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 understand the current practice status of central venous access device(CVAD)maintenance among intensive care unit(ICU)nurses in secondary and above medical institutions in Shandong province,and to provide a basis for further implementation of effective measures to reduce the incidence of central catheter-related bloodstream infections.Methods The CVAD maintenance practice questionnaire was compiled based on domestic and international evidence related to CVAD maintenance,and a survey was conducted in October 2022 to investigate the status of ICU nurses' CVAD maintenance practice in secondary and above medical institutions in Shandong Province.Results There were 1 492 nurses participated in the survey and 1 461 valid questionnaires were recovered,with a valid recovery rate of 97.92％.The type of CVAD used by the nurses was mainly central venous catheters[92.3％(1349/1461)],and the item with the best assessment at each operation was patency of the catheter[81.1％(1185/1461)],and the worst was the patient's feeling[40.7％(594/1 461)].When assessing catheter patency,[59.8％(873/1 461)]of nurses drew back blood into the catheter.In the use of infusion connectors,three-way connectors[76.0％(1 110/1 461)]and heparin caps[62.3％(910/1 461)]were most frequently used.When sterilizing needleless connectors,most nurses could follow the correct range of disinfection,but the time of disinfection needed to be extended,and the most used items for disinfection were povidone-iodine cotton balls/swabs[44.3％(647/1 461)].The timing of changing infusion connectors needs to be standardized.Most nurses would choose saline for catheter flushing,and the number of nurses choosing saline versus heparinized saline when locking the catheter was about 50％.Most nurses can use correct size syringes and follow standardized techniques for flushing and locking.When performing CVAD maintenance,84.7％(1 237/1 461)of nurses chose a specialized care package kit.The most used skin antiseptic was povidone-iodine[63.7％(931/1 461)].Most nurses could follow the standardized range of skin disinfection,but awareness of drying needs to be improved.Dressings covering puncture points were most frequently transparent[99.7％(1 457/1 461)]and gauze[94.7％(1 383/1 461)],and the frequency of gauze dressing changes needs to be standardized.Hand hygiene and aseptic awareness of nurses during CVAD maintenance was good,but hand hygiene and the timing of wearing sterile gloves need to be standardized.Conclusions ICU nurses' CVAD maintenance practices were generally in line with the latest evidence-based recommendations,but assessment,use of maintenance-related items,and hand hygiene and aseptic technique need to be further standardized.It is recommended that nursing administrators enhance ICU nursing human resource allocation as much as possible and form a central line associated bloodstream infection(CLABSI)prevention and control management system to gradually reduce the morbidity of CLABSI within the ICU.