on chromosome 17.

5.
Artigo em Inglês | MEDLINE | ID: mdl-33259931

RESUMO

BACKGROUND: There is a paucity of data on the rates of ipsilateral breast tumor recurrence (IBTR) in BRCA1/2-associated breast cancer (BC). Scarcer yet is outcomes data in BRCA1/2 mutation carriers in the setting of newer mastectomy techniques such as skin-sparing (SSM) and nipple-sparing (NSM) mastectomies. PATIENTS AND METHODS: Data was extracted from the medical records of BRCA1/2 carriers who were diagnosed with BC and treated at a single institution between 2006-2020. Data extracted included patient demographics, tumor characteristics, disease stage, surgical treatment, use of radiation therapy (RT) and disease outcome. RESULTS: Overall, 255 BC patients with BRCA1/2 germline mutations were identified. Of these, 128 (50.2%) underwent mastectomy (SSM or NSM in 82% of them): 76 (59.4%) without postmastectomy RT (non-PMRT) and 52 (40.6%) with PMRT; and 127 (49.8%) participants elected for breast conserving treatment (BCT). The non-PMRT group had earlier disease stage (82.3% were Tis and T1N0) compared to the PMRT and BCT groups (3.6% and 48.1%, respectively, p<0.05). The IBTR cumulative rate was 9/76 (11.8%) in the non-PMRT cohort compared with 0/52 in the PMRT group (p=0.01), and 6/127 (4.7%) in the BCT group (p=0.06). Cumulative incidence of IBTR at 5 and 10 years was 9.8% and 27.4% in the non- PMRT vs 2% and 11.3% in BCT group, respectively (p=0.0183). No significant difference in overall survival was observed at the time of follow-up. CONCLUSIONS: BRCA1/2 mutation carriers treated with mastectomy without PMRT had higher rates of IBTR than those who underwent mastectomy and PMRT or BCT, despite earlier stage disease. The safety of SSM/NSM should be evaluated in a prospective trial.

6.
Fam Cancer ; 2020 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-33165727

RESUMO

Germline pathogenic sequence variants (PSVs) in BRCA1 substantially increase risk for developing breast (BC) and ovarian cancer (OvC). Yet, incomplete penetrance suggests that modifier factors affect phenotypic expression of mutant BRCA1 alleles. Analysis of identical BRCA1 PSV carriers of diverse ethnicities may provide further evidence for modifier factors. Female carriers of the 185delAG BRCA1 PSV identified through high-risk clinics in Israel, and Manchester England from 1998-2018 were eligible. Data were retrieved from patients records and confirmed (in Israel) by cross referencing with the Israeli National Cancer Registry. Overall, 2503 female carriers were included: 1715 (71.4%) Ashkenazi Jews (AJ), 201 (8.3%) Iraqi Jews and 383 (15.9%) of mixed ethnicity. In 102 (4.2%) cases ethnicity could not be ascertained. Of Israeli AJ carriers 649 (37.8%), 256 (14.9%) and 62 (3.6%) were diagnosed with BC, OvC or both cancers, respectively. For the Iraqi Jews these frequencies were 76 (37.8%), 43 (21.4%), and 8 (3.98%), respectively. Age at diagnosis of BC in AJ and Iraqi Jews was 46.7 ± 12.3 years and 52.8 ± 12.2 years, respectively (p = 0.001). For OvC age at diagnosis for AJ was 53.5 ± 10.7 years and for Iraqi Jews 50.1 ± 8.8 years (p = 0.0027). No differences in these parameters were noted between English Jews (n = 110) and non-Jews (n = 32). Age at diagnosis of BC and OvC differs between AJ and Iraqi Jews who carry an identical BRCA1 PSV. This finding supports the existence of modifier factors that may be ethnic specific.

7.
Onco Targets Ther ; 13: 11637-11644, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33235458

RESUMO

Background: The prognosis of gastric cancer (GC) is poor with a median overall survival (OS) of less than 12 months in advanced-stage disease. The search for distinct genetic subgroups of GC patients and predictive biomarkers is ongoing. While BRCA1 or BRCA2 germline mutations (gBRCAm) have potential therapeutic implications in ovarian, breast and pancreatic cancers, their significance in GC patients has not been established. Patients and Methods: A retrospective multi-center data analysis of GC patients with gBRCAm was conducted, detailing the clinical characteristics and disease course in this unique subset of patients. Results: Ten GC patients with gBRCAm were identified, six of them with metastatic disease. The median OS of all ten GC patients was 47.5 (13-192) months. Median OS for patients diagnosed with operable disease was 55.5 (13-192) months and of the patients with metastatic disease (calculated from metastatic disease diagnosis) 32 (15-52) months with an exceptional 1-, 2- and 3-year survival rate of 100%, 83.3% and 50%, respectively. Conclusion: These preliminary data suggest that gBRCAm in GC patients are associated with a favorable prognosis. Furthermore, gBRCAm might be a predictive biomarker to DNA-damaging agents response in GC patients, similarly to its established role in other malignancies. Further research is needed to confirm our findings.

8.
Artigo em Inglês | MEDLINE | ID: mdl-33000375

RESUMO

BACKGROUND: The rate of risk-reducing bilateral mastectomy (RRBM) among cancer-free Israeli female BRCA1/BRCA2 mutation carriers was reportedly 13% in 2010. Current RRBM rates in Israel and factors seemingly associated with opting for RRBM were reevaluated. METHODS: Israeli female cancer-free BRCA1/BRCA2 mutation carriers, who were followed at the high-risk clinic at Sheba Medical Center between January 2011 and April 2020 were eligible. Univariate Cox regression and log-rank test were used to study the crude association between potential predictors and performance of RRBM. RESULTS: Overall, 427 cancer-free BRCA1 (n = 218) or BRCA2 (n = 209) mutation carriers were included. Median age at genotyping was 33.6 years (interquartile range 26.8-41.8 years), median follow-up 4.4 years (range 0.1-7.6 years). Overall, 41/427 (9.6%) participants underwent RRBM, all of them within 5 years of genotyping. Being married (HR-2.57, p = 0.017) and having a first degree relative with breast cancer (BC) (HR-2.19, p = 0.017) were positively associated with RRBM, whereas any previous benign breast biopsy was negatively associated (HR-0.48, p = 0.029) with performing RRBM. CONCLUSIONS: RRBM is still infrequently elected by Israeli BRCA1/BRCA2 mutation carriers, with married women with one relative with BC who have not undergone previous breast biopsy more likely to opt for RRBM.

9.
J Natl Cancer Inst ; 2020 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-32785646

RESUMO

BACKGROUND: The aetiology of male breast cancer (MBC) is poorly understood. In particular, the extent to which the genetic basis of MBC differs from female breast cancer (FBC) is unknown. A previous genome-wide association study (GWAS) of MBC identified two predisposition loci for the disease, both of which were also associated with risk of FBC. METHODS: We performed genome-wide single nucleotide polymorphism (SNP) genotyping of European ancestry MBC case subjects and controls, in three stages. Associations between directly genotyped and imputed SNPs with MBC were assessed using fixed-effects meta-analysis of 1,380 cases and 3,620 controls. Replication genotyping of 810 cases and 1,026 controls was used to validate variants with P-values < 1 x 10-06. Genetic correlation with FBC was evaluated using LD score regression, by comprehensively examining the associations of published FBC risk loci with risk of MBC and by assessing associations between a FBC polygenic risk score (PRS) and MBC. All statistical tests were two-sided. RESULTS: The GWAS identified three novel MBC susceptibility loci that attained genome-wide significance (P < 5 x 10-08). Genetic correlation analysis revealed a strong shared genetic basis with estrogen-receptor (ER) positive FBC. Males in the top quintile of genetic risk had a four-fold increased risk of breast cancer relative to those in the bottom quintile (odds ratio = 3.86, 95% confidence interval = 3.07 to 4.87, P = 2.08 x 10-30). CONCLUSIONS: These findings advance our understanding of the genetic basis of MBC, providing support for an overlapping genetic aetiology with FBC and identifying a four-fold high risk group of susceptible men.

10.
Genet Res (Camb) ; 102: e3, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32354376

RESUMO

Pheochromocytoma (PCC) is a rare, mostly benign tumour of the adrenal medulla. Hereditary PCC accounts for ~35% of cases and has been associated with germline mutations in several cancer susceptibility genes (e.g., KIF1B, SDHB, VHL, SDHD, RET). We performed whole-exome sequencing in a family with four PCC-affected patients in two consecutive generations and identified a potential novel candidate pathogenic variant in the REXO2 gene that affects splicing (c.531-1G>T (NM 015523.3)), which co-segregated with the phenotype in the family. REXO2 encodes for RNA exonuclease 2 protein and localizes to 11q23, a chromosomal region displaying allelic imbalance in PCC. REXO2 protein has been associated with DNA repair, replication and recombination processes and thus its inactivation may contribute to tumorigenesis. While the study suggests that this novel REXO2 gene variant underlies PCC in this family, additional functional studies are required in order to establish the putative role of the REXO2 gene in PCC predisposition.

11.
Breast Cancer Res Treat ; 181(2): 445-453, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32303989

RESUMO

BACKGROUND: Carriers of pathogenic variants (PVs) in moderate-high-penetrance cancer susceptibility genes are offered tailored surveillance schemes for early cancer diagnosis. The clinical implications of low-penetrance variant carriers are less clear. METHODS: Clinical and demographic data were retrieved for a cohort of Israeli individuals who underwent oncogenetic testing by the 30-gene cancer panel at Color Genomics laboratory, between 04/2013 and 12/2018. RESULTS: Of 758 genotyped individuals, 504 had been diagnosed with cancer prior to testing: 283 (56%) had breast cancer and 106 (21%) colorectal cancer. Pathogenic or likely pathogenic (P/LP) variants were detected in 123 (16%) individuals. Overall, 44 different P/LP variants were detected in 18/30 cancer susceptibility genes; 20 of them were founder/recurrent mutations. Of the carriers, 39 (32%), 10 (8%), and 74 (60%) carried high-, moderate-, or low-penetrance variants, respectively. After excluding low-penetrance variants, 7% (33/504) of all cancer patients, 6% of breast or ovarian cancer patients were found to be carriers, as well as 7% (14/203) of individuals with colonic polyps, and 4% (11/254) of cancer-free individuals. CONCLUSIONS: The diagnostic yield of moderate- and high-penetrance PVs using multigene panel testing was 6%, with 3.7% carriers of non-recurrent PVs. This yield should be discussed during pre-test counseling, and emphasizes the need for harmonized recommendations regarding clinical implications of low-penetrance variants.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias da Mama/diagnóstico , Detecção Precoce de Câncer/métodos , Grupos Étnicos/genética , Predisposição Genética para Doença , Testes Genéticos/métodos , Mutação , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/genética , Estudos de Coortes , Grupos Étnicos/estatística & dados numéricos , Feminino , Seguimentos , Humanos , Israel/epidemiologia , Pessoa de Meia-Idade , Penetrância , Prognóstico , Adulto Jovem
12.
Genes Chromosomes Cancer ; 59(9): 503-516, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32337806

RESUMO

Activating point mutations in two codons (R201 and Q227) in the alpha subunit of the stimulatory GTP binding protein (GNAS) gene-coined gsp mutations-were originally reported in growth hormone secreting pituitary adenomas. In these tumor types, gsp activating mutations were associated with uncontrolled intracellular cAMP accumulation leading to cellular proliferation and tumor formation. Since the original description of gsp mutations in pituitary and later thyroid neoplasia, many more tumors were genotyped for these specific activating mutations. In this paradigm, GNAS is an oncogene that can be activated by other molecular mechanisms, such as DNA amplification and translocation. Herein, we describe the largest account to date of tumor types that harbor pathogenic GNAS genomic alterations (GAs) including the "classical" gsp activating point mutations, delineate some common features of these tumors, and speculate as to the possible mechanisms whereby GNAS activating GAs are associated with the various stages of tumorigenesis.

13.
Cancer Biomark ; 28(3): 269-273, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32280079

RESUMO

BACKGROUND: Female carriers of BRCA1 or BRCA2 germline mutations are at a substantially increased risk for developing breast and ovarian cancer. The lack of effective early detection schemes for ovarian cancer, mandate surgical removal of adnexa at age 35-40 years in these high-risk women. The role of circulating cell-free DNA (cfDNA) levels as a marker for early detection in high-risk women has rarely been reported. OBJECTIVE: To quantify cfDNA levels in BRCA1BRCA2 carriers. METHODS: Serum cfDNA levels, measured by direct fluorometric assay in cancer-free female BRCA1BRCA2 mutation carriers were compared with cancer-free controls recruited from among women undergoing breast biopsy or routine colonoscopy. RESULTS: Overall, 10 BRCA1 (185delAG) and 10 BRCA2 (6174delT) mutation carriers, 20 breast biopsy controls, and 20 colonoscopy controls participated. cfDNA levels [Median (95% CI)], were 472 (317-589) ng/ml and 525 (339-621) ng/ml in breast biopsy and colonoscopy controls, respectively. Median levels of cfDNA in BRCA1 and BRCA2 mutation carriers combined were 921 (835-1087) ng/ml, significantly higher than in both controls (P< 0.0001). CONCLUSIONS: cfDNA levels are significantly higher in BRCA1 and BRCA2 mutation carriers compared with non-carriers. This finding, if validated, may facilitate development of early detection breast/ovarian cancer biomarker in high-risk women.

14.
Sci Rep ; 10(1): 4974, 2020 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-32165689

RESUMO

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

15.
Endocr Pathol ; 31(1): 14-20, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32034658

RESUMO

Thyroid cancer, predominantly of papillary histology (PTC), is a common cancer mostly diagnosed sporadically. Hereditary PTC is encountered in ~ 5% of cases and may present at an earlier age, with greater risks of metastasis and recurrence, compared with sporadic cases. The molecular basis of hereditary PTC is unknown in most cases. In this study, the genetic basis of hereditary PTC in three Brazilian families was investigated. Whole exome sequencing (WES) was carried out for probands in each family, and validated, pathogenic/likely pathogenic sequence variants (P/LPSVs) were genotyped in additional family members to establish their putative pathogenic role. Overall, seven P/LPSVs in seven novel genes were detected: p.D283N*ANXA3, p.Y157S*NTN4, p.G172W*SERPINA1, p.G188S*FKBP10, p.R937C*PLEKHG5, p.L32Q*P2RX5, and p.Q76*SAPCD1. These results indicate that these novel genes are seemingly associated with hereditary PTC, but extension and validation in other PTC families are required.


Assuntos
Predisposição Genética para Doença/genética , Câncer Papilífero da Tireoide/genética , Neoplasias da Glândula Tireoide/genética , Adulto , Brasil , Feminino , Mutação em Linhagem Germinativa , Humanos , Masculino , Linhagem , Sequenciamento Completo do Exoma
16.
Int J Radiat Oncol Biol Phys ; 107(2): 353-359, 2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-32084523

RESUMO

PURPOSE: Radiation therapy (RT), a standard breast cancer (BC) treatment modality, is associated with a small increased risk of in-field second primary malignancy (SPM). SPM rates after RT in BRCA mutation carriers have rarely been reported. An elevated risk of SPM would affect the safety of breast conservation for early BC or prophylactic radiation as a method of prevention. We analyzed a population of BRCA carriers irradiated for BC to determine whether there is an elevated rate of SPM. METHODS AND MATERIALS: Patients with BC who were BRCA1 or BRCA2 carriers and were treated with breast and/or chest wall RT with or without regional lymph nodes between 1991 and 2012 at a single institution were retrospectively identified. Only those with ≥5 years of follow-up with adequate demographic, tumor, and radiation data were included. SPMs were recorded, and previously delivered RT doses to the organ and site of malignancy were determined. RESULTS: Two hundred thirty women, of whom 80% carried an Ashkenazi Jewish founder mutation, met entry criteria with 3-dimensional RT delivered to 266 breasts or chest walls, including regional nodes in 110 (41%). With a median follow-up of 10 years (range, 5-27; mean 11.4) comprising 3042 person-years, 6 SPMs developed, of which only 1 (papillary thyroid carcinoma) was within the radiation field (crude rate of 0.38% of irradiated breasts or chest walls), diagnosed 17 years after RT. This corresponds to an incidence of 0.32 per 1000 woman-years. The Kaplan-Meier estimate of 20-year freedom from a radiation-induced SPM is 99.5%. Calculated dose exposure to the out-of-field SPMs ranged from 0.1 to 1 Gy. No patient developed an in-field skin cancer or sarcoma. CONCLUSIONS: In this largest cohort of women treated with radiation therapy for BRCA-associated breast cancer, we identified no signal for an increased risk of radiation-induced SPMs compared with the general BC population, and the risk is extraordinarily small. Although larger cohorts and longer follow-up are needed, these results support the safety of RT in BRCA carriers.

17.
Sci Rep ; 10(1): 2542, 2020 02 13.
Artigo em Inglês | MEDLINE | ID: mdl-32054879

RESUMO

The dopamine D5 receptor (D5R) is a Gαs-coupled dopamine receptor belonging to the dopamine D1-like receptor family. Together with the dopamine D2 receptor it is highly expressed in striatal cholinergic interneurons and therefore is poised to be a positive regulator of cholinergic activity in response to L-DOPA in the dopamine-depleted parkinsonian brain. Tonically active cholinergic interneurons become dysregulated during chronic L-DOPA administration and participate in the expression of L-DOPA induced dyskinesia. The molecular mechanisms involved in this process have not been elucidated, however a correlation between dyskinesia severity and pERK expression in cholinergic cells has been described. To better understand the function of the D5 receptor and how it affects cholinergic interneurons in L-DOPA induced dyskinesia, we used D5R knockout mice that were rendered parkinsonian by unilateral 6-OHDA injection. In the KO mice, expression of pERK was strongly reduced indicating that activation of these cells is at least in part driven by the D5 receptor. Similarly, pS6, another marker for the activity status of cholinergic interneurons was also reduced. However, mice lacking D5R exhibited slightly worsened locomotor performance in response to L-DOPA and enhanced LID scores. Our findings suggest that D5R can modulate L-DOPA induced dyskinesia and is a critical activator of CINs via pERK and pS6.


Assuntos
Dopamina/metabolismo , Discinesia Induzida por Medicamentos/genética , Levodopa/efeitos adversos , Receptores de Dopamina D5/genética , Animais , Neurônios Colinérgicos/efeitos dos fármacos , Neurônios Colinérgicos/metabolismo , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Modelos Animais de Doenças , Discinesia Induzida por Medicamentos/patologia , Humanos , Interneurônios/efeitos dos fármacos , Interneurônios/metabolismo , Sistema de Sinalização das MAP Quinases/genética , Camundongos , Camundongos Knockout , Oxidopamina/farmacologia , Doença de Parkinson/genética , Doença de Parkinson/patologia
18.
Menopause ; 27(1): 82-87, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31688415

RESUMO

OBJECTIVE: BRCA-mutation carriers are offered risk-reducing bilateral salpingo-oophorectomy (RRBSO) at age 35 to 40 years, leading to major life-quality and health-related issues associated with early menopause. Hormone therapy (HT) may significantly alleviate menopausal symptoms without increasing breast or ovarian cancer risk in BRCA carriers. We investigated attitudes of Israeli healthcare providers to HT post-RRBSO in BRCA carriers, before and after a brief educational intervention. METHODS: In this pre-post survey of gynecologic departments in Israel, healthcare providers were given questionnaires (based on scores of 1-4) assessing attitudes to prescribing HT in different clinical scenarios, before and after an educational intervention on current knowledge about HT in BRCA-mutation carriers. Higher scores indicated higher tendency to prescribe HT. Mean and median scores were calculated for each scenario, and the association between scores and various healthcare providers' characteristics were assessed. The change in attitude pre versus postintervention was evaluated, and the Cohen's d effect size was calculated. RESULTS: Of the 200 healthcare providers who were offered participation, 162 responded. Of them, 25.3% were obstetricians, 13.6% gynecologists, 5.55% gynecologic-oncologists, 8% medical oncologists, 38.9% obstetrics-gynecology residents, and 8.6% were nurses. Median age was 44 (interquartile range 36-58); 42.6% were males. Higher score correlated weakly with older age, but did not correlate with gender or personal HT/menopause experience. Significantly higher mean and median preintervention scores were obtained by gynecologists (3.2±0.96; 4 [2.25-4]) and gynecologic-oncologists (3.6 ±â€Š0.78; 4 [3.6-4.0]) than by medical oncologists (2.6 ±â€Š1.06; 2.13 [1.88-3.81]), obstetricians (2.7 ±â€Š1.09; 2.25 [1.88-4.0]), residents (2.48 ±â€Š0.99; 2 [1.69-3.56]) or nurses (2.2 ±â€Š0.92; 2 [1.5-2.69]). Overall scores were higher postintervention (P < 0.001, effect size d = 0.901). The change in scores postintervention was most prominent among younger participants and nurses. CONCLUSIONS: In Israel, it is acceptable to offer HT post-RRBSO to healthy BRCA-mutation carriers. Younger healthcare workers and nurses tend to be more hesitant, yet they are more likely to adopt a pro-HT attitude after an educational intervention. Such intervention is likely to improve overall care for BRCA-mutation carriers.

19.
Endocrine ; 67(1): 204-208, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31782130

RESUMO

PURPOSE: Parathyroid cancer is a rare tumor associated with poor prognosis particularly when disseminated. While chemotherapy and/or radiotherapy are of no clinical value in disseminated disease, immunotherapy should be considered. SUBJECT AND RESULTS: A patient with CDC73-associated metastatic parathyroid carcinoma was treated with combined anti-hPTH immunotherapy and surgery. CONCLUSIONS: Following five courses of anti-hPTH immunotherapy and subsequent surgery, a 12-year long remission of disseminated parathyroid cancer is reported. This case further supports the ever-expanding spectrum of cancers that may benefit from immunotherapy.

20.
Breast ; 49: 81-86, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31760168

RESUMO

BACKGROUND: Annual MRI screening is associated with a significant reduction in advanced-stage breast cancer diagnosis in BRCA1/2 mutation carriers. The impact that early detection has on subsequent oncological treatment is less frequently reported. In this study we compared disease stage and therapeutic approaches in BRCA1/2 mutation carriers who developed breast cancer while adhering to the recommended surveillance scheme ("known carriers"), with women who became aware of their BRCA mutation status after breast cancer diagnosis ("latent carriers"). METHODS: Data on tumor characteristics, disease stage, and therapeutic decisions were collected on BRCA1/2 mutation carriers treated for breast cancer at the Chaim Sheba Medical Center. RESULTS: Data were available for 298 BRCA1/2 carriers. Median follow-up was 77.4 months (range, 3.5-520). Age at diagnosis was not statistically different between known carriers (n = 96; median age at diagnosis 44.7 years) and latent carriers (n = 202; 43.7 years); p = 0.8284. Of known carriers, 19.8% were diagnosed with carcinoma in situ vs. 5% of latent carriers (p = 0.0012). Stage T1N0 disease was diagnosed in 54/96 (56.3%) of known carriers vs. 59/202 (29.2%) of latent carriers (p < 0.00001). Neoadjuvant or adjuvant chemotherapy was administered to 46/96 (47.9%) of known carriers compared with 162/202 (80.2%) of latent carriers (p < 0.00001). CONCLUSIONS: While early stage breast cancer was diagnosed frequently among known BRCA1/2 carriers under tight surveillance, almost half of these women were treated with chemotherapy. Healthy BRCA1/2 mutation carriers should be informed about these rates while discussing risk-reducing surgical options.


Assuntos
Idade de Início , Neoplasias da Mama/prevenção & controle , Detecção Precoce de Câncer/estatística & dados numéricos , Predisposição Genética para Doença/prevenção & controle , Vigilância da População , Adulto , Fatores Etários , Proteína BRCA1 , Proteína BRCA2 , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/genética , Detecção Precoce de Câncer/métodos , Feminino , Humanos , Pessoa de Meia-Idade , Mutação , Terapia Neoadjuvante/estatística & dados numéricos , Estadiamento de Neoplasias
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