[Clinical characteristics and prognosis analysis of pulmonary sarcomatoid carcinoma].

Objective: To summarize the clinical characteristics, treatment, and outcomes of patients with pulmonary sarcomatoid carcinoma (PSC) in order to improve clinicians' understanding of this disease. Methods: The clinical data of patients diagnosed with PSC in our hospital from January 1, 2015 to November 30, 2023 were retrospectively analyzed. According to whether radical resection was performed, the patients were divided into resectable group and unresectable group. The characteristics and treatments of PSC in different groups were compared. The survival curves were drawn by Kaplan-Meier method to compare the prognosis of different groups of patients. Results: A total of 43 PSC patients were included, including 32 males, with an average age of (62.79±9.59) years, and 31 smokers. Peripheral-type tumors were more common, with imaging showing predominantly solid soft tissue masses, and the maximum diameter of the tumor was more than 5 cm in 14 patients. Among the 23 patients who underwent NGS gene testing, the KRAS mutation rate was 43.5%, the TP53 mutation rate was 30.4%, and the MET mutation rate was 8.7%, all of which were MET-14 exon skipping mutations. PD-L1 expression was detected in 13 patients, 10 of whom showed high expression. The median overall survival (mOS) of the 43 patients with PSC was 24.6 months (13.0-52.7 months). Among them, 22 patients underwent radical lobectomy plus mediastinal lymph node dissection, 13 patients had postoperative recurrence, and 7 patients died during follow-up. The median disease-free survival (mDFS) was 12.3 months, the mOS was not achieved and the 1-year OS rate was 77.3 %. Twenty-one patients had unresectable locally advanced or advanced stage, and 15 patients died. The mDFS was 2.5 months, the mOS was 6.2 months, and the 1-year OS rate was 42.9 %. Seventeen patients received immunotherapy, and 1 patient received targeted therapy with the MET inhibitor glumetinib. Conclusions: PSC has a higher incidence in the elderly, smokers, and males, is highly malignant and has a poor prognosis. Based on its molecular biological characteristics, PD-L1 expression and tumor molecular detection can be performed to guide treatment options.

[The association between baseline TPOAb and/or TgAb positivity and thyroid immune-related adverse events in patients with malignancies following treatment with immune checkpoint inhibitors].

Objective: To investigate the association between positive anti-thyroid peroxidase antibody (TPOAb) and/or anti-thyroglobulin antibody (TgAb) and the occurrence of thyroid immune-related adverse events (irAEs) in patients with malignant tumors who treated with immune checkpoint inhibitors (ICIs). Methods: A case-control study. A total of 116 patients with malignant tumor who received ICIs treatment and underwent thyroid function evaluation at Peking Union Medical College Hospital from January 2017 to April 2023 were enrolled retrospectively, including 77 males and 39 females, with a median age of (M(Q1, Q3)) 63.0 (55.0, 70.0) years. The patients were divided into the euthyroid group (n=58) and the thyroid irAEs group (n=58) according to whether thyroid irAEs occurred after ICIs treatment. The clinical characteristics and baseline anti-thyroid antibodies associated with the occurrence of thyroid irAEs after ICIs treatment in patients with malignant tumors were evaluated. Variables with statistical significance in univariate analysis were included in multivariate logistic regression model to analyze the risk factors for thyroid irAEs in patients with malignant tumors who received ICIs treatment. Results: In irAEs group, therewore 4 (3.4%) cases of clinical thyrotoxicosis, 23(19.8%) cases of subclinical thyrotoxicosis, 23 (19.8%) cases of clinical hypothyroidism, and 8(6.9%) cases of subclinical hypothyroidism. The positive rate of anti-thyroid antibodies at baseline in the thyrioid irAEs group was higher than that in the euthyroid group［16/58（27.6%）vs 3/58（5.2%），P=0.001］. After at least one course of ICIs treatment, the incidence of thyroid irAEs in patients with positive anti-thyroid antibodies at baseline was 84.2% (16/19), whereas it was 43.3% (42/97) in patients with negative anti-thyroid antibodies(P=0.001). Univariate logistic regression analysis showed that gender (OR=2.812, 95%CI:1.257-6.293), baseline thyroid autoantibodies were positive (OR=6.984, 95%CI: 1.909-25.547), baseline TgAb positivity (OR=8.909, 95%CI: 1.923-41.280), and baseline TPOAb positivity (OR=7.304, 95%CI: 1.555-34.308) were associated with thyroid irAEs (all P<0.05). Multivariate logistic regression analysis indicated that baseline TgAb positivity (OR=7.637, 95%CI: 1.617-36.072) was a risk factor for thyroid irAEs (P=0.01). Conclusions: The incidence of thyroid irAEs is higher in patients who are positive for baseline TPOAb and/or TgAb compared to those who are negative for TPOAb and TgAb. Patients with positive TgAb at baseline are at high risk of developing thyroid irAEs.

[Clinical features and prognostic analysis of checkpoint inhibitor pneumonitis in patients with non-small cell lung cancer].

Objective: To describe the clinical characteristics of patients with non-small cell lung cancer (NSCLC) who developed checkpoint inhibitor pneumonitis (CIP) and to explore potential prognostic factors. Methods: NSCLC patients who were complicated with CIP after immune checkpoint inhibitors (ICIs) therapy in our institute were enrolled in this study from 1 July 2018 to 30 November 2022. Clinical data of NSCLC-CIP patients were collected, including clinical and radiological features and their outcomes. Results: Among the 70 enrolled NSCLC-CIP patients, there were 57 males (81%) and 13 females (19%). The mean age at the diagnosis of CIP was (65.2±6.3) years. There were 46 smokers (66%), 26 patients (37%) with emphysema, 19 patients (27%) with previous interstitial lung disease, and 26 patients (37%) with a history of thoracic radiation. The mean interval from the first application of checkpoint inhibitor to the onset of CIP was (122.7±106.9) days (range: 2-458 days). The main chest CT manifestations were coincided with non-specific interstitial pneumonia (NSIP) pattern and organizing pneumonia (OP) pattern. Most patients had grade 2 (21 cases) or grade 3 (34 cases) CIP. Seventeen patients had been concurrent with other immune-related adverse events such as rash, hepatitis, colitis, and thyroiditis. Half of the enrolled patients (36 patients/51%) had fever, and most patients had elevated C-reactive protein (52 patients/72%) and all patients had elevated erythrocyte sedimentation rate (70 patients/100%). Serum lactate dehydrogenase was elevated in 34 CIP patients. Prednisone≥1 mg·kg-1·d-1 (or equivalent) was the most commonly used initial treatment in CIP patients (50 patients/71.4%). Complications with pulmonary infections (OR=4.44, P=0.03), use of anti-fungal drugs (OR=5.10, P=0.03) or therapeutic dose of sulfamethoxazole (OR=4.86, P=0.04), longer duration of prednisone≥1 mg·kg-1·d-1 (or equivalent) (Z=-2.33, P=0.02) were probable potential risk factors for poor prognosis. Conclusions: Older males with smoking history might be predisposed to develop NSCLC-CIPs after ICIs therapy. NSIP pattern and OP pattern were common chest CT manifestations. Complications with pulmonary infections (especially fungal infection or Pneumocystis jirovecii pneumonia), longer duration, longer duration of high-dose corticosteroids were likely potential risk factors for poor prognosis.

[Comparison of the predictive value of Padua and the IMPEDE assessment scores for venous thromboembolism in patients with newly diagnosed multiple myeloma: A single institution experience].

Objective: To compare the predictive efficacy of the two thrombosis risk assessment scores (Padua and IMPEDE scores) in venous thromboembolism (VTE) within 6 months in patients with newly diagnosed multiple myeloma (NDMM) in China. Methods: This study reviewed the clinical data of 421 patients with NDMM hospitalized in Beijing Jishuitan Hospital from April 2014 to February 2022. The sensitivity, specificity, accuracy, and Youden index of the two scores were calculated to quantify the thrombus risk assessment of VTE by the Padua and IMPEDE scores. The receiver operating characteristics curves of the two evaluation scores were drawn. Results: The incidence of VTE was 14.73%. The sensitivity, specificity, accuracy, and Youden index of the Padua score were 100%, 0%, 14.7%, and 0% and that of the IMPEDE score was 79%, 44%, 49.2%, and 23%, respectively. The areas under the curve of Padua and IMPEDE risk assessment scores were 0.591 and 0.722, respectively. Conclusion: IMPEDE score is suitable for predicting VTE within 6 months in patients with NDMM.

[Establish a whole-process comprehensive surveillance management mode for immune checkpoint inhibitor pneumonitis].

The application of immune checkpoint inhibitors (ICIs) has shown impressive anti-tumor efficacy across multiple malignant tumors, leading to the prolonged survival period of tumor patients. However, immune-related adverse events should not be ignored. Checkpoint inhibitor pneumonitis (CIP) is a pulmonary adverse event that can occur in malignant tumor patients after receiving ICIs treatment. The incidence of CIP has been reported to range from 2.7% to 20.0% in clinical trials and real-world research. Furthermore, some patients might suffer from serious or fatal CIP, and the prognosis of such patients will be poor. Early detection, diagnosis and treatment may improve the prognosis of these patients. The establishment of a whole-process CIP comprehensive surveillance management mode covering the health care system and patients during ICIs treatment might be helpful to improve the early diagnosis and treatment capacity of CIP, which is a key measure to improve the prognosis of these patients.

[Clinical and pathological characteristics of immune-mediated liver injury caused by immune checkpoint inhibitors].

Objective: Cancer immunotherapy can lead to various side effects, termed immune-related adverse events (irAE). This study summarized and analyzed the clinical and pathological characteristics of immune-mediated liver injury caused by immune checkpoint inhibitors (ILICI). Methods: This is a retrospective case series study involving 11 patients diagnosed with ILICI at the Peking Union Medical College Hospital from November 2019 to November 2021. Patient demographic information and clinical data, including gender, age, ILICI onset, clinical and radiological manifestations, pathological features, treatment, and resumption of ICI were retrospectively collected and analyzed. Results: The patients were primarily males (9/11) with a median age of 65 (range: 32-73) years. ICI mainly resulted in either partial remission (4/11) or stable disease (3/11). ILICI occurred after a median of two cycles of anti-programmed cell death-1 (PD-1) therapy, with a median time from the initial and last anti-PD-1 therapy to ILICI onset of 57 days and 17 days, respectively. ILICI was mostly severe (3/11) or very severe (6/11). While the clinical and radiological manifestations were non-specific, the pathological features were active lobular hepatitis and portal inflammation, with prominent CD8+T lymphocyte infiltration. The basic treatment was hepatoprotective drugs (10/11). Glucocorticoids were used as the primary therapy (9/11) but were ineffective in 4 of 9 cases. Of these, 3 of 9 cases received combined treatment with mycophenolate mofetil (MMF), only one of whom achieved remission. By the end of the study, 2 of 11 cases had resumed ICI and neither had experienced an ILICI relapse. Conclusion: The ILICI patients in this study had a corresponding history of ICI treatment and pathological features. The main treatment included hepatoprotective drugs and glucocorticoids. Immunosuppressive drugs were added for some cases but had poor efficacy.

[Effects of one-stop hybrid operation on the risk and prognosis of brain arteriovenous malformations with posterior feeding artery].

Objective: To explore the effect of the combination of posterior circulation embolization and micro-resection on the risk and prognosis in patients with brain arteriovenous malformations (bAVMs) supplied by posterior circulation in a one-stop hybrid operation setting. Methods: Patients with bAVMs supplied by posterior circulation who received surgical treatment in Beijing Tiantan Hospital, Capital Medical University, were enrolled from January 2016 to December 2019 from a prospective, multicentral cohort (NCT03209804). The patients were divided into the posterior circulation embolization group and the non-posterior circulation embolization group. Propensity score matching (PSM) (1∶1) was performed according to the baseline information, the morphology of bAVMs, vascular architecture, and Spetzler-Martin grade of brain lesions. The primary endpoint was the deterioration of neurological function. The secondary endpoints were perioperative complications. The differences in surgical risk and clinical prognosis between the two groups were compared. Results: Five hundred and forty-five patients were enrolled in the cohort, and 38.3% met the included criteria (n=209 cases), with 42 cases in the posterior circulation embolization group and 167 cases in the non-posterior circulation embolization group. Depending on whether the patients were posterior circulation embolized, 39 patients in the posterior circulation embolization group and 39 patients in the non-posterior circulation embolization group were finally included after performing PSM. There were 50 males and 28 females, aged 5-58 (30±13) years. The exacerbation rate of neurological dysfunction in the posterior circulation embolization group was higher than that in the non-posterior circulation embolization group three months after surgery, however there was no statistically significant difference between the two groups [15.4% (6/39) vs 2.6% (1/39), P=0.107]. The intraoperative blood loss in the embolization group was significantly less than that in the non-embolization group [650 (500, 1 500) ml vs 1 200 (800, 2 000) ml, P=0.002]. There was no significant difference in microsurgery time between the two groups [437 (374, 521) min vs 424 (359, 601) min, P=0.865]. Likewise, there were no statistically significant differences in the incidence of postoperative complications and aggravation of neurological dysfunction, including postoperative bAVMs residual [5.1%(2/39) vs 7.7%(3/39), P=1.000], hemorrhagic complications [5.1%(2/39) vs 0(0), P=0.494], postoperative ischemic complications [10.3%(4/39) vs 5.1%(2/39), P=0.675], neurological dysfunction at discharge (17.9% vs 15.4%, P=0.755), and one-year neurological dysfunction [5.1%(2/39) vs 2.6%(1/39), P=1.000]. Conclusions: Posterior circulation embolization of bAVMs in a one-stop hybrid operation can effectively reduce intraoperative bleeding and surgical risk. Embolization of the feeding artery has no significant impact on the perioperative complications and neurological outcomes.

[Diagnostic value of surgical lung biopsies for diffuse parenchymal lung disease: the change of disease spectrum in the past 28 years in a single institution in China].

Objective: To investigate the changes of disease spectrum in diffuse parenchymal lung disease (DPLD) diagnosed by surgical lung biopsy, and to explore the diagnostic value of surgical lung biopsy in DPLD. Methods: Four hundred and fifty-five consecutive DPLD patients, who underwent surgical lung biopsy in Peking Union Medical College Hospital during the past 28 years, were analyzed retrospectively. Results: There were 211 males and 244 females. The average age at biopsy was (45±14) years. Four hundred and eleven cases (90.3%) were diagnosed by pathologic findings. Four hundred and forty-one cases (96.9%) were diagnosed by clinical-radiologic-pathologic multidisciplinary discussion. The 30-day mortality and 90-day mortality were 2.4% and 3.3% respectively. The disease spectrum included interstitial pneumonia in 209 cases (45.9%) (nonspecific interstitial pneumonia in 105 cases, usual interstitial pneumonia in 33 cases), other miscellaneous DPLD in 166 cases (36.5%) (including hypersensitivity pneumonitis in 49 cases), tumor in 39 cases (8.6%), and infectious diseases in 27 cases (5.9%). In the three consecutive periods (1993-2002, 2003-2012 and 2013-2020), the number of biopsies was 76 (16.7%), 297 (65.3%) and 82 (18%) respectively. The disease spectrum changes over time: in the above three periods, the percentage of interstitial pneumonia in DPLD was 68.4%, 45.1% and 28%, other miscellaneous DPLDs were 22.4%, 39.4% and 39.0%, the tumors were 2.6%, 7.4% and 18.3%, the infectious diseases were 5.3%, 5.1% and 9.8%. Conclusions: This study presented the changes of disease spectrum in DPLD diagnosed by surgical lung biopsy through single center real-world data, reflecting the progress of clinicians' understanding of DPLD and interstitial pneumonia. Surgical lung biopsy is still valuable for some difficult and complicated DPLD cases.

[Protective effect and mechanism of Lactobacillus rhamnosus on immune checkpoint inhibitors related colitis in mice].

Objective: Modeling the immune-related adverse events (irAE) colitis in mice, and explore the protective effect and related mechanism of Lactobacillus rhamnosus GG (LGG) on irAE colitis. Methods: C57BL/6 mice were divided into dextran sodium sulfate (DSS) group (n=3), DSS+anti-programmed death receptor 1 (PD-1) group (n=4), DSS+anti-PD-1+anti-cytotoxic T lymphocyte associated protein 4 (CTLA-4) Group (n=4), DSS+anti-PD-1+anti-CTLA-4+LGG group (n=4), all were given corresponding drugs and probiotics intervention. The severity of colitis were assessed by weight loss, disease activity index (DAI), colon length, colon histopathological score. The inflammatory cytokines and T cell immunity of CD4+, CD8+, FoxP3+regulatory T cells (Treg), were detected by real-time quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and immunohistochemical staining respectively. Results: Compared to DSS group, the Day 9 weight [(87.40±1.79)% vs (94.57±0.53)%, P<0.05], colon length [(5.33±0.27)cm vs (6.63±0.12)cm, P<0.05] were lower, and DAI score(2.66±0.24 vs 0.89±0.48), colon histopathological score (12.50±1.04 vs 5.67±0.33), tumor necrosis factor-α (TNF-α) (6.73±1.68 vs 0.91±0.40) (P<0.05), as well CD8+T cells (156.80±8.84 vs 89.00±6.66) and FoxP3+Treg cells (103.80±2.66 vs 48.33±3.18) (P<0.05) were higher in DSS+anti-PD-1+anti-CTLA-4 group. Compared to DSS+anti-PD-1+anti-CTLA-4 group, the DAI score(1.83±0.17 vs 2.66±0.24), colonic histopathology score (8.75±0.63 vs 12.50±1.04), TNF-α level (1.32±0.18 vs 6.73±1.68) (P<0.05) were lower; and CD8+T cells(97.75±3.75 vs 156.80±8.84, P<0.01) level was lower with higher FoxP3+Treg cells (126.00±8.33 vs 103.80±2.66, P=0.046) in DSS+anti-PD-1+anti-CTLA-4+LGG group. Conclusion: DSS combined with anti-PD-1 and anti-CTLA-4 can successfully modeling the irAE colitis in mice, LGG can reduce irAE colitis severity by regulating Treg cells.

Effects of intravenous arginine infusion on inflammation and metabolic indices of dairy cows in early lactation.

Enhancing the supply of arginine (Arg), a semi-essential amino acid, has positive effects on immune function in dairy cattle experiencing metabolic stress during early lactation. Our objective was to determine the effects of Arg supplementation on biomarkers of liver damage and inflammation in cows during early lactation. Six Chinese Holstein lactating cows with similar BW (508 ± 14 kg), body condition score (3.0), parity (4.0 ± 0), milk yield (30.6 ± 1.8 kg) and days in milk (20 ± days) were randomly assigned to three treatments in a replicated 3 × 3 Latin square design balanced for carryover effects. Each period was 21 days with 7 days for infusion and 14 days for washout. Treatments were (1) Control: saline; (2) Arg group: saline + 0.216 mol/day l-Arg; and (3) Alanine (Ala) group: saline + 0.868 mol/day l-Ala (iso-nitrogenous to the Arg group). Blood and milk samples from the experimental cows were collected on the last day of each infusion period and analyzed for indices of liver damage and inflammation, and the count and composition of somatic cells in milk. Compared with the Control, the infusion of Arg led to greater concentrations of total protein, immunoglobulin M and high density lipoprotein cholesterol coupled with lower concentrations of haptoglobin and tumor necrosis factor-α, and activity of aspartate aminotransferase in serum. Infusion of Ala had no effect on those biomarkers compared with the Control. Although milk somatic cell count was not affected, the concentration of granulocytes was lower in response to Arg infusion compared with the Control or Ala group. Overall, the biomarker analyses indicated that the supplementation of Arg via the jugular vein during early lactation alleviated inflammation and metabolic stress.

Effects of arginase inhibition via jugular infusion of Nω-hydroxy-nor-l-arginine on metabolic and immune indices in lactating dairy cows.

Transformation of Arg to nitric oxide and ornithine (Arg-Orn) constitutes the main route of Arg metabolism in mammals. The primary objective of this work was to determine the effects of inhibiting the Arg-Orn pathway via Nω-hydroxy-nor-l-arginine (nor-NOHA) on health of lactating cows. Furthermore, we also explored the effect of Arg-Orn inhibition on the efficiency of nitrogen utilization to find support for previous research that showed the inhibition of Arg-Orn inhibited milk protein synthesis. Six healthy Chinese Holstein cows of similar body weight (550.0 ± 20 kg), parity (4.0 ± 0), body condition score (3.0 ± 0), milk yield (21.0 ± 1.0 kg), and days in milk (80 ± 2 d) were selected and randomly assigned to 3 treatments in a replicated 3 × 3 Latin square design with 22 d for each period (7 d for infusion and 15 d for washout). The treatments were (1) saline infusion (control); (2) infusion of 125 mg/L of nor-NOHA; and (3) infusion of 125 mg/L of nor-NOHA with 9.42 g/L of Arg. Dry matter intake, apparent digestibility of nutrients, urinary N, N in milk, and blood indices of metabolism and immune function were determined. Compared with the control, the infusion of nor-NOHA had no effect on the concentrations of cholesterol, high-density lipoproteins, IgA, IL-1ß, tumor necrosis factor-α, and alanine transaminase. In addition, the dry matter intake, apparent digestibility of N, and the concentration of milk protein N in the Nor-NOHA did not differ from the control; however, the infusion of nor-NOHA and Arg resulted in greater concentrations of high-density lipoprotein, IgA, IL-1ß, and tumor necrosis factor-α, and lower concentrations of cholesterol in serum compared with the control. Moreover, the addition of Arg to cows infused with nor-NOHA increased the concentration of nitrate (the indicator of nitric oxide) in serum and was associated with greater milk protein N production due to greater milk yield compared with those infused with nor-NOHA. Overall, the results indicated important roles of Arg in immunity and mammary N utilization, whereas a minor role of the Arg-Orn pathway in these physiologic processes was found.

Feeding corn grain steeped in citric acid modulates rumen fermentation and inflammatory responses in dairy goats.

Cereal grains treated with organic acids were proved to increase ruminal resistant starch and can relieve the risk of ruminal acidosis. However, previous study mainly focussed on acid-treated barley, the effects of organic acid-treated corn is still unknown. The objectives of this study were to evaluate whether feeding ground corn steeped in citric acid (CA) would affect ruminal pH and fermentation patterns, milk production and innate immunity responses in dairy goats. Eight ruminally cannulated Saanen dairy goats were used in a crossover designed experiment. Each experimental period was 21 day long including 14 days for adaption to new diet and 7 days for sampling and data collection. The goats were fed high-grain diet contained 30% hay and 70% corn-based concentrate. The corn was steeped either in water (control) or in 0.5% (wt/vol) CA solution for 48 h. Goats fed CA diet showed improved ruminal pH status with greater mean and minimum ruminal pH, and shorter (P<0.05) duration of ruminal pH<5.6 and less area of ruminal pH<5.6, 5.8 and 6.0. Concentration of total volatile fatty acid and molar proportion of propionate were less but the molar proportion of acetate was greater (P<0.05) in goats fed the CA diet than the control diet. Concentration of ruminal lipopolysaccharide (LPS) was lower (P<0.05) and that of lactic acid also tended (P<0.10) to be lower in goats fed CA than the control. Although dry matter intake, actual milk yield, yield and content of milk protein and lactose were not affected, the milk fat content and 4% fat-corrected milk tended (P<0.10) to be greater in goats fed CA diet. For the inflammatory responses, peripheral LPS did not differ, whereas the concentration of LPS binding protein and serum amyloid A tended (P<0.10) to be less in goats fed CA diet. Similarly, goats fed CA diet had less (P<0.05) concentration of haptoglobin and tumour necrosis factor. These results indicated that feeding ground corn treated with CA effectively improved ruminal pH status, thus alleviated the risk of ruminal acidosis, reduced inflammatory response, and tend to improve milk yield and milk fat test.

[Efficacy and safety of anlotinib in 16 patients with advanced non-small cell lung cancer].

Objective: To evaluate the efficacy and safety of anlotinib in patients with advanced non-small cell lung cancer (NSCLC). Methods: Patients with stage ⅢB/Ⅳ NSCLC who progressed after two lines or more regimens were randomized into anlotinib group (12 mg daily from day 1 to 14 of a 21-day cycle) or placebo group with ratio of 2∶1. Study drugs or placebo were given until disease progression or intolerable toxicity. The primary endpoint was overall survival (OS), and the second endpoints were progression free survival (PFS), objective response rate, and disease control rate. Results: Between April 2015 and December 2015, twenty-four patients were assigned at Peking Union Medical College Hospital. The baseline characteristics of the anlotinib group (n=16) and placebo group (n=8) were fairly comparable. The median OS was 12.7 months in anlotinib group and 11.1 months in placebo group (P=0.460).The median PFS was 4.0 months in anlotinib group and 1.4 months in placebo group (P=0.065).The common adverse events were manageable such as hypertension, hand-foot syndrome, thyroiddy sfunction. No drug-related mortality occurred. Conclusions: Anlotinib had a trend of improvement in OS and PFS as third-line treatment or beyond in advanced NSCLC compared with placebo with manageable toxicity. ClinicalTrials:: NCT02388919.

Rapid Communication: Period2 gene silencing increases the synthesis of αs-casein protein in bovine mammary epithelial cells.

(), a core clock gene, encodes a circadian rhythm protein which has been shown to control mammary metabolism in rodents. Whether regulates milk component synthesis such as α-casein protein in bovine mammary cells is unknown. Thus, we used gene silencing technology to determine if silencing could affect α-casein synthesis and cell growth in cultured primary bovine mammary epithelial cells (BMEC). The BMEC were established by enzymatic digestion of mammary tissue from mid-lactation cows. A transient-transfection technique was used to insert a small interfering RNA (siRNA) oligonucleotide specific for to inhibit transcription. Control and siRNA-transfected cells were cultured for 48 h. qRT-PCR and ELISA analysis showed that silencing enhanced the synthesis of 2 kinds of α-casein ( < 0.05) through upregulating the mRNA level of and ( < 0.01). Furthermore, the 3-(4, 5-dimethyl-2-thiazolyl)-2, 5-diphenyl-2-H-tetrazolium bromide (MTT) results demonstrated that cell proliferation was not affected ( > 0.05). These data led us to hypothesize that PER2 protein may potentially play an important role in the control of milk protein synthesis and, hence, represents a target that can be used to regulate protein synthesis rate during lactation.

[Immune-related pneumonitis caused by programmed death-1 inhibitor Pembrolizumab: a case report and literature review].

Objective: To investigate the risk factors, clinical manifestations, radiological features, diagnosis, treatment and prognosis of immune-related pneumonitis caused by programmed death-1(PD-1)/PD-L1 inhibitors. Methods: The clinical data of immune-related pneumonitis caused by PD-1 inhibitor Pembrolizumab in a patient with advanced esophageal carcinoma admitted to the 307(th) Hospital of Chinese People's Liberation Army was retrospectively analyzed and the related literatures were reviewed. We searched Medline database using the keywords"PD-1 inhibitor","PD-L1 inhibitor","Pembrolizumab","Nivolumab","Atezolizumab"combined with"Pneumonitis"by Mar 31, 2017. Results: The patient was a 60-year-old male presented with progression disease after surgery, local radiation and couples of chemotherapy for his esophageal carcinoma. Then pembrolizumab, a kind of PD-l inhibitors, was given intravenously every 3 weeks with the average dosage 3 mg per kg. After six cycles of pembrolizumab, the patient began to have fever, cough and dyspnea, which aggravated gradually. Chest CT showed diffuse ground glass opacity, exudation and consolidation in both lungs and little pleural effusion in the right side. Cellular interstitial pneumonitis was confirmed by pathological examination. The patient's symptoms were alleviated after enough steroids and chest CT showed pulmonary infiltration was also absorbed. But the pneumonitis reoccurred twice after stopping or tapering steroids quickly and could also be controlled by using steroids again. Now the patient was still given steroids treatment and the primary esophageal cancer remained stable. 14 articles were retrieved and 88 cases of immune-related pneumonitis caused by PD-1/PD-L1 inhibitors were reported. Among these 89 cases with immune-related pneumonitis, both male and female could attack and the median age was 67 years old. Most cases were grade 1 or 2. The common clinical manifestations were dyspnea, cough, fever and other immune-related damages. And about 20% patients had no symptoms. Ground glass opacities, reticular opacities, consolidation and centrilobular nodules were the common radiological features. The commonest histologic pattern of pneumonitis associated with anti-PD-1/PD-L1 therapy on lung biopsy was organizing pneumonia. Adequate steroid and tapering slowly is the standard treatment. Immunosuppressive agents could be added in some serious cases. The prognosis was relatively good. Most patients were alleviated but few patients died of progression disease or infections during treatment. Conclusions: Immune-related pneumonitis associated with PD-l/PD-L1 inhibitor should be aware of; early detection, early treatment, and the prognosis could be better.

Short communication: Arginase inhibition reduces the synthesis of casein in bovine mammary epithelial cells.

The main purpose of this work was to determine the effect of arginase inhibition via Nω-hydroxy-nor-l-arginine (nor-NOHA) on casein synthesis in bovine mammary epithelial cells (BMEC). Passage 2 BMEC isolated from dairy cows were seeded to 6-well plates and randomly divided into 4 treatments: (1) control [Dulbecco's modified Eagle medium:Nutrient Mixture F-12 medium (DMEM/F12)]; (2) nor-NOHA (DMEM/F12 + 1 mmol/L nor-NOHA); (3) nor-NOHA + arginine (DMEM/F12 + 1 mmol/L nor-NOHA + 3.2 mmol/L Arg); and (4) nor-NOHA + ornithine (DMEM/F12+ 1 mmol/L nor-NOHA + 1 mmol/L Orn). Then, we determined the activity of enzymes related to Arg metabolism and casein synthesis in BMEC and the proliferation of cells. The addition of nor-NOHA reduced the activity of arginase and ornithine decarboxylase but had no effect on the activity of nitric oxide synthase, and these responses were the same at the gene expression level. In addition, supplementation of nor-NOHA in BMEC reduced cellular proliferation and casein synthesis. Addition of Arg to nor-NOHA resulted in cellular proliferation and casein synthesis similar to that of nor-NOHA alone. In contrast, addition of Orn to the medium with nor-NOHA increased the synthesis of casein and cellular proliferation compared with Nor-NOHA. In conclusion, suppression of the Arg-arginase-Orn pathway reduced casein synthesis and cellular proliferation, which indicated that this pathway is an important regulator of the synthesis of casein in BMEC.

[Epidermal growth factor tyrosine kinase inhibitors used in the treatment of NSCLC patients with leptomeningeal metastasis].

Objective: The aim of this study was to identify the clinical features and prognostic factors of leptomeningeal metastasis (LM) in non-small cell lung cancer (NSCLC) patients undergoing treatment with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). Methods: Twenty-five cases of NSCLC with LM, treated in our hospital during January 1, 2003 to October 31, 2013, were enrolled in this study. Medical records were reviewed for clinical features and treatments, and the survival and prognostic factors were analyzed. Results: NSCLC-LM were more common in female patients (64.0%), and most were adenocarcinomas (72.0%). Twenty (80.0%) patients underwent anti-cancer treatment, among them 17 patients underwent EGFR-TKIs treatment.The median overall survival (mOS) after the diagnosis of LM was 4.9 months for the whole group (25 cases). Patients receiving EGFR-TKIs treatment had a longer median survival than patients not receiving EGFR-TKIs (5.3 months vs. 1.2 months, P=0.022). Eleven patients who developed LM before the targeted therapy had a prolonged median survival of 8.1 months after EGFR-TKIs treatment. The univariate analysis showed that female gender and EGFR-TKIs treatment were favorable prognostic factors influencing the survival (P<0.05), while age, LM at the time of initial diagnosis, LM developed during the EGFR-TKIs treatment, whole-brain radiotherapy (WBRT), intrathecal chemotherapy, or systemic cytotoxic chemotherapy were not associated with mOS (P>0.05 for all). The multivariate analysis showed that female gender (P=0.012) and EGFR-TKIs treatment (P=0.008) were significant predictors of a good prognosis. Conclusions: EGFR-TKIs treatment may confer benefit for NSCLC-LM patients. Female patients and EGFR-TKIs treatment are favorable prognostic factors for survival.

The preliminary study on the effects of growth hormone and insulin-like growth factor-I on κ-casein synthesis in bovine mammary epithelial cells in vitro.

The effects of growth hormone (GH) and insulin-like growth factor-I (IGF-I) on protein synthesis and gene expression of κ-casein in bovine mammary epithelial cell in vitro were studied. The treatments were designed as follows: the growth medium without serum was set as the control group, while the treatments were medium supplemented with GH (100 ng/ml), IGF-I (100 ng/ml), and GH (100 ng/ml) + IGF-I (100 ng/ml). The quantity of κ-casein protein was measured by ELISA, and the κ-casein gene (CSN3) expression was examined by real-time quantitative PCR (RT-qPCR). Compared with the control group, all the experimental groups had greater (p < 0.05) expression of CSN3. The concentration of κ-casein followed a similar response as CSN3, but the difference between the treatments and the control was not statistically significant (p > 0.05). Furthermore, no synergistic effect of GH and IGF-I was observed for both the κ-casein concentration and CSN3 expression. It is therefore concluded that GH or IGF-I can independently promote the expression of CSN3 in bovine mammary epithelial cells in vitro.