bluuebunny/crossref_metadata_2025_split huggingface dataset:
Initial clinical experience with the first-in-class anti-metastasis therapeutic TTX-MC138.
Authors: Medarova Zdravka , Robertson Neil , Ghosh Subrata , Duggan Susan , Varkaris Andreas 
Published: June 2024

e15072 Background: TransCode is focused on developing nucleic acid-based cancer therapies. Through scientific discovery efforts, miRNA-10b was identified as a master regulator of the viability of metastatic tumor cells. This knowledge allowed development of a therapeutic strategy based on miR-10b inhibition. miR-10b was targeted using antagomirs delivered to metastatic sites by an iron oxide nanocarrier, termed TTX-MC138. Results demonstrated that TTX-MC138 could cause complete and persistent regressions of metastases in cancer models. Methods: TransCode has an active eIND and is conducting a Phase 0 clinical study with radiolabeled TTX-MC138 in patients with advanced metastatic cancer of multiple tissue origins. TTX-MC138 was radiolabeled with Cu64 through a NODAGA chelator. IND enabling studies were conducted in rats and non-human primates to support FDA activation (eIND163800) for the Phase 0 clinical study. In the trial, a single intravenous microdose of Cu-64 labeled TTX-MC138 is administered, which allows for direct visualization of drug tissue distribution in cancer patients via PET-MR imaging. Results: Non-clinical studies were conducted to support the TTX-MC138 clinical development program. In rats, when TTX-MC138 was infused intravenously at a dose of 27 mg/kg, results displayed a blood half-life of 16.7±9.35 hrs. At 24-h, concentrations were highest in the liver and spleen. In non-human primates injected with Cu64-labeled TTX-MC138 at a dose of 100 microg, the organs with the highest uptake were the liver, heart, lung and spleen. The mean whole blood half-life was 12.2 ± 2.3 h (mean ± standard deviation). RadioHPLC analysis of plasma samples showed that the drug is very stable with respect to metabolism. A study in rats involved a single injection with 0, 0.5 or 1 mg/kg followed by a 2-day or 14-day observational period. The drug was well-tolerated at levels up to 1 mg/kg, which was considered to be the no-observed-adverse-effect-level (NOAEL). Preliminary results from the Phase 0 clinical study showed that the first patient tolerated the dosing with no reported adverse reactions, the drug remained stable in circulation, and circulated with a long half-life of 20 hours. Lesion to blood ratios of radioactivity in the region of the metastatic lesions was consistent with accumulation of TTX-MC138. Enrollment, data monitoring, and analysis is ongoing. Conclusions: The results of the non-clinical studies and Phase 0 clinical study have the potential to address the question of delivery to the target tissue. The process leading to the implementation of TTX-MC138 in the clinic is critically dependent on the innate tropism of the TTX delivery platform to tumors and represents a first step towards developing effective nucleic-acid based therapeutics against cancer. Clinical trial information: NCT05908773 .
A phase II study of liposomal irinotecan-based chemotherapy with or without PD-1 inhibitor in patients with unresectable locally advanced or metastatic biliary tract cancer.
Authors: Ying Jieer , Cheng Xiangdong , Xu Qi , Li Jingjing , Zhuo Yiwen , Liu Yanping , Yuan Jing 
Published: June 2024

e15077 Background: Clinical outcomes for advanced biliary tract cancer (BTC) patients (pt) progressed on first-line therapy remain dismal. Liposomal irinotecan (LI) (HE072) is a formulation encapsulating I in a lipid bilayer vesicle and was approved in China in September 2022. It was used with 5-fluorouracil (5-FU) and leucovorin (LV) for patients with metastatic pancreatic cancer progressing on gemcitabine treatment. We conducted an phase II study to investigate HE072 in combination with 5-FU and LV with or without a novel PD-1 inhibitor SG001 in patients with advanced BTC progressed on prior gemcitabine-based chemotherapy. Methods: This is a multi-center, non-randomized, open label phase II study in pts with unresectable locally advanced or metastatic BTC. Key inclusion factors were ECOG PS 0-1, prior gemcitabine-based chemotherapy, evidence of disease progression with at least one measurable lesion and adequate haematological/organ function. Key exclusion factor was brain metastases. Pts were treated with liposomal irinotecan (70 mg/m2) plus LV (400 mg/m2f) and 5-FU (2400 mg/m2) with or without SG001 (240mg) IV every 2 weeks for up to 2 years in absence of disease progression or unacceptable toxicity. Tumor assessments based on RECIST 1.1 were performed every 6 weeks by investigators. Primary endpoint was objective response rate (ORR). Secondary endpoints include progression free survival (PFS), overall survival (OS), disease control rate (DCR) and safety. Results: As of April 25, 2023, 17 BTC pts were enrolled into liposomal irinotecan-based chemotherapy arm (n = 7) and liposomal irinotecan-based chemotherapy plus SG001 arm (n = 10). ORR and DCR were 14.3% and 71.4% for chemotherapy arm, 20% and 40% for chemotherapy+ SG001 arm. Median OS and PFS for chemotherapy arm was 11.5(95% CI, 3.9-NE) and 4.2(95% CI, 1.4-NE) months, and for chemotherapy+PD-1 arm was 15.3 (95% CI, 3.6-17.0) and 3.8(95% CI, 1.4-6.9) months. All pts experienced treatment-related adverse events (TRAEs). The incidence of grade≥3 TRAEs was 58.8%(10/17), which occurred in 57% (4/7) of pts treated in chemotherapy arm vs 60% (6/10) in chemotherapy+SG001 arm. Among all patients, the most frequent grade ≥3 TRAEs were fatigue (29.4%), neutropenia (23.5%) and leukopenia (23.5%). One grade 4 TRAE leading to dose reduction in liposomal irinotecan was febrile neutropenia in chemotherapy arm. There were no treatment-related deaths. Conclusions: These preliminary results suggested that liposomal irinotecan plus 5-FU and LV was well-tolerated and showed promising and durable clinical activity in advanced BTC pts progressed on first-line treatment. Combined use of SG001 further improved clinical outcome in these pts without increased toxicity. Combination of liposomal irinotecan, 5-FU, LV and PD-1 inhibitor is a treatment strategy which is worthy of further exploration.
Performance of surufatinib in treating advanced neuroendocrine neoplasms: Insights from a real-world study.
Authors: Zhu Linhui , Ye Xuan , She Youjun , Liu Wensheng , Du Qiong , Zhai Qing 
Published: June 2024

e15124 Background: Current comparisons of targeted treatments for advanced neuroendocrine neoplasms (NENs)-specifically surufatinib, sunitinib, and everolimus—are lacking. This study aims to assess their efficacy and safety in a real-world setting. Methods: A retrospective, observational study was conducted at Fudan University Shanghai Cancer Center, including patients with advanced NENs prescribed surufatinib, sunitinib or everolimus between July 2020 and April 2023. The primary outcome was median progression-free survival (PFS), and secondary outcomes included objective response rate (ORR), disease control rate (DCR) and adverse events (AE). Results: A total of 123, 56 and 68 locally advanced or metastatic NEN patients treated with surufatinib, sunitinib or everolimus were enrolled. In pancreatic NENs (pNEN), surufatinib demonstrated superior efficacy over sunitinib and everolimus combined (mPFS: 8.67 vs 6.37 months, P=0.02; ORR: 17.1% vs 8.3%). Specifically, surufatinib outperformed sunitinib (mPFS: 8.67 vs 6.40 months, P=0.04; ORR: 17.1% vs 10.9%) and everolimus (mPFS: 8.67 vs 5.37 months, P=0.05; ORR: 17.1% vs 3.8%) individually. In extrapancreatic NENs (epNEN), surufatinib showed enhanced efficacy compared to everolimus (mPFS: 9.47 vs 6.70 months, P=0.15; ORR: 8.3% vs 5.3%). On multivariate Cox analysis, male, functional status, Ki67 index>20%, previous SSA and germline mutation, poor differentiation, liver metastasis, multi treatment lines were identified as negative effect (P<0.05) for PFS in pNEN and epNEN patients respectively. The most common adverse events (AEs) were hypertension (12.2%) in surufatinib-treated patients, manageable with medication. Sunitinib led to decreased neutrophil counts (10.7%), and everolimus was associated with anemia (4.4%). Conclusions: Utilizing real-world data, this study reveals surufatinib significantly enhances progression-free survival (PFS) over sunitinib and everolimus in advanced neuroendocrine neoplasms (NENs), guiding future targeted treatment choices.
Clinical efficacy of a next-generation sequencing (NGS) and immunohistochemistry (IHC) panel in patients with advanced cancer in Argentina.
Authors: Cantarella Florencia , Mendoza Bertelli Andrea , Girotti Romina , Marino AnaClara , Brest Esteban , Dibarbora Delfina , Mahmoud Yamil , Veigas Florencia , Enrico Diego Hernán , Tsou Florencia , Lacava Juan A. , Piazzoni Luciano , Riso Aldo Alejandro , Martinengo Gastón L. , Rodriguez Andres , Beguelin Zenon , Cerrato Sebastian , Jerez Ignacio , Salanova Ruben 
Published: June 2024

e15154 Background: The analysis of somatic genomic alterations, evaluation of DNA mismatch repair (MMR) proteins, and examination of PD-L1 expression in tumor biopsies are crucial for prognosis and informed therapeutic decisions. However, their clinical implementation in Argentina faces challenges due to economic costs and lack of evidence. To address this, we conducted a retrospective study to assess the impact of this molecular panel testing on treatment decisions and clinical management of cancer patients in Argentina. Additionally, we evaluated its ability to detect clinically relevant alterations and analyzed the frequency and co-occurrence of mutations in our cohort. Methods: Tumor tissue samples from 266 patients with primary tumors, representing 26 different anatomical sites (53% lung cancer), underwent molecular testing using the Optimus panel developed by Biomakers. The assay integrates somatic sequencing of 52 genes through NGS with IHC assessment of MMR and PD-L1 proteins. A retrospective evaluation of the clinical effectiveness of the test was conducted on 133 patients. Genomic and clinical data were analyzed using R with the pairwise Fisher’s exact test applied for statistical analysis. Results: This panel facilitates molecular characterization, identifying clinically relevant genetic alterations in 65% of patients and detecting deficiency in MMR proteins in 3%. Findings align with global clinical trial availability for identified alterations in 97% of cases. KRAS is the most frequently mutated gene (38%), followed by EGFR (19%), PIK3CA (12%), BRAF (9%), CDK4, and CTNNB1 (5% each), correlating with lung cancer overrepresentation. Simultaneous alterations in EGFR, PIK3CA, CTNNB1, and KIT genes were observed. Pan-tumoral interaction analysis revealed mutual exclusivity between KRAS mutations and those in EGFR, BRAF, CDK4, and CTNNB1. CTNNB1 mutations co-occurred with EGFR mutations, akin to KIT and PDGFRA (p<0.05). The retrospective analysis indicated that the Optimus panel contributed to clinical management of patients in 56% of cases, with 85% detecting clinically relevant variants, aiding treatment definition in 74% of these cases. Conclusions: The Biomakers-developed Optimus panel empowers the molecular characterization of genomic and proteomic biomarkers across tumor types. Its significance in clinical practice lies in contribution to vital decision-making processes, particularly in treatment selection.
Characterization of Von Hippel Lindau gene variants by race.
Authors: Shao Yusra F. , Alloghbi Abdurahman , Kim Seongho , Al-Share Bayan A , Kokenakes Courtney , Heath Elisabeth I. 
Published: June 2024

e15158 Background: Autosomal dominant (AD) pathogenic/ likely pathogenic (P/LP) variants in the VHL gene cause Von Hippel Lindau syndrome, historically studied in White populations. We aimed to characterize VHL variants and disease phenotypes in both Non-White (NW) patients, which include Asian and African-American (AA), and in Non-Hispanic White (NHW) patients. Methods: Patients undergoing germline genetic testing (GGT) at Invitae Corporation from November 2014 to March 2022, carrying a P/LP AD variant in VHL gene were identified. Demographic and clinical data were obtained from Test requisition forms. Fisher's exact test and Wilcoxon rank-sum tests were performed for categorical and continuous variables, respectively, to compare groups. Results: The final analysis included 363 patients (NW=27%). Hemangioblastoma was predominant in all groups (NHW=13%, NW=27%, p=0.004). Breast cancer exclusively occurred in NHW patients (7%, p=0.019). NHW and NW patients had a higher family history of breast cancer (NHW=7%, NW=1%, p=0.046) and hemangioblastoma (NHW=3%, NW=8%, p=0.037), respectively. Distribution of VHL variants between NW and NHW patients varied significantly (p<0.001, Indels p=0.009, substitution variants p<0.001). Deletion exon 2 was predominant in all groups (NHW=15%, NW=35%) P.Leu188Val was exclusive to NHW patients (26%)while p.Arg167Trp (NHW=6%, NW=11%) and p.Arg167Gln (NHW=2%, NW=10%) were more common in NW patients. Several unique variants in AA and Hispanic patients were seen. Conclusions: This study reveals differences in P/LP VHL variant distribution and disease phenotype between NHW and NW races. Ethnicity-specific characterization uncovers unique variants in AA and Hispanic patients. This dataset informs future research on VHL disease and treatment in diverse populations.
Establishing optimized staining protocol and cutoff values of pan-TRK immunohistochemistry for detecting NTRK fusions in solid tumors: A Chinese multicenter cross-sectional study.
Authors: Wu Shafei , Han Yuchen , Zhang Zhihong , Chen Gang , Wang Jian , Yang Wentao , Meng Bin , Sun Yan , Liu Yang , Li Wencai , Li Shenglei , Wang Lifeng , Zhang Hongying , Guo Lingchuan , Liu Yueping , Liu Xiaoding , Hong Ruping , Li Kaimi , Liang Zhiyong 
Published: June 2024

e15160 Background: Using IHC to screen NTRK+ patients, followed by NGS confirmation, is a strategy recommended by ESMO guidelines. However, the current IHC staining protocol (Protocol) and cutoff value (CV) are suboptimal, resulting in limited screening performance. This study aims to optimize the Protocol and redefine the CV to improve the efficacy of pan-TRK IHC in screening NTRK fusions. Methods: 126 NTRK+ and 162 NTRK- solid tumor samples (spls), previously confirmed by NGS and/or FISH, were collected retrospectively from 12 hospitals across China in 2023. All spls were stained with VENTANA pan-TRK IHC assay by using two different Protocols: 1) the conventional one recommended by the manufacturer's instruction and 2) an amplification one that included additional amplification steps to enhance the staining. The IHC stained spls were interpreted based on the manufacturer's instruction, and the results were analyzed to calculate the CVs. The sensitivity, specificity, accuracy, PPV, and NPV based on these CVs and the CV reported in the literature were calculated. Results: 126 NTRK+ spls involve 25 fusion-partner types and 23 tumor types. IHC showed 35 NTRK- spls without staining, and 253 spls (126NTRK+/127NTRK-) stained. The staining predominantly localized to the cytoplasm and nucleus (132 cytoplasmic positive, 105 cytoplasmic and nuclear positive). Due to the limited samples with membrane staining, only CVs for cytoplasmic and nuclear staining were defined. In order to enhance the sensitivity and feasibility of the pan-TRK IHC assay in NTRK+ screening, the statistically calculated CVs were adjusted, and we recommended using the following CVs in clinical practice: 1) ≥1 intensity of cytoplasmic staining in ≥50% of tumor cells and/or 2) ≥1 intensity of nuclear staining in any percentage of tumor cells. Compared with the statistically calculated CVs, although the accuracy of the recommended CVs was slightly reduced (87.5% vs 93.75%), the sensitivity was improved (94.44% vs 89.68%). The sensitivity and specificity of the recommended CVs were higher than that of the previously reported CV (≥1%): sensitivity (94.44% vs. 87.9%) and specificity (82.1% vs. 81.1%). Conclusions: The pan-TRK IHC assay demonstrated high sensitivity while maintaining good specificity and accuracy, improving screening and enrichment efficacy for identifying NTRK fusions in solid tumors by utilizing the amplification protocol and the recommended CVs. Clinical trial information: ChiCTR2200066850 . [Table: see text]
Experience of personalizing cancer treatment in economically-constrained and resource-restricted community oncology practice in India through cost-effective broad spectrum NGS and survival outcomes: An observational study of 3 years.
Authors: Maheshwari Udip , Morzaria Dr Disha , Maniar Vashishth , Joshi Ashish , Bose Chirantan , Jobanputra Kunal , Shivchhand Akshay , Dave Ritu , Kalaskar Pritam , Pethe Chandrashekhar , Joshi Kshitij , Kendre Pradip 
Published: June 2024

e15173 Background: NGS based mutational findings are increasingly used in oncology practice to personalize treatment strategies. We elucidate the impact of comprehensive genomic profiling and the new avenues it opens for personalized precision medicine. Methods: This was a retrospective study evaluating patients who underwent a cost-effective (<US $1000), inhouse developed comprehensive NGS test. Descriptive data was tabulated & mutational distribution, therapeutic strategies and survival outcomes were evaluated. Results: A total of 336 patients were evaluated from a community oncology practice over the last 3 years in Western India. The mean age was 59.2 years; with F:M being 1.04:1 and stage distribution being 3.5%, 5.9%, 9.5% and 80.9% for Stage I, II, III and IV respectively. Comprehensive NGS was performed to evaluate SNVs, CNVs, and indels spanning across over 15000 loci for 1080 tumor specific genes wherein 71.7% were tissue-based, 24.4% were liquid biopsy-based and 3.8% were combined tissue-DNA and ctDNA-based analysis. Majority (69.9%) of the patients were pre-treated while 30% were therapy naïve. The most common cancers evaluated were Lung (18.1%), Pancreatobiliary (15.1%), Breast (11.3%), Gynaec (9.5%), and Lower GI (9.5%). Pathogenic mutations were reported in 83.6% of the cohort while in 16.3% no mutations were detected. Most common mutations observed in this retrospective study were TP53 (38.3%), KRAS (16.6%), PIK3CA (9.5%), EGFR (7.4%) and PTEN (5.6%); and the distribution was largely similar in untreated as well as pre-treated cohorts. Furthermore, genomic alterations for each cancer type are described in Table 1. MSI high and TMB high (>10) were reported in 0.5% and 7.4% respectively. PDL1 positive IHC was reported in 3.2% of tissue samples, whereas HRD high (>50) was reported in 2.3% of the cohort of which the majority (11.5%) were from Upper GI tumors. Targetable genomic alterations were detected in 53.8% (181/336) of which 38.1%(69/181) received the suggested targeted therapy. Clinical response was seen as PR in 14.4% and CR in 2.8% of patients. Of 336 patients 4.76% received modified therapeutic regimens which differed from the standard of care, wherein median PFS was 8 mo [CI 95% (5.3-10.7)] while median OS was 55.1 mo [CI 95% (25.8-NA)]. Conclusions: This observational study outlines the potential benefit of personalizing treatment regimens in the management of solid organ cancers, especially in scenarios where standard-of-care regimens may have failed and the need to incorporate broad-spectrum NGS. [Table: see text]
Effect of indole 3-propionic acid from microbiota on the immunity of CD8+ T cell to improve chemotherapy of colorectal cancer.
Authors: Xie Hongyu , Xu Haoyang , Wu Jinjie , Yang Jingyi , Zeng Wanyi , Jin Sanqing , He Zhen , Lan Ping 
Published: June 2024

e15194 Background: Sensitivity of chemotherapy is a great challenge to improve the treatment efficacy in patients with colorectal cancer (CRC). Increasing study has revealed the role of microbiota in the modulation of chemotherapy sensitivity. However, the mechanism how microbiota regulates the efficacy of 5-fluorouracil (5-FU) is far from clear. Methods: We used germ-free mice and antibiotic-treated mice to demonstrate the impact of the gut microbiota on 5-FU sensitivity. Metabolomics analysis of serum from patients with CRC or mice experiments were applied to identify the key metabolite, indole 3-propionic acid (IPA). Specific pattern of microbiota with capability to produce IPA was revealed by metagenomics analysis of the mice feces. Single-cell RNA (scRNA) sequencing was subsequently used and antibody blockade experiments as well as T cell adoptive transfer experiment were conducted to confirm the role of CD8+ T cells in 5-FU treatment. AHR KO mice model was used to reveal how IPA regulate the immunity of CD8+ T cells. Engineering Escherichia coli strain BL21 with capability to produce IPA was constructed to modulate the chemotherapy sensitivity. Results: Decreased sensitivity of 5-FU chemotherapy was observed in both germ-free mice and antibiotic-treated mice models. Accumulation of serum IPA was found in mice with vancomycin intervention and verified in CRC patient with chemotherapy resistance. Additionally, metagenomic analysis of mice feces revealed that Clostridium sporogenes capable of producing IPA, are crucial for 5-FU chemotherapy sensitivity. Supplementation with IPA or Clostridium sporogenes could obviously improve the sensitivity of 5-FU chemotherapy. Subsequently scRNA sequencing analysis of tumor tissue revealed a higher infiltration of CD8+ T cells after IPA intervention. The role of IPA-induced CD8+ T cells in 5-FU treatment was confirmed by antibody blockade experiments and T cell adoptive transfer experiment. Further, improved therapeutic sensitivity by IPA and the infiltration of CD8+ T cells were vanished in AHR KO mice model. Biosynthesis of IPA by engineering bacteria was found to enhance the sensitivity of 5-FU chemotherapy. Conclusions: Indole 3-propionic acid from microbiota enhances the immunity of CD8+ T cell via activation of AHR signaling pathway, thus providing potential therapeutic strategies to improve the efficacy of chemotherapy in colorectal cancer.