Comparison of radiotherapy versus surgical resection following neoadjuvant chemoimmunotherapy in potentially resectable stage III non-small-cell lung cancer: A propensity score matching analysis.

BACKGROUND: Neoadjuvant chemoimmunotherapy followed by surgery is recommended for resectable non-small-cell lung cancer (NSCLC). However, a considerable proportion of patients do not undergo surgery and opt for alternative treatments such as radiotherapy. The efficacy of radiotherapy in this context remains unclear. METHODS: This retrospective study analyzed data from patients with stage III NSCLC who received neoadjuvant chemoimmunotherapy followed by either surgery or radiotherapy. Propensity score matching (PSM) was used to balance the heterogeneity between the groups. Efficacy outcomes, safety profiles, and disease recurrence patterns were assessed. RESULTS: In total, 175 patients were included; 50 underwent radiotherapy, and 125 underwent surgery. Prior to matching, radiotherapy was inferior to surgery in terms of progression-free survival (PFS; Hazard ratio [HR], 2.23; P = 0.008). Following a 1:1 PSM adjustment, each group consisted of 40 patients. The median PFS was 30.8 months in the radiotherapy group and not reached in the surgery group (HR, 1.46; P = 0.390). The 12- and 24-month PFS rates were 90.4 % and 69.0 % for the radiotherapy group compared to 94.1 % and 73.9 % for the surgery group, respectively. Subgroup analyses after PSM showed that patients with stage IIIA disease tend to benefit more from surgery than those with stage IIIB disease (HR, 3.00; P = 0.074). Grade 3-4 treatment-related adverse events (TRAEs) occurred in 62.5 % of patients in the radiotherapy group and 55.0 % in the surgery group, with no grade 5 TRAEs reported. The incidence of grade 3-4 treatment-related pneumonitis or pneumonia was 7.5 % and 2.5 % in the radiotherapy and surgery groups, respectively. CONCLUSION: Radiotherapy may be a viable alternative to surgery in patients with resectable NSCLC who do not undergo surgical resection after initial neoadjuvant chemoimmunotherapy, offering comparable efficacy and a manageable safety profile. Larger prospective studies are needed to validate these findings and optimize the treatment strategies for this patient population.

Immune responses and reinfection of SARS-CoV-2 Omicron variant in patients with lung cancer.

A significant Omicron wave emerged in China in December 2022. To explore the duration of humoral and cellular response postinfection and the efficacy of hybrid immunity in preventing Omicron reinfection in patients with lung cancer, a total of 447 patients were included in the longitudinal study after the Omicron wave from March 2023 to August 2023. Humoral responses were measured at pre-Omicron wave, 3 months and 7 months postinfection. The detected severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) specific antibodies including total antibodies, anti-receptor binding domain (RBD) specific IgG, and neutralizing antibodies against SARS-CoV-2 wild type (WT) and BA.4/5 variant. T cell responses against SARS-CoV-2 WT and Omicron variant were evaluated in 101 patients by ELISpot at 3 months postinfection. The results showed that Omicron-infected symptoms were mild, while fatigue (30.2%), shortness of breath (34.0%) and persistent cough (23.6%) were long-lasting, and vaccines showed efficacy against fever in lung cancer patients. Humoral responses were higher in full or booster vaccinated patients than those unvaccinated (p < .05 for all four antibodies), and the enhanced response persisted for at least 7 months. T cell response to Omicron was higher than WT peptides (21.3 vs. 16.0 SFUs/106 PBMCs, p = .0093). Moreover, 38 (9.74%) patients were reinfected, which had lower antibody responses than non-reinfected patients (all p < .05), and those patients of unvaccinated at late stage receiving anti-cancer immunotherapy alone were at high risk of reinfection. Collectively, these data demonstrate the Omicron infection induces a high and durable immune response in vaccinated patients with lung cancer, which protects vaccinated patients from reinfection.

Risk factors associated with severe adverse events in patients with relapsing polychondritis undergoing flexible bronchoscopy.

BACKGROUND: Patients with relapsing polychondritis (RP) sometimes experience upper airway collapse or lower airway stenosis, and bronchoscopy may provide a valuable typical image to confirm the diagnosis. This study aimed to identify potential risk factors associated with severe adverse effects during bronchoscopy. METHODS: We performed a retrospective cohort study of 82 consecutive patients with RP hospitalized at Peking Union Medical College Hospital between January 1, 2012 and December 31, 2022. Clinical features and disease patterns were compared among patients with RP undergoing bronchoscopy with or without severe adverse effects. Binary logistic regression analysis was performed to identify the associated risk factors. RESULTS: For patients with RP undergoing bronchoscopy with severe adverse effects, the forced vital capacity (FVC), forced vital capacity percent predicted values (FVC%), and peak expiratory flow were significantly lower (P = 0.001, P = 0.001, and P = 0.021, respectively) than those in the non-severe adverse effect subgroup. Binary logistic regression analysis revealed that low FVC% (odds ratio, 0.930; 95% confidence interval, 0.880-0.982; P = 0.009) was an independent risk factor for severe adverse events in patients undergoing bronchoscopy. CONCLUSIONS: Low FVC or FVC% suggests a high risk of severe adverse effects in patients with RP undergoing bronchoscopy. Patients with such risk factors should be carefully evaluated before bronchoscopy and adequately prepared for emergency tracheal intubation or tracheostomy.

Osimertinib versus comparator first-generation epidermal growth factor receptor tyrosine kinase inhibitors as first-line treatment in patients with advanced EGFR-mutated non-small cell lung cancer: a Chinese, multicenter, real-world cohort study.

Background: In the phase 3 FLAURA trial, osimertinib was compared with first-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) as a first-line treatment for EGFR-mutant non-small cell lung cancer (NSCLC). Osimertinib showed longer progression-free survival (PFS), overall survival (OS), and a similar safety profile. However, more studies demonstrating the effectiveness and safety of osimertinib as a first-line strategy are needed in real-world populations. Methods: We enrolled 1,556 patients with EGFR-mutated stage IIIc-IV NSCLC from the CAPTRA-Lung database. All patients received either osimertinib (n=202) or a first-generation EGFR-TKI (n=1,354) as their initial treatment. To adjust for differences in baseline characteristics between two groups, 1:2 propensity score matching (PSM) was performed. Propensity scores included gender, age, Eastern Cooperative Oncology Group performance status score, smoking history, family history of tumor, pathology, EGFR mutations, and central nervous system (CNS) metastases. The standardized mean differences (SMD) before and after PSM were calculated to examine the balance of covariate distributions between two groups. Results: After PSM, 202 patients receiving osimertinib and 404 patients receiving first-generation EGFR-TKIs were finally identified. SMD of each matched variable is less than 0.10. The median PFS was 19.4 months [95% confidence interval (CI): 14.3-24.4] in the osimertinib arm and 10.9 months (95% CI: 9.3-12.5) in the comparator arm [hazard ratio (HR) for progression, 0.47; 95% CI: 0.38-0.59; P<0.001). The median OS was 40.5 months (95% CI: 27.1-54.0) vs. 34.3 months (95% CI: 30.6-38.0) in two groups, respectively (HR for death, 0.76; 95% CI: 0.58-1.00; P=0.045). The incidence of grade 3 adverse events (AEs) between the two groups was 1% and 4.2%, respectively. No grade 4 AEs and treatment-related deaths were reported in both groups. Conclusions: In real-world settings, osimertinib demonstrates longer PFS and OS, with a similar safety profile to that of comparator EGFR-TKIs when used as a first-line strategy in NSCLC patients.

Osimertinib Improves overall survival of EGFR-mutant NSCLC patients with leptomeningeal metastases.

OBJECTIVE: Osimertinib is a third-generation, irreversible, small-molecule epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that can effectively penetrate the blood brain-barrier (BBB). This study mainly explored the factors affecting the prognosis of EGFR-mutant advanced non-small cell lung cancer (NSCLC) patients with leptomeningeal metastases (LM), and whether osimertinib could improve the survival benefit in these patients compared with those not treated with osimertinib. METHODS: We retrospectively analyzed patients who had been admitted with EGFR-mutant NSCLC and cytologically confirmed LM to the Peking Union Medical College Hospital between January 2013 and December 2019. Overall survival (OS) was defined as the primary outcome of interest. RESULTS: A total of 71 patients with LM were included in this analysis, with a median OS (mOS) of 10.7 months (95% CI [7.6, 13.8]). Among them, 39 patients were treated with osimertinib after LM while 32 patients were untreated. Patients treated with osimertinib had a mOS of 11.3 months (95%CI [0, 23.9]) compared with the untreated patients who had a mOS of 8.1 months (95%CI [2.9, 13.3]), with a significant difference between the groups (hazard ratio [HR]): 0.43, 95%CI:0.22-0.66, p = 0.0009). Multivariate analysis revealed the use of osimertinib were correlated with superior OS with a HR of 0.43 (95%CI [0.25, 0.75]), with a statistically significant difference (p = 0.003). CONCLUSIONS: Osimertinib can prolong the overall survival of EGFR-mutant NSCLC patients with LM and improve patient outcomes.

Study protocol of KeyPemls-004: A phase 2 study of pembrolizumab in combination with plinabulin and docetaxel in previously treated patients with metastatic non-small cell lung cancer and progressive disease (PD) after immunotherapy (PD-1/PD-L1 inhibitor) alone or in combination with platinum-doublet chemotherapy.

INTRODUCTION: Immune checkpoint inhibitor (ICI)-based treatment regimens have become the standard of care for first-line treatment of metastatic epidermal growth factor receptor (EGFR)/anaplastic lymphoma kinase (ALK) wild-type non-small cell lung cancer (NSCLC). Nevertheless, most patients inevitably develop disease progression, and the mechanisms of resistance to first-line immunotherapy are not clear. ICIs in combination with agents targeting other pathways may serve as second-line therapy options. Plinabulin is a selective immunomodulating microtubule-binding agent which inhibits the polymerization of tubulin monomers, with multiple mechanisms to inhibit tumor growth. Clinical studies have demonstrated preliminary the antitumor efficacy of this agent. Therefore, we hypothesize that a combination of plinabulin with programmed death 1 (PD-1) inhibitor and docetaxel may result in higher efficacy and fewer side effects leading to better tolerance. METHODS: In this investigator-initiated, single-arm, open-label, phase II trial, metastatic NSCLC patients who acquired resistance to first-line immunotherapy-based therapy will be enrolled. Participants will receive pembrolizumab 200 mg D1, plinabulin 30 mg/m2 D1 and D8, and docetaxel 75 mg/m2 D1 intravenously for a 21-day cycle. The study intervention will be given until disease progression, intolerable toxicity, informed consent withdrawal or investigator decision. The primary endpoint is investigator-based objective response rate per Response Evaluation Criteria in Solid Tumors, version 1.1. The secondary endpoints are progression-free survival, overall survival, duration of response, and safety. DISCUSSION: This trial will provide evidence of the benefit and safety of pembrolizumab in combination with plinabulin and docetaxel in metastatic NSCLC patients who have been exposed and developed resistance to first-line PD-1/PD-L1 inhibitor either as monotherapy or in combination with chemotherapy.

The development of a tumor-associated autoantibodies panel to predict clinical outcomes for immune checkpoint inhibitor-based treatment in patients with advanced non-small-cell lung cancer.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have become one important therapeutic strategy for advanced non-small-cell lung cancer (NSCLC). It remains imperative to identify reliable and convenient biomarkers to predict both the efficacy and toxicity of immunotherapy, and tumor-associated autoantibodies (TAAbs) are recognized as one of the promising candidates for this. PATIENTS AND METHODS: This study enrolled 97 advanced NSCLC patients with ICI-based immunotherapy treatment, who were divided into a training cohort (n = 48) and a validation cohort (n = 49), and measured for the serum level of 35 TAAbs. According to the statistical association between the serum positivity and clinical outcome of each TAAb in the training cohort, a TAAb panel was developed to predict the progression-free survival (PFS), and further examined in the validation cohort and in different subgroups. Similarly, another TAAb panel was derived to predict the occurrence of immune-related adverse events (irAEs). RESULTS: In the training cohort, a 7-TAAb panel composed of p53, CAGE, MAGEA4, GAGE7, UTP14A, IMP2, and PSMC1 TAAbs was derived to predict PFS (median PFS [mPFS] 9.9 vs. 4.3 months, p = 0.043). The statistical association between the panel positivity and longer PFS was confirmed in the validation cohort (mPFS 11.1 vs. 4.8 months, p = 0.015) and in different subgroups of patients. Moreover, another 4-TAAb panel of BRCA2, MAGEA4, ZNF768, and PARP TAAbs was developed to predict the occurrence of irAEs, showing higher risk in panel-positive patients (71.43% vs. 28.91%, p = 0.0046). CONCLUSIONS: Collectively, our study developed and validated two TAAb panels as valuable prognostic biomarkers for immunotherapy.

Circulating tumor cells PD-L1 expression detection and correlation of therapeutic efficacy of immune checkpoint inhibition in advanced non-small-cell lung cancer.

INTRODUCTION: This study investigated whether programmed death-ligand 1 (PD-L1) expression of circulating tumor cells (CTCs) in peripheral blood can serve as a predictive biomarker for immunotherapy efficacy in patients with advanced non-small-cell lung cancer (NSCLC). METHODS: We employed a negative enrichment method to isolate CTCs. We identified PD-L1 + CTCs as PD-L1+/4',6-diamidino-2-phenylindole (DAPI)+/CD45-circulating tumor cells through an immunofluorescence method. Tumor tissue PD-L1 expression was determined by immunohistochemical staining. The correlation between CTC PD-L1 expression and patients' prognostic features was estimated through the Kaplan-Meier method. RESULTS: CTCs released a higher detection rate of PD-L1 expression than tumor tissues (53.0% vs. 42.1%). No correlation was observed between them. Forty-nine NSCLC patients received anti-PD-1/PD-L1 immunotherapy (three with combined anti-PD-1/PD-L1 and cytotoxic T lymphocyte-associated antigen-4 (CTLA-4), two with four cycles of combined immune checkpoint inhibitors [ICIs] plus chemotherapy and ICI monotherapy for maintenance). Patients with PD-L1 expression on tissue or CTCs had a median progression-free survival (mPFS) of 5.6 months (n = 36, 95% confidence interval [CI] 3.6-7.5 months), significantly longer than those without PD-L1 detection (n = 9, mPFS of 1.4 months, 95% CI 1.3-1.5 months, log-rank p = 0.032). The multivariable Cox proportional-hazard model suggested that the tissue or CTC PD-L1 expression was associated with a lower risk of progression (hazard ratio 0.45, 95% CI 0.21-0.98, p = 0.043). CONCLUSIONS: CTCs and tumor tissues reveal heterogeneous expression of PD-L1 in NSCLC patients. Patients with baseline PD-L1 expression on CTCs or tissue showed prolonged mPFS and may help to identify the subsets of patients who potentially benefit from immunotherapy.

Prognostic Factors and Survival Benefits of Antitumor Treatments for Advanced Non-Small Cell Lung Cancer Patients With Central Nervous System Metastasis With or Without Driver Genes: A Chinese Single-Center Cohort Study.

Background: The prognosis of non-small cell lung cancer (NSCLC) patients with central nervous system (CNS) metastasis is poor. The treatment for CNS metastasis could prolong the overall survival of NSCLC patients. We aimed to investigate the prognostic factors of Chinese NSCLC patients with CNS metastasis and the survival benefits of various treatments for CNS metastasis in NSCLC patients with or without driver genes. Methods: Based on the CAPTRA-Lung database, NSCLC patients with CNS metastasis admitted at the Peking Union Medical College Hospital between January 2010 and October 2018 were enrolled in the study. The prognostic factors were analyzed using univariate and multivariate Cox regression analyses. Results: Overall, 418 patients were enrolled in the study. A total of 206 patients (49.3%) had CNS metastasis with positive driver genes, while 97 patients (23.2%) had negative driver genes. The median survival time after CNS metastasis was 20.8 months. In the multivariable analysis, an Eastern Cooperative Oncology Group performance status of ≥2 (hazard ratio [HR]: 1.750, 95% confidence interval [CI]: 1.184-2.588, P=0.005), number of CNS metastases ≥5 (HR: 1.448, 95% CI: 1.084 -1.934, P=0.012), and CNS metastasis developed during treatment (HR: 1.619, 95% CI: 1.232-2.129, P=0.001) were independent risk factors for poor survival. Lung adenocarcinoma (HR: 0.490, 95% CI: 0.279-0.861, P=0.013) and driver gene positivity (HR: 0.464, 95% CI: 0.302-0.715, P=0.001) were independent predictors of prolonged survival. Radiotherapy for CNS metastasis showed a survival benefit in NSCLC patients in the entire groups (HR: 0.472, 95% CI: 0.360-0.619, P <0.001), and in patients with positive driver genes. Conclusion: Performance status, number of CNS metastases, timing of CNS metastasis, histological subtype, and driver gene status are prognostic factors for NSCLC patients with CNS metastasis. Furthermore, radiotherapy improved the survival in NSCLC patients with CNS metastasis.

Leptomeningeal enhancement in magnetic resonance imaging predicts poor prognosis in lung adenocarcinoma patients with leptomeningeal metastasis.

BACKGROUND: To investigate the prognostic value of magnetic resonance imaging (MRI) findings in the prognosis of patients with leptomeningeal metastasis from lung adenocarcinoma. METHODS: Patients with lung adenocarcinoma complicated with cytologically confirmed leptomeningeal metastasis who visited Peking Union Medical College Hospital (blinded for review) between January 2012 and July 2019 were retrospectively reviewed. We collected the patients' clinical and neuroimaging findings and pathological data. The presence of leptomeningeal enhancement on initial contrast MRI was used to divide patients into MRI-positive and MRI-negative groups. Univariate and multivariate analyses were performed to evaluate prognostic factors. RESULTS: Eighty-six patients (38 men and 48 women; median age = 56 [range, 25-80]) were included. Seventy-three patients (84.9%) had targetable genetic alterations. Only 30 patients (34.88%) had leptomeningeal enhancement on initial contrast MRI. No significant differences were observed in the distribution of demographics, driver gene status, intracranial pressure, complicated brain/spinal metastasis, or treatment strategies between the two groups. The median overall survival of patients in the MRI-positive group was significantly shorter than that in the negative group (182 days vs. 352 days, p = 0.036). Cox regression analysis indicated that the presence of leptomeningeal enhancement on the initial diagnostic magnetic resonance imaging was an independent predictor of an unfavourable prognosis of leptomeningeal metastasis (hazard ratio = 1.707, p = 0.044). CONCLUSIONS: This is the first time that positive initial contrast-enhanced magnetic resonance imaging of the neuroaxis has been proposed as a risk factor for the prognosis of leptomeningeal metastasis from lung adenocarcinoma with contemporary survival data.

Immune checkpoint inhibitor-related adverse events in lung cancer: Real-world incidence and management practices of 1905 patients in China.

BACKGROUND: Immune checkpoint inhibitors (ICIs) are the standard treatment for advanced lung cancer, but immune-related adverse events (irAEs) remain poorly understood, especially in a real-world setting. METHODS: A multicenter observational study was conducted. Medical records of lung cancer patients treated with ICIs at 26 hospitals from January 1, 2015, to February 28, 2021, were retrieved. Types of ICIs included antiprogrammed cell death 1 or antiprogrammed cell death ligand 1 (PD-L1) monotherapy, anticytotoxic T-lymphocyte antigen-4 monotherapy, or combination therapy. RESULTS: In total, 1905 patients with advanced lung cancer were evaluated. The median age was 63 (range 28-87) years, and the male/female ratio was 3.1:1 (1442/463). The primary histological subtype was adenocarcinoma (915). A total of 26.9% (512/1905) of the patients developed 671 irAEs, and 5.8% (110/1905) developed 120 grade 3-5 irAEs. Median duration from ICI initiation to irAEs onset was 56 (range 0-1160) days. The most common irAEs were thyroid dysfunction (7.2%, 138/1905), pneumonitis (6.5%, 124/1905), and dermatological toxicities (6.0%, 115/1905). A total of 162 irAEs were treated with steroids and 11 irAEs led to death. Patients with positive PD-L1 expression (≥1%) and who received first-line ICI treatment developed more irAEs. Patients who developed irAEs had a better disease control rate (DCR, 71.3% [365/512] vs. 56.0% [780/1145]; p < 0.001). CONCLUSIONS: The incidence rate of irAEs was 26.9% in a real-world setting. IrAEs might be related to a better DCR, but clinicians should be more aware of irAE recognition and management in clinical practice.

Correlations between peripheral blood biomarkers and clinical outcomes in advanced non-small cell lung cancer patients who received immunotherapy-based treatments.

BACKGROUND: Peripheral blood-based biomarkers (PBB) predicting response, survival and immune-related adverse events (irAEs) in patients with advanced non-small cell lung cancer (NSCLC) treated with immune checkpoint inhibitors (ICIs) are still a matter of debate. Thus, we investigated the associations between PBB, the efficacy of ICIs and the incidence of irAEs. METHODS: Patients with advanced NSCLC, who had been treated at Peking Union Medical College Hospital and received ICIs or chemoimmunotherapy from January 2015 to December 2020, were retrospectively identified. PBBs results were retrieved from medical records. Associations with overall response rate, survival, and incidence of irAEs were assessed using Kruskal-Wallis, Kaplan-Meier analysis, Pearson's chi-squared and Student's t-tests as required. Cox proportional hazards and logistic regression models were used to determine independent risk factors. Analyses were performed on the whole population (n=103), patients receiving ICIs only (n=32), and patients receiving chemoimmunotherapy (n=71). Changes in pretreatment and on-treatment PBB were also analyzed. RESULTS: Among 103 patients, 38 (36.9%) developed irAEs. Pretreatment absolute lymphocyte count (ALC) was related to an increased risk of irAEs in the whole population [odds ratio (OR), 2.165; 95% confidence interval (CI): 1.040 to 4.509, P=0.039] and patients receiving ICIs only (OR, 6.461; 95% CI: 1.067 to 39.112; P=0.042). A low prognostic nutritional index (PNI ≤45) was associated with worse progression-free survival (PFS) and overall survival (OS) in the whole population, in patients receiving ICIs only, and in patients receiving chemoimmunotherapy. High pretreatment interleukin (IL)-6 was associated with both worse PFS and OS in the whole population (IL-6 >13.80 pg/mL), in patients receiving ICIs only (IL-6 >11.30 pg/mL), and in patients receiving chemoimmunotherapy (IL-6 >11.85 pg/mL). Increase of IL-6 during treatment was associated with inferior OS in the whole population (P<0.001). CONCLUSIONS: Pretreatment ALC has the potential to predict irAEs in patients with advanced NSCLC treated with ICIs. Additionally, a low level of pretreatment PNI and high level of IL-6 may be associated with shorter survival.

Characterization of Somatic Mutations That Affect Neoantigens in Non-Small Cell Lung Cancer.

Purpose: Immune checkpoint inhibitors (ICIs) have recently emerged as an important option for treating patients with advanced non-small cell lung cancer (NSCLC). Neoantigens are important biomarkers and potential immunotherapy targets that play important roles in the prognosis and treatment of patients with NSCLC. This study aimed to evaluate and characterize the relationships between somatic mutations and potential neoantigens in specimens from patients who underwent surgical treatment for NSCLC. Patients and Methods: This prospective study evaluated specimens from patients with NSCLC who underwent surgical treatment at the Peking Union Medical College, China, from June 2019 to September 2019. Whole-exome sequencing was performed for tumor tissues and corresponding normal tissues. Candidate neoantigens were predicted using generative software, and the relationships between various mutation characteristics and number of neoantigens were evaluated. Results: Neoantigen-related gene mutations were less frequent than mutations affecting the whole genome. Genes with high neoantigen burden had more types and higher frequencies of mutations. The number of candidate neoantigens was positively correlated with missense mutations, code shift insertions/deletions, split-site variations, and nonsense mutations. However, in the multiple linear regression analysis, only missense mutations were positively correlated with the number of neoantigens. The number of neoantigens was also positively correlated with base transversions (A>C/C>A, T>G/G>T, and C>G/G>C) and negatively correlated with base transitions (A>G/G>A and C>T/T>C). Conclusion: The number of candidate neoantigens in NSCLC specimens was associated with mutation frequency, type of mutation, and type of base substitution.

Factors contributing to diagnostic delay of Caroli syndrome: a single-center, retrospective study.

BACKGROUND: Caroli syndrome (CS) is a rare congenital disorder without pathognomonic clinical symptoms or laboratory findings; therefore, the diagnosis is often delayed. The objective of this study was to investigate the diagnostic delay and associated risk factors in CS patients. METHODS: This was a retrospective analysis of 16 CS patients admitted to a single tertiary medical center on mainland China. The diagnostic timelines of CS patients were reviewed to demonstrate the initial findings of CS at diagnosis, the risk factors associated with diagnostic delay, and potential clues leading to early diagnosis. RESULTS: The median diagnostic delay was 1.75 years (range: 1 month to 29 years, interquartile range: 6.2 years) in 16 enrolled CS patients. Sex, age, and initial symptoms were not associated with diagnostic delay. 87.5% of CS patients were diagnosed by imaging, and the accuracies of ultrasonography, computed tomography (CT), and magnetic resonance cholangiopancreatography were 25, 69.2, and 83.3%, respectively. The median diagnostic delays for patients with or without CT performed at the first hospital visited according to physician and radiologist suspicion of the diagnosis were 7.4 months and 6 years, respectively (p = 0.021). Hepatic cysts with splenomegaly were detected by ultrasound in over half of CS patients. CONCLUSIONS: The majority of CS patients were not diagnosed until complications of portal hypertension had already developed. Recognition and early suspicion of the disease were important factors influencing diagnostic delay of CS. Hepatic cysts plus splenomegaly detected by US might raise the clinical suspicion to include CS in the differential diagnosis.

[Clinical-radiological-pathological Characteristics of 297 Cases of Surgical Pathology Confirmed Benign Pulmonary Lesions in Which Malignancy Could Not Be Excluded in Preoperative Assessment: A Retrospective Cohort Analysis in a Single Chinese Hospital].

BACKGROUND: Low dose computed tomography (LDCT) for lung cancer screening is widely employed in China as a result of increasing cancer screening awareness. Although some pulmonary lesions detected by LDCT are cancerous, most of the pulmonary nodules are benign. It is important to make effective preoperative differentiation of pulmonary lesions and to obviate the need for surgery in some patients with benign disease. METHODS: From January 1, 2017 to December 31, 2018, patients in our institution with surgical pathology confirmed benign pulmonary lesions in which malignancy could not be excluded in preoperative assessment were enrolled in this study. Retrospective analysis of clinical data was conducted. RESULTS: 297 cases were collected in this study. Prevalence of benign disease in patients underwent resection for focal pulmonary lesions is 9.8% in our institution. In 197 patients (66.3%), pulmonary lesions were detected by LDCT screening. A total of 323 assessable pulmonary lesions were detected by chest CT. The average diameter of pulmonary lesions was (17.9±12.1) mm, and 91.0% of which were greater than or equal to 8 mm. Solid nodules accounted for 65.6% of these lesions. Imaging characteristics suggesting malignancy were common, including spicule sign (71/323, 22.0%), lobulation (94/323, 29.1%), pleural indentation (81/323, 25.1%), vascular convergence sign (130/323, 40.2%) and vacuole sign (23/323, 7.1%). 292 patients (98.3%) underwent video-assisted thoracoscopic surgery (VATS). Pulmonary wedge resection was performed in 232 cases (78.1%), segmental resection in 13 cases (4.4%) and lobotomy in 51 cases (17.2%). Surgical complications occurred in 4 patients (1.3%). The most frequent findings on surgical pathology analysis were: infectious lesions in 98 cases (33.0%), inflammatory nodules in 96 cases (32.3%), and hamartoma in 64 cases (21.5%). CONCLUSIONS: Solid nodules accounted for most of these benign pulmonary lesions in which malignancy could not be excluded preoperatively, and imaging characteristics suggesting malignancy were common. VATS is an important biopsy method to identify etiology and pathology for lesions. The most frequent benign pulmonary diseases that are suspected to be malignant and underwent surgical resection are: infectious lesions, inflammatory nodules and hamartoma.

Early-Onset Convulsive Seizures Induced by Brain Hypoxia-Ischemia in Aging Mice: Effects of Anticonvulsive Treatments.

Aging is associated with an increased risk of seizures/epilepsy. Stroke (ischemic or hemorrhagic) and cardiac arrest related brain injury are two major causative factors for seizure development in this patient population. With either etiology, seizures are a poor prognostic factor. In spite of this, the underlying pathophysiology of seizure development is not well understood. In addition, a standardized treatment regimen with anticonvulsants and outcome assessments following treatment has yet to be established for these post-ischemic seizures. Previous studies have modeled post-ischemic seizures in adult rodents, but similar studies in aging/aged animals, a group that mirrors a higher risk elderly population, remain sparse. Our study therefore aimed to investigate early-onset seizures in aging animals using a hypoxia-ischemia (HI) model. Male C57 black mice 18-20-month-old underwent a unilateral occlusion of the common carotid artery followed by a systemic hypoxic episode (8% O2 for 30 min). Early-onset seizures were detected using combined behavioral and electroencephalographic (EEG) monitoring. Brain injury was assessed histologically at different times post HI. Convulsive seizures were observed in 65% of aging mice post-HI but not in control aging mice following either sham surgery or hypoxia alone. These seizures typically occurred within hours of HI and behaviorally consisted of jumping, fast running, barrel-rolling, and/or falling (loss of the righting reflex) with limb spasms. No evident discharges during any convulsive seizures were seen on cortical-hippocampal EEG recordings. Seizure development was closely associated with acute mortality and severe brain injury on brain histological analysis. Intra-peritoneal injections of lorazepam and fosphenytoin suppressed seizures and improved survival but only when applied prior to seizure onset and not after. These findings together suggest that seizures are a major contributing factor to acute mortality in aging mice following severe brain ischemia and that early anticonvulsive treatment may prevent seizure genesis and improve overall outcomes.

Activation of the kinin system in the ovary during ovulation: role of endogenous progesterone.

BACKGROUND: Previous work by our group and others has implicated a role for kinins in the ovulatory process. The purpose of the present study was to elucidate whether endogenous progesterone, which is an intraovarian regulator of ovulation, might be responsible for induction of the kinin system in the ovary during ovulation. The gonadotropin-primed immature rat was used as the experimental model, and the role of endogenous progesterone was explored using the antiprogestin, RU486. RESULTS: The results of the study revealed that RU486 treatment, as expected, significantly attenuated ovulation. Activity of the kinin-generating enzyme, kallikrein, was elevated in the ovary in control animals prior to ovulation with peak values observed at 4 h post hCG, only to fall to low levels at 10 h, with a recovery at 20 h post hCG. RU486 treatment had no significant effect on ovarian kallikrein activity as compared to the control group. Total ovarian kininogen levels in control animals increased significantly at 12-14 h after hCG - coinciding with initiation of ovulation. Thereafter, ovarian kininogen levels fell to low levels at 20 h, only to show a rebound from 24-38 h post-hCG. RU486 treatment had no significant effect on the rise of total ovarian kininogen levels from 12-14 h after hCG; however, from 30-40 h post hCG, RU486-treated animals had significantly higher total ovarian kininogen levels versus control animals, suggesting that endogenous progesterone may act to restrain elevations of kininogens in the post-ovulatory ovary. This robust elevation of ovarian kininogen levels by RU486 was found to be primarily due to an increase in T-kininogen, which is a potent cysteine protease inhibitor. CONCLUSIONS: Taken as a whole, these results suggest that endogenous progesterone does not regulate kallikrein activity or kininogens prior to ovulation, but may provide a restraining effect on T-kininogen levels in the post-ovulatory ovary.