[Response characteristics of tislelizumab combined with chemotherapy in first-line treatment of locally advanced or metastatic non-squamous non-small cell lung cancer].

Objective: To investigate the response characteristics of patients with locally advanced/metastatic non-squamous non-small cell lung cancer (nsq-NSCLC) treated with tislelizumab in combination with chemotherapy in the first line. Methods: Patients with nsq-NSCLC who achieved complete or partial remission after treatment with tislelizumab in combination with chemotherapy or chemotherapy alone in the RATIONALE 304 study, as assessed by an independent review board, were selected to analyze the response characteristics and safety profile of the responders. Time to response (TTR) was defined as the time from randomization to the achievement of first objective response. Depth of response (DpR) was defined as the maximum percentage of tumor shrinkage compared with the sum of the baseline target lesion length diameters. Results: As of January 23, 2020, 128 patients treated with tislelizumab in combination with chemotherapy achieved objective tumor response (responders), representing 57.4%(128/223) of the intention-to-treat population, with a TTR of 5.1 to 33.3 weeks and a median TTR of 7.9 weeks. Of the responders (128), 50.8%(65) achieved first remission at the first efficacy assessment (week 6), 31.3%(40) at the second efficacy assessment (week 12), and 18.0%(23) at the third and subsequent tumor assessments. The percentages of responders who achieved a depth of tumor response of 30% to <50%, 50% to <70% and 70% to 100% were 45.3%(58/128), 28.1%(36/128) and 26.6%(34/128), respectively, with median progression-free survival (PFS) of 9.0 months (95% CI: 7.7 to 9.9 months), 11.5 months (95% CI: 7.7 months to not reached) and not reached (95% CI: 11.8 months to not estimable), respectively. Tislelizumab plus chemotherapy were generally well tolerated in responders with similar safety profile to the overall safety population. Conclusion: Among responders to tislelizumab in combination with chemotherapy for nsq-NSCLC, 82.0%(105/128) achieves response within the first two tumor assessments (12 weeks) and 18.0%(23/128) achieves response at later (18 to 33 weeks) assessments, and there is a trend toward prolonged PFS in responders with deeper tumor response.

[A phase I study of subcutaneous envafolimab (KN035) monotherapy in Chinese patients with advanced solid tumors].

Objective: To evaluate the safety and antitumor activity of envafolimab monotherapy in Chinese patients with advanced solid tumors. Methods: This open-label, multicenter phase I trial included dose escalation and dose expansion phases. In the dose escalation phase, patients received subcutaneous 0.1, 0.3, 1.0, 2.5, 5.0 or 10.0 mg/kg envafolimab once weekly (QW) following a modified "3+ 3" design. The dose expansion phase was performed in the 2.5 mg/kg and 5.0 mg/kg (QW) dose cohorts. Results: At November 25, 2019, a total of 287 patients received envafolimab treatment. During the dose escalation phase, no dose-limiting toxicities (DLT) was observed. In all dose cohorts, drug-related treatment-emergent adverse events (TEAEs) for all grades occurred in 75.3% of patients, and grade 3 or 4 occurred in 20.6% of patients. The incidence of immune-related adverse reactions (irAE) was 24.0% for all grades, the most common irAEs (≥2%) included hypothyroidism, hyperthyroidism, immune-associated hepatitis and rash. The incidence of injection site reactions was low (3.8%), all of which were grades 1-2. Among the 216 efficacy evaluable patients, the objective response rate (ORR) and disease control rate (DCR) were 11.6% and 43.1%, respectively. Median duration of response was 49.1 weeks (95% CI: 24.0, 49.3). Pharmacokinetic (PK) exposure to envafolimab is proportional to dose and median time to maximum plasma concentration is 72-120 hours based on the PK results from the dose escalation phase of the study. Conclusion: Subcutaneous envafolimab has a favorable safety and promising preliminary anti-tumor activity in Chinese patients with advanced solid tumors.

[Analysis on echocardiographic data of fetal heart defects at high altitude in Yunnan province and surrounding high altitude areas].

Objective: To explore the current situation of fetal heart defects in Yunnan Province and surrounding high altitude areas and the social factors affecting pregnancy outcome. Methods: This is a retrospective study. Pregnant woman who underwent fetal echocardiography and diagnosed as fetal cardiac defects in Yunnan Fuwai Cardiovascular Hospital from June 2017 to January 2021 were included. According to the clinical prognostic risk scoring system and grading criteria of fetal cardiac birth defects, the cases were divided into grade Ⅰ to Ⅳ. The disease distribution and proportion of each prognostic grade, pregnancy outcomes were analyzed and compared. The cases were divided into continued pregnancy group and terminated pregnancy group according to pregnancy outcome. The social factors that may affect the selection of pregnancy outcomes were analyzed by multivariate logistic regression analysis. Results: A total of 4 929 fetal echocardiography examination data were collected, and 4 464 cases (90.57%) were from Yunnan Province and surrounding high altitude areas. 2 166 cases of heart defects were finally analyzed, including 998 cases of congenital heart disease (CHD), 93 cases of cardiac tumors, cardiomyopathy and arrhythmia, 1 075 cases of foramen ovale, ductus arteriosus abnormalities and normal variations. The pregnant women were (29.2±5.0) years old with (25.6±3.8) gestational weeks. The number of cases with prognostic grade from Ⅰ to Ⅳ was 1 037 (47.88%), 620 (28.62%), 314 (14.50%), and 44 (2.03%), respectively. And 151 cases (6.97%) were not classified. The cases of normal variation and thin aortic arch development accounted for 42.66% (924/2 166), 5.22% (113/2 166), respectively. The top 3 diseases of grade Ⅱ were ventricular septal defect, coarctation of aorta and mild-moderate pulmonary stenosis, respectively, and their distribution was 11.63% (252/2 166), 3.92% (85/2 166) and 2.35% (51/2 166) respectively in all cases of heart defects, and 25.25% (252/998), 8.52% (85/998) and 5.11% (51/998) respectively in cases of CHD. Among the cases rated as grade Ⅲ and Ⅳ, most of them were complicated congenital heart disease, and the disease types are scattered. The more common cases in grade Ⅲ were complete transposition of great arteries (accounting for 2.40% (52/2 166) of all cases with heart defects, 5.21% (52/998) of all cases with CHD) and pulmonary artery occlusion (type Ⅰ to Ⅲ) with ventricular septal defect (accounting for 2.17% (47/2 166) of all cases with heart defects, and 4.71% (47/998) of all cases with CHD). In grade Ⅳ, single ventricle (0.74% (16/2 166) of all cases with heart defects, 1.60% (16/998) of all cases with CHD) and left ventricular dysplasia syndrome (0.65% (14/2 166) of all cases with heart defects, 1.40% (14/998) of all cases with CHD) are more common. A total of 1 084 cases were successfully followed up, and 675 cases were born, 392 cases were terminated, spontaneous abortion occurred in 17 cases. The proportion of terminated pregnancy cases was significantly increased from grade Ⅰ to Ⅳ, accounting for 5.24% (21/401), 27.78% (70/252), 89.54% (214/239) and 95.56% (43/45), respectively. Among the terminated pregnancy cases, those with grade Ⅲ accounted for the highest proportion (54.59% (214/392)). The distribution of terminated pregnancy cases was mainly complex congenital malformations or diseases with very poor prognosis (pregnancy outcome grade Ⅲ and Ⅳ), and proportion of terminated pregnancy with pregnancy outcome grade Ⅰ and Ⅱ cases (normal variation or good prognosis) accounted for 5.36% (21/392) and 17.86% (70/392), respectively. The results of multivariate logistic regression analysis showed that pregnant women with low education (high school and below: OR=2.73, 95%CI 1.26-5.93, P<0.001; illiteracy: OR=3.27, 95%CI 1.29-7.10, P<0.001) and low family income (Annual income<100 000 yuan: OR=2.47, 95%CI 1.69-5.12, P<0.001) were more likely to choose termination of pregnancy in case of fetal heart defect. Conclusion: In Yunnan province and the surrounding high altitude areas, the disease distribution of fetal heart defect is mainly simple or low-risk disease, but the complex malformation, especially the disease with poor pregnancy outcome, accounts for a relative high proportion. Pregnancy termination also occurs in some cases with good pregnancy outcome. The education level and family income of pregnant women may affect their choice of pregnancy outcome in case of fetal heart defect.

[Early onset Epstein-Barr virus-negative diffuse large B cell lymphoma after bilateral lung transplantation: a case report].

Lymphoma after solid organ transplantation is one of the manifestations of post-transplant lymphoproliferative disorders(PTLD). Here we reported a 39-year-old male patient presented with intermittent fever, markedly elevated level of peripheral blood lymphocytes and lactate dehydrogenase(LDH), rapid decrease in hemoglobin and platelet count ten months after bilateral lung transplantation. After systematic evaluation, the patient excluded infectious diseases. Positron emission tomography-computed tomography (PET/CT) revealed diffuse increasing of standard uptake value in bones throughout the body. The bone marrow aspiration, flow cytometric analysis and histopathology confirmed the diagnosis of diffuse large B-cell lymphoma (DLBCL) with negative Epstein-Barr virus-encoded small RNA (EBER) hybridization in situ. Meanwhile, complicated hemophagocytic lymphohistiocytosis was also diagnosed in the patient based on hypertriglyceridemia, abnormally elevated level of serum ferritin and solvable CD25 (sCD25). Treatment regimen included reduction of immunosuppression, anti-CD20 antibody (CD20+ B cell inhibitor, rituximab) and etoposide. Repeated PET/CT and bone marrow biopsy showed complete remission of lymphoma after 4 months of therapy.

Expression of barley SUSIBA2 transcription factor yields high-starch low-methane rice.

Atmospheric methane is the second most important greenhouse gas after carbon dioxide, and is responsible for about 20% of the global warming effect since pre-industrial times. Rice paddies are the largest anthropogenic methane source and produce 7-17% of atmospheric methane. Warm waterlogged soil and exuded nutrients from rice roots provide ideal conditions for methanogenesis in paddies with annual methane emissions of 25-100-million tonnes. This scenario will be exacerbated by an expansion in rice cultivation needed to meet the escalating demand for food in the coming decades. There is an urgent need to establish sustainable technologies for increasing rice production while reducing methane fluxes from rice paddies. However, ongoing efforts for methane mitigation in rice paddies are mainly based on farming practices and measures that are difficult to implement. Despite proposed strategies to increase rice productivity and reduce methane emissions, no high-starch low-methane-emission rice has been developed. Here we show that the addition of a single transcription factor gene, barley SUSIBA2 (refs 7, 8), conferred a shift of carbon flux to SUSIBA2 rice, favouring the allocation of photosynthates to aboveground biomass over allocation to roots. The altered allocation resulted in an increased biomass and starch content in the seeds and stems, and suppressed methanogenesis, possibly through a reduction in root exudates. Three-year field trials in China demonstrated that the cultivation of SUSIBA2 rice was associated with a significant reduction in methane emissions and a decrease in rhizospheric methanogen levels. SUSIBA2 rice offers a sustainable means of providing increased starch content for food production while reducing greenhouse gas emissions from rice cultivation. Approaches to increase rice productivity and reduce methane emissions as seen in SUSIBA2 rice may be particularly beneficial in a future climate with rising temperatures resulting in increased methane emissions from paddies.

[Modified posteromedial approach via lateral side of flexor hallucis longus for the treatment of posterior Pilon fracture].

Objective: To compare the clinical efficacy and the level of muscle and soft tissue damage between modified posteromedial approach via lateral side of flexor hallucis longus and modified posteromedial approach in the treatment of posterior Pilon fracture. Methods: Total of 43 patients (27 males and 16 females, aged from 19 to 71 years) diagnosed with posterior Pilon fracture from June 2016 to June 2018 in Foshan Hospital of Traditional Chinese Medicine were randomly divided into observation group (modified posteromedial approach via lateral side of flexor hallucis longus, 21 cases) and control group (modified posteromedial approach, 22 cases) according to the operation approach. The preoperative waiting time, intraoperative time, intraoperative blood loss, hospitalization time and the complications were recorded and compared between the two groups. The differences of blood creatine kinase (CK), myoglobin (Myo) and C-reactive protein (CRP) at different time points before and after operation were compared between the two groups to elevate the level of muscle and soft tissue damage. The fracture reduction qualities of the two groups were compared by Burwell-Charnley criteria. The differences of fracture healing time, range of motion of metatarsophalangeal joint of the great toe (MTP-ROM), ankle range of motion (Ankle-ROM), American Orthopaedic Foot & Ankle Society (AOFAS) score and visual analogue scale (VAS) score of pain were compared between the two groups at the last follow-up. Results: The observation group and the control group were followed-up for (19±6) months and (16±8) months, respectively; there was no significant difference between the two groups (P>0.05). There were no significant differences in preoperative waiting time, intraoperative blood loss, hospitalization time and fracture healing time between the two groups (all P>0.05). At the last follow-up, there was no significant difference in the MTP-ROM and Ankle-ROM between the two groups (both P>0.05); the AOFAS score of the observation group was 88.2±7.8 and it was 84.5±7.6 in the control group (P>0.05); the VAS score of the observation group was (0.9±1.0) and it was (1.3±0.8) in the control group(P>0.05). Anatomical reduction rate in observation group was higher than that in control group (90.5% vs 81.8%, P>0.05). The operation time in the observation group was (87±16) min and it was (98±11) min in the control group (P<0.05). CK, Myo and CRP were increased in both groups after surgery, but there was no statistical significance between groups at the same time point (all P>0.05). There was no nerve injury in the observation group, while 2 cases (9.0%) of nerve paralysis occurred in the control group. No incision infection and checkrein deformity of the Hallux was found in the two groups. Conclusion: The modified posteromedial approach via lateral side of flexor hallucis longus can obtain good operative field exposure, and does not increase muscle and soft tissue injury, with shorter operative time and fewer complications, without nerve injury and checkrein deformity, it is a safe approach for the treatment of posterior Pilon fracture.

[Clinicopathological analysis of clear cell renal cell carcinoma with hemangioblastoma component].

Objective: To investigate the clinicopathological features, differential diagnosis and molecular characteristics of clear cell renal cell carcinoma (ccRCC) with hemangioblastoma component (ccRCC-HBc). Methods: Two ccRCC-HBc cases diagnosed at Fujian Provincial Hospital in September 2015 and March 2016, respectively, were included. Their morphological, immunohistochemical and molecular features were analyzed, including fluorescence in situ hybridization (FISH) detection of TFE3, TFEB and VHL genes. Related literature was reviewed to reveal the characteristics of this tumor. Results: The two cases occurred in 2 women, aged 33 and 66 years, respectively. The maximum diameters of the tumors were 4.0 cm and 8.5 cm, respectively. Histologically, the ccRCC component, representing approximate 10%-20% of the neoplasm, while the tumor cells arranged in flaky, nested, and solid distribution. The tumor cells had conspicuous nucleoli, with rich thin-wall capillary network in the stroma. The hemangioblastoma-like component, representing approximate 60%-70% of the neoplasm, showed a rich capillary network of single-layered flat endothelial cells enclosing stromal cells. The latter cell type showed a pale or eosinophilic cytoplasm exhibiting occasional lipid droplets. Rare cell nuclei appeared enlarged, pleomorphic, or bizarre. The two components were intermingled with each other. Immunohistochemically, the tumor cells were positive for PAX8, CKpan, EMA, vimentin, CD10, RCC, CAⅨ, and P504s in ccRCC area; in another area, the tumor cells were positive for α-inhibin, CD34 and vimentin, while CD10 were weakly positive. Neither TFE3 or TFEB gene split signal was detected in the 2 cases (0/2), nor was VHL gene mutation in case 2 (0/1). Conclusion: ccRCC-HBc is an extremely rare entity of ccRCC. The diagnosis is mainly based on clinical and pathological characteristics, as well as immunohistochemistry. Molecular pathology is helpful for its differential diagnosis. The primary approach of treating ccRCC-HBc is complete surgical excision and chemotherapy. The targeted treatment is helpful if possible.

[Primary extraskeletal osteosarcoma: a clinicopathological study of ten cases].

Objective: To investigate the clinicopathologic features, differential diagnosis, immunohistochemical profiles and molecular characteristics of primary extraskeletal osteosarcoma (ESOS). Methods: Ten cases of ESOS diagnosed and treated in Fujian Provincial Hospital, Fuzhou, China from January 2003 to January 2019 were collected and subjected to immunohistochemical staining and molecular analyses. The patients were followed up by telephone interview. Relative literature was also reviewed to assess the characteristics of this tumor. Results: The ten cases occurred in 3 women and 7 men, aged from 36 to 85 years (median, 60 years). The sizes of these tumors ranged from 5.5 to 17.5 cm (median, 11.0 cm). Histologically, at low magnification, the tumors were nodular, leafy and lobulated. They were composed of spindle cells, neoplastic osteoid cells, and cartilage tissues, with unequally-proportional mixture of these components. The three components intermingled with each other. Immunohistochemistry profiling showed that the tumor cells were positive for SATB2 (9/9), while α-SMA (4/10) and EMA (1/10) stains were focally positive. Ki-67 proliferation index was 10%‒50%. Desmin, CD68, S-100 protein, SOX10, HMB45, CD117, DOG1, CD34, CKpan, GATA3 and PAX8 stains were negative. MDM2/CDK4 gene amplification signals were not detected in the 6 cases (0/6), which were subjected to the FISH. The SSX18 break-apart signal and the C-KIT and PDGFR-α mutations were not detected (0/5 and 0/3, respectively). Conclusions: Primary ESOS is an extra-osseous osteogenic tumor. The diagnosis is mainly dependent on clinical, radiological and pathological characteristics. Immunohistochemistry and molecular profiling are helpful for making the correct diagnosis.

[Clinicopathological features and prognosis of primary mediastinal large B-cell lymphoma: a series of sixty cases].

Objective: To investigate the clinicopathological features and prognostic factors of primary mediastinal large B-cell lymphoma (PMBL). Methods: The clinical data of 60 patients with PMBL including 44 biopsy cases and 16 consultation cases from September 2000 to November 2019 in the Department of Pathology, China-Japan Friendship Hospital (14 cases) and Peking Union Medical College Hospital (46 cases) were enrolled. Pathologic features, immunophenotype, immunoglobulin (Ig) gene rearrangement and microRNA expression profile were retrospectively studied. Results: Of the 60 patients, 23 were males and 37 were females, age ranged from 15 to 64 years (median 28 years). Immunohistochemical staining showed that the tumor cells were positive for pan-B cell antigens, CD30 (77.4%, 24/31), CD23 (73.1%, 19/26), MUM1 (45.8%, 11/24), Ki-67 index ≥70 % (90.6%, 29/32). EBER in situ hybridization was analyzed in 21 PMBL, only one case (4.8%) was positive. Ig gene rearrangement was performed in 20 cases, and seven were positive (35.0%). MicroRNA gene expression profiles were analyzed in seven cases of PMBL and nine cases of diffuse large B-cell lymphoma, and there were 33 microRNAs with significant difference (P<0.05). Univariate analysis indicated that the poor prognostic factors included serum lactate dehydrogenase (LDH) level,International Prognostic Index (IPI) score ≥3, stages Ⅲ-Ⅳ, chemotherapy not combined with rituximab and MUM1 positivity (P<0.05). Multivariate analysis showed that the treatment combined with rituximab was independently related to prognosis (P<0.05). Conclusions: PMBL is different from diffuse large B-cell lymphoma in clinicopathologic features, immunophenotypic presentation and molecular features. The prognostic factors, molecular genetics and immunological characteristics reveal that this study has enriched our understanding of the biology of PMBL, thus providing evidence and strategies for treatment.

[Clinicopathological features of bronchiolar adenoma versus mixed squamous cell and glandular papilloma: a comparative analysis].

Objective: To observe the clinicopathological features of bronchiolar adenoma (BA) and mixed squamous cell and glandular papilloma (MSGP). The relationship between them was also analyzed. Methods: Clinical data of eight patients with BA and four patients with MSGP diagnosed in China-Japan Friendship Hospital were collected from January 2018 to January 2020. Hematoxylin-eosin staining and immunohistochemical staining (EnVision method) were used to compare their histopathological characteristics. The hotspots regions of cancer-associated driver genes in lung cancer, using real-time quantitative PCR, were detected in all the cases and the literatures were reviewed. Results: The clinical and imaging manifestations of BA and MSGP were analogous. Histologically they had a two-layer structure including bronchial or bronchiolar-type epithelium and a continuous layer of basal cells,similar to bronchial/bronchiole mucosae. P16 protein was highly expressed in 7/8 of BA and 1/4 of MSGP. Mutations of cancer-associated genes were detected in 4/8 of BA, but none in MSGP. Conclusions: BA and MSGP, derived from different parts of the respiratory tract in the lungs, are rare and benign. Their morphological features overlapped with each other, and some cases are accompanied by genetic changes. It is necessary to pay attention to the differential diagnosis between them and lung adenocarcinoma, especially during the intraoperative diagnosis; and be alert to the potentially malignant components in the tumor or combined cancers.

[Clinicopathological characteristics of pulmonary artery intimal sarcoma].

Objective: To describe the clinicopathological features of pulmonary artery intimal sarcoma (PAIS), and to understand its molecular alterations. Methods: Sixty cases of pulmonary artery endarterectomy performed at the China-Japan Friendship Hospital, Beijing, China from January 2017 to January 2020 were reviewed. Clinical data of 5 patients with pulmonary artery intimal sarcoma were collected. Hematoxylin-eosin staining, immunohistochemistry staining and fluorescence in situ hybridization (FISH) were performed to evaluate the pathological features. RNA sequencing was conducted to assess the fusion gene changes in PAIS. Results: The detection rate of PAIS was 8.3% (5/60), with the median age of 49 years and a female predominance. Their clinical manifestations were non-specific. Histopathological examination showed that the tumors were composed of malignant spindle or epithelioid cells, with various degrees of atypia. Focal heterologous osteosarcomatous or leiomyosarcomatous differentiation was noted. The tumor cells could express PDGFRA, CDK4 and MDM2 with co-amplification of MDM2, CDK4 and EGFR genes. RNA sequencing detected multiple in-frame fusions in the tumors. Conclusions: PAIS is a rare, highly heterogeneous, and poorly-or un-differentiated sarcoma accompanied by complex changes of multiple genes.It has no known effective treatments, and thus has a poor prognosis.

[Intelligent prediction of HER2 status based on breast histopathology].

Objective: To study the association between histopathological features and HER2 overexpression/amplification in breast cancers using deep learning algorithms. Methods: A total of 345 HE-stained slides of breast cancer from 2012 to 2018 were collected at the China-Japan Friendship Hospital, Beijing, China. All samples had accurate diagnosis results of HER2 which were classified into one of the 4 HER2 expression levels (0, 1+, 2+, 3+). After digitalization, 204 slides were used for weakly supervised model training, and 141 used for model testing. In the training process, the regions of interest were extracted through cancer detected model and then input to the weakly supervised classification model to tune the model parameters. In the testing phase, we compared performance of the single- and double-threshold strategies to assess the role of the double-threshold strategy in clinical practice. Results: Under the single-threshold strategy, the deep learning model had a sensitivity of 81.6% and a specificity of 42.1%, with the AUC of 0.67 [95% confidence intervals (0.560,0.778)]. Using the double-threshold strategy, the model achieved a sensitivity of 96.3% and a specificity of 89.5%. Conclusions: Using HE-stained histopathological slides alone, the deep learning technology could predict the HER2 status using breast cancer slides, with a satisfactory accuracy. Based on the double-threshold strategy, a large number of samples could be screened with high sensitivity and specificity.

[Analysis of the safety and efficacy of bronchial thermoplasty for severe asthma with the first second forced expiratory volume (FEV(1)) as a percentage of the predicted value (FEV(1)%pred)<60].

Objective: To investigate the efficacy and safety of bronchial thermoplasty (BT) in severe asthma patients with the first second forced expiratory volume (FEV(1)) as a percentage of the predicted value (FEV(1)%pred) <60%. Methods: A retrospective analysis was performed on 75 patients with asthma who were treated with BT at Shenzhen University Hospital of the Chinese Academy of Sciences from January 2016 to January 2018. The patients were divided into two groups based on the FEV(1)%pred before treatment: FEV(1)%pred <60% group (39 cases) and FEV(1)%pred ≥60% group (36 cases). Comparative analysis of glucocorticoid consumption, times of acute attack, asthma control test (ACT) score, changes in lung function, and adverse reactions at 3 weeks after treatment were performed between the two groups of patients. Results: Before BT treatment, the consumption of oral prednisone, the amount of budesonide inhaled, and the times of acute attack [M (Q(1), Q(3))] in the FEV(1)%pred <60% group were significantly greater than those in the FEV(1)%pred ≥60% group, and the ACT score was significantly lower than the FEV(1)%pred ≥60% group [10.00 (0, 20.00) vs 0(0, 3.75) mg/d, 960 (320, 960) vs 320 (320, 640) µg/d, 5(4, 8) vs 4 (4, 5) times/year, 13 (9, 15) vs 17 (13, 19) scores] (all P<0.05). Except that the oral prednisone dosage in the FEV(1)%pred<60% group was still higher 1 year after treatment [0 (0, 5.00) vs 0 (0, 0) mg/d] (P=0.009), there was no significant difference in the remaining indicators between the two groups 1 year after treatment and 2 years after treatment (all P>0.05). After 1 year and 2 years of treatment, all indicators in the two groups were better than before treatment (all P<0.05). The inhaled budesonide amount and the times of acute exacerbation in the FEV(1)%pred <60% group 2 years after treatment were less than those 1 year after treatment [320 (320, 320) vs 320 (320, 640) µg/d, 0 (0, 0) vs 0(0, 1) times/year] (all P<0.05), and there was no significant difference in the remaining indicators. In the FEV(1)%pred ≥60% group, there was no significant difference between 2 years after treatment and 1 year after treatment in the above indicators except the amount of inhaled budesonide (all P>0.05). In the FEV(1)%pred <60% group, FEV(1) and the FEV(1)%pred were significantly lower than the FEV(1)%pred ≥60% group before treatment, 1 year after treatment and 2 years after treatment [FEV(1):(1.21±0.41) vs (2.26±0.80)L, (1.84±0.73) vs (2.30±0.78)L, (1.70±0.66) vs (2.38±0.76)L; FEV(1)%pred:46.2 (38.5, 53.7)% vs 80.8(66.5, 93.6)%, 60.1 (48.2, 71.6)% vs 87.4 (68.5, 96.5)%, 58.5 (48.6, 74.8)% vs 86.6 (73.0, 97.3)%] (all P<0.05). In the FEV(1)%pred <60% group, FEV(1) and FEV(1)%pred 1 year after treatment and 2 years after treatment were all increased compared with before treatment (all P<0.05). In the FEV(1)%pred ≥60% group, there was no statistical difference in FEV(1) at each time point before and after treatment (all P>0.05), but the FEV(1)%pred at 2 years after treatment was higher than before treatment (P<0.05). There were no significant differences in adverse events between the two groups (all P>0.05). Conclusion: BT can significantly improve the lung function, reduce the times of acute attack and the dosage of glucocorticoids in severe asthma patients with FEV(1)% pred<60%, which is safe and effective.

[The study of self-constructed brainstem fiber bundle by neurosurgeon through using 3D-Slicer software].

Objective: To explore the methods and appliaction value for self-constructing brainstem fiber bundles by neurosurgeon through 3D-Slicer software in neurosurgical preoperative planning. Methods: The DCIOM format imaging data of 31 patients with neurosurgical brainstem lesions were collected who admitted to Neurosurgery Department at the First Affiliated Hospital of Chongqing Medical University from June 2018 to May 2019 and imported into the 3D-Slicer software system. The neurosurgery specialists independently constructed the fiber bundles to generate two-dimensional Fraction Anisotropy maps, Directionally Encoded Color maps and three-dimensional fiber bundle tracing maps. Building a preopertive virtual pathological anatomical imaging system and understanding the three-dimensional pathological anatomical relationship between lesions and brain stem fiber bundles to develop an accurate surgical approach and simulate surgicalprocedures before surgery. Results: All cases were reconstructed by neurosurgeon, and the self-constructed 3D virtual images were used to develop the surgical plan. All the operations were successfully completed under the assistance of microsurgical techniques and neuroendoscopy while avoiding fiber bundles as much as possible, and the total or subtotal tumor was achieved without damage to the fiber bundle. After operation, the symptoms of new brainstem fiber bundle injury were mild. 31 patients were followed up 3 months after operation without obvious symptoms of brainstem fiber bundle injury, and 31 patients were followed up 6 months after operation without obvious symptoms of brainstem fiber bundle injury. Conclusions: Constructing brainstem fiber bundles by neurosurgeon can accurately and purposefully reconstruct the shape of brainstem fiber bundles, so that neurosurgeons can more accurately understand the three-dimensional pathological anatomical relationship between tumor and brain stem fiber bundles. In order to formulate the surgical plan in a more reasonable way, choose the optimal surgical approach, understand the location of the "relative safe area" , and be more confident to avoid damage to the brain stem fiber bundle while achieving subtotal or total resection of the tumor,also the nerve function of the patient is preserved as much as possible.

[Clinicopathological characteristics of indeterminate dendritic cell tumor of four cases].

Objective: To investigate the clinicopathologic features, diagnosis, differential diagnosis and molecular pathological characteristics of indeterminate dendritic cell tumor (IDCT). Methods: Four cases of IDCT were collected at Peking Union Medical College Hospital (3 cases) and Fujian Provincial Hospital (1 case). The 4 cases were analyzed, with focus on morphology, immunohistochemistry and BRAF V600E detection. Related literature was reviewed to reveal the characteristics of this tumor. Results: There were 2 males and 2 females aged 30-52 years (mean=40 years). Histopathological characteristics of the tumor cells were round, polygonal. The nuclei were round, with rich eosinophils cytoplasm. The tumor cells arranged in diffuse, sheet, whorl, and fascicle patterns. Mitosis was variable [generally(1-3)/10 HPF] and nucleoli were obvious. Lymphocytes, plasma cells and other infiltrates could be seen in the stroma. Immunohistochemically, tumor cells were positive for S-100 (4/4), CD1a (4/4), CD68 (4/4) and cyclin D1 (3/3), while CD207/Langerin, CKpan, CD21, HMB45, ALK and actin were negative. Ki-67 index was 5%-30%. Gene detection showed BRAF V600E mutations were not present in any of the four cases. Conclusions: IDCT is a rare type of dendritic cell tumor. There are no specific morphology characteristics. The diagnosis depends on clinical, histopathological and immunophenotype. Thus, electron microscopy and molecular testing are helpful if necessary.

[Clinicopathological and genetic characteristics of lung cancer in the lungs of explanted from lung transplant recipients].

Objective: To describe the clinicopathological features of the lung cancers in the lungs explanted from lung transplant recipients, and to understand the molecular alterations of these cancers. Methods: The patients who underwent lung transplantation in China-Japan Friendship Hospital from March 2017 to December 2018 were reviewed. Clinical data of the patients with lung cancer associated with end-stage interstitial lung diseases (ILD) were collected. Hematoxylin-eosin staining and immunohistochemistry were performed to evaluate the pathological feature. Real-time quantitative PCR was performed to analyze the hotspots and targeted regions of 9 cancer-associated genes. Results: Among the 154 identified patients, 10 met the inclusion criteria and were included. The detection rate of lung cancer in the lung transplantation patients was 6.5%(10/154). All of the included 10 patients were male, with an average age of 59 years. They all had a history of heavy smoking. Three cases had a lung cancer diagnosed before operation, while the other 7 cases were concealed in the specimen of end-stage ILD. All of lung cancers were non-small-cell carcinoma, including 8 cases of adenocarcinoma and 2 cases of squamous cell carcinoma. The proportion of mucinous adenocarcinoma components was 3/10. The mutations in KRAS gene exon 2 were detected in two patients with mucous adenocarcinoma, while no alterations in NRAS, EGFR, ALK, ROS1, BRAF, HER2, PI3KCA and RET were detected in the remaining patients. Conclusions: Lung cancers are difficult to detect in patients with end-stage ILD. They are mainly adenocarcinomas and associated with a higher frequency of mutations in KRAS gene. These cancers have limited treatment options and a poor prognosis.

[Clinicopathological features and differential diagnosis of eosionphilic chromophobe renal cell carcinoma].

Objective: To investigate the clinicopathological characteristics of eosionphilic Chromophobe renal cell carcinoma (eChRCC), and differences in morphology, immunophenotype and clinical prognosis betweeneChRCC, renal oncocytoma(RO) and classic Chromophobe renal cell carcinoma (cChRCC). Methods: The clinicopathologic data of 17 patients diagnosed as eChRCC from the Affiliated Hospital of Qingdao University (13 cases) and 971 Hospital of PLA Navy (4 cases) from October 2006 to February 2019 were collected. Immunohistochemical analysis was carried out to compare the immunophenotypes between 17 cases with ChRCC, 27 cases with RO and 30 cases with cChRCC. Resuls: Among the 17 patients, seven were males and ten were females, and the age ranged from 40 to 75 years (median 54 years). Clinically, 15 cases of 17 were found accidentally by physical examination. The tumor size ranged from 1.8 cm to 10.0 cm (average 5.7 cm) and the cut surface of 15 cases were solid, one case was solicl and cystic, and one was cystic. Most showed gray to red, and partially soft, gray to yellow appearances. Microscopically, most tumors presented solid growth pattern with vary number of alveolar structures (12 cases). Some were predominately characterized by cystic structure (3 cases), alveolar structure(1 case) and microcapsule structure (1 case). There were boundaries with varying degrees of clarity between tumor cells in 16 cases. The cytoplasm of tumor cells was eosinophilic and the nuclei were small round or irregular with focal perinuclear haloes in 14 cases. Large polygonal cells with light-stained cytoplasm appeared focally in 9 cases, and edematous areas with scarce tumor cells were found in 4 cases. Among 7 cases, 4 cases focally invaded peripheral renal parenchyma, 2 cases invaded adipose tissues outside the renal capsule, and 1 case presented invasion of renal sinus. Immunohistochemically, all cases were moderate to strong positive for EMA and claudin-7. CK7, CD117 and Ksp-cad were highly expressed with the expression rates of 12/17, 15/17, 14/17, respectively. Cyclin D1, AMACR, CD10, S100A1, and RCC were rarely expressed with the expression rates of 4/17, 3/17, 4/17, 1/17 and 1/17, respectively. On the contrary, all cases were negative for vimentin, CAⅨ, HMB45 and Melan A. The Ki-67 proliferation index of the 17 cases was 1%‒5%. Follow-up data were available for all 17 patients from 7 to 154 months. Among them, 15 patients were alive without tumor recurrence or metastasis, one patient died of pulmonary metastasis after 31 months of surgery and one patient died of hepatic metastasis after 38 months of surgery. Conclusion: eChRCC has overlapping morphology and immunophenotype with RO. eChRCC is characterized by solid nest or alveolar structure, distinct border between tumor cells, perinuclear halos and lacking of interstitial looseness and edema. Scattered large polygonal cells with light-stained cytoplasm in tumor tissue play a significant role in the diagnosis of eChRCC. The positive expression of CK7, CD117, claudin-7 and Ksp-cad, and negative expression of cyclin D1, S100A1 are helpful to the diagnosis and differential diagnosis of eChRCC. The prognosis of eChRCC after complete surgical resection is excellent and few cases may have long-term metastasis. There is no significant difference in prognosis between eChRCC and cChRCC, but eChRCC shows better outcome than RO.

Transcriptomes in rat sciatic nerves at different stages of experimental autoimmune neuritis determined by RNA sequencing.

Guillain-Barré syndrome (GBS) is characterized by acute immune-mediated peripheral neuropathy, which may result in rapidly progressive paralysis and fatal respiratory failure. As the underlying pathological mechanisms of GBS are unclear, we surveyed the transcriptome of rats with experimental autoimmune neuritis (EAN), a model of GBS. Briefly, sciatic nerves on both sides were collected from 8-10-week-old Lewis rats during early (10 days post-induction), peak (19 days) and late neuritis (30 days). Total RNA was sequenced to identify differentially expressed genes. Compared to control rats without induced neuritis, 33 genes were differentially expressed in the early phase (14 up-regulated and 19 down-regulated), with an adjusted P-value < 0·05 and |log2 fold-change| >1, as were 137 genes in the peak phase (126 up-regulated and 11 down-regulated) and 60 genes in the late phase (58 up-regulated and two down-regulated). Eleven of these genes were common to all stages, suggesting their crucial roles throughout the disease course. Analysis of protein-protein interactions revealed Fos, Ccl2, Itgax and C3 as node genes at different stages. Functional analysis of differentially expressed genes identified biological processes and pathways that are activated as neuritis progresses. This is the first genomewide gene expression study of peripheral nerves in experimental autoimmune neuritis model. Dynamic gene expression and significantly altered biological functions were detected in different phases of the disease, increasing our understanding of the molecular mechanisms underlying EAN and highlighting potential targets for its diagnosis and treatment.

[Clinical pathologic characteristics of extranodal follicular dendritic cell sarcoma].

Objective: To investigate the clinical pathologic characteristics of extranodal follicular dendritic cell sarcoma (FDCS). Methods: We collected 7 cases of extranodal FDCS, HE staining, immunohistochemical study were performed. The V600E mutation of BRAF in 7 cases were detected by real-time PCR and EBER in situ hybridization was performed on 4 cases. Results: Among the 7 cases of FDCS, 5 cases were male and 2 cases were female, the median age was 55 years old, including 4 cases of low-grade FDCS and 3 cases of high-grade FDCS. The tumor location of 2 cases was in mediastinum, the tumor locations of others were in nasopharynx, kidney, lung, rectum and liver, respectively. The results of immunohistochemistry showed that, the tumor cells were diffusely or focally positive for CD21, CD23, CD35, D2-40, EGFR and CXCL13, but negative for S-100, CD68, HMB45, SMA, Desmin, CD117, Dog-1, CD34, CD30, EMA and CK.Five cases were positive for PD-L1 and the its expression in high-grade FDCS were higher than that in low-grade FDCS.Two cases of low-grade FDCS were positive for BRAF V600E, but the BRAF V600E mutation weren't detected in all of 7 cases. The result of EBER in-situ hybridization showed that only the nasopharynx FDCS was positive.The follow-up information of 5 patients were available (7~43 months), 4 patients died and 1 still alive with rectum metastasis. Conclusions: FDCS is a rare malignant disease with relapse and metastatic tendency. The combined applications of the first-line antibodies including CD21, CD23, CD35 and second-line antibodies including D2-40, CXCL13, EGFR are helpful for its diagnosis and differential diagnosis. The high expression of PD-L1 implicates the potential benefit of FDCS patients acquired from immunotherapy.

[Clinicopathological and molecular features of Erdheim-Chester disease accompanied with Langerhans cell histiocytosis].

Objective: To investigate the clinicpathological and molecular features of Erdheim-Chester disease (ECD) as well langerhans cell histiocytosis (LCH). Methods: The clinical, histopathological, molecular findings, immunophenotype, treatment and prognosis in 4 cases of ECD combined LCH were evaluated from February 2015 to September 2018 with review of the relevant literature. Results: 2 cases were male, and 2 were female, aged from 7-55 years. Microscopically, there were two different areas, in the first area, the lesions were composed of foamy histiocytes, spindle-shaped fibroblasts, scattered multinucleated giant cells. Lymphocytes, plasma cells, and giant cells were also found. In the other, the lesions were composed of histiocytes with obvious nuclear groove, associated with a variable number of eosinophils, lymphocytes and plasma cells. Immunephenotype, In the second area, histiocytes were positive for CD1a (4/4), S-100 (4/4),CD207/Langerin (4/4), cyclin D1(4/4), and in the two different area, the histiocytes were positive for CD68, CD163, Braf. Ki-67 positive index 1%-10% BRAF V600E gene mutation was detected in three cases. Conclusion: ECD combined LCH was a very rare histiocytosis tumor and its correct diagnosis relies on histopathologic features, immunohistochemical staining, and BRAF V600E gene detection.