Advantages and limitations of estrogen replacement therapy on hypogonadal survivors of childhood cancer.

BACKGROUND: Hypogonadism is a significant late complication in childhood cancer survivors (CCS). The aim of this study was to elucidate the advantages and limitations of estrogen replacement therapy (ERT) for CCS with hypogonadism. METHODS: Seventeen CCS were divided into two groups: gonadal hypogonadism (GH) group (n = 8) and central hypogonadism (CH) group (n = 9). Pearson correlation coefficients were used to investigate the impact of cancer management on final height, bone density, and uterine development. RESULTS: Seven of GH group had hematologic malignancies, and all of them underwent total body irradiation before bone marrow transplantation. The GH group showed significant positive correlations between the onset age of disease treatment and final height (p < 0.05, R = 0.712) and uterine size following ERT (p < 0.05, R = 0.775). All CCS in the CH group had brain tumors, and seven of them received chemotherapy. There were trends towards positive and negative correlations between the onset age of disease treatment and final height (p = 0.09, R = 0.598) or uterine size (p = 0.07, R = - 0.669), respectively. A negative correlation trend was observed between the age at ERT initiation and final height (p = 0.07, R = - 0.769) or bone density (p = 0.18, R = - 0.626) in six CH patients who received growth hormone therapy. Five CCS in both groups experienced osteoporosis, despite receiving ERT. CONCLUSION: Individualized management strategies beyond ERT are essential to reduce long-term complications in CCS with hypogonadism, considering the type and timing of cancer treatment.

Repeated intestinal perforations in vascular Ehlers-Danlos syndrome: a case report of a novel mutation in the COL3A1 gene.

BACKGROUND: Ehlers-Danlos syndrome is an inherited connective-tissue disorder characterized by skin hyperextensibility, joint hypermobility, and tissue fragility. Intestinal perforation is one of the fatal manifestations of this syndrome, and its management is complicated. CASE PRESENTATION: A 58-year-old woman with a familial history of Ehlers-Danlos syndrome visited the emergency department due to a sudden onset of lower abdominal pain. Plain abdominal computed tomography showed abdominal free air. We found a perforated descending colon and subsequently resected this lesion and performed ileostomy. Fifty-one days after this first operation, the patient had transverse colon perforation and thus underwent the Hartmann procedure as the second operation. In addition, she was diagnosed with small bowel perforation 53 days after the first operation and consequently underwent a third operation-partial resection of the jejunum with functional end-to-end anastomosis. Fifty-eight days after the first operation, she complained of acute abdominal pain. Plain abdominal computed tomography showed fluid collection near the jejunojejunal anastomosis. We detected dehiscence at the entry hole of the linear stapler during the operation and thus performed partial resection of the affected jejunum, followed by jejunostomy. The postoperative course of the fourth operation was uneventful. Genetic testing revealed a novel missense mutation (c.2095G>T, p.Gly699Cys) in the COL3A1 gene, which is presumed to be a pathogenic variant of vascular Ehlers-Danlos syndrome. CONCLUSION: Vascular Ehlers-Danlos syndrome should be considered in the case of repeated intestinal perforation. The identified missense mutation in the COL3A1 gene (c.2095G>T, p.Gly699Cys) might be a novel pathogenic variation causing vascular Ehlers-Danlos syndrome. Careful postoperative screening and multidisciplinary management are required.

Lynch syndrome-associated chordoma with high tumor mutational burden and significant response to immune checkpoint inhibitors.

Chordoma is a rare malignant bone tumor arising from notochordal tissue. Conventional treatments, such as radical resection and high-dose irradiation, frequently fail to control the tumor, resulting in recurrence and re-growth. In this study, genetic analysis of the tumor in a 72-year-old male patient with refractory conventional chordoma of the skull base revealed a high tumor mutational burden (TMB) and mutations in the MSH6 and MLH1 genes, which are found in Lynch syndrome. The patient and his family had a dense cancer history, and subsequent germline genetic testing revealed Lynch syndrome. This is the first report of a chordoma that has been genetically proven to be Lynch syndrome. Chordomas usually have low TMB; however, this is an unusual case, because the TMB was high, and immune checkpoint inhibitors effectively controlled the tumor. This case provides a basis for determining the indications for immunotherapy of chordoma based on the genetic analysis. Therefore, further extensive genetic analysis in the future will help to stratify the treatment of chordoma.

Prevalence of common aneuploidy in twin pregnancies.

The incidence of chromosomal abnormalities in twin pregnancies is not well-studied. In this retrospective study, we investigated the frequency of chromosomal abnormalities in twin pregnancies and compared the incidence of chromosomal abnormalities in dichorionic diamniotic (DD) and monochorionic diamniotic (MD) twins. We used data from 57 clinical facilities across Japan. Twin pregnancies of more than 12 weeks of gestation managed between January 2016 and December 2018 were included in the study. A total of 2899 and 1908 cases of DD and MD twins, respectively, were reported, and the incidence of chromosomal abnormalities in one or both fetuses was 0.9% (25/2899) and 0.2% (4/1908) in each group (p = 0.004). In this study, the most common chromosomal abnormality was trisomy 21 (51.7% [15/29]), followed by trisomy 18 (13.8% [4/29]) and trisomy 13 (6.9% [2/29]). The incidence of trisomy 21 in MD twins was lower than that in DD twins (0.05% vs. 0.5%, p = 0.007). Trisomy 21 was less common in MD twins, even when compared with the expected incidence in singletons (0.05% vs. 0.3%, RR 0.15 [95% CI 0.04-0.68]). The risk of chromosomal abnormality decreases in twin pregnancies, especially in MD twins.

Evaluation of the clinical performance of noninvasive prenatal testing at a Japanese laboratory.

AIM: We aimed to evaluate the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of noninvasive prenatal testing (NIPT) in high-risk pregnant women. METHODS: Pregnant women who underwent GeneTech NIPT, the most commonly used NIPT in Japan, between January 2015 and March 2019, at Japan NIPT Consortium medical sites were recruited for this study. The exclusion criteria were as follows: pregnant women with missing survey items, multiple pregnancy/vanishing twins, chromosomal abnormalities in the fetus other than the NIPT target disease, and nonreportable NIPT results. Sensitivity and specificity were calculated from the obtained data, and maternal age-specific PPV and NPV were estimated. RESULTS: Of the 45 504 cases, 44 263 cases fulfilling the study criteria were included. The mean maternal age and gestational weeks at the time of procedure were 38.5 years and 13.1 weeks, respectively. Sensitivities were 99.78% (95% confidence interval [95% CI]: 98.78-99.96), 99.12% (95% CI: 96.83-99.76), and 100% (95% CI: 88.30-100) for trisomies 21, 18, and 13, respectively. Specificities were more than 99.9% for trisomies 21, 18, and 13, respectively. Maternal age-specific PPVs were more than 93%, 77%, and 43% at the age of 35 years for trisomies 21, 18, and 13, respectively. CONCLUSION: The GeneTech NIPT data showed high sensitivity and specificity in the detection of fetal trisomies 21, 18, and 13 in high-risk pregnant women, and maternal age-specific PPVs were obtained. These results could provide more accurate and improved information regarding NIPT for genetic counseling in Japan.

Oncogenic transformation of human ovarian surface epithelial cells with defined cellular oncogenes.

Ovarian surface epithelium (OSE) is considered to give rise to epithelial ovarian carcinomas (EOCs). To elucidate early processes contributing to the development of EOCs from the OSE, two batches of primary human OSE cells were transduced with non-viral human genes (mutant Cdk4, cyclinD1 and hTERT) so as to efficiently establish normal diploid OSE cells without chromosomal instability. Then defined genetic alterations frequently observed in EOCs were transduced into the OSE cells. A combination of p53 inactivation and oncogenic Kras transduction did not confer tumor-forming ability in immunodeficient mice, though additional transduction of Akt or combined transduction of c-myc with bcl-2 did result in tumor formation. In the latter case, tumors demonstrated phenotypes reminiscent of human EOCs, including cytokeratin expression, a highly aggressive phenotype, metastatic behavior and formation of ascites. These results indicate that inactivation of p53 and activation of the Ras pathway play critical roles in ovarian carcinogenesis in co-operation with the Akt or c-myc pathways. This first in vitro model system faithfully recapitulating the development of EOCs using normal human OSE cells should greatly facilitate further studies of EOCs.

Interaction of SmpB with ribosome from directed hydroxyl radical probing.

To add a tag-peptide for degradation to the nascent polypeptide in a stalled ribosome, an unusual translation called trans-translation is facilitated by transfer-messenger RNA (tmRNA) having an upper half of the tRNA structure and the sequence encoding the tag-peptide except the first alanine. During this event, tmRNA enters the vacant A-site of the stalled ribosome without a codon-anticodon interaction, but with a protein factor SmpB. Here, we studied the sites and modes of binding of SmpB to the ribosome by directed hydroxyl radical probing from Fe(II) tethered to SmpB variants. It revealed two SmpB-binding sites, A-site and P-site, on the ribosome. Each SmpB can be superimposed on the lower half of tRNA behaving in translation. The sites of cleavages from Fe(II) tethered to the C-terminal residues of A-site SmpB are aligned along the mRNA path towards the downstream tunnel, while those of P-site SmpB are found almost exclusively around the region of the codon-anticodon interaction in the P-site. We propose a new model of trans-translation in that the C-terminal tail of SmpB initially recognizes the decoding region and the mRNA path free of mRNA by mimicking mRNA.