Systemic platelet inhibition with localized chemotherapy by an injectable ROS-scavenging gel against postsurgical breast cancer recurrence and metastasis.

Early solid tumors benefit from surgical resection, but residual stubborn microtumors, pro-inflammatory microenvironment and activated platelets at the postoperative wound site are prone to recurrence and metastasis, resulting in poor prognosis. Here, we developed a dual-pronged strategy consisting of (i) in-situ forming ROS-scavenging gels loaded with anticancer drugs at the postoperative wound site to improve the tumor microenvironment and inhibit the recurrence of residual microtumors after orthotopic surgery, and (ii) systemic administration of clopidegrol via albumin nanoparticles for inhibiting activated platelets in the circulation thus inhibiting tumor remote migration. In a mouse model of postoperative recurrence and metastasis of orthotopic 4T1 breast cancer, the dual-pronged strategy greatly inhibited postoperative orthotopic tumor recurrence and reduced lung metastasis. This work provides an effective strategy for the postoperative intervention and treatment of solid tumors to inhibit postoperative tumor recurrence and metastasis, which has the potential to improve the prognosis and survival of patients with postoperative solid tumors. STATEMENT OF SIGNIFICANCE: Early-stage solid tumors benefit from surgical resection. However, the presence of residual microtumors, pro-inflammatory tumor microenvironment, and activated platelets at the postoperative wound site lead to recurrence and metastasis, ultimately resulting in poor prognosis. Here, we have devised a dual-pronged approach that includes (i) in-situ forming ROS-scavenging gels loaded with anticancer drugs (TM@Gel) at the wound site after surgery to enhance the tumor microenvironment (TME) and hinder the reappearance of residual microtumors, and (ii) systemic administration of clopidegrol through albumin nanoparticles (HHP) for inhibiting activated platelets in the circulation thus impeding tumor distant migration. This work provides a viable option for postoperative intervention and treatment of solid tumors to suppress postoperative tumor recurrence and metastasis.

Adjuvant chemoradiotherapy vs chemotherapy for resectable biliary tract cancer: a propensity score matching analysis based on the SEER database.

BACKGROUND: Although the role of adjuvant chemotherapy (CT) for resectable biliary tract cancer (BTC) is gradually recognized, the benefit of adjuvant chemoradiotherapy (CRT) is still controversial. Our study is designed to compare the prognosis of CRT versus CT in BCT patients. METHODS: Clinicopathologic characteristics of patients with operable gallbladder cancer (GBCA), intrahepatic bile duct cancer (IHBDC), or extrahepatic bile duct cancer (EHBDC) were obtained from the Surveillance, Epidemiology and End Results (SEER) database (2004-2015). Univariate and multivariate analyses were performed to identify prognostic factors for overall survival (OS). Selection bias were reduced by propensity-score matching (PSM). Kaplan-Meier analysis was used to estimate the survival time. RESULTS: Within 922 patients, 53.9% received adjuvant CRT, and 46.1% received adjuvant CT. Multivariate analysis showed age, primary tumor site, T stage, N stage, tumor size, number of removed lymph nodes, and treatment were independent risk factors for OS. Similar improvement of CRT on survival was identified by PSM in the matched cohort compared with CT (28.0 months vs. 25.0 months, p = 0.033), particularly in GBCA cohort (25.0 months vs. 19.0 months, p = 0.003). Subgroup analysis indicated CRT improved outcomes of patients with age ≥ 60, female, lymph nodes positive, tumor size ≥ 5 cm, and none removed lymph node diseases. CONCLUSION: Adjuvant CRT correlated with improved survival in patients with resected BTC compared with adjuvant CT, particularly in GBCAs. In addition, patients with age ≥ 60, female, lymph nodes positive, tumor size ≥ 5 cm, and none removed lymph node diseases may receive more benefits from adjuvant CRT.

The effect of parental carrier of de novo mutated vs. inherited balanced reciprocal translocation on the chance of euploid embryos.

OBJECTIVE: To evaluate whether the effect of de novo mutated balanced reciprocal translocation on the rate of euploid embryos varied from inherited balanced reciprocal translocation. DESIGN: A retrospective cohort study compared the percentage of euploid embryo and proportion of patients with at least 1 euploid embryo between de novo mutated balanced reciprocal translocation (i.e., the group of de novo mutated carriers) and inherited balanced reciprocal translocation (i.e., the group of inherited carriers). SETTING: An academic fertility center. PATIENT(S): A total of 413 couples with balanced reciprocal translocation (219 female carriers and 194 male carriers) who underwent their first cycle of preimplantation genetic testing for structural rearrangements were included. INTERVENTION(S): Carriers of balanced reciprocal translocation either de novo mutated or inherited. MAIN OUTCOME MEASURE(S): The percentage of euploid embryo and proportion of patients with at least 1 euploid embryo. RESULT(S): The carriers of the de novo mutated balanced reciprocal translocation had a lower percentage of euploid embryos (19.5% vs. 25.5%), and were less likely to have at least 1 euploid embryo (47.1% vs. 60.1%) compared with the carriers of the inherited balanced reciprocal translocation. In the male-carrier subgroup, the percentage of euploid embryos (16.7% vs. 26.7%) and proportion of patients with at least 1 euploid embryo (41.9% vs. 67.5%) were lower among the de novo mutated carriers than those among the inherited carriers. However, in the female-carrier subgroup, there was no statistically significant difference in the percentage of euploid embryos (22.4% vs. 24.4%) or the proportion of patients with at least 1 euploid embryo (52.3% vs. 53.7%) between the de novo mutated carriers and inherited carriers. CONCLUSION(S): The de novo mutated balanced reciprocal translocation was associated with a lower percentage of euploid embryos and lower chance of obtaining at least 1 euploid embryo than the inherited balanced reciprocal translocation.

Finite element analysis of conductive hearing loss caused by fixation and detachment of ligament and tendon in the middle ear.

BACKGROUND AND OBJECTIVE: The fixation of ligament and tendon of the middle ear often occurs after chronic otitis media surgery. However, there are relatively few studies on the effect of ligament and tendon on sound transmission in the human middle ear. Here, the finite element model and lumped parameter model are used to study the effect of ligament and tendon fixation and detachment on sound transmission in human ear. METHODS: In this paper, the finite element model including the external auditory canal, middle ear and simplified inner ear is used to calculate and compare the middle ear frequency response of the normal and tympanosclerosis under pure tone stimulation. In addition, the lumped parametric model is taken into account to illustrate the effect of ligament and tendon stiffness on the human ear transmission system. RESULTS: The results indicate that the motion of the tympanic membrane and stapes is reduced by ligament and tendon fixation. Although ligament and tendon detachment have a limited effect in the piston-motion direction, the stability of motion in the plane perpendicular to the piston-motion direction is significantly reduced. Most significantly, the ligament and tendon fixation cause a hearing effect of about 18 dB, which is greater in the plane perpendicular to the piston-motion direction after ligament and tendon detachment than in the piston-motion direction. CONCLUSIONS: In this study, the calculation accuracy of the lumped parameter and the finite element model is studied, and the effect of ligament and tendon on hearing loss is further explored through the finite element model with high calculation accuracy, which is helpful to understand the role of ligament and tendon in the sound transmission mechanism of the human middle ear. The study of ligament and tendon on conductive hearing loss provides a reference for clinical treatment of tympanosclerosis.

Enhanced 1,3-propanediol production with high yield from glycerol through a novel Klebsiella-Shewanella co-culture.

BACKGROUND: 1,3-Propanediol (1,3-PDO) is a platform compound, which has been widely used in food, pharmaceutical and cosmetic industries. Compared with chemical methods, the biological synthesis of 1,3-PDO has shown promising applications owing to its mild conditions and environmental friendliness. However, the biological synthesis of 1,3-PDO still has the problem of low titer and yield due to the shortage of reducing powers. RESULTS: In this study, Klebsiella sp. strain YT7 was successfully isolated, which can synthesize 11.30 g/L of 1,3-PDO from glycerol in flasks. The intracellular redox regulation strategy based on the addition of electron mediators can increase the 1,3-PDO titer to 28.01 g/L. Furthermore, a co-culturing system consisting of strain YT7 and Shewanella oneidensis MR-1 was established, which can eliminate the supplementation of exogenous electron mediators and reduce the by-products accumulation. The 1,3-PDO yield reached 0.44 g/g and the final titer reached 62.90 g/L. The increased titer and yield were attributed to the increased redox levels and the consumption of by-products. CONCLUSIONS: A two-bacterium co-culture system with Klebsiella sp. strain YT7 and S. oneidensis strain MR-1 was established, which realized the substitution of exogenous electron mediators and the reduction of by-product accumulation. Results provided theoretical basis for the high titer of 1,3-PDO production with low by-product concentration.

Integrative Clinical and Genomic Characterization of MTAP-deficient Metastatic Urothelial Cancer.

Deficiency of MTAP (MTAPdef) mainly occurs because of homozygous loss of chromosome 9p21, which is the most common copy-number loss in metastatic urothelial cancer (mUC). We characterized the clinical and genomic features of MTAPdef mUC in 193 patients treated at MD Anderson Cancer Center (MDACC) and 298 patients from the phase 2 IMvigor210 trial, which investigated atezolizumab in cisplatin-ineligible and platinum-refractory disease. In the MDACC cohort, visceral metastases were significantly more common for MTAPdef (n = 48) than for MTAP-proficient (MTAPprof; n = 145) patients (75% vs 55.2%; p = 0.02). MTAPdef was associated with poor prognosis (median overall survival [mOS] 12.3 vs 20.2 mo; p = 0.007) with an adjusted hazard ratio of 1.93 (95% confidence interval 1.35-2.98). Similarly, IMvigor210 patients with MTAPlo (n = 29) had a higher incidence of visceral metastases than those with MTAPhi tumors (n = 269; 86.2% vs 72.5%; p = 0.021) and worse prognosis (mOS 8.0 vs 11.3 mo; p = 0.042). Hyperplasia-associated genes were more frequently mutated in MTAPdef tumors (FGFR3: 31% vs 8%; PI3KCA: 31% vs 19%), while alterations in dysplasia-associated genes were less common in MTAPdef tumors (TP53: 41% vs 67%; RB1: 0% vs 16%). Our findings support a distinct biology in MTAPdef mUC that is associated with early visceral disease and worse prognosis. PATIENT SUMMARY: We investigated the outcomes for patients with the most common gene loss (MTAP gene) in metastatic cancer of the urinary tract. We found that this loss correlates with worse prognosis and a higher risk of metastasis in internal organs. There seems to be distinct tumor biology for urinary tract cancer with MTAP gene loss and this could be a potential target for treatment.

A novel and sensitive DNA methylation marker for the urine-based liquid biopsies to detect bladder cancer.

BACKGROUND: Better prognostic outcome is closely correlated with early detection of bladder cancer. Current non-invasive urianalysis relies on simultaneously testing multiple methylation markers to achieve relatively high accuracy. Therefore, we have developed an easy-to-use, convenient, and accurate single-target urine-based DNA methylation test for the malignancy. METHODS: By analyzing TCGA data, 344 candidate markers with 424 primer pairs and probe sets synthesized were systematically screened in cancer cell lines, paired tissue specimens, and urine sediments from bladder cancer patients and normal controls. The identified marker was further validated in large case-control cohorts. Wilcoxon rank sum tests and c2 tests were performed to compare methylation levels between case-control groups and correlate methylation levels with demographic and clinical characteristics. In addition, MSP, qMSP, RT-PCR, western blot analysis, and immunohistochemistry were performed to measure levels of DNA methylation, mRNA transcription, and protein expression in cancer cell lines and tissues. RESULTS: A top-performing DMRTA2 marker identified was tested in both discovery and validation sets, showing similar sensitivity and specificity for bladder cancer detection. Overall sensitivity in the aggregate set was 82.9%(179/216). The specificity, from a control group consisting of patients with lithangiuria, prostatoplasia, and prostatitis, is 92.5%(468/506). Notably, the methylation assay had the highest sensitivities for tumors at stages of T1(90.4%) and T2(95.0%) compared with Ta (63.0%), T3(81.8%), and T4(81.8%). Furthermore, the test showed admirable detection rate of 80.0%(24/30) for recurring cancers. While methylation was observed in 39/54(72.2%) urine samples from patients with carcinomas of renal pelvis and ureter, it was detected at extremely low rate of 6.0%(8/133) in kidney and prostate cancers. Compared with SV-HUC-1, the normal bladder epithelial cell line, DMRTA2 was hypermethylated in 8/9 bladder cancer cell lines, consistent with the results of MSP and qMSP, but not correlated with mRNA and protein expression levels in these cell lines. Similarly, DMRTA2 immunostaining was moderate in some tissues but weak in others. Further studies are needed to address functional implications of DMRTA2 hypermethylation. CONCLUSIONS: Our data demonstrated that a single-target DNA methylation signature, mDMRTA2, could be highly effective to detect both primary and recurring bladder cancer via urine samples.

Analysis of Aneuploidy Rate and Pregnancy Outcomes in Unexplained Recurrent Pregnancy Loss Couples With Chromosome Polymorphism After PGT-A.

Purpose: The study aims to investigate whether chromosomal polymorphism affects embryo development and pregnancy outcomes of unexplained recurrent pregnancy loss (uRPL) couples undergoing PGT-A. Methods: A total of 585 couples with uRPL history who performed PGT-A were included in the retrospective study from January 2016 to December 2020. We included 415 couples with normal karyotype and 170 couples with chromosomal polymorphism. Furthermore, the polymorphism group was divided into two subgroups: 113 couples in the male group and 57 couples in the female group. The embryo development and pregnancy outcomes were analyzed in different groups. Results: The blastocyst rate and aneuploidy rate are statistically different in the normal group, male polymorphism group, and female polymorphism group. Compared with normal and female groups, the male group has a lower blastocyst rate, which is statistically different (48.3 vs. 53.9%, p = 0.003; 48.3 vs. 54.1%, p = 0.043). Moreover, the aneuploidy rate of the male polymorphism group is significantly higher than female carriers (29.5 vs. 18.6%, p = 0.003). However, there were no statistically significant differences in clinical pregnancy rate, early miscarriage rate, and live birth rate after PGT-A (p > 0.05). Conclusion: Male with chromosome polymorphism (CPM) have a lower blastocyst rate and a higher aneuploidy rate than female carriers in uRPL couples undergoing PGT-A. However, when a euploid blastocyst was first transferred, no difference in pregnancy outcomes was found between the male and female polymorphism carriers. It indicated that CPM may have an adverse effect on the embryos of male carriers with uRPL history, and the occurrence of uRPL may be decreased in male polymorphism carriers after PGT-A.

Non-Assisted Hatching Trophectoderm Biopsy Does Not Increase The Risks of Most Adverse Maternal and Neonatal Outcome and May Be More Practical for Busy Clinics: Evidence From China.

OBJECTIVE: This study was conducted in order to investigate whether non-assisted hatching trophectoderm (TE) biopsy increases the risks of adverse perinatal outcomes in livebirths following elective single cryopreserved-thawed blastocyst transfer. PATIENTS AND METHODS: A total of 5,412 cycles from 4,908 women who achieved singleton livebirths between 2013 and 2019 were included in this retrospective cohort study. All embryos in this study were fertilized by intracytoplasmic sperm injection (ICSI) and cryopreserved through vitrification. The main intervention is to open the zona pellucida (ZP) of day 5/6 blastocyst immediately for biopsy without pre-assisted hatching. The main outcome measures are the common maternal and neonatal outcomes, including hypertensive disorders of pregnancy (HDPs), gestational diabetes mellitus (GDM), abnormal placentation, abnormalities in umbilical cord and amniotic fluid, preterm birth, cesarean section, low birth weight, postpartum hemorrhage, and prolonged hospital stay (both mothers and infants). The generalized estimation equation (GEE) was used to control the effects of repeated measurements. The non-conditional logistic regression model was used to examine the associations between embryo biopsy status and each adverse perinatal event. Given that the selection bias and changes in learning curve might affect the results, we selected 1,086 similar (matching tolerance = 0.01) cycles from the ICSI group via propensity score matching (PSM) for second comparisons and adjustment (conditional logistic regression). RESULTS: After adjusting for confounders, we confirmed that the non-assisted hatching protocol did not increase the risks of most adverse maternal and neonatal outcomes. Despite this, there were increased risks of GDM (aOR: 1.522, 95% CI: 1.141-2.031) and umbilical cord abnormalities (aOR: 11.539, 95% CI: 1.199-111.067) in the biopsy group. In the second comparisons after PSM, GDM incidence in the biopsy group was still higher (7.26% vs. 5.16%, P = 0.042), yet all measurement outcomes were equally likely to occur in both groups after the second adjustment. CONCLUSIONS: The non-assisted hatching TE biopsy does not increase the risks of most adverse perinatal outcomes. However, there is a higher GDM incidence in the biopsy group, and this association warrants further study. Considering its safety and simplicity, the non-assisted hatching protocol has the potential to become the preferred option for TE biopsy, especially in busy clinics and IVF laboratories.

High PD-L1 level of advanced hepatic lymphoepithelioma-like carcinoma response favorably to lenvatinib plus toripalimab.

Lymphoepithelioma-like carcinoma (LELC) is an uncommon subtype of primary liver cancer with predominant lymphocyte infiltration and a relatively favorable outcome. However, no standard treatment for advanced hepatic LELC has been established. Here, we give a first report of a 60-year-old man with advanced hepatic LELC who had a high expression of PD-L1 in tumor cells and a high level of tumor-infiltrating leukocytes (TILs) in the tumor microenvironment (TME). After receiving six cycles of multiple receptor tyrosine kinase inhibitor (rTKI) with lenvatinib plus PD-1 inhibitor toripalimab treatment, the patient achieved persistent partial response (PR). Our report indicates that advanced hepatic LELC with high expression of PD-L1 may benefit from the combination of rTKI and PD-L1/PD-1 blockade. Therefore, this potential strategy should be considered when treating those rare liver cancers.

The Role of Neoantigens in Cancer Immunotherapy.

Somatic mutation-derived neoantigens, expressed only on tumor cells, may elicit antitumor T-cell responses in cancer immunotherapies with minimal immune tolerance. Neoantigens can be identified by multiple bioinformatics technologies, mainly based on whole-exome sequencing. Personalized cancer vaccines and adoptive T cell therapies are two primary treatment modalities targeting neoantigens, and both of them have shown promising therapeutic effects. This review, summarizes the history of neoantigen-related tumor control, introduces recent neoantigen screening and identification methods, and discusses the role of neoantigen in cancer immunotherapies. Moreover, we propose the challenges of targeting neoantigens for cancer treatment.

Preimplantation genetic testing is not a preferred recommendation for patients with X chromosome abnormalities.

STUDY QUESTION: Should women with X chromosome abnormalities (XCAs) be recommended to have embryos selected by both morphological and cytogenetic assessment through preimplantation genetic testing (PGT) rather than morphological assessment only in conventional IVF/ICSI treatment? SUMMARY ANSWER: PGT is not a preferred recommendation for women with XCAs in the absence of other PGT indications. WHAT IS KNOWN ALREADY: XCAs are the most frequent sort of chromosomal aberrations in infertile women. Patients with a complete or partial absence of one X chromosome, diagnosed as Turner Syndrome (TS), demonstrate low spontaneous pregnancy rates (5-7%) and high miscarriage rates (22.8-30.8%), as well as high chances of birth defects (20%). PGT is known to improve pregnancy rates and decrease the incidence of miscarriage in couples with chromosomal aberrations such as Robertsonian and reciprocal translocations and Klinefelter Syndrome. STUDY DESIGN, SIZE, DURATION: A retrospective cohort study was conducted with 394 women with XCAs and undergoing their first oocyte retrieval and first embryo transfer cycle from June 2011 to August 2019 in the Reproductive Hospital Affiliated to Shandong University. PARTICIPANTS/MATERIALS, SETTING, METHODS: Pregnancy outcomes were compared between the conventional IVF/ICSI group (n = 284) and the PGT group (n = 110) in the first fresh or frozen embryo transfer cycle for each woman with XCAs. Three platforms were applied in PGT: fluorescence in situ hybridisation (FISH, n = 34), array comparative genomic hybridisation (aCGH, n = 24) and next-generation sequencing (NGS, n = 51). The embryo aneuploidy rate and distribution of embryonic chromosomal aberrations revealed by aCGH or NGS were analysed and stratified by maternal age and type of XCAs to assess the effect of maternal XCAs on embryo karyotypes. MAIN RESULT AND THE ROLE OF CHANCE: The live birth rate (LBR) per embryo transfer was similar between the PGT group and IVF/ICSI group both in the first cycle of fresh or frozen embryo transfer respectively (39.13% in PGTFISH vs 42.58% in IVF/ICSI, Padj=0.558; 66.67% in PGTFISH vs 52.08% in PGTaCGH/NGS vs 53.06% in IVF/ICSI, Padj=0.756), as was the clinical pregnancy rate (60.87% in PGTFISH vs 50.97% in IVF/ICSI, Padj =0.672; 88.89% in PGTFISH vs 58.33% in PGTaCGH/NGS vs 69.39% in IVF/ICSI, Padj =0.480) and the pregnancy loss rate (35.71% in PGTFISH vs 16.46% in IVF/ICSI, Padj =0.136; 12.50% in PGTFISH vs 10.71% in PGTaCGH/NGS vs 23.53% in IVF/ICSI, Padj =0.352). The rates of maternal and neonatal complications were also comparable between the PGT and IVF/ICSI groups with fresh and frozen transfers respectively (10.00% vs 8.85%, P = 1.000; 21.74% vs 14.55%, P = 0.272). Intriguingly, the distribution of embryonic chromosome abnormalities was more frequent on autosomes 22 (20.39%), 21 (18.45%) and 16 (17.47%), compared with the X chromosome (8.73%). LIMITATIONS, REASONS FOR CAUTION: Selection bias is an inherent drawback of a retrospective study. First, our participants hosted 4.84% X chromosome mosaicism with few typical somatic anomalies of TS. Second, the incidences of history of recurrent miscarriage and abnormal offspring in the PGT group were higher than in IVF/ICSI group although binary logistic regression analysis was performed to attenuate the modifying effect of confounding factors. Third, FISH performed in this study only used X/Y probes and lacked the reference of autosome, which might have resulted in misdiagnosis and bias. Finally, intrinsic disadvantages could not be totally avoided due to the retrospective nature of this study. WIDER IMPLICATION OF THE FINDINGS: In the current study, comparable pregnancy outcomes were revealed among a large cohort of women with XCAs undergoing their first cycles of PGT or conventional IVF/ICSI treatment. Moreover, the X chromosome abnormality was illustrated to cause no higher frequency of aberrations in embryos. Our data provided perspectives for genetic and reproductive counselling to XCAs individuals and their families. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by National Research and Development Plan (2016YFC1000604 and 2017YFC1001100), the National Natural Science Foundation of China (81701406), Shandong Science Fund for Distinguished Young Scholars (JQ201720), Taishan Scholars Program for Young Experts of Shandong Province (tsqn20161069) and Projects of Medical and Health Technology Development Program in Shandong Province (202005010520, 202005010523 and 2016WS0368). There is no conflict of interest to declare. TRIAL REGISTRATION NUMBER: N/A.

Effects of PGT-A on Pregnancy Outcomes for Young Women Having One Previous Miscarriage with Genetically Abnormal Products of Conception.

In this retrospective study, the effect of preimplantation genetic testing for aneuploidy (PGT-A) was evaluated in women younger than 38 years with a history of one prior miscarriage and embryonic chromosomal abnormalities were detected in previous products of conception (POCs). Abnormal karyotypes were detected in POCs at our center between January 2014 and December 2017. Of the women included in this analysis, 124 continued with conventional in vitro fertilization/intracytoplasmic sperm injection cycles (non-PGT-A group) and 93 chose PGT-A cycles (PGT-A group), and the pregnancy outcomes in both groups were compared. Although the clinical pregnancy rate per embryo transfer was significantly higher in the PGT-A group (67.23% vs. 51.85%, p-adj = 0.01), no between-group differences were found in the live birth rate or miscarriage rate (45.38% vs. 40.74%, p-adj = 0.59; 16.25% vs. 14.29%, p-adj = 0.15). Women in both groups had comparative cumulative live birth rates (PGT-A vs. non-PGT-A, 58.06% vs. 53.23%, p = 0.48). The main results of this study suggest that PGT-A is not associated with an increased likelihood of a live birth or a decreased rate of miscarriage among women younger than 38 years without recurrent pregnancy loss and with a history of POCs with embryonic chromosomal abnormalities.

Chemoradiotherapy Is Inferior to Chemotherapy Alone in Adjuvant Setting for Signet Ring Cell Containing Gastric Cancer.

BACKGROUND: Signet ring cell containing gastric cancer (SRCGC) is a rare subtype of gastric cancer, and its adjuvant therapy is based on general gastric cancer. However, the effectiveness of radiotherapy for those SRCGC patients remains unknown. PURPOSE: The purpose of the study was to analyze whether the addition of radiotherapy to adjuvant chemotherapy (CT) can benefit survival in resected SRCGC patients. METHODS: Patients with SRCGC, who underwent D2 gastrectomy followed by adjuvant chemotherapy or chemoradiotherapy (CRT), were retrospectively collected. According to the proportion of signet ring cells, patients were histologically classified as pure SRCGC (pSRCGC) containing 100% of signet ring cells, mixed SRCGC (mSRCGC) containing >50% of signet ring cells, and contaminated SRCGC (cSRCGC) containing <50% of signet ring cells. Among the 272 patients, 156 were treated by CT alone and 116 by CRT. The primary endpoint was 3-year overall survival rate (3-year OS rate). RESULTS: With a median follow-up of 80.5 months, the 3-year OS rate was significantly higher in the CT group (70.5% vs. 58.6%, HR = 0.633, P = 0.017) compared with CRT group. Three independent characteristics were predictive of a poor overall survival: CRT treatment (P = 0.019), tumor size ≥5 cm (P < 0.001), and the presence of vessel invasion (P = 0.009). Subgroup analyses showed CRT significantly impaired prognosis in SRCGC patients in the cSRCGC subset, as well as lesions located in lower-middle sites, subtotal gastrectomy, male, <60 year, and no vessel invasion. Peritoneal was the most common recurrence site in SRCGC patients. The adverse events leukopenia and neutropenia were more common in the CRT group (P = 0.007). CONCLUSIONS: Adjuvant chemoradiotherapy was associated with poor survival compared with adjuvant chemotherapy in SRCGC patients with D2 gastrectomy.

Predictive Risk Factors and Online Nomograms for Synchronous Colon Cancer With Liver Metastasis.

OBJECTIVES: To develop and validate predictive nomograms of cancer specific survival (CSS) and overall survival (OS) for synchronous colon cancer with liver metastasis (SCLM) patients. METHODS: Patients with pathologically diagnosed colon cancer with liver metastasis were retrieved from the SEER database between 2010 and 2015. Only SCLM patients were included. Univariate and multivariate cox regression analyses were conducted to identify the potential predictors of patients' survival outcomes. The selected variables were integrated to create predictive nomograms via R tools. Furthermore, the concordance index Harrell's C statistic (C-index) was calculated to describe the discrimination of nomograms. Calibration (1000 bootstrap resamples) curves were plotted to compare the predictions of nomograms with the observed outcomes. Decision curve analysis (DCA) and clinical impact curves were performed to evaluate the clinical effects of nomograms. RESULTS: A total of 22,378 SCLM patients were included. The median time of OS and CSS was 13 and 17 months, respectively. The 1-, 2-, and 3-year rate of OS was 50.6, 28.1, and 14.8%, respectively. While the 1-, 2-, and 3-year rate of CSS was 58.7, 36.8, and 22.5%, respectively. SCLM patients with increased age, left primary tumor location, AJCC IVb stage, and no chemotherapy were associated with an obviously reduced OS and CSS. Variables including age, histological grade, T/N/M stage, tumor size, bone/lung metastasis, CEA, surgery of primary site, and chemotherapy were closely related to the prognoses of SCLM patients. Nomograms of OS and CSS were built and displayed online for convenient utilization. The C-index of OS and CSS monograms were 0.74 and 0.73, respectively, indicating relatively good discrimination of the nomograms. The calibration curves suggested a good agreement between the actual observation and the nomogram prediction. DCAs and clinical impact curves reflected favorable potential clinical effects of predictive nomograms. CONCLUSION: Chemotherapy, surgery of primary site, and age were important independent risk factors for the CSS and OS of SCLM patients. We built and validated two reliable nomograms of OS and CSS to predict the prognoses of SCLM patients, which can be accessed online at (https://predictive-tool.shinyapps.io/CSS-DynNomapp/; https://predictive-tool.shinyapps.io/OS-DynNomapp/).

Clinical outcomes of Preimplantation genetic testing (PGT) application in couples with chromosomal inversion, a study in the Chinese Han population.

BACKGROUND: Chromosomal inversion was considered to have adverse effects on pregnancy outcomes through abnormal gametogenesis. The purpose of this retrospective study was to investigate whether preimplantation genetic testing (PGT) improves pregnancy outcomes for couples with chromosomal inversion. METHODS: A total of 188 cycles from 165 couples with one chromosomal inversion carrier were divided into two groups: PGT (136 cycles, 125 couples) and non-PGT (52 cycles, 50 couples). Biochemical pregnancy, clinical pregnancy, ongoing pregnancy, miscarriage and live birth rates of their first transfer cycles, as well as cumulative live birth rates of each cycle and euploidy rates, were analyzed. RESULTS: There were no statistically significant differences in the pregnancy outcomes between the two groups. The euploidy rate of pericentric inversion carriers was not higher than that of paracentric inversion carriers in PGT group (60.71% vs 50.54%, P = 0.073). Similarly, the euploid rate of male carriers was not higher than that of female carriers (61.2% vs 56.1%, P = 0.256). CONCLUSIONS: Due to limitation of retrospective study and small sample size, our current data showed that PGT cannot provide prominent benefits for inversion carriers in the Chinese Han population. Further prospective randomized controlled trials are needed to evaluate the effects of PGT.

Coexistence of the BRCA1 and KRAS mutations in a patient with salivary gland carcinoma arising in mediastinal mature teratoma.

Teratoma with malignant transformation is a rare type of malignant teratoma. In the present case, we describe a patient with salivary gland carcinoma (SGC) generating in mediastinal mature teratoma. Next-generation sequencing showed BRCA1 and KRAS somatic mutations, which might be associated with malignant transformation of the mediastinal mature teratomas. To our knowledge, the present case is the first report of coexistence of BRCA1 and KRAS mutations in mature cystic teratoma with malignant transformation to SGC. And the tumor showed a good response to chemotherapy with cisplatin and paclitaxel according to the transformed histology.

Application of improved single blastomere fixation technique in preimplantation genetic diagnosis.

To modify a fixation method improving the intensity and clarity of the single blastomeric signal detection by fluorescence in situ hybridization (FISH) in preimplantation genetic diagnosis. 333 cycles of assisted reproduction with preimplantation genetic diagnosis FISH (PGD-FISH) performed in our hospital were analyzed and a total of 3452 single blastomeres were obtained. For the conventional fixation method, the blastomeres were kept in 0.1% sodium citrate with 0.2 mg/ml bovine serum albumin (BSA) for 2-5 min. FISH was performed and the internal relationship between embryo quality and fixed rate, signal detection rate, and signal determination rate was explored. With the modified method, 91.54% of blastomeres were fixed, while 88.30% were fixed with the conventional method. The signal detection rate was significantly increased for the modified group than for the conventional group (compared 98.53% with 94.78%, P < 0.001). Especially, the signal determination rate also showed a significant difference between the two methods (compared 90.51% with 74.17%, P < 0.001). After the development of the fixation method, the fixation efficiency and the signal determination rate were greatly improved, providing more definite diagnosis for the patient. It will hopefully allow more assisted reproduction programs to offer their patients preimplantation genetic diagnosis with FISH.

Comprehensive analysis of the associations between previous pregnancy failures and blastocyst aneuploidy as well as pregnancy outcomes after PGT-A.

PURPOSE: To investigate the associations of previous pregnancy failures, including implantation failures (IFs), biochemical pregnancy losses (BPLs), and early (EMs) and late miscarriages (LMs), with blastocyst aneuploidy and pregnancy outcomes after PGT-A. METHODS: This study included 792 couples who underwent PGT-A after multiple pregnancy failures. Subgroup analyses were used to compare the blastocyst aneuploidy rate (BAR), implantation rate (IR), early miscarriage rate (EMR), and live birth rate (LBR). Multiple linear and logistic regression models were used to evaluate the associations. The control group comprised couples with ≤ 2 IFs, ≤ 1 BPL, ≤ 1 EM, and no LM. RESULTS: Notably, a history of ≥ 4 IFs was significantly associated with an increase in aneuploid blastocysts (42.86% vs. 33.05%, P = 0.044, B = 10.23 for 4 IFs; 48.80% vs. 33.05%, P = 0.002, B = 14.43 for ≥ 5 IFs). Women with ≥ 4 prior EMs also harbored more aneuploid blastocysts (41.00% vs. 33.05%, P = 0.048; B = 9.23). Compared with the control group, women with ≥ 4 prior EMs had a significantly higher EMR (6.58% vs. 31.11%, P < 0.001, OR = 6.49) and a lower LBR (53.49% vs. 34.18%, P = 0.007, OR = 0.56) after euploid transfer. Moreover, a history of LM(s) was associated with adverse pregnancy outcomes after PGT-A (OR for EM = 3.16; OR for live birth = 0.48). However, previous BPLs and 2 EMs were not associated significantly with blastocyst aneuploidy and pregnancy outcomes after PGT-A. CONCLUSION: A history of high-order IFs or EMs and existence of LM(s) were significantly associated with blastocyst aneuploidy and adverse pregnancy outcomes after PGT-A, whereas no such associations were observed with BPLs or 2 EMs.

Pregnancy outcomes of reciprocal translocation carriers with two or more unfavorable pregnancy histories: before and after preimplantation genetic testing.

PURPOSE: To report the normal live birth and birth defect rates pre- and post- preimplantation genetic testing for chromosomal structural rearrangements (PGT-SR) in reciprocal translocation carriers who have experienced two or more unfavorable pregnancy histories. METHODS: We conducted a retrospective cohort study of 194 couples who underwent 265 PGT-SR cycles between January 2013 and August 2016. The rates of miscarriage, normal live birth, and birth defect pre- and post- PGT-SR treatment were recorded. The types of birth defect were also categorized. RESULTS: Before PGT-SR treatment, the 194 couples with reciprocal translocation had a previous reproductive history consisting of 592 pregnancies in total: 496 (83.8%) were miscarriages; 29 (4.9%) ended by induced abortion due to unintended pregnancy; 36 (6.1%) had birth defects; and 17 (2.9%) were normal live births. After PGT-SR treatment, there were 118 clinical pregnancies. Of these pregnancies, 13 (11.0%) were miscarriages, 101 (85.6%) were normal live births, and 4 (3.4%) had birth defects. In total, 14 different disorders were noted in the prenatal and postnatal examinations. Before the PGT-SR treatment, multiple birth defects, central nervous system abnormalities, and congenital heart defects were the three most common congenital malformations. Excluding for methylmalonic acidemia, there were only single and mild birth defects after the PGT-SR treatment. CONCLUSIONS: After the PGT-SR treatment, the reciprocal translocation carriers who had previously experienced two or more unfavorable pregnancy outcomes had a low risk of miscarriages and birth defects. The rate of normal live births per pregnancy was higher after PGT-SR treatment.