Background and purpose:Intrathecal chemotherapy is one of the mainstay treatment options for leptomeningeal metastases(LM)from solid tumors.A previous phase Ⅰ study demonstrated the safety and potential efficacy of intrathecal anti-programmed death receptor 1(anti-PD-1)for LM from melanoma.The synergistic efficacy of systemic chemotherapy combined with anti-PD-1 has been widely known.This study aimed to evaluate the safety and feasibility of intrathecal chemotherapy(pemetrexed)and anti-PD-1(toripalimab)for LM patients from solid tumors.Methods:The subjects were patients with LM from solid tumors who were treated at Affiliated Huizhou Hospital of Guangzhou Medical University/Third People's Hospital of Huizhou City.A 3+3 dose de-escalation strategy was implemented to determine the recommended dose with an initial dose of PD-1 inhibitor(toripalimab)40 mg and pemetrexed 15 mg.Pemetrexed was administered twice weekly for the initial 2 weeks of induction therapy,once weekly for the subsequent 4 weeks of consolidation therapy,and once monthly during maintenance therapy.PD-1 inhibitor was initiated at the 4th administration of pemetrexed,administered every 2 weeks for 6 weeks;subsequently,responders continued monthly maintenance therapy alongside pemetrexed.The primary objective was to assess safety based on adverse events and the recommended dose.All participants were observed to investigate the clinical response rate(CRR),disease control rate(DCR)and overall survival(OS).This study was approved by the ethics committee of Affiliated Huizhou Hospital of Guangzhou Medical University/Third People's Hospital of Huizhou City(ethics number:2024-KY-029-01).Results:Seven patients(male:3,female:4,median age:57 years)were enrolled between June and September 2024,including non-small cell lung cancer(6)and breast cancer(1).All patients presented with positive cerebrospinal fluid(CSF)cytology.Six patients presented LM-related neurological dysfunction.Five patients showed LM-related neuroimaging findings.Six patients completed the induction and consolidation therapy,and subsequently received maintenance therapy.One patient,due to bacterial meningitis,did not complete the final administration of toripalimab during consolidation therapy,and maintenance therapy was administered after infection control.Adverse events rate was 100%(7/7),including myelosuppression(100.00%,n=7),elevation of hepatic aminotransferases(42.86%,n=3),fatigue(28.57%,n=2)and hypothyroidism(14.29%,n=1).Three(42.86%)patients had grade 3 adverse events(myelosuppression).The immune-related adverse event(irAE)rate was 14.29%,manifested as hypothyroidism(Grade 2).No dose-limiting toxicity(DLT)was observed.Thus,no de-escalation was applied.The recommended dose was determined to be PD-1 inhibitor 40 mg in combination with pemetrexed 15 mg.Three patients showed improved neurological dysfunction,1 with CSF cytological response,and 2 with neuroimaging improvement.CRR was 57.14%(4/7)by response assessment in neuro-oncology(RANO)proposal criteria.DCR was 100%(7/7).Three patients exhibited abscopal effects with regression of brain metastasis lesions,primary lung lesion and mediastinal lymph nodes,respectively.As of April 10,2025,1 patient died.The median follow-up time was 7.7(5.9-9.3)months.The median OS was not reached with a 6-month OS rate of 85.71%.Conclusion:The combination therapy of intrathecal pemetrexed and a PD-1 inhibitor was well-tolerated and feasible,while also exhibiting potential clinical efficacy in treating LM from solid tumors including non-small cell lung cancer.

Background and purpose:Intrathecal chemotherapy is one of the mainstay treatment options for leptomeningeal metastases(LM)from solid tumors.A previous phase Ⅰ study demonstrated the safety and potential efficacy of intrathecal anti-programmed death receptor 1(anti-PD-1)for LM from melanoma.The synergistic efficacy of systemic chemotherapy combined with anti-PD-1 has been widely known.This study aimed to evaluate the safety and feasibility of intrathecal chemotherapy(pemetrexed)and anti-PD-1(toripalimab)for LM patients from solid tumors.Methods:The subjects were patients with LM from solid tumors who were treated at Affiliated Huizhou Hospital of Guangzhou Medical University/Third People's Hospital of Huizhou City.A 3+3 dose de-escalation strategy was implemented to determine the recommended dose with an initial dose of PD-1 inhibitor(toripalimab)40 mg and pemetrexed 15 mg.Pemetrexed was administered twice weekly for the initial 2 weeks of induction therapy,once weekly for the subsequent 4 weeks of consolidation therapy,and once monthly during maintenance therapy.PD-1 inhibitor was initiated at the 4th administration of pemetrexed,administered every 2 weeks for 6 weeks;subsequently,responders continued monthly maintenance therapy alongside pemetrexed.The primary objective was to assess safety based on adverse events and the recommended dose.All participants were observed to investigate the clinical response rate(CRR),disease control rate(DCR)and overall survival(OS).This study was approved by the ethics committee of Affiliated Huizhou Hospital of Guangzhou Medical University/Third People's Hospital of Huizhou City(ethics number:2024-KY-029-01).Results:Seven patients(male:3,female:4,median age:57 years)were enrolled between June and September 2024,including non-small cell lung cancer(6)and breast cancer(1).All patients presented with positive cerebrospinal fluid(CSF)cytology.Six patients presented LM-related neurological dysfunction.Five patients showed LM-related neuroimaging findings.Six patients completed the induction and consolidation therapy,and subsequently received maintenance therapy.One patient,due to bacterial meningitis,did not complete the final administration of toripalimab during consolidation therapy,and maintenance therapy was administered after infection control.Adverse events rate was 100%(7/7),including myelosuppression(100.00%,n=7),elevation of hepatic aminotransferases(42.86%,n=3),fatigue(28.57%,n=2)and hypothyroidism(14.29%,n=1).Three(42.86%)patients had grade 3 adverse events(myelosuppression).The immune-related adverse event(irAE)rate was 14.29%,manifested as hypothyroidism(Grade 2).No dose-limiting toxicity(DLT)was observed.Thus,no de-escalation was applied.The recommended dose was determined to be PD-1 inhibitor 40 mg in combination with pemetrexed 15 mg.Three patients showed improved neurological dysfunction,1 with CSF cytological response,and 2 with neuroimaging improvement.CRR was 57.14%(4/7)by response assessment in neuro-oncology(RANO)proposal criteria.DCR was 100%(7/7).Three patients exhibited abscopal effects with regression of brain metastasis lesions,primary lung lesion and mediastinal lymph nodes,respectively.As of April 10,2025,1 patient died.The median follow-up time was 7.7(5.9-9.3)months.The median OS was not reached with a 6-month OS rate of 85.71%.Conclusion:The combination therapy of intrathecal pemetrexed and a PD-1 inhibitor was well-tolerated and feasible,while also exhibiting potential clinical efficacy in treating LM from solid tumors including non-small cell lung cancer.

Objective? To explore the effects of the flipped classroom based on micro-lecture in the standardized training for new nurses. Methods? A total of 65 new nurses in Shenzhen Hospital, Beijing University of Traditional Chinese Medicine who were recruited from July 2015 to July 2016 were selected and divided into observation group(n=32)and control group (n=33) by random number table method. The control group received the routine standard training, while the observation group received the flipped classroom based on micro-lecture in addition to the routine standard training. After training, the nurses' theoretical and clinical practise competence were analyzed and compared based on their performance in the Self-initiated Learning Ability Scale, Registered Nurses' Core Competence Assessment Scale and Satisfaction Questionnaire. Results? After training, the nurses in the observation group achieved higher score in theory (82.68±8.85), clinical practice(83.64±5.93), self-initiated learning(112.32±8.62), and nurses' core competence (162.23±17.96) than the control group with statistical significance (t=3.258, 6.679, 6.085, 3.808;P＜0.01). The satisfaction rate was 87.9% in the observation group and 65.6% in the control group with statistical significance (χ2=4.532,P=0.033). Conclusions? The application of the flipped classroom based on micro- lecture in the standardized training of new nurses can better improve the training efficacy, young nurses' comprehensive and core ability and their autonomous learning ability .

Objective To improve the understanding of leptomeningeal metastasis (LM),we analyzed the data of clinical manifestations,imaging findings and cytological analysis of cerebrospinal fluid (CSF) in a group of patients with LM of malignant solid tumors.Methods The clinical data of 94 patients with LM of malignant solid tumors between 2009 and 2014 in our hospital were retrospectively analyzed.We compared the clinical manifestations and auxiliary examinations of patients with different pathological types of LM.The Chi-square test was used to compare the results.Results The pathological types included adenocarcinoma (61),small cell carcinoma (24),squamous carcinoma (6),melanoma (1),large-cell carcinoma (1),and hepatocellular carcinoma (1).The median age was 58 (37-75) and the median KPS score was 40 (10-80).About 98.9％ (93/94) patients had neurologic symptoms.Neuroimaging examination was performed in 84 patients,with the sensitivity of 88.1％ (74/84);cytological analysis of CSF was performed in 85 patients,with the sensitivity of 88.2％ (75/85);while CSF biochemical examination was performed in 85 patients,with the sensitivity of 90.6％ (77/85).The sensitivity of cytology in adenocarcinoma (96.6％,56/58) was higher than those in small cell carcinoma (80％,16/20;P =0.056).The sensitivity of neuroimaging in small cell carcinoma (95.8％,23/24) was higher than that in adenocarcinoma (83.3％,45/52;P =0.409).However,the sensitivity of cytology (1/5) and neuroimaging (4/6) in squamous carcinoma was low,which led to the need of comprehensive analysis for the diagnosis.The incidence of headache,spinal nerve-related symptoms,ependymal enhancement and metastatic nodules of lumbosacral intraspinal in adenocarcinoma and small cell carcinoma showed statistically significant difference,which was 88.5％ (54/61) and 29.2％ (7/24;P ＜ 0.01),18.0％ (11/61) and 45.8％ (11/24;P =0.008),2/6 and 25.0％ (6/24;P=0.017),1.9％ (1/61)and50.0％ (12/24;P ＜ 0.01),respectively.Conclusions Neuroimaging and CSF examination are still the key points for the diagnosis of LM of malignant solid tumors.The clinical manifestations are correlated with pathological types of primary tumor.

Objective To compare the planning quality and acute toxicity between RapidArc and fixed gantry angle dynamic intensity modulated radiotherapy (IMRT) in the postoperative radiotherapy for cervical cancer patients.Methods All 35 patients with cervical cancer who had received postoperative radiotherapy were studied,including 17 patients with RapidArc and 18 patients with IMRT.All plans were prescribed 50 Gy in 25 fractions.The dose-volume histogram data,the conformity index and homogeneity index of the targets,the monitor units (MUs) and delivery time were compared.During the treatment,the incidence of acute intestinal and bladder side effects were also compared.Results Compared to IMRT,the conformity index of RapidArc was better(t =3.13,P ＜ 0.05),but the homogeneity index was slightly worse (t =-4.25,P ＜ 0.05).The V20 and V30 of femoral head planned by RapidArc was significantly lower than that by IMRT (t =2.56,2.34,P ＜ 0.05).The mean MU for RapidArc was reduced by 52.1％ compared with IMRT.The mean treatment time for RapidArc was decreased by 46.8％ compared with IMRT.There was no difference in the incidence of acute intestinal and bladder toxicity between the two groups.Conclusion For patients with cervical cancer who need prophylactic postoperative radiotherapy,both RapidArc and IMRT plan can achieve equal target coverage and organs at risk(OAR) sparing.There is no significant difference in dosimetric parameters and acute toxicity between the two groups.Compared with IMRT,RapidArc plan has fewer MUs and less treatment time and significantly improves the treatment efficiency.

Objective To investigate the value of application of magnetic resonance imaging (MRI) in diagnosis and treatment of leptomeningeal metastases from malignant solid tumors.Methods A retrospective analysis was conducted depend on the radiological data of 63 patients who had been diagnosed as leptomeningcal metastasis of malignant solid tumors.Results All patients received brain MRI examination.26 patients underwent cervical or lumbar spine MRI examination.The MRI images showed nodular enhancement in the gyri and sulci,leptomeningeal linear enhancement,dura mater thickening and enhancement,ependymal enhancement,intraventricular metastasis,intraspinal metastatic nodules,communicating hydrocephalus,subdural hydroma and negative imaging.Ncuroimages of ependymal enhancenent,intraventricular metastasis and intraspinal implantation metastasis appeared in 5,7 and 9 patients with small cell carcinoma,respectively,which were higher than that of the other pathological types (P =0.002,P =0.009,P ＜ 0.000 1).Seizure occurred in 7 patients after intrathecal chemotherapy,of which 5 patients had pia mater linear enhancement.Among 33 patients treated with radiotherapy combined with intrathecal chemotherapy,3 patients had poor prognosis,of which 2 patients had negative imaging findings.The conditions of 25 patients were improved obviously after treatment,of which 21 patients showed different imaging remission in MRI re-examination.Conclusions The contrast MRI has an important assistant effect in diagnosis of leptomeningeal metastasis of malignant solid tumors.The MRI findings and clinical features are related with the pathological types.The pia mater linear enhancement indicates a high possibility of seizures after inthathecal chemotherapy,and it suggests that the preventive treatment should be given for such patients.MRI is not applicable to evaluate severity,prognosis and curative effect of the disease.

Objective To investigate the efficacy and safety of intrathecal chemotherapy combined with concurrent radiotherapy in patients with leptomeningeal metastases from solid tumors.Methods The clinical and follow-up data of 29 patients with leptomeningeal metastases from malignant solid tumor who had intrathecal chemotherapy combined with concurrent radiotherapy were retrospectively analyzed.The treatment regimen was that 12.5-15.0 mg of methotrexate intrathecal injection once a week for 8 successive weeks combined with whole brain irradiation to a total dose of 40 Gy,20 fractions or with lumbosacral spinal canal irradiation to a total dose of 50 Gy,20-25 fractions.Results Nineteen patients completed the concurrent therapy and 19 patients were dead.There were 9 patients with complete remission of symptoms,11 with obvious improved symptoms,6 with alleviated symptoms,and 3 with no relief.All of the 29 patients,were followed up for 0.4-15.0 months.The median survival was 5 months.The 6-month survival rate was 48％ (11/23),excluding 4 patients with follow-up time less than 6 months and 2 patients noncancer deaths.The main toxicities were myelosuppression,methotrexate-related mucositis,chemical nerve root injuries,chemical meningitis,chronic neurotoxicity,seizures,and radiation-related mucositis.The incidence of severe toxicity was 17％ (5/29).Conclusions Combination of intrathecal methotrexate with concurrent radiotherapy can effectively alleviate the symptoms and improve the life quality of patients.The therapy with low incidence of severe toxicity and good tolerance has the trendency to prolong the median survival.