Neratinib and Ado-Trastuzumab-Emtansine for Pre-treated and Untreated HER2-positive Breast Cancer Brain Metastases: Translational Breast Cancer Research Consortium Trial 022.

PURPOSE: Treatment options for HER2-positive breast cancer brain metastases (BCBM) remain limited. We previously reported central nervous system (CNS) activity for neratinib and neratinib-capecitabine. Preclinical data suggest that neratinib may overcome resistance to ado-trastuzumab-emtansine (T-DM1) when given in combination. In TBCRC 022's cohort 4, we examined the efficacy of neratinib plus T-DM1 in patients with HER2-positive BCBM. PATIENTS AND METHODS: In this multicenter, phase II study, patients with measurable HER2-positive BCBM received neratinib 160 mg daily plus T-DM1 3.6 mg/kg intravenously every 21 days in three parallel-enrolling cohorts (cohort 4A-previously untreated BCBM, cohorts 4B and 4C- BCBM progressing after local CNS-directed therapy without [4B] and with [4C] prior exposure to T-DM1). Cycle 1 diarrheal prophylaxis was required. The primary endpoint was the Response Assessment in Neuro-Oncology-Brain Metastases (RANO-BM) by cohort. Overall survival (OS) and toxicity were also assessed. RESULTS: Between 2018-2021, 6, 17, and 21 patients enrolled to cohorts 4A, 4B, and 4C. Enrollment was stopped prematurely for slow accrual. The CNS objective response rate in cohorts 4A, 4B, and 4C was 33.3% (95% confidence interval [CI]: 4.3-77.7%), 35.3% (95% CI: 14.2-61.7%), and 28.6% (95% CI: 11.3-52.2%), respectively; 38.1-50% experienced stable disease for ≥6 months or response. Diarrhea was the most common grade 3 toxicity (22.7%). Median OS was 30.2 months (cohort 4A; 95% CI: 21.9, not reached [NR]), 23.3 months (cohort 4B; 95% CI: 17.6, NR), and 20.9 months (cohort 4C; 95% CI: 14.9, NR). CONCLUSION: We observed Intracranial activity for neratinib plus T-DM1, including those with prior T-DM1 exposure, suggesting synergistic effects with neratinib. Our data provide additional evidence for neratinib-based combinations in patients with HER2-positive BCBM, even those who are heavily pre-treated.

Multiparametric MRI-based radiomics nomogram for predicting malignant transformation of sinonasal inverted papilloma.

AIM: To investigate the feasibility of a radiomics nomogram model for predicting malignant transformation in sinonasal inverted papilloma (IP) based on radiomic signature and clinical risk factors. MATERIALS AND METHODS: This single institutional retrospective review included a total of 143 patients with IP and 75 patients with IP with malignant transformation to squamous cell carcinoma (IP-SCC). All patients underwent surgical pathology and had preoperative magnetic resonance imaging (MRI) and computed tomography (CT) sinus studies between June 2014 and February 2022. Radiomics features were extracted from contrast-enhanced T1-weighted images (CE-T1WI), T2-weighted images (T2WI), and apparent diffusion coefficient (ADC) maps. The least absolute shrinkage and selection operator (LASSO) were performed to select the features extracted from the sequences mentioned above. Independent clinical risk factors were identified by multivariate logistic regression analysis. Radiomics nomogram was constructed by incorporating independent clinical risk factors and radiomics signature. Based on discrimination and calibration, the diagnostic performance of the nomogram was evaluated. RESULTS: Twelve radiomics features were selected to develop the radiomics model with an area under the curve (AUC) of 0.987 and 0.989, respectively. Epistaxis (p=0.011), T2 equal signal (p=0.003), extranasal invasion (p<0.001), and loss of convoluted cerebriform pattern (p=0.002) were identified as independent clinical predictors. The radiomics nomogram model showed excellent calibration and discrimination (AUC: 0.993, 95% confidence interval [CI]: 0.985-1.00 and 0.990, 95% CI: 0.974-1.00) in the training and validation sets, respectively. CONCLUSION: The nomogram that the combined radiomics signature and clinical risk factors showed a satisfactory ability to predict IP-SCC.

[Progress in the treatment of sarcopenia in patients with cirrhosis].

Sarcopenia, a common complication of cirrhosis, has an incidence rate as high as 40% ~ 70%. Furthermore, adverse events such as shortened survival, lower quality of life, prolonged hospital stay, increased complications, a higher mortality rate, and sometimes altering the liver transplantation prognostic outcome in patients with liver cirrhosis are closely related. In recent years, some progress has been made in the research on the treatment of sarcopenia, but there is no clear treatment plan at present; thus, research and development by researchers and clinicians still need to be strengthened. This article briefly describes the relevant treatment methods for sarcopenia in patients with cirrhosis.

[Development of an asthenopia survey questionnaire for general surveys].

Objective: To design a visual fatigue questionnaire that can be used for population surveys. Methods: This was a cross-sectional study that involved three stages of subjects' recruitment. In the first stage, by convenience sampling, 150 individuals who complained of visual fatigue were selected at public places in Wenzhou City in May 2016. The 19-Item Asthenopia Survey Questionnaire (ASQ-19) was used to conduct the survey, and the questionnaire was adjusted. In the second stage, 200 outpatient participants were recruited from Wenzhou Medical University Affiliated Eye and Optometry Hospital from June 2016 to May 2017 and were divided into a visual fatigue group and a control group based on clinical diagnosis. The adjusted visual fatigue questionnaire was used for validation. In the third stage, 64 outpatient participants who met the inclusion criteria were continuously recruited from the Wenzhou Medical University Affiliated Eye and Optometry Hospital in July 2022. They were tested using the adjusted visual fatigue questionnaire and retested one week later. During the questionnaire adjustment stage, factor analysis and feedback were used to adjust the scoring method and items of the ASQ-19 questionnaire. The adjusted questionnaire was then analyzed for reliability, validity, accuracy, and subject acceptance during the validation and retest stages. Results: A total of 403 participants were included, and 456 questionnaires were distributed. Eventually, 432 valid questionnaires were collected from 379 participants, resulting in a valid response rate of 94.7%. During the questionnaire adjustment phase, there were 140 valid questionnaires from 140 participants consisting of 56 males and 84 females with an average age of (35.2±12.4) years. In the questionnaire validation phase, there were 186 valid questionnaires from 186 participants. Sixty-two participants had visual fatigue and 124 were controls. During the questionnaire retesting phase, 53 participants yielded 106 valid questionnaires. The group consisted of 20 males and 33 females with an average age of (22.8±4.9) years. After factor analysis, the symptom severity graded as none, mild, moderate, severe, and very severe was scored as 0, 1, 2, 3, and 4 points, respectively. The total score was 44, and the final questionnaire consisted of 11 items (numbered 1, 2, 3, 5, 6, 8, 10, 15, 17, 18, and 19). The 11-Item Asthenopia Survey Questionnaire (ASQ-11) had a Cronbach's α coefficient of 0.89, a split-half reliability of 0.82, and a test-retest Pearson correlation coefficient of 0.90 (P<0.001). The structural validity was 51.26%, and the discriminative validity was a t-value of 9.19 (P<0.001). On average, it took (2.82±0.43) minutes for participants to complete the questionnaire. The receiver operating characteristic curve had a cutoff value of 8.5, with a sensitivity of 74.19% and a specificity of 80.65%. Conclusion: The ASQ-11, with fewer items and a shorter completion time, is easy for participants to use and is suitable for screening or self-assessment of visual fatigue in the general population. Additionally, it is convenient for clinical and epidemiological studies related to visual fatigue.

Differentiation of malignant from benign orbital tumours using dual-energy CT.

AIM: To investigate the diagnostic accuracy of dual-energy computed tomography (DECT)-derived iodine concentration (IC), effective atomic number (Zeff), and spectral attenuation information for differentiating malignant and benign orbital tumours. MATERIALS AND METHODS: Data from 41 patients with orbital tumours from November 2019 to March 2021 were analysed retrospectively. Each patient underwent contrast-enhanced DECT using a 128-section dual-source computed tomography (DSCT) system. Dual-energy information, including IC, normalised iodine concentration (NIC), Zeff, virtual monoenergetic images (VMIs) reconstructed from 40 to 120 keV and slope (k) value were determined. Quantitative measurement of DECT parameters was undertaken by two independent radiologists blinded to clinical data. Differences in parameters were assessed using independent sample t-test. Diagnosis performance was calculated by the receiver operating characteristic (ROC) curve analysis. Radiation doses of conventional CT and DECT were compared by paired t-tests. RESULTS: Forty-one patients with histopathologically confirmed tumours were enrolled, including 10 malignant cases and 21 benign cases. Malignant orbital tumours exhibited significantly greater IC, NIC, Zeff, CT attenuation of VMIs at 40-105 keV, and k values compared to benign orbital tumours (p<0.05). In ROC analyses, 40 keV VMI demonstrated the highest diagnostic performance of single parameters (area under the ROC curve [AUC], 0.940), and combined parameters achieved the best performance (AUC, 0.971; sensitivity, 90%; specificity, 93.55%). Radiation doses were significantly reduced in DECT than conventional CT (p<0.001). CONCLUSIONS: Quantitative DECT analysis can be a useful technique, which yields excellent diagnostic accuracy, in the differentiation of malignant and benign orbital tumours with low radiation dose.

Muscle insulin-like growth factor-I modulates murine craniofacial bone growth.

Insulin-like growth factor I (IGF-I) is essential for muscle and bone development and a primary mediator of growth hormone (GH) actions. While studies have elucidated the importance of IGF-I specifically in muscle or bone development, few studies to date have evaluated the relationship between muscle and bone modulated by IGF-I in vivo, during post-natal growth. Mice with muscle-specific IGF-I overexpression (mIgf1+/+) were utilised to determine IGF-I- and muscle-mass-dependent effects on craniofacial skeleton development during post-natal growth. mIgf1+/+ mice displayed accelerated craniofacial bone growth when compared to wild-type animals. Virus-mediated expression of IGF-I targeting the masseter was performed to determine if post-natal modulation of IGF-I altered mandibular structures. Increased IGF-I in the masseter affected the mandibular base plane angle in a lateral manner, increasing the width of the mandible. At the cellular level, increased muscle IGF-I also accelerated cartilage thickness in the mandibular condyle. Importantly, mandibular length changes associated with increased IGF-I were not present in mice with genetic inhibition of muscle IGF-I receptor activity. These results demonstrated that muscle IGF-I could indirectly affect craniofacial growth through IGF-I-dependent increases in muscle hypertrophy. These findings have clinical implications when considering IGF-I as a therapeutic strategy for craniofacial disorders.

Sinonasal synovial sarcoma: evaluation of the role of radiological and clinicopathological features in diagnosis.

AIM: To explore the value of radiological and clinicopathological features in the diagnosis of sinonasal synovial sarcomas (SS). MATERIALS AND METHODS: Six patients with sinonasal SS were studied retrospectively using computed tomography (CT; n=6) and magnetic resonance imaging (MRI; n=4). The radiological and clinicopathological findings in this series were reviewed. RESULTS: Three lesions were located, in both the nasal cavity, and the paranasal sinuses; one was located in the nasal cavity and nasopharynx, and the remaining two were located restrictively within the nasal cavity. An aggressive nature (invasion of adjacent structure) was found in four cases. At CT, lesions were found with isodensity with calcification mainly in the peripheral areas. Bony changes were visible in all cases. Five cases showed marked heterogeneous enhancement, and three cases contained necrotic or cystic areas. At MRI, haemorrhage was observed in three cases. All cases demonstrated the "triple sign", and two high-grade SS showed a "cobblestone-like" appearance on T2-weighted imaging (WI). All time-signal intensity curves (TICs) were of the washout type. The mean apparent diffusion coefficient (ADC) values of the two high-grade cases were lower than those of the low-grade or intermediate-grade cases. Histopathologically, all but one was of the monophasic type. During the 8-40 month period of follow-up, recurrence occurred in four cases. CONCLUSIONS: A sinonasal tumour exhibiting characteristic calcification and bony change, together with haemorrhage, "triple sign" or "cobblestone-like" appearance, should engender a diagnosis of SS.

[Clinical application and analysis of single-port laparoscopic and thoracoscopic McKeown esophagectomy for esophageal cancer].

Objective: To explore the application value of single-port laparoscopic and thoracoscopic McKeown esophagectomy for esophageal cancer. Methods: A retrospective study was conducted to collect clinical data of 34 patients with esophageal cancer who were admitted to the Department of Thoracic Surgery, the First Affiliated Hospital of Fujian Medical University, from August to November 2020. All of them, 24 males and 10 females aged from 43 to 75 with an average of (62±4) years, underwent single-port laparoscopic and thoracoscopic McKeown esophagectomy.In the thoracic part, esophageal separation and mediastinal lymph node dissection were performed with conventional 4-ports thoracoscopy in the left lateral-prone position. In the abdominal part, gastric separation and lymph node dissection were accomplished with single-port laparoscopic retrograde three-step gastric separation: firstly, the lesser omentum was dissociated, the left liver lobe was suspended with purse-string needle and thread, after that the left gastric blood vessel and lymph node was dissected; secondly, the esophageal hiatus was separated, and the gastric cardia was cut off; finally, the spleen and stomach ligaments were dissociated to complete these steps. The operation time,volume of intraoperative blood loss, time for out-of-bed activities, time of postoperative drainage tube removal,volume of thoracic drainage fluid, short-term postoperative commplications,the postoperative pathological diagnoses, the time of their discharge from hospital and results of follow-up were observed. Results: All patients underwent successfully single-port laparoscopic and thoracoscopic esophagectomy without any conversion to open surgery; the operative time of the patients was 194-285 (240±21)min, including 53-105(60±13)min for the thoracic part and 40-73(49±7)min for the abdominal part. The volume of intraoperative blood loss was 15-110(60±20) ml. The numbers of mediastinal lymph node dissected and abdominal lymph nodes harvested were 10-25(13±3), 6-16(9±3)respectively. The 34 patients resumed out-of-bed activities on the 2nd to 3rd day after the operation. The thoracic closed drainage tube and left cervical drainage were removed 2 days after the operation. The thoracic Abel drainage tube was removed 5 days after the operation. The total volume of postoperative thoracic drainage fluid was 100-500(300±100)ml. No obvious sign of anastomotic leakage, anastomotic stenosis, chylothorax or gastric emptying disorder was found after the operation. Eight cases were complicated with temporal hoarseness, and 4 patients with pneumonia which was cured by antibiotics. The mean postoperative hospital stay was 8 days(6, 8), and patients were discharged after they could take a routine semi-liquid diet. The postoperative pathological diagnoses of all patients were squamous cell carcinoma, and the postoperative pathological stage was T1-3N0-1M0. Thirty-four patients were followed up for 60 (40, 75) days after the operation. During the follow-up period, no complication or death occurred. In addition, neither recurrence nor metastasis was observed. Conclusion: Single-port laparoscopic and thoracoscopic McKeown esophagectomy for esophageal carcinoma is safe and feasible, with good short-term efficacy. Therefore we consider it an alternative minimally invasive surgery for esophageal cancer.

[Analysis of genetic abnormalities and clinical outcome of fetus with ultrasonic nonstructural abnormality].

Objective: To analysis the incidence of abnormal genetics and the clinical outcome of fetuses with ultrasonic nonstructural abnormality. Methods: This study was conducted retrospectively. 631 pregnant women were enrolled in the Prenatal Diagnostic Center of Fujian Maternal and Child Health Hospital due to ultrasonic nonstructural abnormality from January 2016 to January 2019. According to different gestational weeks, amniotic fluid or umbilical cord blood samples were collected for chromosome karyotype analysis and SNP-array. According to the number of nostructural abnormalities, they were divided into 1 nostructural abnormality group, 2 nostructural abnormalities group, and ≥3 nostructural abnormalities group. Chi-square test was used for comparison between groups. Results: Of the 631 cases, 34 cases (5.4%, 34/631) had abnormal karyotypes, including 20 cases with abnormal chromosome number and 14 cases with abnormal chromosome structure. In results of SNP-array, there were 53 abnormal results (8.4%, 53/631), including 32 cases of pathogenic copy number variations (CNV) and 21 cases of variations of uncertain clinical significance (VOUS). The rates of pathogenic CNV were 4.57% (21/260), 4.76% (7/147) and 16.67% (4/24) in the group of 1, 2 and ≥3 nostructural abnormalities, respectively. The rate of the three groups showed a linear trend, and the difference was statistically significant (χ²=7.419,P<0.05). In the single nostructural abnormality group, the rate of pathogenic CNV of nasal bone dysplasia, fetal growth restriction (FGR) and thickened nuchal translucency (NT) were 8.11% (3/37), 7.04% (5/71) and 5.60% (7/125), respectively. Conclusions: Compared with the karyotype analysis, SNP-array can significantly improve the detection rate of genetic abnormalities in ultrasonic nonstructural abnormality. When multiple ultrasonic nonstructural abnormality were combined, the risk of genetic abnormalities showed an upward trend.

[A new valid and reliable questionnaire of asthenopia: development and evaluation].

Objective: To design a valid and reliable questionnaire to determine various causes of asthenopia for use by clinicians and researchers. Methods: The items to be included in the first version questionnaire were selected based on its definition and literature review. The second version was improved from patients interviews and the Delphi method. In this phase, 17 experts, 97 patients [47 males, 50 females, age (34.42±14.62) years old] with asthenopia and 20 controls [9 males, 11 females, age (33.50±7.31) years old] were involved to generated item list. In the Validation phase, we conducted two round interview through 275 asthenopia patients [97 males,186 females,age (34.42±14.62) years old] and 49 controls [17 males,32 females,age (35.79±8.88) years old]for item reduction and questionnaire validity and reliability assessment. Exploratory factor analysis was performed to reduce items and derive the subscale that each item belongs to. Internal consistency was calculated for all resulting subscales, using Cronbach's α coefficient, spilt-half reliability and repeatability. The repeatability of the questionnaire was measured by Pearson correlation analysis. Results: Our initial questionnaire contained 52 symptoms and 2 self-evaluation questions. After the item reduction and assessment, 19 items were selected and classified into three domains through factor analysis. Cronbach α for the three subscales of this version was between 0.79 and 0.85, while for the complete questionnaire it was 0.90, with a spilt-half reliability of 0.80. Factor analysis showed the three components had eigenvalues>3 and these explained 54.3% of the variance. Conclusions: The 19-item asthenopia questionnaire has acceptable psychometric properties, making it a valid and reliable tool for ophthalmologists and optometrists to evaluate asthenopia as well as to seek causes. It has the potential to be used in clinical trials and outcome research. (Chin J Ophthalmol, 2021, 57:284-291).

Prevalence and mutational determinants of high tumor mutation burden in breast cancer.

BACKGROUND: High tumor mutation burden (TMB) can benefit immunotherapy for multiple tumor types, but the prevalence of hypermutated breast cancer is not well described. The aim of this study was to evaluate the frequency, mutational patterns, and genomic profile of hypermutated breast cancer. PATIENTS AND METHODS: We used de-identified data from individuals with primary or metastatic breast cancer from six different publicly available genomic studies. The prevalence of hypermutated breast cancer was determined among 3969 patients' samples that underwent whole exome sequencing or gene panel sequencing. The samples were classified as having high TMB if they had ≥10 mutations per megabase (mut/Mb). An additional eight patients were identified from a Dana-Farber Cancer Institute cohort for inclusion in the hypermutated cohort. Among the patients with high TMB, the mutational patterns and genomic profiles were determined. A subset of patients was treated with regimens containing PD-1 inhibitors. RESULTS: The median TMB was 2.63 mut/Mb. The median TMB significantly varied according to the tumor subtype (HR-/HER2- >HER2+ >HR+/HER2-, P < 0.05) and sample type (metastatic > primary, P = 2.2 × 10-16). Hypermutated tumors were found in 198 patients (5%), with enrichment in metastatic versus primary tumors (8.4% versus 2.9%, P = 6.5 × 10-14). APOBEC activity (59.2%), followed by mismatch repair deficiency (MMRd; 36.4%), were the most common mutational processes among hypermutated tumors. Three patients with hypermutated breast cancer-including two with a dominant APOBEC activity signature and one with a dominant MMRd signature-treated with pembrolizumab-based therapies derived an objective and durable response to therapy. CONCLUSION: Hypermutation occurs in 5% of all breast cancers with enrichment in metastatic tumors. Different mutational signatures are present in this population with APOBEC activity being the most common dominant process. Preliminary data suggest that hypermutated breast cancers are more likely to benefit from PD-1 inhibitors.

Phase I dose-escalation trial of tucatinib in combination with trastuzumab in patients with HER2-positive breast cancer brain metastases.

BACKGROUND: Brain metastases are frequent in HER2-positive breast cancer. ONT-380 (tucatinib) is a potent selective inhibitor of HER2 with intracranial activity in preclinical models. PATIENTS AND METHODS: This was a phase I study of tucatinib with trastuzumab, without chemotherapy, in patients with progressive, measurable HER2-positive brain metastases. The study tested two schedules of tucatinib: cohort A was twice daily and cohort B was once daily. The primary objective was determination of the maximum tolerated dose (MTD). Secondary end points included objective response (intracranial and extracranial) using modified RECIST and clinical benefit rate (CBR). RESULTS: Overall, 41 patients were enrolled (cohort A, n = 22; cohort B, n = 19). Patients had a median of two prior treatments for metastatic breast cancer and 83% had progressed after prior brain radiation. The MTD of tucatinib for cohort A was 300 mg twice daily and for cohort B was 750 mg once daily. The most common dose-limiting toxicities included thrombocytopenia and aspartate transaminase/alanine aminotransferase elevation. Grade 3/4 aspartate transaminase/alanine aminotransferase elevation occurred in nine of 41 patients (22%). Intracranial responses were observed in two of 17 (12%) patients in cohort A and one of 17 (6%) patients in cohort B treated at the MTD. In cohort A, CBR at 16 weeks was 35% (n = 6). In cohort B, CBR at 16 weeks was 53% (n = 9). Of 15 patients overall who experienced clinical benefit, 12 (80%) had received prior neratinib and/or lapatinib. Median progression-free survival for cohorts A and B was 3.4 and 4.1 months, respectively. CONCLUSION: The combination of tucatinib and trastuzumab is tolerable and demonstrated preliminary evidence of efficacy in patients with HER2-positive brain metastases. CLINICAL TRIAL REGISTRATION: NCT01921335.

Reversion and non-reversion mechanisms of resistance to PARP inhibitor or platinum chemotherapy in BRCA1/2-mutant metastatic breast cancer.

BACKGROUND: Little is known about mechanisms of resistance to poly(adenosine diphosphate-ribose) polymerase inhibitors (PARPi) and platinum chemotherapy in patients with metastatic breast cancer and BRCA1/2 mutations. Further investigation of resistance in clinical cohorts may point to strategies to prevent or overcome treatment failure. PATIENTS AND METHODS: We obtained tumor biopsies from metastatic breast cancer patients with BRCA1/2 deficiency before and after acquired resistance to PARPi or platinum chemotherapy. Whole exome sequencing was carried out on each tumor, germline DNA, and circulating tumor DNA. Tumors underwent RNA sequencing, and immunohistochemical staining for RAD51 foci on tumor sections was carried out for functional assessment of intact homologous recombination (HR). RESULTS: Pre- and post-resistance tumor samples were sequenced from eight patients (four with BRCA1 and four with BRCA2 mutation; four treated with PARPi and four with platinum). Following disease progression on DNA-damaging therapy, four patients (50%) acquired at least one somatic reversion alteration likely to result in functional BRCA1/2 protein detected by tumor or circulating tumor DNA sequencing. Two patients with germline BRCA1 deficiency acquired genomic alterations anticipated to restore HR through increased DNA end resection: loss of TP53BP1 in one patient and amplification of MRE11A in another. RAD51 foci were acquired post-resistance in all patients with genomic reversion, consistent with reconstitution of HR. All patients whose tumors demonstrated RAD51 foci post-resistance were intrinsically resistant to subsequent lines of DNA-damaging therapy. CONCLUSIONS: Genomic reversion in BRCA1/2 was the most commonly observed mechanism of resistance, occurring in four of eight patients. Novel sequence alterations leading to increased DNA end resection were seen in two patients, and may be targetable for therapeutic benefit. The presence of RAD51 foci by immunohistochemistry was consistent with BRCA1/2 protein functional status from genomic data and predicted response to later DNA-damaging therapy, supporting RAD51 focus formation as a clinically useful biomarker.

Non-invasive cell-free fetal DNA testing for aneuploidy: multicenter study of 31 515 singleton pregnancies in southeastern China.

OBJECTIVE: To analyze the non-invasive prenatal testing (NIPT) for aneuploidy results of 31 515 singleton pregnancies in Fujian province, southeastern China, and assess its performance in low-, moderate- and high-risk pregnancies. METHODS: Women were categorized into groups according to whether their risk for fetal abnormality was low, moderate or high. Cell-free plasma DNA extracted from peripheral blood samples was subjected to low-coverage whole-genome sequencing. Standard Z-score analysis of the mapped sequencing reads was used to identify fetal aneuploidy, including the three main trisomies (T21, T18 and T13) and sex chromosome aneuploidy (SCA). NIPT-positive results were confirmed by amniocentesis and karyotyping. The performance of NIPT for detection of T21, T18, T13 and SCA was assessed by calculating the sensitivity and specificity. RESULTS: The rate of chromosomal abnormality detected by NIPT in the study population was 1.38%. A higher rate of chromosomal abnormality was found in the high-risk group (1.57%) compared to the moderate-risk (1.05%) and low-risk (1.18%) groups (P < 0.05). Sensitivity and specificity, respectively, were 98.96% (95/96) and 99.94% (31 274/31 292) for detection of T21, 100% (25/25) and 99.96% (31 352/31 363) for T18, 100% (7/7) and 99.97% (31 373/31 381) for T13 and 100% (61/61) and 99.74% (31 245/31 327) for SCA. Positive predictive values were high for T21 (84.07%) and T18 (69.44%) and moderate for T13 (46.67%) and SCA (42.66%). CONCLUSION: Our findings support the application of NIPT for reliable and accurate testing of the general population of reproductive-age women for clinically significant fetal aneuploidy. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

[Clinical featuers of adult patients with post-viral-encephalitis autoimmune encephalitis].

Objective: To explore the clinical features of post-viral-encephalitis autoimmune encephalitis (PVEAE). Methods: Ten cases of PVEAE, who were hospitalized in the Neurology Department of Peking Union Medical College Hospital (PUMCH) between November 2014 and October 2019, were retrospectively reviewed. Clinical manifestation, immunology, neuroradiology, treatment and outcomes were analyzed. Results: There were 5 males and 5 females, with a median age of 44 (18, 66) years. Of 9 cases, the median interval between the two onsets of encephalitis was 37 (24, 60) days, and there was no obvious interval in case 7. In viral encephalitis phase, the peak modified Rankin scale (mRS) was 4.5 (4.0, 5.0) and the remission mRS was 2.0 (1.0, 3.0). In autoimmune encephalitis (AE) phase, the peak mRS was 4.0 (3.0, 5.0). Symptoms of AE included mental and behavioral abnormalities (10/10), amnesia (10/10), motor disorders (5/10), autonomic dysfunction (5/10), speech disorders (4/10), seizures (2/10) and consciousness disturbance (2/10). On average, each case presented with 4 (2, 6) symptoms. In AE phase, the positive rate of anti-N-methyl-D-aspartate (anti-NMDA) receptor antibody in cerebrospinal fluid (CSF) was 80% (8/10), while in serum it was only 20% (2/10). Neuroimaging showed that in AE phase, the lesions expanded in 8 cases, remained unchanged in 1 case and shrank in 1 case. In AE phase, 10 cases received first line treatments, and 2 cases accepted long-course immunotherapy. After treatment, symptoms of 9 cases were obviously relieved. The mRS for short-term and long-term outcomes was 2.0 (1.0, 4.0) and 1.0 (0, 2.0), respectively. Conclusions: PVEAE might present with either typical biphasic course or monophasic/pseudo-monophasic course. In AE phase, anti-NMDA receptor antibody turned positive in most cases. Much importance should be attached to the recognition and diagnosis of PVEAE and treat it actively thereafter.

[Dihydromyricin alleviates doxorubicin-induced myocardial injury by inhibiting NLRP3 inflammasome in rats].

Objective: To investigate the protective effect of dihydromyricetin (DHM) on doxorubicin (DOX)-induced myocardial injury and its mechanism. Methods: Twenty-four healthy male SD rats were divided into 4 groups: control group, DOX group, DOX+DHM100 group and DOX+DHM200 group. Echocardiography was used to measure cardiac function. At the end of the 6th week, the rats were anesthetized and sacrificed, and the pathological changes of the cardiac tissues were observed by HE staining, Masson staining and WGA staining. Cardiomyocyte apoptosis was observed by TUNEL staining, and protein levels of NLRP3, caspase-1, IL-1ß, bax and bcl-2 were detected by Western blot and immunohistochemistry. Results: Compared with the control group, the left ventricular ejection fraction and left ventricular fractional shortening decreased significantly in DOX group, while left ventricular internal dimension at systole and left ventricular internal dimension at diastole increased. In DOX+DHM group, both left ventricular ejection fraction and left ventricular fractional shortening increased, while left ventricular internal dimension at systole and left ventricular internal dimension at diastole decreased (P<0.05). Furthermore, DOX group showed significant myocardial injury histologically, while DOX+DHM group significantly inhibited DOX-induced myocardial injury in rats. Meanwhile, cardiomyocyte hypertrophy was found in the DOX group, while the cardiomyocyte hypertrophy was notably inhibited in the DOX+DHM group. Compared with the control group, the apoptotic rates of cardiomyocytes and the levels of bax/bcl-2　ratio were significantly increased in DOX group, which were significantly alleviated in the DOX+DHM group (P<0.05). In addition, the levels of NLRP3, caspase-1 and IL-1ß were increased as compared with control group, while the levels of the above indicators were remarkably reversed in DOX+DHM group as compared with DOX group (P<0.05). Conclusion: DHM alleviates DOX-induced myocardial injury in rats by inhibiting NLRP3 inflammasome and reducing cardiomyocyte apoptosis.

[Paraganglioma of urinary bladder: a clinicopathological features analysis of 23 cases].

Objective: To investigate the clinicopathological features, diagnosis, differential diagnosis and immunohistochemical (IHC) characteristics of paraganglioma of urinary bladder (PUB). Methods: The clinical and pathological data of 23 cases of PUB were collected at the Second Affiliated Hospital of Fujian Medical University (7 cases); Fujian Provincial Hospital (8 cases); Fujian Medical University Union Hospital (6 cases); and First Affiliated Hospital of Fujian Medical University (2 cases) from May 2010 to November 2018. IHC staining for CK, GATA3, CD56, Syn, CgA, S-100 protein, HMB45, SDHB, OCT3/4 and Ki-67 was done using EliVision method; and the relevant literature was reviewed. Results: There were 14 women and 9 men, aged ranged from 21 to 73 years (median 51 years). Clinically, patients presented with headache, vertigo, palpitation, hypertensive crisis during micturition, hypertension, blurred vision, gross hematuria and paroxysmal pallor. The tumor sizes ranged from 0.9 to 6 cm (mean2.5 cm). Macroscopically, most tumors were exophytic and well delineated within the lamina propria or muscularis propria. The tumors were firm and nodular and showed grayish-tan cut surface. Histologically,the tumor growth pattern was expansive or showed interpenetrating infiltrative growth within the lamina propria or muscularis propria; the tumor cells were typically arranged in distinctive nests (Zellballen) with organoid arrangement; pseudo-rosette were seen in some cases. The cells were rounded or polygonal and had rich, acidophilic or amphophilic cytoplasm and may contain pigmented granules and vacuoles; the nuclei were central or eccentric, with small nucleoli, although occasionally some nuclei were pleomorphic and hyperchromatic. Spindled sustentacular cells could be seen around the nests of tumor cells in some cases. There were abundant vessels that were fissure-like, hemangioma-like or dilated. By IHC, the tumor cells were positive for GATA3 (2/23), OCT3/4 (2/23), CD56 (22/23), Syn (23/23), CgA (22/23), S-100 (sustentacular cell, 23/23) and SDHB (23/23); and negative for CK and HMB45; Ki-67 index was 1%-5%. At follow-up, there was no recurrence or metastasis in 18 cases. Conclusions: The diagnosis of PUB relies on the morphologic and IHC features; but there may be histomorphologic heterogeneity. The most important differential diagnosis is invasive urothelial carcinoma. The tumor cells may show aberrant cytoplasmic expression of OCT3/4; there is no clear correlation between SDHB and OCT3/4 expression in the group.

[Primary skull base chondrosarcoma: a clinicopathological analysis].

Objective: To investigate the clinicopathological features, immunophenotype, molecular characteristics and differential diagnosis of primary skull base chondrosarcoma. Methods: Nine cases of primary skull base chondrosarcoma were collected at the First Affiliated Hospital of Fujian Medical University, from January 2006 to June 2019, reviewed for the clinical and radiologic data and morphologic features, immunophenotype and molecular characteristics. Results: Among all the 9 cases, six were male, three were frmale, with average age 47 years, and median age 47 years; five cases were WHO gradeⅠ, and four were WHO grade Ⅱ. Microscopically, the tumor showed lobulated growth pattern with low-medium cellularity within a chondroid or mucoid background. The tumor cells showed mild-moderate atypia, with binucleated forms, and mitosis was rare or occasional. Immunohistochemistry (IHC) showed tumor cells were positive for S-100 protein, vimentin, SOX-9 and D2-40, and negative for Brachyury, CK, EMA and CK8/18; the Ki-67 index was low (1% to 5%). Molecular analysis showed IDH1 R132C mutation in four cases. Conclusions: Skull base chondrosarcoma is a rare cartilaginous malignant tumor with a good prognosis. Its characteristic morphologies, combined with IHC and molecular detection are helpful for the differential diagnosis.

Duration of EEG suppression does not predict recovery time or degree of cognitive impairment after general anaesthesia in human volunteers.

BACKGROUND: Burst suppression occurs in the EEG during coma and under general anaesthesia. It has been assumed that burst suppression represents a deeper state of anaesthesia from which it is more difficult to recover. This has not been directly demonstrated, however. Here, we test this hypothesis directly by assessing relationships between EEG suppression in human volunteers and recovery of consciousness. METHODS: We recorded the EEG of 27 healthy humans (nine women/18 men) anaesthetised with isoflurane 1.3 minimum alveolar concentration (MAC) for 3 h. Periods of EEG suppression and non-suppression were separated using principal component analysis of the spectrogram. After emergence, participants completed the digit symbol substitution test and the psychomotor vigilance test. RESULTS: Volunteers demonstrated marked variability in multiple features of the suppressed EEG. In order to test the hypothesis that, for an individual subject, inclusion of features of suppression would improve accuracy of a model built to predict time of emergence, two types of models were constructed: one with a suppression-related feature included and one without. Contrary to our hypothesis, Akaike information criterion demonstrated that the addition of a suppression-related feature did not improve the ability of the model to predict time to emergence. Furthermore, the amounts of EEG suppression and decrements in cognitive task performance relative to pre-anaesthesia baseline were not significantly correlated. CONCLUSIONS: These findings suggest that, in contrast to current assumptions, EEG suppression in and of itself is not an important determinant of recovery time or the degree of cognitive impairment upon emergence from anaesthesia in healthy adults.