bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multi-dimensional measurements of long-term quality of life and recovery patterns of patients with cervical cancer after treatment.
Authors: Qiu Ling , Zhu Shurong , Wang Hui , Feng Hao , Luo Shen , Yang Xiaoyi , Hou Yingchun , Zhang Tao , Zhao Junda , Qiao Danze , Du Yan , Jiang Hua , Wu Xin 
Published: July 2024

e17533 Background: Cervical cancer is a prevalent malignancy affecting the female reproductive system globally, and its incidence among younger individuals is on the rise. This study employed the CC-PRO137 scale to evaluate the long-term quality of life and recovery patterns of cervical cancer patients post- treatment. Clinicians are guided to provide individualized treatment and psychological support. Methods: This study recruited patients with primary cervical cancer who underwent primary surgical treatment at the Obstetrics and Gynecology Hospital of Fudan University from October 2018 to June 2021. The CC-PRO137 (Cervical Cancer Patient Reported Clinical Outcome Assessment Scale) was used for follow-up to assess changes in the patients' physical, psychological, and social life states. The data was analyzed to examine variations in the recovery status of the patients across 13 modules: urinary function (URI), bowel function (BOW), pelvic organ prolapse (POP), ovarian function (OVA), lymphatic function (LYM), nervous function (NEU), sexual function (SEX), anxiety (ANX), depression (DEP), shame (SHA), belief (BEL), social support (SUP), and daily life (LIF). Subgroup analysis was conducted based on different stages, surgical methods, and adjuvant treatment plans. Results: A total of 304 participants were tested both 6 months and 12 months after the completion of treatment. The scores for URI, NEU, and SEX were significantly higher after one year compared to within 6 months (URI: t=-3.519, p=0.001; NEU: t=-2.138, p=0.033; SEX: t=-2.338, p=0.021). This suggests a notable improvement in urinary function, nervous function, and sexual function after 12 months. In terms of the psychological domain, DEP scores were significantly higher after 12 months compared to within 6 months ( t=-2.517, p=0.012). The LIF index showed a significant improvement after 12 months ( t=-5.224, p<0.001). Subgroup analysis revealed that Stage II had worse outcomes compared to Stages I and III, particularly in terms of URI ( F(2,297) = 10.619, p < 0.001) and POP ( F(2,299) = 8.559, p< 0.001) indexes. The laparoscopy had a greater impact on the urinary system ( t = 2.157, p = 0.046). The adverse effects of concurrent chemoradiotherapy on URI ( F(2,297) = 11.497, p < 0.001) and DEP ( F(2,299) = 4.149, p = 0.017) functions were more significant than those of chemotherapy. Conclusions: The recovery of patients following cervical cancer treatment is primarily observed in improvements in urinary, bowel, and nervous functions in the physiological domain. In the psychological domain, there is a noticeable improvement in depressive state, while the social life domain also shows signs of improvement over time. By focusing on the disease impact within a limited time frame, the scale helps clinicians provide targeted guidance and advice based on the main issues.
An open, prospective, single arm, phase II study of cadonilimab (PD-1/CTLA-4 bispecific antibody) with neoadjuvant chemotherapy in patients with advanced ovarian cancer: Interim analysis from the AK104-IIT-003 study.
Authors: Tang Jie , Tian Wenfang , Huang Si , Yang Jun , Yang Hongying , Zhang Jieqing 
Published: July 2024

e17552 Background: There is an unmet need to improve neoadjuvant chemotherapy (NAC) to decrease postoperative residual disease (R0 rate: 50%) and improve prognosis in ovarian cancer (OC). R0 rate and histopathological response of interval cytoreductive surgery (IDS) after NAC combined with immune checkpoint blockades were reported to be encouraging. Cadonilimab (AK104) is a tetravalent bispecific antibody targeting PD-1 and CTLA-4. In this study, we report the efficacy and safety of AK104 with NAC in patients with advanced-stage ovarian cancer (NCT05430906). Methods: This study is an open-label, prospective, single arm, phase II study of evaluating the efficacy and safety of cadonilimab combined with chemotherapy as neoadjuvant treatment for advanced ovarian cancer. Patients received neoadjuvant therapy of cadonilimab plus platinum-taxane chemotherapy (3 to 4 cycles) followed by surgery. Surgery would be performed within 30 days of completion of neoadjuvant therapy. The primary endpoint was the R0 rate. The secondary endpoints included objective response rate (ORR), disease control rate (DCR), chemotherapy response score (CRS), pathologic complete response(pCR), progression-free survival (PFS), and safety. A sample size of 35 achieves 80% power to detect a difference of 0.2 using a two-sided Z-test to estimate the standard deviation with a significance level (alpha) of 0.1. And the sample size was expected to be 40 cases to ensure that the FAS set contains 35 cases for analysis. Results: 17 patients were enrolled from Dec 12, 2022, to Dec 6, 2023. The median patient age was 57 years (range 45–70 years), and most patients presented with high-grade serous carcinoma (94.1%) and stage IVa (5.9%), IVb disease (76.5%). 15 (88.2%) patients had undergone IDS, with an R0 resection rate of 66.7%. ORR was 94.1%, with 1patient achieved CR and 15 patients achieved PR. 11.8% achieved pathological complete response, and 17.6% had a chemotherapy response score (CRS) of 3. PFS or OS data are not mature by cut-off date. Safety and adverse event (AE) were analyzed after completion of neoadjuvant therapy. Treatment-related AEs (TRAEs) of any grade were evaluated for all study populations. TRAEs of any grade occurred in 13 (76.5%) patients. Grade ≥3 TRAEs occurred in 3 (17.6%) patients. The most common TRAEs were thyroid dysfunction (23.5%) and bone marrow suppression (17.6%). Grade ≥ 3 irAE (immune⁃mediated colitis) occurred in 1 (5.9%) patient. All of the TRAEs, including severe AEs, were manageable, with no new safety concerns in this study. Conclusions: This study showed promising activity with a durable clinical response, supporting the potential of NAC with bispecific antibody AK104 in advanced-stage ovarian cancer. Meanwhile, long-term efficacy evaluation still needs following up. Clinical trial information: NCT05430906 .
Enhanced anti-ovarian cancer efficacy with MSLN-chimeric antigen receptor T cells secreting anti-CD39 antibody.
Authors: Zhu Haiyan , Li Xiaopei , Deng Qi , Zhang Yuchen , Wang Huajing , He Xiaowen , Li Xian-Yang 
Published: July 2024

e17553 Background: The effectiveness of chimeric antigen receptor (CAR) T cell therapy directed at mesothelin (MSLN) in solid tumors, such as ovarian cancer, is hindered by the immunosuppressive tumor microenvironment (TME), where adenosine plays a crucial role in impairing CAR-T cell function. Preclinical and clinical studies have demonstrated that targeting CD39, a pivotal enzyme catalyzing the conversion of extracellular ATP into adenosine, yields significant antitumor effects. Therefore, combining MSLN CAR-T with an anti-CD39 antibody emerges as a potential therapeutic strategy against cancer. Methods: We have previously designed OriA631, an antibody antagonist targeting CD39 in VHH format. Our preclinical investigation has highlighted the outstanding potential of OriA631, showcasing superior performance in binding affinity, effective inhibition of CD39 enzyme activity, and remarkable in vivo high anti-tumor efficacy. Subsequently, we undertook further engineering of MSLN CAR-T cells to secrete the VHH component of OriA631 (MSLN CAR-T-CD39-VHH) and systematically assessed its antitumor effects in NSG mice. Results: Our data reveals that MSLN CAR-T cells exhibit a significant upregulation of CD39 upon activation by ovarian cancer cells in both in vitro and in the tumor microenvironment (TME). To assess the combined effect of MSLN CAR-T with anti-CD39, B-NDG mice were subcutaneously inoculated with 3x10^6 ovarian cancer cells (SKOV3-MSLNhi-CD39hi). Subsequently, different T cells (1x10^7 cells/mouse) were injected when the tumor reached around 80 mm³, and the groups were divided into Mock T, MSLN CAR-T, MSLN CAR-T-CD39-VHH, and MSLN CAR-T in combination with locally injected CD39 Ab (OriA631). The data demonstrated that MSLN CAR-T inhibited tumor growth from approximately 1000mm³ (Mock T group) to 300mm³ at day 30 relative to T cell injection. Tumors in the MSLN CAR-T in combination with OriA631 group were around 100mm³, suggesting a significant combination anti-tumor efficacy of MSLN CAR-T in conjunction with CD39 targeting. Furthermore, MSLN CAR-T-CD39-VHH, where MSLN CAR-T cells secrete the VHH component of OriA631, completely eliminated the tumor at day 18 with no relapse during the experimental period. This result underscores the superior anti-tumor efficacy of MSLN CAR-T-CD39-VHH, with the high level of VHH component of CD39 Ab observed in the TME. Importantly, the low or undetectable level of VHH component of CD39 Ab in the serum also indicates the safety of the product. Conclusions: Our study introduces the innovative therapeutic agent MSLN CAR-T-CD39-VHH, showcasing superior anti-tumor efficacy and the potential for reduced antibody-associated side effects. These findings strongly endorse the application of MSLN CAR-T-CD39-VHH as a promising and impactful therapeutic approach for the treatment of ovarian cancer.
Prospective observational study of nutritional and immunological indices as predictive biomarkers of response to immune checkpoint inhibitors in non-small cell lung cancer (ICI-PREDICT study).
Authors: Takamori Shinkichi , Shimokawa Mototsugu , Yamaguchi Masafumi , Mori Masahide , Kuyama Shoichi , Oki Masahide , Nishimura Yoshifumi , Nakatomi Katsumi , Yanai Hidetoshi , Sukoh Noriaki , Hatakeyama Nobuo , Kita Toshiyuki , Fujiwara Keiichi , Chibana Kenji , Okamoto Masaki , Takenoyama Mitsuhiro 
Published: July 2024

e20524 Background: Nutritional and immunological indices, including controlling nutritional status (CONUT) score, skeletal muscle area (SMA), and neutrophil-to-lymphocyte ratio (NLR) have been reported as predictors of response to immune checkpoint inhibitor (ICI) in non-small cell lung cancer (NSCLC). The aim of this prospective, multicenter study is to evaluate the clinical impact of pre- or early post-treatment changes in nutritional and immunological indices on treatment outcomes in patients with advanced NSCLC treated with first-line ICIs. Methods: We enrolled 301 advanced NSCLC patients treated with ICIs (monotherapy or combined with chemotherapy) as first-line therapy, without any oncogene mutations, and available data on programmed cell death-ligand 1 (PD-L1) expression (150 in training and 151 in validation cohorts) from March 2020 to November 2022. The CONUT score, SMA at the L3 level (cm2/m2), and NLR, were evaluated before treatment initiation and at the first response evaluation. Cut-off values were determined by receiver operating characteristic curves with objective response as the outcome in the training cohort. The primary endpoint was progression-free survival (PFS). For exploratory study, serum before treatment was collected to measure 15 muscle-derived cytokines (Apelin, BDNF, CX3CL1, EPO, FABP3, FSTL1, FGF21, IL-6, IL-15, Irisin, LIF, Musclin, Myostatin, OSM, and SPARC) (n = 123). Results: The median follow-up period and PFS was 17.5 (range: 7.3-39.4) and 6.9 (range: 0.1-31.5) months, respectively. In the training cohort, men (hazard ratio [HR]: 0.52, 95% confidence interval [CI]: 0.30-0.90, p = 0.0183), ΔCONUT < 0 (HR: 0.59, 95% CI: 0.35-0.98, p = 0.0431), and ΔSMA > −0.13 (HR: 0.56, 95% CI: 0.33-0.96, p = 0.0333) were independent predictors for PFS. In the validation cohort, PD-L1 ≥ 50% (HR: 0.54, 95% CI: 0.34-0.84, p = 0.0061), NLR < 3.65 (HR: 0.47, 95% CI: 0.30-0.74, p = 0.0011), and ΔSMA > −0.13 (HR: 0.61, 95% CI: 0.38-0.98, p = 0.0421) were independent predictors for PFS. In the exploratory study, multivariate analysis including muscle-derived cytokines (continuous variables) revealed that performance status = 0 (HR: 0.24, 95% CI: 0.12-0.48, p < 0.0001), without baseline prednisone (≥ 10 mg/day) (HR: 0.17, 95% CI: 0.05-0.58, p = 0.0213), smoking history (HR: 0.34, 95% CI: 0.14-0.81, p = 0.0269), and FSTL1 (HR: 0.97, 95% CI: 0.93-0.99, p = 0.0185) were independent predictors of PFS. Conclusions: ΔSMA was the only factor validated as an independent predictor of PFS. The underlying biological mechanisms may be related to skeletal muscle-derived FSTL1. Clinical trial information: UMIN000040450.
Exposure-response (ER) analyses of efficacy and safety of trastuzumab deruxtecan (T-DXd) to inform dosing recommendation in HER2-mutant non-small cell lung cancer (NSCLC).
Authors: Khatri Amit , Polhamus Daniel , Cobbina Enoch , Garcia Ramon , Yoder Todd , Abutarif Malaz , Garimella Tushar 
Published: July 2024

e20545 Background: T-DXd, a novel human epidermal growth factor receptor 2 (HER2) targeting antibody drug conjugate, was evaluated at doses of 5.4 and 6.4 mg/kg every three weeks in Phase 1 or 2 trials in HER2 mutant (HER2m) NSCLC subjects, including Destiny-Lung01 (DL-01) and DL-02 trials1,2. ER analyses of key efficacy and safety endpoints were conducted to support the dosing recommendation of T-DXd in HER2m NSCLC. Methods: Exposure-efficacy (EE) analysis was performed using confirmed objective response (cORR) data from HER2m NSCLC in Phase 1-2 trials (N = 181). The dataset included primary analysis data cut from DL-011 and interim analysis data cut from DL-02. Exposure-safety (ES) analyses of T-DXd were performed, using pooled data from 11 Phase 1-3 trials (N = 1850) across tumor types, including DL-01 and DL-02, for safety endpoints of adverse events (AEs) associated with dose reduction or discontinuation, Grade3+ (G3+) AEs, serious AEs, G3+Anemia, G3+neutropenia, G3+thrombocytopenia, adjudicated any grade interstitial lung disease (ILD), and G3+ ILD. cORR and all safety endpoints, except ILD were analyzed by logistic regression; any grade ILD was analyzed by parametric time-to-event analysis. The T-DXd or DXd exposure metric and numerous patient-specific covariates were tested in the analysis. Results: T-DXd exposure had a positive but shallow relationship with cORR. The predicted cORR varied from 57% (95% credible interval (CrI): [36, 77]) to 65% (95% CrI: [41, 84]) across 5th and 95th percentile of T-DXd exposure respectively. No clinically meaningful difference in cORR was estimated across 5.4 and 6.4 mg/kg doses with predicted cORR values of 53% (95% CrI: [44, 60]) and 55% (95% CrI: [47, 62]) at T-DXd doses of 5.4 mg/kg and 6.4 mg/kg, respectively. ES relationships were consistent with previous T-DXd ES analyses in breast cancer (BC). Model-predicted AE rates were lower (up to 9%) in 5.4 mg/kg compared to the 6.4 mg/kg dose. Model-predicted safety at 5.4 mg/kg dose in HER2m NSCLC was similar to the approved dose of 5.4 mg/kg in BC. Conclusions: The ER analyses showed no clinically meaningful difference in efficacy between 5.4 and 6.4 mg/kg doses of T-DXd; and safety events were lower in 5.4 mg/kg, thus supporting the 5.4 mg/kg recommended dose for HER2m NSCLC. These findings were later confirmed based on primary analysis in DL-022 and support the utility of ER analyses in dosing recommendation. Reference: Li BT et al. N Engl J Med 2022;386:241-51 Goto K et al. J Clin Oncol 41:4852-4863. Clinical trial information: NCT03505710 , NCT04644237 .
Survival in de novo metastatic merkel cell carcinoma according to sites of metastases.
Authors: Khaddour Karam , Liu Mofei , Giobbie-Hurder Anita , Kim Emily , Thakuria Manisha , Silk Ann W. 
Published: July 2024

e21511 Background: Merkel cell carcinoma (MCC) is an aggressive neuroendocrine skin cancer with a propensity to form regional and distant metastases. Due to the low incidence of MCC, there is a dearth of studies evaluating the impact of the sites of metastases on clinical outcomes. Recently, we found that liver and bone metastases were associated with shorter overall survival (OS) in patients with recurrent metastatic MCC. Herein, we report on the prognostic impact associated with specific metastatic sites in patients who presented with de novo Stage IV MCC at Dana-Farber Cancer Institute. Methods: Patients were included if they consented to participate in a biobanking study (DF/HCC #09-156) and presented with one or more distant sites of metastases on imaging at the time of diagnosis due to MCC. The following data were collected: age at diagnosis, gender, race, metastatic site(s) at the time of diagnosis, date of diagnosis, first-line treatment, treatment type, best response on imaging, progression, and vital status. Overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan-Meier method. Fisher’s exact test was used for response rate analysis. Results were considered statically significant if p < 0.05. Results: 34 participants presented with one or more distant metastatic sites of MCC between the years 2010 and 2022. There was no association between the number of metastatic sites at presentation and OS (p= 0.58), PFS (p= 0.79), or response rates (p= 0.53). Among the organ sites we examined, bone metastases were associated with shorter OS (8.2 versus 25.2 months, HR = 2.4; 95% CI 1.01 – 5.7, p= 0.04). There were non-significant associations between OS and metastases in lymph nodes (p= 0.07) and in liver (p= 0.16). The location of metastases was not associated with the response rate to first-line treatment. There was no statistically significant association between any site of metastases and PFS. Conclusions: In this cohort of patients with de novo metastatic MCC, the presence of bone metastases, but not the number of overall organs involved, was associated with significantly worse overall survival. If bone involvement is confirmed to be a negative prognostic factor in an independent dataset, it would warrant mechanistic studies to further our understanding of this interplay and a re-examination of the AJCC staging for metastatic disease.
Spatially mapping the single-cell immune landscapes of melanoma brain metastases using imaging mass cytometry.
Authors: Magrill Jamie , Allard-Puscas Sarah , Gu Claris , Ramsay LeeAnn , Lajoie Mathieu , Karimi Elham , Maritan Sarah M , Dankner Matthew , Rezanejad Morteza , Zuo Dongmei , Wei Yuhong , Petrecca Kevin , Guiot Marie-christine , Routy Bertrand , Siegel Peter M , Quail Daniela , Walsh Logan , Mihalcioiu Catalin Liviu Dragos , Stagg John , Watson Ian 
Published: July 2024

e21517 Background: Up to 60% of metastatic melanoma patients develop brain metastases, and 5% develop leptomeningeal disease (LD), which presents with the worst prognosis of any melanoma brain metastasis (MBM) infiltration pattern. Median survival duration for MBM is ~12 months, however for LD patients it can be < 10 weeks. The spatial immune landscape of MBM with and without LD remains poorly understood. Methods: To spatially characterize the tumor microenvironment (TME) of MBM, we performed CyTOF Imaging Mass Cytometry (CyTOF-IMC) on a highly multiplexed panel of 35 antibodies for 21 MBMs (13 with LD, 8 without LD). We performed a novel cell segmentation, cell type assignment and identification approach to identify cell lineages to spatially characterize the TME of MBMs, segmenting and classifying 130,000 cells into 19 cell types. Results: We found enrichment of dendritic cells in the direct neighbourhood of melanoma cells of patients with LD (p = 0.019) and trends towards elevation of anti-tumoral monocyte populations in the TME of patients without LD. To investigate survival outcomes, we divided our cohort into long (≥365days) and short-survivors ( < 365 days), and found significant elevation of anti-tumoral T-cell populations (Total T-cells, CD8+ T-cells, CD4+ T-cells and CD3+CD4-CD8- T-cells, p < 0.05), and closer proximity of T-cells (CD8+ & CD4+ T-cells) to melanoma cells (p < 0.05). Survival analysis using median cell-proportion for each T-cell subset showed statistically significant (p < 0.05) survival differences between patients with high and low cell-proportions of CD8+ T-cells and CD4+ T-cells, with similar trends observed for a subset of patients (n = 13) with LD and a subset of patients treated with ICIs (n = 10), and results were confirmed by a Cox Regression Model. Cellular neighborhood (CN) analysis was performed generating N = 12 stable CNs. We found patients with higher proportions of CN9 (M1-like-microglia/M2-like-microglia/melanoma), CN10 (M1-like-macrophages/M2-like-macrophages/melanoma) and CN12 (Cytotoxic-T-cells/Helper-T-cells/melanoma) was associated with longer overall survival after diagnosis with MBM (p < 0.01). Conclusions: Proportion and proximity of anti-tumoral monocyte and T-cell populations may play a key role in modulating tumor response and overall survival for patients with MBM, including for patients with LD or for patients treated with ICIs.
Innovative infusion center assessments of chemotherapy-induced neurotoxicities: A pilot study supporting early and routine screenings as part of survivorship programs.
Authors: Rooker Jennessa , Anderson Matthew L. , Rutherford Thomas , Schwarzberg Rebecca , Sanchez Victoria Ann 
Published: July 2024

e24102 Background: More than 50% of patients treated with taxane and platinum chemotherapy experience neurotoxic adverse events due to treatment, including neuropathy, hearing loss or cognitive impairment. However, because risk factors and clinical trajectory of these toxicities remain poorly understood, it is not yet clear how or when patients should be screened. Innovative technology, such as tablet-based screening tools, create unique opportunities to capture patient symptoms, better understand potentially long-lasting side effects, and determine when to start either preventive or treatment/rehabilitation options. Methods: We assembled a multidisciplinary team from oncology, nursing, and audiology. IRB permission was obtained to perform a longitudinal observational pilot to assess the feasibility of performing chair-side neurotoxicity screenings in the infusion center of an urban safety net health system. Five infusion center nurses were recruited to collect data using a tablet-based application on 55 patients who met the inclusion criteria including chemotherapy-naive patients and fluent in English. Neuropathy and cognitive impairment were measured by validated standardized subjective scales (the Chemotherapy Induced Peripheral Neuropathy Assessment Tool, and the Attentional Function Index, respectively) and objective pure-tone audiometry (SHOEBOX Audiometry). Descriptive statistics were used to summarize outcome data. Results: Baseline assessments were completed on 48/55 patients with 37 completing at least one or up to 6 repeated assessments. All participants had baseline assessments before their first cycle by a chemo-certified RN in the infusion chair. Our sample included 55 adults aged 29 to 81 years, of whom 75% were females. 61% of participants were diagnosed with a gynecologic cancer, and 51% consented to receive Paclitaxel and Carboplatin chemotherapy regimen, 29% consented to receive Cisplatin chemotherapy, the remaining 20% consented to receive Oxaliplatin, Docetaxel, or Carboplatin alone. Significant changes occurred in all 3 symptoms by cycle 6 of chemotherapy with 45% of participants experiencing neuropathy, 13% experiencing a clinically significant change in hearing, and 30% experiencing self-reported cognitive concern by the 6th cycle. Ototoxicity and neurotoxicity scores followed the same trajectory of an increase or worsening in scores over time from cycle 1 to cycle 6. Conclusions: Use of innovative, portable tablet-based screening tool can be effectively used to capture symptoms of neuropathy chair-side as patients undergo chemotherapy. These observations support the need to better assess these approaches so that they can be used to optimize clinical outcomes and patient quality of life.