Background: To compare the concordance between trophectoderm (TE) analysis and whole blastocyst analysis of embryos from chromosomal structural rearrangement (SR) carriers. Method: Sixty-three abnormal blastocysts identified by preimplantation genetic testing for chromosomal structural rearrangement (PGT-SR) were included. The whole blastocysts were processed through multiple displacement amplification cycle and sequenced for 24-chromosome aneuploidy screening by next-generation sequencing (NGS). The sequencing results were compared with those of TE biopsy from the same blastocysts and the primary chromosomal rearrangement of the couples.Results: Analysis of the 63 blastocysts showed 68% (43/63) complete concordance between TE sequencing analysis and whole blastocyst results. Approximately one third (20/63, 32%) of the sequencing results showed some level of discordance between the two samples. Of these, 14% (9/63) of the embryos were identified as euploid after whole blastocyst sequencing. Among them, seven blastocysts were classified as chromosome mosaicism (five whole chromosomes, two segmental) after TE analysis, while two displayed non-SR related segmental changes in the TE biopsy. Of the original analyses, 70% (44/63) of findings were associated with the primary parental chromosomal rearrangement, while 30% (19/63) had no association. Conclusions: TE biopsy with NGS for PGT-SR is an efficient strategy to identify embryos suitable for transfer. While there was a high concordance between TE and whole blastocyst chromosome results, some embryos classified as mosaic in the original analysis and therefore unsuitable for transfer were reclassified as chromosomally balanced. To maximize the number of embryos available for PGT-SR patients, we suggest that embryos with mosaic non-SR chromosomal rearrangement should be stored and considered for transfer after appropriate counseling.
ObjectivesTo compare successful beta-thalassemia (β-thalassemia) detection rates obtained using spent culture medium and spent culture medium containing blastocoelic fluid (BF).MethodThis study involved data from 10 couples who underwent preimplantation genetic testing (PGT) for β-thalassemia. A total of 26 samples of spent culture medium containing BF (group A) and 33 samples without BF (group B) were collected and analyzed. The DNA concentration and β-thalassemia detection rates were evaluated.ResultsThe HBB mutation analysis results of 34 samples were concordant with the biopsy results (34/59, 57.6%). In group A, the HBB mutation analysis results of 19 of 26 samples (73.1%) were concordant with the biopsy results. The concordance rate in group A was higher than that in group B (15/33, 45.5%; P < 0.05). The haplotyping results of 38 samples were concordant with the biopsy results (38/59, 64.4%). The concordance rate in group B was 17/33 (51.5%), which was significantly lower than that in group A (21/26, 80.8%) (P < 0.05). In group A, the mean DNA concentration of samples with <10% fragmentation was 107.3 ± 70.1 ng/μL, which was lower than that of samples with ≥10% fragmentation (194.6 ± 28.0 ng/μL) (P < 0.05). However, the detection rates of <10% and ≥10% fragmentation were not significantly different (P > 0.05).ConclusionThe β-thalassemia detection rate with non-invasive PGT using the spent culture medium containing BF was higher than that using the spent culture medium alone. Fragmentation is associated with DNA concentration in the spent culture medium containing BF.
Background This study aimed to evaluate the ability of next-generation sequencing (NGS) to conduct preimplantation genetic testing (PGT) for thalassemia using affected embryos. Methods This study included data from 36 couples who underwent PGT for thalassemia without probands and relative pedigrees. NGS results were compared with prenatal diagnosis results. Results Thirty-six couples (29 α-thalassemia and 7 β-thalassemia) underwent 41 PGT cycles (31 α-thalassemia and 10 β-thalassemia). Analysis using NGS produced conclusive results for all biopsied blastocysts (100%, 217/217). One hundred and sixty (73.7%, 160/217) were unaffected by thalassemia. Preimplantation genetic testing for aneuploidy revealed that 112 (70.0%, 112/160) were euploid. Single blastocysts were transferred into the uteri of 34 women (53 frozen embryo transfer [FET] cycles). Thirty-two cycles resulted in clinical pregnancies, with a clinical pregnancy rate of 60.1% (32/53) per FET cycle. Twenty-two cycles (22 couples) resulted in 23 live births, with a live birth rate of 43.4% (23/53; 3 cycles were ongoing pregnancies). All 25 embryos’ prenatal diagnosis results and/or thalassemia gene analyses after delivery were concordant with the NGS-PGT results. Seven embryos (21.9%, 7/32) were miscarried before 12 weeks’ gestation, and the abortion villus in four showed a normal karyotype and thalassemia results consistent with the NGS-PGT results. Aborted fetus samples from 3 cycles were not available because the pregnancy lasted less than 5 weeks. Conclusion NGS can be used to conduct PGT for thalassemia using affected embryos as a reference. Trial registration Retrospectively registered.
a phase 2 clinical trial with a combination of the SYK inhibitor GS9973 and idelalisib, 13.6% of CLL and/or non-Hodgkin lymphoma patients developed severe pneumonitis leading to early termination of the study. 15 The underlying pathophysiology of how signal transduction inhibitors are associated with pulmonary toxicities remains to be defined.Given the findings of a nonmalignant inflammatory infiltrate, we hypothesize that inhibiting signal transduction pathways enhances expression of proinflammatory cytokines and the innate immune system. BTK also appears to serve as a critical mediator of lipopolysaccharide-induced dendritic cell maturation and macrophage polarization. Several studies have reported an increase in alveolar infiltration of T helper 2 proinflammatory cytokines in BTK-deficient mice, resulting in airway inflammation. 16,17 Our findings have important clinical implications. We propose that patients may receive counseling about this potential toxicity prior to initiating ibrutinib therapy and that any respiratory illness be taken seriously and evaluated effectively. Management strategies could include dose interruption and/or drug discontinuation along with initiation of steroids in severe cases. Further studies and better understanding of this toxicity are needed as the use of ibrutinib for treating lymphoid malignancies is expected to increase in the near future.Contribution: A.R.M. designed the study, collected data, wrote and edited the manuscript, had full access to all data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis; P.I., C.D., and L.S. collected data and wrote and edited the manuscript; A.H.K. performed the radiology review; S.B. performed the pathology review; A.G. was involved in drug dosing, management, and the writing and editing of the paper; S.N., D.L.P., J.S., and S.J.S. provided patient care and edited the manuscript; and C.N. wrote and edited the manuscript.Conflict-of-interest-disclosure: J.S. receives research funding from Seattle Genetics, Celegene, Pharmacyclics, and MedImmune. D.L.P. receives research funding, intellectual property, and royalty payments from Novartis. His spouse is employed by Genentech. S.J.S. receives research funding from Pharmacyclics, Novartis, Gilead, Janssen, Celgene, and Hoffman-LaRoche; receives consultancy fees from Pharmacyclics, Celgene, and Genentech; and serves on the Nordic Nanovector Board of Directors or advisory committees. A.R.M. receives research funding from TG Therapeutics, Acerta, Gilead, Celgene, and Pharmacyclics and has received consulting fees from TG Therapeutics, Gilead, and Celgene. The remaining authors declare no competing financial interests.
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