bluuebunny/crossref_metadata_2025 huggingface dataset:
Efficacy and safety of low-dose versus standard-dose immune checkpoint inhibitor as monotherapy in patients with solid tumors: A meta-analysis and systematic review.
Authors: Qian Yu , Wu Yuan , Qin Jianing , Jin Xin
Published: August 2024

188

Background: Immunotherapy is a novel anti-cancer therapy with different mechanisms compared with chemotherapy. Several studies have reported that low dose of immune checkpoint inhibitors (ICIs) is effective. However, it is unknown whether the efficacy of low-dose immunotherapy is inferior to that of standard dose immunotherapy. We aimed to compare the existing randomized clinical trials on the efficacy of immunotherapy at low dose and standard dose as a single agent for patients with solid tumors. Methods: We searched PubMed, EMBASE, and the Cochrane Library for randomized clinical trials with the clinical outcomes of low dose and standard dose of programmed cell death-1 (PD-1)/programmed cell death ligand 1 (PD-L1) inhibitor as monotherapy until November 30, 2023. The low dose is defined as lower than the dose approved by FDA. The hazard ratio (HR) and 95% confidence interval (CI) of overall survival (OS) and disease control rate (DCR) were collected. The Stata 15.0 software was used to analyze the data. Results: Twenty-two studies with 3226 patients with five ICIs for 22 solid tumors were included. There is no difference in OS (HR 1.12, 95% CI = 0.97-1.31; p > 0.05), ORR (Odds ratio (OR) 0.92, 95% CI = 0.76-1.11; p > 0.05) and DCR (OR 0.83, 95% CI = 0.65-1.06; p > 0.05) for patients with low dose and standard dose of PD-1/PD-L1 inhibitors. Conclusions: Our results suggested that PD-1/PD-L1 inhibitor as monotherapy with a low dose may be as effective as standard dose for patients with solid tumors. The regular dose-response relationship may not be appropriate for ICIs. Further work is needed to explore the optimal dose of ICIs based on the comprehensive consideration of efficacy, safety, and economic assessment.
Exploring depression risk among breast cancer survivors: A nationwide cohort study in South Korea.
Authors: Choi Hea Lim , Kim Bongsung , Han Kyungdo , Shin Dong Wook
Published: August 2024

19

Background: With advances in early diagnosis and treatment, the population of breast cancer survivors globally continues to grow. Depression among these survivors poses a significant concern for their long-term survivorship and overall quality of life. This study aims to investigate the incidence of depression among breast cancer survivors and identify associated risk factors. Methods: We used the National Health Insurance Service database of Korea from 2010 to 2016 and examined 59,340 breast cancer survivors and 1:2 age-matched individuals without breast cancer to investigate the incidence of depression. Cox proportional hazards regression was used to calculate the hazard ratio (HR) and 95% confidence interval (CI). The risk of depression was assessed based on age, categorizing individuals as under or over 50 years old. We conducted 1-year, 3-year, and 5-year lag sensitivity analysis to demonstrate changes in risk over time. The study identified risk factors for developing depression through multivariable Cox regression, and Kaplan-Meier analysis was conducted to illustrate the incidence probabilities of depression in breast cancer survivors. Results: Breast cancer survivors exhibited a 39% increased risk of depression compared to individuals without breast cancer, and those under the age of 50 years facing higher risk than their older counterparts (HR 1.64, 95% CI 1.58-1.70 and HR 1.23, 95% CI 1.20-1.27, respectively). Chemotherapy (anthracycline and taxane) and endocrine therapy (tamoxifen and aromatase inhibitor) emerged as potential risk factors for depression among breast cancer survivors. Sensitivity analysis revealed a decreasing trend in depression risk over time, particularly among survivors aged older than 50 years. Conclusions: This study highlights a significant increase in depression risk among breast cancer survivors, particularly those under 50 years old. Specific treatments such as chemotherapy and endocrine therapy were identified as potential risk factors. These findings emphasize the necessity for targeted interventions and support strategies to address the heightened risk of depression in breast cancer survivors, ultimately improving their long-term well-being and quality of life.
Accuracy of gravity based automatic infusion system applied to chemoport for intravenous infusion.
Authors: Choi Jonggwon
Published: August 2024

191

Background: When a vesicant drug is administered to the peripheral vein, a gravity drip method rather than an peristaltic infusion pump is recommended. In addition, it is reported that the gravity based pump has less particle generation than the peristaltic pump that injects fluid through constant peristaltic movement. However, it is pointed out that the disadvantage of gravity based pump is that the rate of administration can easily change according to the change in the location of the injection site. We evaluate the accuracy of new gravity based pump (pressure-sensitive speed control fluid injection device, Accudrip made by Hanvit MD ) at various injection rates and hanging heights common to hospital settings. Methods: The accuracy and safety of the intravenous (IV) flow controller were evaluated for patients receiving IV chemotherapy in the oncology department. It was verified whether the accurate injection rate could be maintained even in various fluid heights, fluid amounts, and types of anticancer drugs that could affect the injection rate. Various anticancer drugs, including immune checkpoint inhibitor, were mixed with 250 ml/500 ml of normal saline and administered for 30 min/60 min, and glucose 500 ml/1000 ml was administered for 60 min/120 min to measure accuracy, each progressed 25 times. Medical staff were surveyed on the ease and limitations of medical practice for each peristaltic infusion pump and new gravity based pump. In addition, side effects occurring in patients during fluid administration were recorded. Results: The mean degree of error in the estimated end time of gravity based automatic infusion system was 3.09% (2.09 ~ 4.10). The error of the gravity based automatic infusion system was statistically significant depending on the patient age (p=.001) and the infusion time (p=.016), but the degree of error according to the type of fluids (p=.302) and fluid concentration (p=.844) was not statistically significant. Among the subjects of the study, nurses' satisfaction with the application of gravity based pump was 4.10 (±0.62) out of 5, and among the general characteristics of nurses, age ( p<.078), and working department (p<.91) did not show a statistically significant difference, but work experience ( p <.021) showed a statistically significant difference. Conclusions: The accuracy of Gravity based automatic infusion system was determined because the degree of error in the expected end time of infusion was not significant according to the infusion variable. In a survey of nurses who have used gravity based pump directly, it was found that the ease of use and satisfaction were similar to those of the conventional peristaltic pump. These findings will contribute greatly to the precise drug administration (over or under-administration) and minimization of adverse events in real-world hospital settings.
Acupuncture for patients with cancer in a palliative care team in Japan: A prospective case series study.
Authors: Masuyama Shoko , Yamashita Hitoshi , Amino Tamami , Kawamoto Ryouko , Tsuji Ryota , Nakanishi Hiromoto , Yoshida Hiroshi
Published: August 2024

193

Background: In the joint guideline of the Society for Integrative Oncology and ASCO, acupuncture is recommended for general or musculoskeletal pain from cancer, chemotherapy-induced peripheral neuropathy, and other conditions. However, Japanese acupuncture needles are thinner and less stimulating than those used in other countries. To assess whether adding Japanese-style acupuncture to usual palliative care alleviates subjective symptoms in hospitalized cancer patients, we conducted a prospective case series study at an urban core hospital in Japan. Methods: Acupuncture treatment was administered to participating cancer patients once or twice a week, for a maximum of six sessions over three weeks. Each treatment session lasted approximately 30 minutes. Patients in the study continued to receive standard care. The main outcome measure was the change in the 10 cm visual analog scale (VAS) for the primary subjective symptoms immediately after treatment. We regarded a reduction in VAS of 20% or more as a minimal clinically important difference (MCID). The protocol of the study was approved by the Clinical Research Ethics Committee of Osaka General Medical Center (CRB5180013). Results: During the study period, 83 cancer patients gave written consent to receive acupuncture treatment. The mean age was 66.1 years (SD 10.7), with 66% of patients in stage 4, and 70% using opioids. Significant reductions in VAS scores for subjective symptoms were observed immediately after treatment for pain (1st session: from 5.4 to 3.9 on average, P<0.001; 2nd: 4.9 to 3.4, P<0.001; 3rd: 3.9 to 2.6, P<0.001; 4th: 4.7 to 2.8, P=0.002), edema (2nd: 5.5 to 3.7, P<0.001), paresthesia (2nd: 6.2 to 4.6, P=0.005), nausea (1st: 6.5 to 3.9, P=0.012; 2nd: 3.3 to 2.0, P=0.008), stiffness (1st: 6.8 to 3.1, P=0.011; 2nd: 4.3 to 2.8, P=0.022), and breathing difficulty (1st: 5.9 to 3.2, P=0.012). However, there was no significant improvement in malaise across any sessions. The maximum percentages of patients experiencing symptom relief beyond MCID in pain, edema, paresthesia, nausea, stiffness, and breathing difficulty were 67%, 75%, 60%, 80%, 88%, and 83%, respectively, across the treatment sessions for each symptom. There was no significance in odds ratios for age, sex, previous acupuncture experience, or opioid use associated with clinically meaningful pain reduction. All recorded adverse events were mild and transient. Conclusions: The symptom relief observed in this study is only a short-term effect immediately after treatment and includes non-specific effects such as the placebo effect. Future research should explore the specific effects of acupuncture using an exploratory trial design. However, determining the appropriate control group for acupuncture trials remains controversial. At least from a clinical perspective, acupuncture may be a possible option for palliative care for cancer patients, including in Japan.
Identifying risk factors associated with self-reported lower quality of life (QoL) in individuals with PTEN hamartoma tumor syndrome.
Authors: Schmidt Terralyn , Anthony Kristin , Gorman Nicholas , George Amy , Ales Claudio
Published: August 2024

194

Background: PTEN Hamartoma Tumor Syndrome (PHTS) is a multisystem disorder that affects various organs and systems in the body, presenting with a range of clinical manifestations. Individuals with PHTS face elevated risks of cancer and neurological symptoms, along with significant physical and psychological challenges, which underscores the need for ongoing research and the development of effective management strategies. The purpose of this study is to identify risk factors that are associated with a lower self-reported quality of life in individuals with PHTS using quantitative data from the PTEN Hamartoma Tumor Syndrome Foundation's patient registry surveys. Methods: Spearman correlation analysis of survey answers from 232 registry members in the foundation revealed negative correlations between quality of life and clinical features such as autism spectrum disorder (-.20**) and cancer diagnoses (-.21**). Results: This suggests that the more severe and penetrant cases of PHTS on the spectrum of variability face challenges that negatively impact quality of life. Additionally, 72.6% of participants reported that reducing cancer risk is a top priority. Conclusions: The findings highlight the need for healthcare providers to anticipate the need for extra care and psychosocial attention for individuals with PHTS who have an autism diagnosis, and to provide education and counseling about cancer prevention strategies to those with a heightened cancer risk. [Table: see text]
Assessing the efficacy and safety of a novel, registration-free, CT-guided percutaneous transthoracic needle biopsy navigation system (RC120): A multicenter, prospective, single-arm clinical trial.
Authors: Zhou Caicun , Wang Lei , Min Xuhong , Song Biao , Zhang Zheng , Bo Bing , Xiong Anwen , Ye Lingyun , Xie Dacheng , Li Juanjuan , Wang Shanghu , Li Yuan , Song Qilong , Wang Zhaohua , Wang Mengjie , Cao Yanan , Liu Jian , Niu Bing , Fang Chunfu , Shen Shuting
Published: August 2024

197

Background: Current optical and electromagnetic navigation systems for CT-guided percutaneous transthoracic needle biopsies (PTNB) have limitations. They require surface markers on the patient and intraoperative registration. Specific patient positioning during biopsies is required. Our team developed a new navigation system that addresses these issues. It doesn’t rely on patient surface markers or intraoperative registration, and it provides more flexibility in patient positioning during biopsies. Our research evaluates the effectiveness and safety of this system. Methods: A single-arm prospective study was conducted, including participants aged 18-80 years prepared for percutaneous lung core biopsy at two clinical centers in China. The primary endpoint was the success rate of biopsies within 2 needle adjustments. The secondary endpoint was the success rate of biopsies within a single needle adjustment. Safety endpoints were defined by the occurrence of adverse events. The number of CT scans patients underwent during the procedure was used to assess radiation dosage. Follow-up was conducted on subsequent pathological and molecular diagnoses. Results: The study included 98 patients from two sites, with a median age of 64 years. Most participants were males, accounting for 72.45% (71 out of 98). The primary endpoint was achieved with a biopsy success rate of 98.98%, requiring a maximum of two needle adjustments. The secondary endpoint was met, demonstrating a biopsy success rate of 97.96% with a maximum of one needle adjustment. The overall success rate was 98.98%, with a 95% confidence interval (CI) of 94.45% to 99.97%, significantly exceeding the target value of 85% (P < 0.0001). The median number of CT scans was 3, ranging from 3 to 12. The average duration of the procedure was 18.0 minutes. Regarding safety endpoints, the two most common adverse events were hemorrhage in the lesion (14 instances, 29.17%) and pneumothorax (8 instances, 16.67%). Other adverse events included elevated blood pressure (5 instances, 10.42%), hemoptysis (4 instances, 8.33%), and other common adverse events such as cough, constipation, anemia, and bloody sputum, each occurring twice. There were 9 other less common adverse events, each occurring once. These adverse events are common in PTNB and can be attributed to the puncture operation itself, not our navigation system. Conclusions: Our new registration-free navigation system proved to be an effective, efficient, safe, and well-utilized system for assisting percutaneous lung biopsies in clinical practice. Clinical trial information: ChiCTR2300072197 .
Intracranial outcomes of 1L selpercatinib in advanced RET fusion-positive NSCLC: LIBRETTO-431 study.
Authors: Uh Minji , Perol Maurice , Goto Koichi , Solomon Benjamin J. , Park Keunchil , Nadal Ernest , Bria Emilio , Martin Claudio , Bar Jair , Williams Justin , Puri Tarun , Li Jian , Lin Boris K. , Zhou Caicun
Published: August 2024

199

Background: Selpercatinib is a highly selective and potent CNS active RET inhibitor approved for treatment of advanced RET fusion-positive ( RET+) NSCLC. Treatment or prevention of CNS disease is critical in RET+ NSCLC patients (pts), who have nearly a 50% lifetime prevalence of brain metastases (mets) (Drilon et al. JTO 2018). LIBRETTO-431 is the first study to compare intracranial (IC) efficacy of a targeted therapy to chemo/IO in pts with oncogene driven NSCLC. Methods: LIBRETTO-431 (NCT04194944) is a randomized, open-label, phase 3 trial comparing 1L selpercatinib vs chemotherapy (cisplatin/carboplatin + pemetrexed) +/- pembrolizumab. As previously reported, the study met its primary endpoint of PFS by blinded independent central review (BICR) at the pre-planned interim analysis. IC analyses included CNS and non-CNS PD, IC PFS and IC responses by BICR per RECIST 1.1 in all pts who had a baseline and one or more post-baseline CNS scans (CNS-evaluable) and were designated to receive pembrolizumab if randomized to the control arm (CNS-pembro population). Adverse events were evaluated in the CNS safety population. Results: A total of 192 of 261 pts enrolled were CNS-evaluable (selpercatinib: 120, control: 72). Baseline characteristics were generally balanced with the selpercatinib arm having a slightly lower proportion of pts with BICR-assessed baseline brain mets (21% vs 25%) and prior CNS radiotherapy (RT; 6% vs 10%) compared to the control arm. Selpercatinib delayed CNS PD as evidenced by a lower 12 mo cumulative incidence rate (CIR) for CNS PD, as well as delaying non-CNS PD compared to control in pts with and without brain mets (Table). In pts with measurable brain mets at baseline (n=29), median time to IC response per RECIST 1.1 was similar between selpercatinib and control (1.4 mo [range: 1.2-2.9] vs 1.6 mo [range: 1.2-2.9]); however, as previously reported the IC response rates were higher (82% vs 58%) and more durable (12 mo DOR rate 76% vs 63%) with selpercatinib vs control (Zhou et al. NEJM 2023). IC responses to selpercatinib were more common in pts without prior CNS RT (14/15, 93%) than with prior CNS RT (3/6, 50%). Conclusions: Selpercatinib delayed IC progression in advanced RET+ NSCLC pts with or without baseline brain mets and achieved higher IC response rates compared to chemotherapy + pembrolizumab. LIBRETTO-431 is the first study to demonstrate IC efficacy improvement of a targeted therapy vs chemo/IO in a biomarker selected NSCLC population. These data further support selpercatinib as the preferred 1L regimen in pts with advanced RET+ NSCLC. Clinical trial information: NCT04194944 . [Table: see text]
Updated efficacy of anti-TROP2 ADC ESG401 for first-line metastatic TNBC in phase 1b study.
Authors: Ma Fei , Qiu Fuming , Tong Zhongsheng , Shi Yehui , Yu Guohua , Wu Xinhong , Wang Hong , Wang Jiani , Yang Hua , Liu Anwen , Zhang Yan , Zheng Hongmei , Lan Qiongyu , Zhang Yongqiang , Cheng Ying , Zhou Qing , Xing Xiaoyan , Chen Xiaomei
Published: August 2024

2

Background: ESG401, a novel ADC comprising a humanized anti-TROP2 IgG1 monoclonal antibody conjugated to SN-38, with a Drug-Antibody Ratio of 8 and a stable cleavable linker, demonstrated preliminary efficacy and tolerability in the Phase Ia trial (Ma, ASCO 2023). This report presents updated results from the first-line mTNBC cohort of the Phase Ib trial and results from patients with brain metastases. Methods: Patients (pts) aged ≥18 years with confirmed local advanced/unresectable or metastatic TNBC, without prior metastatic treatment, received ESG401 (16 mg/kg IV on Day 1,8, and 15, with a 28-day cycle) until unacceptable toxicity, progressive disease, or consent withdrawal. Results: As of the cutoff date (Apr 7th, 2024), 24 pts in the cohort received ≥1 dose of ESG401. Median age was 53 years (range: 33-73), 33.3% were ECOG 0, 25.0% were de novo stage IV, 70.8% had visceral disease (8.3% brain, 33.3% liver, 50.0% lung). Updated efficacy results are shown in the Table. Thirteen pts (68.4% of 19 efficacy evaluable pts) remained on treatment, with the longest on-treatment duration being 10.3 mons. Median PFS has not been reached. Two pts in this cohort had brain metastases, with one achieving a complete intracranial response and an overall response of PR, and the other demonstrating overall PR with a -13.8% reduction in brain lesion size. Totally 16 pts with brain metastases were enrolled in the entire Phase Ia/1b trials, for these pts, the best overall intracranial response rate was 31%, with an intracranial disease control rate of 75%, while the corresponding overall response rate and disease control rate were 50% and 69%, respectively. The response of intracranial lesions to the treatment is consistent with that of extracranial lesions. The safety profile of ESG401 remained consistent with previous reports, showing no new or unexpected safety signals. Conclusions: ESG401 monotherapy demonstrates promising antitumor activity in 1L mTNBC pts, characterized by a high response rate and durable response. The ORR numerically exceeded that reported in the BEGONIA Study arm 7 in which pts with the same indication were treated with TROP-2 ADC and PD-L1 combination therapy. Additionally, ESG401 shows clear potential for treating HER2-negative breast cancer with brain metastases, including mTNBC and HR+/HER2- BC. These results support further clinical investigation of ESG401. Clinical trial information: NCT04892342 . [Table: see text]
Outcomes of EGFR, ALK, ROS1, BRAF, MET, and RET mutated non-small cell lung cancer with brain metastases (NSCLC BM).
Authors: Li Xiaoyan , Shi Weiwei
Published: August 2024

201

Background: Non-small cell lung cancer (NSCLC) is a leading cause of brain metastases. Advances in gene-directed therapies have shifted the focus away from traditional platinum-based chemotherapies. Key targeted mutations in NSCLC include EGFR, ALK, BRAF, MET exon skipping, RET fusions, and ROS1 rearrangements. This retrospective study aims to explore overall survival (OS) and progression-free survival (PFS) in NSCLC BM patients with these gene mutations. Methods: In this retrospective study, conducted by the Department of Medical Oncology at Beijing Tiantan Hospital and the First Medical Center, PLA General Hospital, we reviewed 1526 patients with NSCLC brain metastasis from 2010 to 2022. Data collected included molecular marker status, systemic therapies, and dates of progression. The analysis focused on determining OS and PFS from the time of brain metastasis diagnosis to the last follow-up or death. Statistical analysis used the Cox proportional hazards model. Results: The study reviewed 1526 patients, identifying the following mutation distribution: EGFR mutations in 628 patients, ALK rearrangements in 207 patients, ROS1 rearrangements in 64 patients, BRAF mutations in 31 patients, MET exon skipping in 55 patients, and RET fusions in 42 patients. Significant variations in median OS (mOS) and median PFS (mPFS) were observed across these mutation groups. Patients with EGFR and ALK mutations demonstrated longer mOS and mPFS. Patients with RET and ROS1 mutations also showed better outcomes compared to those with BRAF and MET mutations. Conclusions: This study highlights the importance of molecular mutations in NSCLC BM as prognostic indicators and therapeutic targets. EGFR and ALK mutations were associated with more favorable outcomes, emphasizing the need for personalized medicine in managing NSCLC BM. The study suggests further research focused on specific mutation types is crucial to refine treatment strategies and improve patient care.
Differential expression in potential therapeutic target protein by treatment in small cell lung cancer with and without transformation.
Authors: Murata Saori , Horinouchi Hidehito , Yatabe Yasushi , Kashima Jumpei , Masuda Ken , Shinno Yuki , Okuma Yusuke , Yoshida Tatsuya , Goto Yasushi , Yamamoto Noboru , Watanabe Shun-ichi , Matsumoto Yuji , Okuma Kae , Ohe Yuichiro
Published: August 2024

202

Background: Small cell lung cancer (SCLC) is a disease with a poor prognosis. Besides combination strategy with immune checkpoint inhibitors (ICIs) and cytotoxic agents, antibody-drug conjugates (ADCs) and bispecific T-cell engagers (BiTE) are being developed. These drugs target tumor-associated surface protein. Whether prior treatment affect the transition of protein expression has not been fully investigated especially in the era of ICIs. The purpose of this study is to evaluate changes in protein expression in SCLC tissues before and after treatment. Methods: We included patients diagnosed with SCLC by surgery or biopsy and underwent re-biopsy after treatment (non-transformed group) at the National Cancer Center Hospital between 2014 and 2023. Patients who were initially diagnosed with non-small cell lung cancer and underwent transformation to SCLC (transformed group) were also included. Tissues were obtained by surgery, bronchoscopy, or CT-guided biopsy with an interval of at least 100 days. We investigated clinicopathological features in paired specimens focusing on DLL3, ASCL1, NEUROD1, POU2F3, and YAP1, which have been reported to be expressed in SCLC, as well as tumor-associated surface proteins potentially related to novel drug development. Results: Fourteen non-transformed group cases and 9 transformed group cases were included. Of these, pathology specimens were evaluable in a total of 15 cases: 9 for the non-transformed group and 6 for the transformed group. The median age was 68 years, 11 (73%) were male, 11 (73%) were smokers, 8 (53%) were in clinical stages I-IIIA, 1 (7%) in stages IIIB and 6 (40%) in stage IV. Among the transformed group, 4 of them were treated by Osimertinib before transformation. Progression free survival from first-line therapy was 298 days (255-446) vs. 314 days (245-NA) and overall survival was 1239 days (567-NA) vs. NA days (517-NA), respectively for non-transformed group and transformed group. For both these group of cases, we have evaluated several protein expressions as described above. The transition of these proteins within each group is presented in the conference. Conclusions: In this study, we focused not only on proteins already reported to be expressed in SCLC, but also on proteins that are potential new therapeutic targets and evaluated changes in protein expression. [Table: see text]
Feasibility of pretreatment FDG PET radiomics in predicting circumferential margin involvement for esophageal cancer after neoadjuvant concurrent chemoradiotherapy.
Authors: Shen Wei-Chih , Chou Ying-Hsiang , Chung Meng-Wei , Wang Guo-Zhi , Lee Jang-Ming , Liao Yi-Han
Published: August 2024

203

Background: Involvement of circumferential resection margin (CRM) proves to be a valuable factor in predicting prognosis for patients with esophageal cancer. This study aimed to explore the feasibility of using pretreatment 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) in predicting CRM involvement for patient received neoadjuvant concurrent chemoradiotherapy (CCRT). Methods: We retrospectively enrolled patients with esophageal cancer who received neoadjuvant CCRT followed by radical surgery between October 2013 and July 2023. All patients received FDG PET/CT examinations before CCRT. The maximum standardized uptake value (SUVmax) within a tumor was identified, and the metabolic tumor volume (MTV) was calculated by using a fixed SUV threshold method (50 % of SUVmax). Descriptive features and five groups of radiomic features (Gray Level Co-occurrence Matrix [GLCM], Gray Level Dependence Matrix [GLDM], Gray Level Run Length Matrix [GLRLM], Gray Level Size Zone Matrix [GLSZM], and Neighboring Gray Tone Difference Matrix [NGTDM]) were further calculated to describe the heterogeneity of the FDG uptakes within MTV. The CRM involvement status was defined by the Royal College of Pathologists (RCP). Tumor presence at or within 1 mm of the cut margin was considered CRM positive. Finally, we used the area under the receiver operating characteristic curve (AUC) to evaluate the predictive performance of radiomic features for CRM. The significance level was set to 0.05. Results: A total of 71 cases of esophageal tumors, encompassing data from 70 patients were included. Of the 70 patients, 94% were male with a mean age 58 years across the entire cohort. Sixteen tumors were proved as CRM positive (16/71, 22.5%). Finally, 2 descriptive features and 10 radiomic features were selected that can effectively predict CRM status. These ten radiomic features exhibit robust predictive power for CRM status, demonstrating significance across various discretization bin number. The best performing feature is Skewness (AUC=0.716, p-value<0.0001). Conclusions: This preliminary result revealed that CRM involvement for esophageal cancer tumors could be predicted by using radiomic features. Future studies are warranted for clinical application. [Table: see text]
Efficacy and safety analysis on the combination of camrelizumab with nab-paclitaxel and cisplatin-based chemotherapy in first-line treatment of advanced or metastatic esophageal squamous cell carcinoma.
Authors: Cong Xiaofeng , Xu Zijun , Liu Ziling
Published: August 2024

205

Background: Nab-paclitaxel has indicated good efficacy during the multi-line esophageal squamous cell carcinoma (ESCC) treatment. Our study summarized the efficacy and safety of the first-line combination treatment of camrelizumab with nab-paclitaxel and platinum in advanced or metastatic ESCC patients. This could provide evidence of the positive effects of using nab-paclitaxel. Methods: We included patients with advanced or metastatic ESCC who received camrelizumab in association with nab-paclitaxel and cisplatin for 3-6 cycles as first-line therapy. The patients were recruited from the First Hospital of Jilin University between August 2021 and December 2023. The primary endpoint was the objective response rate (ORR), while the secondary endpoints were progression-free survival (PFS), overall survival (OS), disease control rate (DCR), PFS, and OS rates at 12, 18, and 24 months, including safety. Results: 43 patients were included in this study, they were assessed based on the therapeutic effect, with 72.1% [95% CI,58.1%-86.1%]ORR and 100% DCR. The median PFS was 25.5 months, and the median OS was not achieved. The OS rates were 96.8%, 86.4%, and 78.6% at 12 months, 18 months, and 24 months, respectively. In contrast, the PFS rates were 90.1%, 75.8%, and 68.3%, respectively. Grade 3 or above treatment-related adverse reactions (TRAEs) occurred in nine patients (20.9%). No patient developed severe grade 5 TRAEs. Conclusions: During the first-line treatment of advanced or metastatic ESCC, applying nab-paclitaxel in associated with camrelizumab and cisplatin -based therapy showed a positive effect. Therefore, the results exhibit an extension of OS and PFS with manageable safety and no new TRAEs.
Programmed cell death ligand 1 (PD-L1) inhibitors versus programmed cell death 1 (PD-1) inhibitors for the first-line therapy of extensive-stage small cell lung cancer: A propensity score-matched study.
Authors: Tian Yaru , Lu Shuangqing , Sun Yulan , Tang Xiaoyong , Sun Zhuoran , Zhao Ke , Du Guochang , Li Wanjing , Zhu Hui
Published: August 2024

206

Background: Addition of programmed cell death ligand 1 (PD-L1) inhibitors or programmed cell death 1 (PD-1) inhibitors to etoposide‐platinum (EP) chemotherapy has become the standard first-line regimen for ES-SCLC. The clinical efficacy and safety between the two types of immune checkpoint inhibitors (ICIs) remain controversial. We conduct the retrospective study and propensity score-matched analysis to explore the potential differences between them. Methods: Patients diagnosed with ES-SCLC and treated by EP plus PD-L1 or PD-1 inhibitors at Shandong Cancer Hospital between March 2019 and November 2022 were reviewed retrospectively. According to PD-L1 or PD-1 inhibitors, they were divided into two groups. Propensity score matching (1:1) was performed to balance the baseline characteristics of the two groups. The baseline characteristics and adverse events between the two groups were compared using the chi-squared test. The survival curves of overall survival (OS) and progression-free survival (PFS) were plotted by the Kaplan-Meier method and differences were analyzed by the log-rank test.The primary endpoints were OS and PFS. Results: As a result, 448 patients were analyzed in this study. 264 patients received PD-L1 inhibitors plus EP and 184 received PD-1 inhibitors plus EP. The median follow-up was 17.6 months. The median OS and PFS was 20.4 months and 7.8 months in the overall population. Before propensity score matching, the median OS was 20.1 months in PD-L1 inhibitor plus EP group and 20.7 months in PD-1 inhibitor plus EP group, respectively (HR 1.043, 95%CI 0.776-1.401; p= 0.781). The median PFS was 7.6 months in the PD-L1 inhibitor plus EP group and 8.5 months in PD-1 inhibitor plus EP group (HR 1.099, 95%CI 0.886-1.364; p= 0.390). After propensity score matching, the median OS and PFS were 20.4 months and 7.8months in PD-L1 inhibitor plus EP group, and those were 20.1 months and 8.6 months in PD-1 inhibitor plus EP group. There was no significant difference in OS and PFS between PD-L1 inhibitors plus EP and PD-1 inhibitors plus EP in the matched population (HR 1.104; p= 0.578 and HR 1.072; p= 0.602, respectively). The overall adverse events were comparable in the two groups. Only ≥3 grade neutropenia was more frequent in the PD-L1 inhibitors plus EP group (77.7% vs 69.0%, p= 0.040). Conclusions: In conclusion, the overall efficacy and safety profile was similar between PD-L1 inhibitors and PD-1 inhibitors for the first-line treatment of ES-SCLC.
A comprehensive meta-analysis of tissue resident memory T cell shaping non-small-cell lung cancer immune microenvironment and patient prognosis.
Authors: Shen Aidan , Garrett Aliesha , Chao Cheng-chi , Liu Dongliang , Zhu Yangzhi , Mai Junhua , Jiang Chongming
Published: August 2024

210

Background: Tissue-resident memory T cells (TRM) are a specialized subset of long-lived memory T cells that reside in peripheral tissues. However, the impact of TRM-related immunosurveillance on the tumor-immune microenvironment (TIME) and tumor progression across various non-small-cell lung cancer (NSCLC) patient populations is yet to be elucidated. Methods: Our comprehensive analysis of multiple independent single-cell and bulk RNA-seq datasets of patient NSCLC samples generated reliable, unique TRM signatures, through which we inferred the abundance of TRM in NSCLC. A machine learning model was developed to prognosticate survival, tested in multiple independent NSCLC cohorts. Model performance was corroborated through Kaplan-Meier survival plots, receiver operating characteristic (ROC) curves, principal component analysis, and t-SNE analyses. Results: We discovered that TRM abundance is consistently positively correlated with CD4+ T helper 1 cells, M1 macrophages, and resting dendritic cells in the TIME. In addition, TRM signatures are strongly associated with immune checkpoint genes and the prognosis of NSCLC patients. A TRM-based machine learning model to predict patient survival was validated and an 18-gene risk score was further developed to effectively stratify patients into low-risk and high-risk categories, wherein patients with high-risk scores had significantly lower overall survival than patients with low-risk. The prognostic value of the risk score was independently validated by the TCGA dataset and multiple independent NSCLC patient datasets. Notably, low-risk NSCLC patients with higher TRM infiltration exhibited enhanced T-cell immunity, nature killer cell activation, and other TIME immune responses related pathways, indicating a more active immune profile benefitting from immunotherapy. However, the TRM signature revealed low TRM abundance and a lack of prognostic association among lung squamous cell carcinoma patients in contrast to adenocarcinoma, indicating that the two NSCLC subtypes are driven by distinct TIMEs. Conclusions: Altogether, this study provides valuable insights into the complex interactions between TRM and TIME and their impact on NSCLC patient prognosis. The development of a simplified 18-gene risk score provides a practical prognostic marker for risk stratification. Keywords: Tissue resident memory T cell, non-small-cell lung cancer, prognosis, tumor immune microenvironment, machine learning.
Predictive and pharmacodynamic biomarkers for combination therapy in stage III-IV melanoma: A Simon phase II trial (NCT03999749).
Authors: Mizutani Teruyuki , Muramatsu Tomoaki , Handzlik Joanna , Kimono Diana , Mitra Ankita , Yang Eddy , Kirchhoff Tomas , Puranik Amrutesh , Weber Jeffrey S.
Published: August 2024

222

Background: The evaluation of biomarkers that predict response and immune-related adverse events (irAEs) is crucial for optimizing melanoma treatment with Immune checkpoint inhibitors (ICIs). We report predictive and pharmacodynamic biomarkers for response and irAEs using high-dimensional flow cytometry in a phase II trial combining nivolumab (3 mg/kg), ipilimumab (1 mg/ml), and the IL-6 receptor inhibitor tocilizumab (4 mg/kg) in unresectable/advanced melanoma patients. Methods: We analyzed serum and blood from melanoma patients at baseline, weeks 7 and 37, categorized them by irAE severity and clinical response. Patients were categorized based on the severity of irAEs (grades 3-5) (TOX), the absence of toxicity or grades 1-2 irAE (NT), clinical benefit (CB), and non-clinical benefit (NCB). Immune monitoring regimen included ELISA for IL-6, gp130, IL-23, osteopontin, and Luminex oncological panel (LXSAHM-22). We employed multi-parametric flow cytometry panels to examine myeloid cells, cytotoxic T cells, and checkpoint protein expression on immune cells. We processed ~1 million PBMCs per sample using various antibodies, with data acquisition performed via Sony’s ID7000 cytometer. The data underwent quality control, normalization PBMCs per patient, concatenation, dimensionality reduction, and clustering in FlowJo. Results: Among the 70 patients administered treatment, we observed a best overall response rate of 57%. Grade 3-5 irAEs occurred in 22% of patients by week 24. Patients manifesting irAEs exhibited notably higher baseline Th17 cell counts (NT=181±18 vs. Tox=311±49, p<0.01) and CD26+ Naive CD4 T-cell populations (NT=5838±801 vs. Tox=9632±1343, p<0.04), suggesting their potential role as predictive markers for toxicity. Additionally, in vitro investigations led us to identify CD26 co-stimulation as a preliminary step in TH17 cell differentiation. Key pharmacodynamic markers included a significant elevation in Treg cells (NCB=1286±71 vs. CB=1492±95, p=0.02) and reduction in serum gp130 levels (NCB=104±5 vs. CB=83±5 ng/ml, p<0.01) at week 7 in addition to IL-6 (NCB=7.5±1.5 vs. CB=4.6±1.1 pg/ml, p<0.01) and osteopontin (NCB=95±15 vs. CB=25±3 ng/ml, p<0.01) by week 37 when compared to baseline. Conclusions: Our findings suggest that Th17 cells can serve as a toxicity biomarker for combination therapy with ipilimumab, nivolumab and tocilizumab. Circulating Treg cells and serum osteopontin have emerged as promising pharmacodynamic biomarkers. Clinical trial information: NCT03999749 .
Validation of a chemotherapy toxicity prediction model in older adults with cancer in Taiwan.
Authors: Chang Chieh-Ying , Hung Yu-Shin , Kuo Ming-Chung , Hsu Chih-Chung , Chen Jen-Shi , Chou Wen-Chi
Published: August 2024

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Background: The Cancer and Aging Research Group (CARG) model is established for predicting chemotherapy-related toxicities in older patients; however, its applicability has not been validated in Taiwanese or non-solid tumor populations. Due to biopsychosocial distinctions in the Taiwanese demographic and inherent disparities between lymphoma and solid tumors, a modified CARG (mCARG) was assessed for its toxicity prediction capabilities. Methods: In this study, 337 consecutive patients aged ≥65 years with solid tumors (N=258) or lymphoma (N=79), slated for first-line chemotherapy, were recruited from a single medical center in Taiwan between 2018 and 2021, with follow-up until December 31, 2021. Patients were categorized into low-, medium-, and high-risk groups based on mCARG, excluding the cancer-type parameter from the original CARG variables. Validation of mCARG involved receiver operating characteristic (ROC) curves, and individual mCARG variables were analyzed using univariate analysis for their impact on chemotherapy toxicities and overall survival. Results: This study included 337 patients (mean age, 70 years; 160 female [47%]; 177 male [53%]) classified as low-(N=112, 33.2%), medium-(N=106, 31.5%), and high-(N=119, 35.3%) risk. Toxicities of grades ≥3 were 41.1%, 50.0%, and 71.4% ( P<0.001), respectively. ROC was 0.665 (95% CI: 0.608–0.722), indicating satisfactory discrimination. However, the lymphoma subgroup exhibited no significant differences in toxicity risk levels (70.0%, 74.1%, and 81.0%; P=0.39). Among mCARG variables, age ≥72 years ( P=0.008), polychemotherapy ( P=0.009), decreased hemoglobin ( P<0.001), falls ( P=0.008), and inability to walk one block ( P=0.01) were associated with toxicities. One-year overall survival rates were 80.6%, 69.4%, and 57.2%, respectively, in ascending-risk groups, with high-risk groups showing decreased survival ( P=0.001). Conclusions: This prognostic study validated the mCARG model in a heterogeneous cancer cohort in Taiwan but failed to do so in the lymphoma subgroup. Although unable to predict all toxicities, mCARG could offer insights into patient survival among older individuals with cancer.
Osteosarcoma patient-derived orthotopic xenograft (PDOX) models for identification of novel and effective therapeutics.
Authors: Higuchi Takashi , Hoffman Robert M. , Tsuchiya Hiroyuki , Yamamoto Norio , Hayashi Katsuhiro , Miwa Shinji , Igarashi Kentaro
Published: August 2024

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Background: Osteosarcoma is the most common malignant primary tumor of bone and mainly occurs in young generations. Due to the heterogeneity, rarity, poor response rate to systemic therapy, and metastatic potential of osteosarcoma, individualized precision medicine and novel drug discovery are greatly needed. Toward this goal, we have established the patient-derived orthotopic xenograft (PDOX) mouse model with surgical orthotopic implantation for all major cancers. The PDOX models recapitulate human tumors better than subcutaneous-transplanted xenografts including patient-derived xenograft (PDX). Metastasis is observed to a greater extent in PDOX models due to the intact histology and correct-organ tumor micro-environment of the orthotopically implanted tissue. Therefore, the PDOX model is highly predictive of drug efficacy and useful for identifying effective drugs for tumors in which new drugs are difficult to develop. Methods: We have reported 18 osteosarcoma PDOX studies evaluating approved and experimental drugs since 2017. The present report reviews our research group’s experience with the osteosarcoma-PDOX model, and the power of the PDOX models to identify effective therapeutics. Results: Effective treatment for drug-resistant osteosarcoma includes regorafenib, as monotherapy, and temozolomide-irinotecan, trabectedin-irinotecan, sorafenib-everolimus, sorafenib-palbociclib, and olaratumab-doxorubicin-cisplatin, as combinations. Experimental therapy with recombinant methioninase, tumor-targeting S. typhimurium A1-R, or combinations of these agents and other drugs have shown surprising efficacy in the recalcitrant-osteosarcoma PDOX models. Conclusions: Owing to the high concordance of drug efficacy between patients and their corresponding PDOX models, these models provide improved and personalized treatment options for patients with osteosarcoma. The patient does not need to suffer from the potential drug toxicity and morbidity of ineffective chemotherapies. In an era of growing promise of new treatment and precision medicine, PDOX models can offer a unique opportunity to provide specific and individualized therapy and novel therapeutic options for osteosarcoma patients.
An exploratory investigator-initiated trial via intrathecal or intracerebroventricular delivery of B7H3-specific allogeneic universal CAR-T cells in patients with recurrent high-grade gliomas.
Authors: Shang Xiaoyun , Li Xuetao , Zhang Xuewen , Huang Yulun
Published: August 2024

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Background: The MT027, developed by T-Maximum, is a B7-H3 (CD276)-directed genetically modified allogeneic T cell, targeting CD276-overexpressed tumor cells. Here, we reported a first-in-human, single-center, open-label investigator-initiated trial (IIT) via intrathecal or Intracerebroventricular delivery targeting recurrent high-grade glioma (ChiCTR2100047968). Methods: As of March 7, 2024, a total of 50 adult patients with recurrent high-grade glioma, B7H3+ expression, and KPS ≥40 were enrolled and administered at least one dose of MT027 (FAS), of whom, 32 received at least 3 doses (PPS1), 15 subjects with ≥3 doses and at least 1 efficacy visit (PPS2). 4 dose levels of 1.0, 1.5, 2.0, 2.5×107 cells per injection were administered once every 4 weeks. Results: The overall results demonstrated the favorable tolerability, safety, PK/PD characteristics, and preliminary efficacy. In FAS, the most common AE were fever and headache, without any CRS, ICANS, GvHD, or drug-related death. There were 4 cases (8%) of grade 3 AE or greater and 3 cases (6%) of SAEs. The copies of CAR in all groups reached 10000-100000 copy/ug, and persisted for > 60 days after a single dose. After multiple doses, the MT027 CAR-T cell numbers maintained at a high level (median 8850 copies /μg (range: 200-385900)) and for a long time. The levels of IL6, TNF-α and IFN-γ in CSF increased significantly and maintained for a long time. The mOS was 13.54 m (95% CI: 7.45; 19.63) and 20.73 m (95% CI: 16.12; 25.34) in PPS1 and PPS2, respectively. The 12-month OS rate was 53.30% (95%CI: 37.5%-75.7%) and 84.60% (95%CI: 67.1%-100%) in PPS1 and PPS2, respectively (historical data: 14%). The objective response rate (ORR) was 33% and the disease control rate (DCR) was 80% in PPS2. Conclusions: In patients with relapsed high-grade glioma, the intrathecal or ICV administration of MT027 cell therapy was found to be safe and well-tolerated. The toxicity of grade 3 or above was 1/5 of similar products. The pharmacokinetics and pharmacodynamics of single-dose and multiple-dose treatments were stable. MT027 exhibited longer persistence in the body of the patients, and the cell numbers and cytokine responses induced in vivo were 1-2 orders of magnitude higher than those of similar products. MT027 cell therapy demonstrated the excellent efficacy in treating relapsed high-grade glioma, with significantly prolonged overall survival and higher objective response rate compared to the historical data and similar product data. Currently, we are preparing for the IND filing in US (expected in 2024) with the recurrent glioblastoma as the first indication. Clinical trial information: ChiCTR2100047968 .