bluuebunny/crossref_metadata_2025_split huggingface dataset:
Functionalized chitosan-G-poly caprolactone vaccine delivery system fabricated to display antigen–antibody immune complexes of Mycobacterium tuberculosis elicits immune response in Ex-vivo model
Authors: Rajadas Sam Ebenezer , Sounderrajan Vignesh , Prabhakaran Rajendran Amarnath , Agrawal Ragini , Jeyadoss Lavanya , Rajan Mariappan , Parthasarathy Krupakar , Harshavardhan Shakila 
Published: June 2024

Abstract
Background
Vaccine development against tuberculosis remains a global health imperative, necessitating robust immunogenicity and safety profiles. Nanoparticle-based delivery systems offer promising avenues to enhance vaccine efficacy while ensuring tolerability. This study explores the utilization of chitosan micelles as a delivery platform for immune complex vaccination against tuberculosis. Leveraging two key antigens of Mycobacterium tuberculosis, namely HspX and Mpt51, known for their relevance in latent tuberculosis and its co-infection with the human immunodeficiency virus, immune complexes were synthesized in vitro using antibodies raised against these antigens. The immune complexes were then conjugated onto chitosan micelles, characterized for their physicochemical properties, and evaluated for their biocompatibility and immunogenicity.

Results
Chitosan nanoparticles conjugated with either antigen or its immune complexes were synthesized as micelles and physicochemical characterizations confirm the formation of micelles without altering the polymer composition. These immune complex-conjugated chitosan micelles were found to be safe, exhibiting no significant hemolytic and cytotoxic activity even at a higher concentration of 400 µg/ml. Peripheral blood mononuclear cells upon stimulation with immune complex-conjugated chitosan micelles showed enhanced cellular uptake and one to two-fold increased expression of key immune markers—interferon gamma and CD-86.

Conclusions
These findings underscore the potential of chitosan nanoparticles as a versatile delivery platform for immune complex vaccination against tuberculosis. While limitations exist, such as including only two markers of immune modulation, this study lays a foundation for future investigations into immune complex vaccine potential in animal models. In conclusion, chitosan micelles carrying immune complexes of HspX and Mpt51 tuberculosis antigens exhibit promising immunogenicity, highlighting their potential as a platform for multi-antigenic vaccine components warranting further in vivo studies.
Neurological manifestations among Egyptian children with familial Mediterranean fever
Authors: Abu Shady Hend Mohamed , Osman Heba Taher , Elshennawy Sherine , Kamel Mona Ahmed 
Published: June 2024

Abstract
Background
Familial Mediterranean fever (FMF) is an auto-inflammatory periodic disorder resulting from mutations in the Mediterranean fever gene. Although it is considered a polyserositis disease, neurological-associated symptoms were also reported among different populations.

Aim of the work
To detect the frequency of neurological manifestations among Egyptian children with FMF and to investigate its association with various disease characteristics and various FMF gene mutations.

Patients and methods
This is an analytical cross-sectional study that enrolled 300 FMF children. Neurological manifestations such as headache, paresthesia, convulsions, tremors, breath-holding attacks, and syncope were reported. The dose, duration, and compliance with colchicine and the international severity scoring system for FMF (ISSF) were recorded. Serum amyloid A and gene mutations were recorded from patients’ files.

Results
The mean age of the patients was 10.35 ± 2.89 years; 158 (52.7%) were females, and 142 (47.3%) were males (F:M, 1.1:1), age at onset 4.67 ± 2.35 years and disease duration 3.28 ± 1.31 years. Genetic testing revealed positive MEFV gene mutation in 89.3%. Serum amyloid A was elevated in 33.7%. All patients were treated with colchicine, and 81.3% were compliant. Neurological manifestations were detected in 160 (53.3%) patients. Headache was the most common symptom in 136 (45.3%), followed by paraesthesia in 76 (25.3%). Epilepsy was present in 7 (2.3%) cases. Headaches were most frequent among patients with compound heterozygous mutation, severe ISSF scores, and poor compliance with colchicine.

Conclusion
Egyptian children with FMF present with various neurological manifestations. Headache and paresthesia were the most frequent, especially with the compound heterozygous mutations, severe ISSF score, and among colchicine non-compliant patients. Rheumatologists and neurologists should be aware of these manifestations and address the importance of disease control and adherence to colchicine to avoid or decrease these manifestations. Persistent unexplained headache or other neurological manifestations, in the presence of other symptoms suggestive of FMF or high serum amyloid A, should raise suspicion of FMF, and genetic testing should be requested. A multidisciplinary approach must be considered when managing these children.
The TAC-GReD trial: The combination of talazoparib and carboplatin in DNA damage repair deficient recurrent high-grade glioma.
Authors: Lecoultre Marc , Woo Peter Yat Ming , Leung Gilberto , Chow Shuk Wan Joyce , Ho Jason , Hong Ji Hyung , Chiang Chi Leung , Leung Dennis Kwok Chuen , Lam Tai-Chung , EL Helali Aya 
Published: June 2024

2047 Background: Recurrent high-grade glioma (rHGG) has a dismal prognosis with limited treatment options. Given that a high proportion of these gliomas harbor deficiencies in the DNA damage repair (DDRd) pathway, this genomic occurrence may confer synergistic lethality and sensitivity to poly (ADP-ribose) polymerase (PARP) inhibitors. Therefore, we hypothesize that DDRd rHGG may be sensitive to the combination of a PARP inhibitor, talazoparib, and carboplatin. Methods: This is a prospective phase II, single-arm open-label biomarker stratified single-institution trial conducted in Hong Kong (NCT04740190). Tumor tissue was sent for comprehensive next-generation sequencing (C-NGS) to screen for genomic aberrations associated with the DDRd pathway. Patients with rHGG (WHO grade III-IV) and at least one pathogenic mutation in the DDR pathway were deemed eligible. Patients were initially treated with whole-brain radiotherapy (2 Gy/1 Fr) on C1D1. Starting at dose level 0, talazoparib (0.75mg on Days 1-4) and carboplatin (AUC 1.5 on Day 1), were administered weekly for a total of 18 cycles, followed by maintenance talazoparib. The primary endpoint was the 6-month progression-free survival (PFS-6). Results: 61 patients were screened and 33 patients with DDRd rHGG were enrolled, 23 males, 10 females, and a median age of 55 years (range: 29-70 years). 73% (n=24) had a baseline ECOG PS of 0-1. Among the recruited patients, 12% (n=4) were classified as WHO grade III, while the remaining 88% (n=29) were WHO grade IV. Dose level escalation was achieved in 27% (n=9) of the cohort. The 6-PFS was 29% (95% CI 16.2-51.9%) and the median PFS was 3.5 months (95% CI: 2.4-6.3 months). The OS at 3 and 12 months were 90.4% (95% CI 80.7-100%) and 30% (95% CI 17-53%), respectively. The most common grade 3-4 toxicities were neutropenia (21.2%, n=7), thrombocytopenia (18.2%, n=6) and anemia (9.1%, n=3). One patient developed a grade 4 thromboembolic event. Dose level reduction was implemented in 54% (n=18) of patients and treatment was terminated in 6.1% (n=2) due to toxicity. Conclusions: Talazoparib and carboplatin in a DDRd-enriched rHGG is feasible and tolerable. Additional analysis including correlation of biomarkers with long-term outcomes is underway. Clinical trial information: NCT04740190 .
High-dimensional longitudinal immune profiling uncovers a dual role of the CXCL9/CXCR3, CXCL13/CXCR5, and CCL11/CCL3 axis in the coupling of immune-related adverse events to immune checkpoint inhibitor response.
Authors: Obeid Michel , Joo Victor , Daoudlarian Douglas , Bartolini Robin , Bouchaab Hasna , Latifyan Sofiya , Mederos Nuria , Abdelhamid Karim , Mosimann Valérie , Ferahta Nabila , Shabafrouz Keyvan , Pantaleo Giuseppe , Peters Solange 
Published: June 2024

2512 Background: Additional characterization is required to understand the immune network signatures and immunophenotypes that link immune-related adverse events (irAEs) to immune checkpoint inhibitor (ICI) therapy responses in cancer patients. Methods: A comprehensive immune profiling analysis was conducted on whole blood and peripheral blood mononuclear cells (PBMC) from 165 oncology patients with various irAEs, including colitis (n=64), myocarditis (n=19), pneumonitis (n=25), arthritis (n=24), and cytokine release syndrome CRS (n=33), and compared to a cohort of 219 cancer patients prior to ICI treatment. Results: Following ICI therapy on cycle 2 day 1 (C2D1), we observed significant increases in IL-6, CCL2, CXCL9, CXCL10, and CXCL13 levels preceding irAEs. CXCL9 was specifically upregulated during the development of colitis, arthritis, CRS, and myocarditis, while CXCL13 increased only in CRS, and CCL3 only in myocarditis and CRS, with no CCL11 upregulation in any irAE. High levels of CXCL9, high CCL11 and low CXCL13 strongly correlated with improved oncologic outcomes in different irAEs. Compared to other cluster, in the high CXCL9 cluster, 5-year overall survival (OS) was significantly improved (HR = 10.26 [95% CI, 1.27-82.82], p = 0.029) in colitis (n=20), in CRS (n=21) (HR = 6.45 [95% CI, 1.60-25.99], p = 0.009), and in arthritis. In the high CCL11 cluster, 5-year OS was significantly improved in pneumonitis (n=15), (HR = 4.04 [95% CI, 1.05-15.46]). Conversely, in myocarditis, the high CXCL13 cluster (n=9) was associated with decreased 2-year OS (HR = 6.05 [95% CI, 1.03-35.48], p = 0.046). It is important to note that the CXCL9-driven immunophenotypes were characterized by low IL-6. Notable observations include CD38 upregulation and large-scale activation of CD8 memory subsets during ICI therapy, concomitant with increased circulation of immature neutrophils at the onset of irAEs diagnosis. This event may increase the migration of TCRγδ, NK, DC, and CD8 cells to tumor sites through CXCR3/CXCL9 interactions. Conclusions: This study unravels intricate connections between immune activation and tumor response. CXCL9, CCL11, and CXCL13 emerge as pivotal biomarkers bridging the gap between ICI therapy effectiveness and distinct irAEs-associated immunophenotypes.
Evaluation of mixed response in tumor size and survival in patients with rare cancers treated with dual checkpoint inhibitor therapy (DART SWOG S1609).
Authors: Chae Young Kwang , Dietrich Eliana , Othus Megan , Chung Liam IL Young , Kim Hye Sung , Ryan Christopher W. , Blanke Charles D. , Patel Sandip Pravin , Kurzrock Razelle 
Published: June 2024

2514 Background: RECIST criteria evaluate changes in tumor burden and have been utilized in cancer research for decades. Changes in the sum of maximum diameters of “target” lesions are used to designate patients into response categories, including complete response, partial response, stable disease, and progressive disease. However, not much is known about the implications of mixed response, where lesions within a patient show contrasting responses to systemic treatment. Here we evaluate the data from the Dual Anti-CTLA-4 and Anti-PD-1 Blockade in Rare Tumors (DART) SWOG S1609 to investigate the association between mixed response and survival among patients treated with dual checkpoint inhibitor therapy. Methods: A total of 796 patients were enrolled on the S1609 DART trial, a basket trial evaluating ipilimumab plus nivolumab across solid rare tumor subtypes. All patients had RECIST-measurable disease at the study entry. Patients were excluded from the analyses due to: ineligibility, n=47; not receiving any protocol therapy, n=23; death before day 65 (landmark for analysis based on first scan), n=86; 1 target lesion, n=153. Thus, 487 patients were analyzed. A 5mm cut-off for increase/decrease in lesions was used to define a mixed response. Cox regression models were used to evaluate associations between survival (landmarked at day 65, stratified by basket) and response category (reference of Stable Disease). Results: 6 groups were identified among the 487 patients: no lesions changed more than 5 mm (n = 105), all lesions increased more than 5mm (n = 69), all lesions decreased more than 5mm (n = 39), one+ lesion increased more than 5mm and one+ lesion decreased more than 5 mm (n = 24), one+ lesion increased more than 5mm and one+ lesion did not change more than 5 mm (either direction) (n =155), one+ lesion decreased more than 5mm and one+ lesion did not change more than 5 mm (either direction) (n =95). Hazard ratios and median survival (mOS) are shown (Table). Conclusions: This is the first evaluation of the association between mixed response and survival outcomes among patients with various tumors receiving dual checkpoint therapy. Our results suggest that survival outcomes are driven by the “worst” performing lesion; in other words, having an increase in any lesion is associated with worse outcomes, even if not all lesions increase. [Table: see text]
Effect of fecal transplantation on patient reported outcomes after immune checkpoint inhibitor colitis.
Authors: Shatila Malek , Varatharajalu Krishnavathana , Shen Shu-En , Herrera Mary , Wang Xin Shelley , Thomas Anusha , DuPont Herbert L. , Wang Yinghong 
Published: June 2024

2517 Background: The use of fecal microbiota transplantation (FMT) has traditionally been reserved for the treatment of recurrent Clostridioides difficile infections (CDI). As the gut microbiome has been increasingly acknowledged to play a role in a variety of bodily processes, FMT has seen its application extended to other gastrointestinal disorders. Immune-mediated colitis (IMC) is a similar entity to inflammatory bowel disease and arises as a side effect of immune checkpoint inhibitor therapy to stimulate the immune response. Treatment of IMC is mostly limited to immunosuppressants e.g. corticosteroids, infliximab, and vedolizumab. Cases refractory to such medications pose a significant challenge. FMT has been shown to be a successful treatment in refractory IMC in small case series, further large studies are needed to determine its efficacy. Methods: We measured the efficacy of FMT for refractory IMC among 37 patients via chart review and clinical assessment and patients’ reported outcome (PRO) via established MD Anderson Symptom Inventory (MDASI). Among them, 9 patients had concurrent CDI as well at the time of diagnosis. Results: Fifty-nine patients were included in our study. Most patients had a peak diarrhea grade ≥ 3 (94.9%) and colitis grade ≥ 2 (91.5%). Ulcerous (26, 44.1%) and non-ulcerous (21, 35.6%) inflammation were the predominant endoscopic findings. Fifty-seven (96.6%) patients received corticosteroids, and 54 patients (91.5%) received add-on infliximab or vedolizumab. IMC symptom response was 84.7% after FMT with median time to response of 4 days. The transient complication rate is 30.5% at 7 days and 18.6% at 30 days. Response rate among the 50 patients without concurrent CDI was 86.0%. Fifty (84.7%) patients demonstrated clinical remission by the end of the study period, and 11 (18.6%) were able to resume ICI treatment, and among them, 9 patients remained in remission. A total of 10 patients (16.9%) in our cohort developed recurrent colitis after FMT requiring immunosuppression; 3 of these recurrent cases were triggered by ICI resumption. On the PRO analysis, we observed a favorable trend of significant patient-reported symptom reduction on diarrhea (61% to 11%, p<0.01) and abdominal bloating (36% to 7%, p<0.05) during 12 weeks after FMT. There was a 49.4% reduction of moderate to severe symptoms with only 44% of patients reporting such symptoms after 12 weeks (down from 89%, p<0.01). Conclusions: FMT may serve as a potential treatment option in IMC refractory to standard treatment to avoid long-term steroid dependency and immunosuppression. It is effective to maintain IMC remission with a low complication rate. The role of the gut microbiome in cancer and the implications for FMT remain uncertain and need further elucidation. Clinical trial information: NCT03819296 .
First-in-human study of ZGGS18, a dual specific antibody targeting VEGF and TGF-β, as monotherapy in patients with advanced solid tumors.
Authors: Zhao Chuan Hua , Shi Jianhua , Chai Xiaoli , Tan Lirong , Wu Lihua , Zheng Li , Cao Dan , Mai Gang , Fan Lianlian , Mi Yanjun , Wang Jufeng , Han Xinghua , Xu Jianming 
Published: June 2024

2523 Background: ZGGS18 is a bifunctional antibody fusion protein, which consists of a monoclonal antibody (optimized Bevacizumab) against vascular endothelial growth factor A (VEGF-A) and an engineered human transforming growth factor-β receptor II extracellular domain (TGF-β RII ECD). It can specifically bind VEGF-A and "capture" TGF- β isomers. It plays a synergistic role in inhibiting tumor growth, such as inhibiting tumor angiogenesis and reducing tumor metastasis. In addition, ZGGS18 can also improve and regulate the tumor microenvironment, so it can enhance the tumor-killing effect in combination with anti-PD-(L) 1 antibody and other tumor immunotherapeutic drugs. We conducted a Phase 1 clinical study to assess the tolerability and safety of this drug. Methods: It was a dose-escalation study. Subjects were patients with advanced solid tumors who failed to the available standard treatments. The dose groups were set from 0.3 to 20 (0.3, 1, 3, 6, 10, 15, 20) mg/kg, intravenous infusion, once every 2 weeks. An accelerated titration design (ATD) was utilized in the first three dose groups and a standard "3+3" design was used in the rest doses. The first 28-day period was defined as the dose-limiting toxicity (DLT) observation period. Subjects could continue to receive ZGGS18 until treatment discontinuation criteria were met. Tumor response was assessed by RECIST1.1. Results: At the data cut-off (4 Jan 2024), 21 patients (14 males and 7 females) were enrolled, with a median age of 60 years. 13 (61.9%) of them received at least 2 lines of antineoplastic therapies. 76.2% (16/21) of patients experienced treatment-related adverse events (TRAEs) and 19.0% (4/21) of patients had grade 3 TRAEs (1 Lower gastrointestinal hemorrhage in the 10 mg/kg, 1 pneumonia in the 15 mg/kg, 1 anemia in the 20 mg/kg, and 1 blood fibrinogen decreased in the 20 mg/kg dose group). Wherein, the grade 3 blood fibrinogen decreased was a DLT event. The most frequent TEAEs (with incidence >10%) were anemia, lymphocyte count decreased, gingival bleeding, epistaxis, hypoalbuminemia, proteinuria, hypocalcemia, hypokalemia, fever, aspartate aminotransferase increased, bile acids increased, and disease progression. There is one subject with endometrial carcinoma who has received 19 infusions of ZGGS18 and is remaining in this study, and another subject with rectal carcinoma had 29.65% tumor shrinkage at week 12. The Cmax and AUC increased from 0.3-20 mg/kg approximately in dose proportion. Conclusions: ZGGS18 demonstrated its safety and tolerability in this dose-escalation study, along with a good PK profile, providing a good basis for monotherapy and/or combination therapy for future use. Clinical trial information: NCT05584800 .
Tocilizumab for advanced non-small cell lung cancer with concomitant inflammatory cachexia: A single-centre study.
Authors: Du Yang , Liu Xiao-Yian , Pan RuiLi , Zhang Xiao-Tong , Si Xiao-Yan , Chen Minjiang , Wang Mengzhao , Zhang Li 
Published: June 2024

2647 Background: Cancer cachexia significantly contributes to morbidity and mortality in patients with non-small cell lung cancer (NSCLC). Inflammatory pathways mediated by interleukin-6 play a crucial role in the development of cancer cachexia. This study aimed to investigate the use of tocilizumab, an anti-interleukin-6 receptor inhibitor, in the management of NSCLC with coexisting inflammatory cachexia. Methods: Data were collected from patients with NSCLC and concurrent inflammatory cachexia who received either tocilizumab plus anti-tumour therapy or anti-tumour therapy alone. The primary endpoints were overall survival (OS) and improved modified Glasgow Prognostic Score (mGPS) at week 12, while secondary endpoints included changes from baseline over 12 weeks in body weight, albumin, C-reactive protein and mGPS. Qualitative improvements in patient self-rated appetite and fatigue were reported as exploratory analysis. Results: The study included 49 patients diagnosed with NSCLC and coexisting inflammatory cachexia, of which 26 received tocilizumab in combination with anti-tumour therapy, and 23 received anti-tumour therapy alone. The tocilizumab group demonstrated a significantly longer median OS compared to the control group (15.1 vs. 3.2 months; hazard ratio 0.18, 95% confidence interval 0.08-0.38; p < 0.001). The rate of patients surviving with mGPS improvement at week 12 was significantly higher in the tocilizumab group than in the control group (OR 168.7, 95% CI 16.3-1746.5; p < 0.001). Over the 12-week period, significant improvements were observed in body weight, albumin, C-reactive protein, and mGPS in the tocilizumab group compared to the control group. Additionally, the tocilizumab group displayed significantly higher rates of improvement in appetite and fatigue. The incidence of grade 3 or higher adverse events was 34.6% in the tocilizumab group compared to 78.3% in the control group. Tocilizumab-related adverse events were observed in three patients (11.5%), including two cases of neutropenia and one case of skin and subcutaneous tissue infection. Conclusions: Tocilizumab demonstrated significant benefits in survival and various clinical parameters, including body weight, albumin, C-reactive protein, mGPS, and symptom burden in patients with NSCLC and concurrent inflammatory cachexia. Given the existing unmet medical need for effective interventions for cancer cachexia, tocilizumab may be considered as a potential treatment option.