Publications by authors named "Anya Kushnir"

9 Publications

  • Page 1 of 1

Oesophageal atresia: sonographic signs may prenatally predict surgical complexity.

Arch Dis Child Fetal Neonatal Ed 2021 Jul 28. Epub 2021 Jul 28.

Obstetrics and Gynecology, Sheba Medical Center at Tel HaShomer, Tel HaShomer, Israel.

Objective: Oesophageal atresia (OA) is a major anomaly of varying severity. The complexity of surgical correction highly depends on the gap length of missing oesophagus and the presence of a distal fistula. The aim of this study was to identify antenatal sonographic findings associated with presence of a distal fistula and type of surgical repair METHODS: Prenatal medical records of neonates postnatally diagnosed with OA were reviewed. Sonographic signs of OA (small/absent stomach, polyhydramnios, oesophageal pouch) and the trimester at sign detection were recorded and compared between (1) OA with and without a distal fistula and (2) early one-step versus delayed two-step anastomosis. Multivariate analysis was performed.

Results: Overall, 80 cases of OA were included. Absence of a distal fistula was significantly associated with higher rates of small/absent stomach (100% vs 28.6%, P<0.0001), oesophageal pouch (100% vs 24.3%, P<0.0001) and severe polyhydramnios (66.7% vs 22.9%, P=0.006), compared with OA with a distal fistula.Cases requiring a delayed two-step repair had higher rates of small/absent stomach (84.2% vs 16.7%, P>0.0001), severe polyhydramnios (47.4% vs 16.7%, P=0.008) and oesophageal pouch (73.7% vs 18.5%, P<0.0001), compared with those corrected in an early one-step anastomosis.Multivariate logistic regression found small/absent stomach and pouch to be significantly and independently associated with a delayed two-step anastomosis.

Conclusion: OA without a distal fistula is associated with higher rates of prenatal sonographic signs. Both small/absent stomach and a pouch are independently associated with a delayed two-step anastomosis. These findings may help improve antenatal parental counselling regarding the anticipated surgical repair.
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http://dx.doi.org/10.1136/archdischild-2021-321836DOI Listing
July 2021

Abnormal nuchal translucency followed by normal microarray analysis is associated with placental pathology-related complications.

Prenat Diagn 2021 Jun 25;41(7):855-860. Epub 2021 Jan 25.

Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

Objective: Identify placental pathology-related complications, labor and neonatal outcomes in pregnancies complicated by pathological nuchal translucency (NT) with normal microarray analysis.

Methods: A retrospective study in which all women with singleton pregnancy who demonstrated NT above 3 mm and a normal microarray analysis were matched to women with normal NT and a normal microarray analysis (2013-2019) in a single tertiary academic center. The following placental pathology-related parameters were measured: preeclampsia, oligohydramnios, suspected intrauterine growth restriction, abnormal Doppler studies or small for gestational age (SGA) neonates. The primary outcome was defined as a composite of complications related to placental pathology including preeclampsia and SGA neonate. Secondary outcomes were labor complications and neonatal morbidity.

Results: A total of 185 women were included in the study: of them, 47 presented an abnormal NT (study group) and 138 presented normal NT (controls). Groups did not significantly differ in baseline characteristics. Regarding primary outcome, all placental-related complications frequencies were higher in the study group, with a composite rate of 17.02% versus 6.52% in controls (p = 0.042%). Secondary outcomes did not differ between groups.

Conclusions: Abnormal NT measurement presented in pregnancies with normal fetal microarray analysis is associated with higher rates of placental-related complications.
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http://dx.doi.org/10.1002/pd.5896DOI Listing
June 2021

The "No ARSA" Sign: A Novel Method of Prenatal Screening for Aberrant Right Subclavian Artery.

J Clin Med 2020 Aug 17;9(8). Epub 2020 Aug 17.

Departments of Obstetrics and Gynecology, Sheba Medical Center, Tel Hashomer, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.

An aberrant right subclavian artery (ARSA) can be overlooked by the conventional method as described by Chaoui et al., due to acoustic shadowing. The aim of this study was to evaluate the feasibility and accuracy of a novel screening method for ARSA by demonstrating the brachiocephalic artery bifurcation, referred to as the "No ARSA" sign. A prospective study conducted at a tertiary care center between 2018 and 2019 included unselected pregnant patients at a median gestational age of 15.1 (14.2-22.1; IQR (inter-quartile range)) weeks, who had been referred for a routine or targeted anomaly scan. All participants were scanned for the presence or absence of ARSA using both the conventional and the novel "No ARSA" methods for validation purposes. A total of 226 unselected patients were enrolled in the study. The "No ARSA" sign was visualized in 218 fetuses (96.5%). In the remaining 8 cases (3.5%), the "No ARSA" sign was not demonstrated. In these fetuses, an ARSA was visualized by the conventional method. The new method exhibited 100% feasibility and was in complete agreement with the conventional method. Intra- and inter-observer agreement was excellent (κ = 1). The results of the study suggest that the "No ARSA" sign is an efficient and reliable screening tool for ARSA.
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http://dx.doi.org/10.3390/jcm9082658DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7463697PMC
August 2020

Esophageal atresia in twins compared to singletons: In utero manifestation and characteristics.

Prenat Diagn 2020 10 5;40(11):1418-1425. Epub 2020 Aug 5.

Department of Obstetrics and Gynecology, Sheba Medical Center, Tel Hashomer, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.

Objective: Esophageal atresia with/without tracheo-esophageal fistula (EA/TEF) is more common among twins. The detection of polyhydramnios might be altered in twins, leading to EA/TEF underdiagnosis, prenatally. The aim of the study was to compare the prenatal manifestation of EA/TEF between twins and singletons.

Methods: A 12-year study of EA/TEF cases was performed at a tertiary center. Cases exhibiting (a) small/absent stomach or (b) polyhydramnios were considered "suspected"; cases with (c) esophageal pouch were considered "detected." We compared the rate and timing of appearance of these signs between the groups.

Results: There were 76 cases of EA/TEF, of which 17 were a co-twin. All twin pairs were EA/TEF discordant. The prevalence of EA/TEF at our center was 1:750 for twins (1:319 monochorionic and 1:1133 dichorionic) and 1:2399 for singletons. The rate of small/absent stomach, polyhydramnios and pouch in twins vs singletons was 23.5%, 47.1%, 29.4% and 39.7%, 72.4%,34.5%, respectively (P = .2, P = .09 and P = .7). Esophageal pouch was detected earlier in twins (P = .03). Twins were scanned more frequently (×1.8 times, P = .01).

Conclusion: EA/TEF is more prevalent in twins. Despite lower rate of polyhydramnios, twins were similarly detected prenatally as singletons, and this was accomplished earlier in pregnancy; perhaps reflecting more frequent scans.
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http://dx.doi.org/10.1002/pd.5785DOI Listing
October 2020

Fetal pleural effusion: Contemporary methods of genetic evaluation.

Prenat Diagn 2019 08 16;39(9):751-757. Epub 2019 Jul 16.

Department of Obstetrics and Gynecology, Sheba Medical Center, Tel Hashomer, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.

Objective: To determine the contribution of chromosomal microarray (CMA) and other advanced genetic tests to the genetic evaluation of fetal pleural effusion (FPE) and to identify parameters that might assist in predicting genetic abnormality.

Methods: A retrospective study of FPE cases referred between 2013 and 2018 was conducted. Cases that underwent genetic evaluation were divided into two groups, chromosomally normal and genetically abnormal. The types and prevalence of genetic abnormalities were reported. Clinical and sonographic parameters were compared. Univariate and multivariate analyses were performed to determine an association between different parameters and genetic abnormality.

Results: Sixty-two cases were included in the study. Forty-eight cases were genetically assessed (karyotype, CMA, whole exome sequencing, Noonan panel, or a combination). A clinically significant genetic abnormality was detected in 29.17% (14/48) of cases. Aneuploidy and single gene disorders were found in 78.6% (11/14) and 21.4% (3/14) of abnormal cases. Four additional cases had microdeletion/duplications detected, yet none were of clinical significance. Multivariate analysis indicated that the presence of anomalies was statistically associated with genetic abnormality (95% CI, 1.144-168.2; 0.039).

Conclusion: In our cohort, CMA did not demonstrate an additional clinical yield over karyotyping. The presence of anomalies was independently associated with underlying genetic abnormality.
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http://dx.doi.org/10.1002/pd.5497DOI Listing
August 2019

Association of type and location of BRCA1 and BRCA2 mutations with risk of breast and ovarian cancer.

JAMA 2015 Apr;313(13):1347-61

Department of Medicine and Genetics, University of California, San Francisco.

Importance: Limited information about the relationship between specific mutations in BRCA1 or BRCA2 (BRCA1/2) and cancer risk exists.

Objective: To identify mutation-specific cancer risks for carriers of BRCA1/2.

Design, Setting, And Participants: Observational study of women who were ascertained between 1937 and 2011 (median, 1999) and found to carry disease-associated BRCA1 or BRCA2 mutations. The international sample comprised 19,581 carriers of BRCA1 mutations and 11,900 carriers of BRCA2 mutations from 55 centers in 33 countries on 6 continents. We estimated hazard ratios for breast and ovarian cancer based on mutation type, function, and nucleotide position. We also estimated RHR, the ratio of breast vs ovarian cancer hazard ratios. A value of RHR greater than 1 indicated elevated breast cancer risk; a value of RHR less than 1 indicated elevated ovarian cancer risk.

Exposures: Mutations of BRCA1 or BRCA2.

Main Outcomes And Measures: Breast and ovarian cancer risks.

Results: Among BRCA1 mutation carriers, 9052 women (46%) were diagnosed with breast cancer, 2317 (12%) with ovarian cancer, 1041 (5%) with breast and ovarian cancer, and 7171 (37%) without cancer. Among BRCA2 mutation carriers, 6180 women (52%) were diagnosed with breast cancer, 682 (6%) with ovarian cancer, 272 (2%) with breast and ovarian cancer, and 4766 (40%) without cancer. In BRCA1, we identified 3 breast cancer cluster regions (BCCRs) located at c.179 to c.505 (BCCR1; RHR = 1.46; 95% CI, 1.22-1.74; P = 2 × 10(-6)), c.4328 to c.4945 (BCCR2; RHR = 1.34; 95% CI, 1.01-1.78; P = .04), and c. 5261 to c.5563 (BCCR2', RHR = 1.38; 95% CI, 1.22-1.55; P = 6 × 10(-9)). We also identified an ovarian cancer cluster region (OCCR) from c.1380 to c.4062 (approximately exon 11) with RHR = 0.62 (95% CI, 0.56-0.70; P = 9 × 10(-17)). In BRCA2, we observed multiple BCCRs spanning c.1 to c.596 (BCCR1; RHR = 1.71; 95% CI, 1.06-2.78; P = .03), c.772 to c.1806 (BCCR1'; RHR = 1.63; 95% CI, 1.10-2.40; P = .01), and c.7394 to c.8904 (BCCR2; RHR = 2.31; 95% CI, 1.69-3.16; P = .00002). We also identified 3 OCCRs: the first (OCCR1) spanned c.3249 to c.5681 that was adjacent to c.5946delT (6174delT; RHR = 0.51; 95% CI, 0.44-0.60; P = 6 × 10(-17)). The second OCCR spanned c.6645 to c.7471 (OCCR2; RHR = 0.57; 95% CI, 0.41-0.80; P = .001). Mutations conferring nonsense-mediated decay were associated with differential breast or ovarian cancer risks and an earlier age of breast cancer diagnosis for both BRCA1 and BRCA2 mutation carriers.

Conclusions And Relevance: Breast and ovarian cancer risks varied by type and location of BRCA1/2 mutations. With appropriate validation, these data may have implications for risk assessment and cancer prevention decision making for carriers of BRCA1 and BRCA2 mutations.
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http://dx.doi.org/10.1001/jama.2014.5985DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4537700PMC
April 2015

Germline mutations in RAD51C in Jewish high cancer risk families.

Breast Cancer Res Treat 2012 Dec 2;136(3):869-74. Epub 2012 Nov 2.

The Susanne Levy Gertner Oncogenetics Unit, Danek Gertner Institute of Human Genetics, Chaim Sheba Medical Center, Tel-Aviv University, 52621 Tel-Hashomer, Tel-Aviv, Israel.

Germline mutations in BRCA1 and BRCA2 account for ~30 % of inherited breast cancer. RAD51C was reported as an additional breast/ovarian cancer susceptibility gene in some populations. There is a paucity of data on the putative contribution of this gene to inherited breast/ovarian cancer in Jewish high risk families. High risk Jewish women, none of whom was a carrier of the predominant Jewish mutations in BRCA1 or BRCA2, were screened for RAD51C germline mutations by direct sequencing of exons and flanking intronic sequences. Overall, 206 high risk women, 79 (38.3 %) of Ashkenazi origin, were genotyped for RAD51C mutations: 190 (92.3 %) with uni- or bilateral breast cancer (mean age at diagnosis 51.3 ± 11.1 years), 14 with ovarian cancer (mean age at diagnosis 55.6 ± 8.7 years), and two with both breast and ovarian cancer. No truncating mutations were noted, and two previously described missense mutations were detected: p.Ile144Thr and p.Thr287Ala in Iraqi and mixed ethnicity Balkan-North African participants, respectively. These missense mutations were evolutionarily conserved, possibly pathogenic, based on some prediction algorithms, and were not detected in any of healthy Iraqi (n = 60) and mixed ethnicity (n = 140), cancer free controls, respectively. Germline mutations in RAD51C contribute marginally to breast and ovarian cancer susceptibility in ethnically diverse, Jewish high risk families. The p.Thr287Ala missense mutation may be a recurring, pathogenic RAD51C mutation in ethnically diverse populations.
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http://dx.doi.org/10.1007/s10549-012-2317-9DOI Listing
December 2012

Germline mutations in BRIP1 and PALB2 in Jewish high cancer risk families.

Fam Cancer 2012 Sep;11(3):483-91

IFOM, Fondazione Istituto FIRC di Oncologia Molecolare, Milan, Italy.

Germline mutations in BRCA1 and BRCA2 account for ~30 % of inherited breast cancer. BRIP1 and PALB2 are likely genes for breast cancer susceptibility, based on their roles in maintaining cellular integrity. Indeed, few pathogenic germline mutations in both genes are reported in ethnically diverse breast cancer families. There is a paucity of data on the putative contribution of both genes to inherited breast cancer in Jewish high risk families. High risk Jewish women, none of whom was a carrier of the predominant Jewish mutations in BRCA1/BRCA2, were screened for BRIP1 germline mutations by combined denaturing gradient gel electrophoresis, high resolution melting and sequencing. Direct sequencing of exons and flanking intronic sequences was used for PALB2 mutational analysis. Overall, 149 women, all of high risk, cancer prone families of Ashkenazi origin, were genotyped for BRIP1 mutations: 127 with breast cancer, 22 with ovarian cancer. No truncating mutations were noted and one novel (p.Ala745Thr) and two previously described missense mutations were detected. For PALB2, 93 women were genotyped (87 with breast cancer) of Ashkenazi (n = 32) and non Ashkenazi Jewish origin. Fifteen sequence variants were detected, of these, none was truncating, four were not previously reported, and two (p.Asp871Gly and p.Leu1119Pro) were seemingly pathogenic based on the PolyPhen2 protein prediction algorithm. These missense mutations were not detected in any of 113 healthy Ashkenazi and 109 Moroccan, cancer free controls. In conclusion, germline mutations in BRIP1 and PALB2 contribute marginally to breast cancer susceptibility in ethnically diverse, Jewish high risk families.
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http://dx.doi.org/10.1007/s10689-012-9540-8DOI Listing
September 2012

Recurrent germline mutations in BRCA1 and BRCA2 genes in high risk families in Israel.

Breast Cancer Res Treat 2012 Jun 8;133(3):1153-7. Epub 2012 Mar 8.

Susanne Levy Gertner Oncogenetics Unit, The Danek Gertner Institute of Human Genetics, Chaim Sheba Medical Center, 52621 Tel-Hashomer, Israel.

The spectrum of germline mutations among Jewish non Ashkenazi high risk breast/ovarian cancer families includes a few predominant mutations in BRCA1 (185delAG and Tyr978X) and BRCA2 (8765delAG). A few additional recurring mutations [A1708E, 981delAT, C61G (BRCA1) R2336P, and IVS2 + 1G > A (BRCA2)] have been reported in Jewish non Ashkenazi families. The 4153delA*BRCA1 C61G*BRCA1 and the 4075delGT*BRCA2 has been reported to recur in Russian/Polish non Jews and Ashkenazim, respectively. The rate of these recurring mutations has not been reported in Israeli high risk families. Genotyping for these recurring mutations by restriction enzyme digest and sequencing method was applied to high risk, predominantly cancer affected, unrelated Israeli individuals of Ashkenazi (n = 827), non Ashkenazi (n = 2,777), non Jewish Caucasians (n = 193), and 395 of mixed ethnicity. Jewish participants included 827 Ashkenazi, 804 Balkans, 847 North Africans, 234 Yemenites, and 892 Asians (Iraq and Iran). Age at diagnosis of breast cancer (median ± SD) (n = 2,484) was 47.2 ± 9.6 for all women participants. Males (n = 236) were also included, of whom 24 had breast cancer and 35 had pancreatic cancer. Overall, 8/282 (2.8%) of the Balkan cases carried the BRCA1*A1708E mutation, 4/180 (2.2%) the R2336P mutation, and 0/270 the IVS2 + 1G > A BRCA2 mutations, respectively. Of North Africans, 7/264 (2.65%) carried the BRCA1*981delAT mutation. The BRCA1*C61G mutation was detected in 3/269 Ashkenazi, non Ashkenazi, and non Jewish Russians; the BRCA1*Tyr978X mutation was detected in 23/3220 individuals of non Ashkenazi origin, exclusively of Asian ethnicity (23/892, 2.6% of the Asians tested). The BRCA1*4153delA mutation was noted in 2/285 non Jewish Caucasians, and none of the Ashkenazim (n = 500) carried the BRCA2*4075delGT mutation. Jewish high risk families of North African, Asian, and Balkan descent should be screened for the 981delAT, Tyr978X, A1708E BRCA1, and the R2336P BRCA2 mutations, respectively.
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http://dx.doi.org/10.1007/s10549-012-2006-8DOI Listing
June 2012
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