bluuebunny/crossref_metadata_2025_split huggingface dataset:
Combining the potency of a neoantigen-expressing DNA vector, an anti-CTLA-4 antibody, and an attenuated poxvirus in a personalized immunization platform: Preclinical studies of ODI-2001.
Authors: Marschall Pierre , Matta Celia , Hugel Cécile , Matta Jessica , Bogaert Cedric , Ghiringhelli François , Balducchi Pascale , Limacher Jean-Marc 
Published: June 2024

e14674 Background: Immune checkpoint inhibitors (ICI) have transformed cancer treatment. Their impressive effectiveness is crucially dependent on pre-existing neoepitope-specific immune responses. ODI-2001 aims at increasing the immune response against tumors by combining a DNA expressing multiple neoepitopes of the tumor, a MVA vaccinia virus as physiologic adjuvant and DNA carrier, and an anti-CTLA4 antibody as amplifier of the immune response. Methods: ODI-2001 was administered by repeated subcutaneous injections after tumor cells implantation in mice melanoma model B16F10 and colorectal cancer model CT26, and both before and after implantation in breast cancer model 4T1. In B16F10 model combination of ODI-2001 with anti-PD1 was assessed also. Neoepitopes were chosen from literature in B16F10 and CT26 models. In 4T1 model they were predicted using a dedicated neoepitope prediction algorithm (ImmunoEngine, myNEO, Gent, Belgium). Tumor volume and mice survival were assessed over time. Tumors were also analysed by immunofluorescence for immune cell infiltration. Each experiment received approval from the ethics committee for animals. Results: A significant improvement in survival was observed in mice treated with ODI-2001 in B16F10, and CT26 syngeneic mice models. In B16F10 the combination of ODI-2001 with anti-PD1 antibody demonstrated synergistic activity and a significant improvement in survival, while anti-PD1 alone or combined with anti-CTLA-4 failed to show any therapeutic effect (ODI-2001 + anti-PD1 vs. anti-CTLA-4 + anti-PD1 p<0.01). ODI-2001 treatment was associated with tumor rejections in the three animal models. In 4T1 model the ImmunoEngine epitope prediction algorithm demonstrated an improved efficacy as compared to a set of neoepitopes chosen from the literature. In B16F10, following immunization with ODI-2001, an increased CD8 immune cell infiltration of the tumor was documented. ODI-2001 was well tolerated by the treated animals. Conclusions: These data demonstrate a significant antitumoral activity of ODI-2001 as a neoantigen immunization platform across different preclinical cancer models, both in monotherapy and combined with anti-PD1. ODI-2001 represents a promising option to induce de novo cancer-specific immune responses, potentially increasing the proportion of patients responding to immunotherapy treatments. Based on this preclinical program a phase I with ODI-2001 in patients with advanced colorectal carcinoma is currently under preparation.
Preliminary results from a first-in-human trial of AMT-116, a topoisomerase I inhibitor containing antibody-drug conjugate (ADC), in patients with advanced solid tumors.
Authors: Coward Jim , Kichenadasse Ganessan , Park John J. , Parakh Sagun , Richardson Gary Edward , Voskoboynik Mark , Powderly John D. , Song Zhengbo , Liu Shutong , Huang Yaling , Liu Shu-Hui , Meng Xun 
Published: June 2024

e15010 Background: CD44v9 is a tumor-associated antigen highly expressed in various solid tumor types including head and neck, lung, esophageal, pancreatic, colorectal, breast, bladder, hepatic, cervical, and gastric cancers. AMT-116 is a first-in-class antibody-drug conjugate (ADC) targeting CD44v9, by conjugating a novel topoisomerase I inhibitor, belotecan derivative named KL610023 (Sichuan Kelun-Biotech) to a humanized anti-CD44v9 immunoglobulin G1 (IgG1) antibody via a hydrolysable linker with an average drug-to-antibody ratio of 7-8. Methods: This is an ongoing first-in-human, non-randomized, open-label, multicenter, Phase 1 study designed to evaluate the safety, tolerability, pharmacokinetics, and preliminary anti-tumor activity of AMT-116 in patients (pts) with advanced solid tumors, unselected for target expression. Pts received escalating doses of AMT-116 Q2W starting from 1.5 mg/kg guided by the Bayesian logistic regression model (BLRM) following escalation with overdose control (EWOC) principle. Results: As of Feb 1, 2024, eight pts (4 pts at 1.5 mg/kg, 3 pts at 3 mg/kg and 1 pt at 5 mg/kg) have been treated in Australia and pts at 1.5 mg/kg and 3 mg/kg completed the 28-day dose-limiting toxicity (DLT) evaluation period. No DLT events were observed, and the maximum tolerated dose (MTD) has not been reached. Treatment related adverse events (TRAEs) were reported in 5 pts out of 8. The most common TRAEs were fatigue (n=3) and nausea (n=3). Only one Grade 3 TRAE (leukopenia) was reported. There were no Grade 4 or 5 TRAEs or treatment-related SAEs. Seven pts have completed at least one post-treatment tumor assessment. At dose level 3 mg/kg, one pt with anal squamous cell carcinoma achieved unconfirmed PR with a 31% tumor shrinkage and one pt with hepatocellular carcinoma achieved SD with a 23% tumor shrinkage from baseline. Subject enrollment in 5 mg/kg is underway. Conclusions: These preliminary data indicate that AMT-116 is well tolerated at the first two dose levels in patients with heavily pretreated advanced solid tumors. Dose escalation is ongoing. Clinical trial information: NCT05725291 .
Effect of sodium thiosulfate anhydrous on cisplatin-induced ototoxicity in pediatric cancers: Turkish compassionate use treatment protocol—Updated results.
Authors: Unal Emel Cabi , Tacyildiz Nurdan , Canpolat Cengiz , Ataseven Eda , Sivrice Ayse Cigdem , Sevinir Betul , celik Ates Dilvin , Tuncel Tolga 
Published: June 2024

e15075 Background: Cisplatin induced ototoxicity (CIO), with permanent hearing loss is observed in >60% pediatric patients in Turkey. PEDMARK (Sodium Thiosulfate anhydrous) reduced the risk of CIO cases with non-metastatic solid tumors observed in Phase 3 studies (SIOPEL 6 & COG ACCL0431). We aimed to evaluate the investigational product PEDMARK provided for pediatric cases via a National Compassionate Use Treatment Protocol (CUP) in Turkey. Methods: Patients (1 month to <18 years) with a localized, nonmetastatic solid tumor, standard-risk hepatoblastoma (HBB), nasopharyngeal carcinoma (NPC) and medulloblastoma MB whose treatment plans were including cisplatin were eligible. PEDMARK was administered intravenously 6 hours after each cisplatin dose infusion. Adverse events, demography, pre and post- hearing were recorded from 21OCT2019-21SEPT2022. Results: The CUP enrolled 12 patients, 8 HBB, 3 NPC and 1 MB in 3 years, from 6 academic institutions. HBB patients' median age was 1year (3mos-3 yrs). All pts had newly diagnosed HBB PRETEXT 3 (n = 5) with a median baseline AFP OF 54.000. 3 NPC age 13-17 yrs, MB 6yrs of age. All patients had Brock Grade 0 on hearing tests prior to treatment Patients received a median 0f 6 cycles (range 4-6) of cisplatin and PEDMARK. Patients with hearing tests available post-treatment (n=11), all maintained Brock Grade 0. At a median of 0.8mos post-treatment, CR were observed in all patients except one HBB with progressive disease. All CRs wer sustained 18.8 mos. AEs in 2 patients were Grade 1-2 nausea/vomiting, no Grade >3 AEs were reported. Conclusions: PEDMARK was well tolerated, provided via a Turkish CUP to reduce the CIO in pediatric patients with nonmetastatic solid tumors. No hearing loss was observed/ detected post-treatment and the tumor outcomes were consistent with the Phase 3 studies. This is very encouraging.
First-in-human study of HMPL-295, an ERK1/2 inhibitor, in patients with advanced solid tumors: Dose-escalation results of monotherapy.
Authors: Yu Xianjun , Zhang Jian , Sun Yuping , Deng Yanhong , Guo Shuangshuang , Hong Wei , Shi Si , Liu Rujiao , Gao Shuiping , Dang Qi , Zhang Jianwei , Su Weiguo , Shi Michael , Fan Songhua , Zhang Bo , Pan Beiqing , Jia Xiaoyun , Wang Jian , Zhong Chen , Ma Luguang 
Published: June 2024

e15112 Background: HMPL-295 (’295) is an extracellular signal-regulated kinase 1 and 2 (ERK1/2) inhibitor with potent activity in non-clinical studies. This is a first-in-human, dose escalation study of ’295 in patients (pts) with advanced solid tumors. Here, we report the results of the mono dose escalation stage. Methods: Pts with advanced solid tumors who have failed standard therapy were enrolled to receive ’295 once daily (QD) in 28-day cycles or ’295 QD 2 weeks on/1 week off (2w on/1w off) in 21-day cycles. The mTPI-2 design was used for dose escalation, having explored from 5 to 75 mg QD in 6 cohorts, as well as 75 mg and 100 mg QD 2w on/1w off. The study aims to determine the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D), safety, tolerability, pharmacokinetics/pharmacodynamics (PK/PD), and preliminary efficacy (best of response, BOR). Results: As of Dec 11, 2023, 47 pts with advanced solid tumors were enrolled (n=1, 1, 3, 6, 12, 5, 13, 6 in 5, 10, 20, 40, 50, 75 mg QD cohorts, 75, 100 mg QD 2w on/1w off cohorts, respectively), with a median age of 58 years, 23 (48.9%) male pts. During the dose escalation from 5 to 75 mg QD cohort, 1 pt given 40 mg QD experienced a dose-limiting toxicity (DLT) of grade 3 dermatitis acneiform and 2 pts given 75 mg QD experienced DLTs of grade 3 rash and acute kidney injury (AKI). As for intermittent-administration cohorts, 2 pts given 100 mg QD 2w on/1w off experienced DLTs of grade 3 AKI and rash maculo-papular. After multiple-dose oral administration, ’295 plasma concentrations reach peak at 1.0-2.0 hours post dose and the exposure (Cmax and AUC) displayed dose dependent increase. The accumulation ratio (AUC) was 2.1–3.4 after repeat dosing, reaching steady-state around day 15. ’295 inhibited ribosomal S6 kinase (RSK) phosphorylation which is a downstream signaling molecule regulated by ERK1/2 and stimulated by phorbol 12-myristate 13-acetate (PMA). The BOR was partial response each in 1 pt with duodenal adenocarcinoma in 40 mg QD cohort,1 pt with endometrial cancer in 50 mg QD cohort and 1 pt with non-small cell lung cancer (NSCLC) in 75 mg QD 2w on/1w off cohort. Stable disease with tumor shrinkage was also observed in 2 pts with NSCLC on 50 mg QD and 75 mg QD 2w on/1w off cohort respectively, and 1 pt with pancreatic ductal adenocarcinoma in 100 mg QD 2w on/1w off cohort. 25 (53.2%) pts reported grade ≥3 TEAEs. The most common (≥10.0%) ≥ grade 3 TEAEs were rash (10.6%) and anemia (10.6%). Conclusions: Considering safety, tolerability, PK/PD and preliminary efficacy results, RP2D was determined to be 50 mg QD. Clinical trial information: NCT04908046 .
Incidence and potential prognostic implications of fibroblast growth factor receptor gene alterations and coexisting mutations in colorectal cancer.
Authors: Lea Vivienne , Lim Stephanie Hui-Su , Chua Wei , Ng Weng Leong , Wang Bin , Wilkinson Kate Jessica , Farzin Mahtab , Habashy Paul , Roberts Tara , Becker Therese , Lee Cheok Soon 
Published: June 2024

e15558 Background: The fibroblast growth factor receptor (FGFR) family comprises four tyrosine kinase receptors (FGFR1-4). FGFR1 amplification (6.3%) as well as overexpression of FGFR1 (10.1%), FGFR2 (5.5%) and FGFR3 (16.2%) have been demonstrated in primary colorectal cancer (CRC, incidence in brackets). The prognostic utility of testing FGFR alterations and association with response to FGFR-inhibitors are still emerging. Here, we report FGFR alteration data with clinicopathological correlations and survival outcomes from a Sydney based Local Health District in Australia. Methods: Clinicopathological data was analysed from 341 ethnically diverse patients with CRC treated at Southwestern Sydney Local Health District from 2014-2021. Next generation sequencing for point mutations, deletions, and amplifications was performed using the Qiagen 30-gene panel. Mismatch repair (MMR) status was determined using immunohistochemical staining. Demographic characteristics, histological features and survival outcomes were recorded from electronic medical records. Results: Of the 341 patients, 42 (12.3%) had FGFR alterations of which 52% were men and 48% women. 32 patients were Caucasian, 4 Middle Eastern, 5 Asian and 1 South American. Median age at diagnosis was 66 years. Of the 42 patients, FGFR1 mutations were present in 26.2%, FGFR1 amplifications in 4.7% and FGFR1 deletions in 4.7%. FGFR2 mutations were present in 16.7%, and 50% had FGFR3 mutations. One patient had concurrent FGFR1 and FGFR3 mutations. The vast majority were adenocarcinoma (81%), followed by mucinous adenocarcinoma (17%) and adenocarcinoma with neuroendocrine features (2%). 21.4% of patients with FGFR alterations had concurrent KRAS mutations, 28.6% had concurrent BRAF mutations (91.6% V600E) and MMR-deficiency was present in 19%. Median overall survival of patients with FGFR alterations was 44 months, for those who also had deficient MMR 48 months, concurrent BRAF V600E mutations 51 months and concurrent KRAS mutations 71 months. 43% (18 patients) were stage 4 at presentation. Of these 18 patients, 7 had FGFR1 mutations, 1 had a FGFR2 mutation and 10 had FGFR3 mutations. The median overall survival of patients with stage 4 disease was 11 months and those with concurrent BRAF V600E mutations 17 months. Two patients had concurrent KRAS mutations (both G12V), with median overall survival of 5.5 months and 1 patient had MMR deficiency, with an overall survival of 9 months. Conclusions: FGFR alterations were identified in 12.3% of patients with colorectal cancer in an ethnically diverse cohort in Australia. Concurrent KRAS and BRAF mutations appear to affect survival outcomes. Further multivariate analyses are underway.
The impact of treatment approach on survival among patients with clinical stage T2N0 and T3N0 rectal cancer.
Authors: Rehman Tauseef Ur , Ceballos Natalie , Samuels Shenae , Ferraro Pablo H. , Gannon Christopher J. , Llaguna Omar H. 
Published: June 2024

e15637 Background: Treatment of early stage rectal cancer requires a multi-disciplinary approach and is often treated with curative intent surgery with use of total neoadjuvant treatment (TNT) or neoadjuvant chemoradiotherapy (nCRT) in select cases pre-operatively. In this study, we determine the various clinicopathologic factors associated with the use of these different approaches (Surgery upfront vs nCRT vs TNT) and their effect on patient survival. Methods: The National Cancer Database (NCDB) was queried for patients with clinical T2N0M0 and T3N0M0 rectal cancer between 2004-2019. Results: 36,869 patients were identified, of which about half had nCRT only while < 15% had received TNT. Patients who underwent nCRT had the highest median OS compared to those who underwent surgery only (106.8 vs 126.5 months, p < 0.001). The surgery upfront cohort had the highest proportion of patients who were seen at a facility with high/very high case volume per year quartiles (surgery: 52.5%, nCRT: 47.3%, and TNT: 48.3%, p < 0.001). The highest median age was among the surgery cohort at 69 years followed by the nCRT cohort at 64 years and TNT cohort at 61 years (p < 0.001). Amongst patients with a Charlson-Deyo co-morbidity score of 2 or more, the surgery upfront cohort had the highest proportion while the TNT cohort had the lowest (p < 0.001). Low anterior resection (LAR) was the most common procedure among all three cohorts. A multivariate logistic regression model revealed that when compared to surgery only, the nCRT (Adjusted Odds Ratio (AOR) = 1.51, p < 0.001) and TNT (AOR = 1.62, p < 0.001) were both associated with an increased likelihood of 5-year long-term survival (LTS), with TNT having a stronger association. Among the various pre-operative characteristics, patients 70 years and older, patient with normal CEA and presence of LVI were less likely to have LTS with TNT as compared to surgery upfront. On the other hand, patients with clinical T3 stage who received TNT were much more likely to have improved LTS as compared to T2 stage (Relative Risk Ratio (RRR) 16.19, p < 0.001). Conclusions: Results of our study show that patients with early stage T2N0 and T3N0 rectal cancer who underwent neoadjuvant treatment had an improved median OS compared to patients who received surgery upfront. Both nCRT and TNT were associated with an increased likelihood of long-term survival, with TNT having a stronger association particularly in the T3N0 cohort.
Adjunctive Statistical Standardization of Adjuvant Estrogen Receptor and Progesterone Receptor in Canadian Cancer Trials Group MA.27 Postmenopausal Breast Cancer Trial of Exemestane Versus Anastrozole
Authors: Chapman Judith-Anne W. , Bayani Jane , SenGupta Sandip , Bartlett John M.S. , Piper Tammy , Quintayo Mary Anne , Virk Shakeel , Goss Paul E. , Ingle James N. , Ellis Matthew J. , Sledge George W. , Budd G. Thomas , Rabaglio Manuela , Ansari Rafat H. , Tozer Richard , D'Souza David P. , Chalchal Haji , Spadafora Silvana , Stearns Vered , Perez Edith A. , Gelmon Karen A. , Whelan Timothy J. , Elliott Catherine , Shepherd Lois E. , Chen Bingshu E. , Taylor Karen J. 
Published: June 2024

PURPOSE ASCO/College of American Pathologists guidelines recommend reporting estrogen receptor (ER) and progesterone receptor (PgR) as positive with (1%-100%) staining. Statistically standardized quantitated positivity could indicate differential associations of positivity with breast cancer outcomes. METHODS MA.27 (ClinicalTrials.gov identifier: NCT00066573 ) was a phase III adjuvant trial of exemestane versus anastrozole in postmenopausal women with early-stage breast cancer. Immunochemistry ER and PgR HSCORE and % positivity (%+) were centrally assessed by machine image quantitation and statistically standardized to mean 0 and standard deviation (SD) 1 after Box-Cox variance stabilization transformations of square for ER; for PgR, (1) natural logarithm (0.1 added to 0 HSCOREs and 0%+) and (2) square root. Our primary end point was MA.27 distant disease-free survival (DDFS) at a median 4.1-year follow-up, and secondary end point was event-free survival (EFS). Univariate survival with cut points at SDs about a mean of 0 (≤–1; (–1, 0]; (0, 1]; >1) was described with Kaplan-Meier plots and examined with Wilcoxon (Peto-Prentice) test statistic. Adjusted Cox multivariable regressions had two-sided Wald tests and nominal significance P < .05. RESULTS Of 7,576 women accrued, 3,048 women's tumors had machine-quantitated image analysis results: 2,900 (95%) for ER, 2,726 (89%) for PgR, and 2,582 (85% of 3,048) with both ER and PgR. Higher statistically standardized ER and PgR HSCORE and %+ were associated with better univariate DDFS and EFS ( P < .001). In multivariable assessments, ER HSCORE and %+ were not significantly associated ( P = .52-.88) with DDFS in models with PgR, whereas higher PgR HSCORE and %+ were significantly associated with better DDFS ( P = .001) in models with ER. CONCLUSION Adjunctive statistical standardization differentiated quantitated levels of ER and PgR. Patients with higher ER- and PgR-standardized units had superior DDFS compared with those with HSCOREs and %+ ≤–1.
Improved HbA1c and Body Weight in GADA-Positive Individuals Treated With Tirzepatide: A Post Hoc Analysis of SURPASS
Authors: Peters Anne L , Buzzetti Raffaella , Lee Clare J , Pavo Imre , Liu Minzhi , Karanikas Chrisanthi A , Paik Jim S 
Published: June 2024

Abstract

Context
People with clinically diagnosed type 2 diabetes (T2D) but positive antiglutamic acid decarboxylase autoantibodies (GADA), referred to here as latent autoimmune diabetes in adults (LADA), may experience more rapid glycemic deterioration than those with T2D and may benefit from effective diabetes treatment with additional metabolic benefits.

Objective
This work aimed to assess glycated hemoglobin A1c (HbA1c) and body weight (BW) changes associated with tirzepatide in GADA-positive vs GADA-negative participants with a clinical T2D diagnosis.

Methods
Post hoc analyses based on pooled data from SURPASS 2-5, using mixed-model repeated measures from the efficacy analysis set, adjusting for study and baseline covariates including age, sex, baseline values, body mass index (BMI), and GADA status, were conducted on 3791 individuals. Intervention included tirzepatide (5, 10, 15 mg). Main outcome measure included change from baseline in HbA1c at weeks 40 (SURPASS-2, -3, -5) and 42 (SURPASS-4) by GADA status.

Results
In participants with confirmed GADA status, 3671 (96.8%) were GADA negative and 120 (3.2%) were GADA positive (76 [63.3%] with low and 44 [36.7%] with high GADA levels). Baseline characteristics were similar between groups, except for slightly lower BMI in GADA-positive vs GADA-negative participants (mean [SD] BMI 32.2 [6.1] vs 33.6 [6.3]). At week 40/42, both groups achieved robust reductions in HbA1c (−2.11% vs −2.32%) and BW (–9.2 kg vs −9.6 kg) (P &lt; .001, both groups). HbA1c reductions were greater in GADA-negative participants (estimated difference [95% CI]: 0.21% [0.03, 0.39]; P = .024) and BW reductions did not differ between groups (0.38 kg [−0.99, 1.75]; P = .588).

Conclusion
In this post hoc analysis, tirzepatide was associated with substantial reductions in HbA1c and BW irrespective of GADA status in adults diagnosed with T2D, suggesting that tirzepatide may improve glycemic control in individuals with LADA.
Renin-angiotensin system inhibitor prescriptions in Chinese hospitalized chronic kidney disease patients
Authors: Zhang Chun , Duan Zhi-Yu , Nie Sa-Sa , Zhang Zhou , Guo Xin-Ru , Zhang Chao-Yang , Dong Jing , Cai Guang-Yan 
Published: June 2024

BACKGROUND
Many guidelines have recommended renin-angiotensin system inhibitors (RASI) as the first-line treatment for patients with chronic kidney disease (CKD). We studied RASI prescription trends from 2010 to 2019, and analyzed the characteristics associated with RASI prescription in Chinese hospitalized CKD patients.
AIM
To study the prescription of renin angiotensin system inhibitors in hospitalized patients with CKD in China.
METHODS
It was retrospectively, cross-sectional reviewed RASI prescriptions in hospitalized CKD patients in China from 2010 to 2019. RASI prescribing trends were analyzed from 2010 to 2019, and bivariate and multivariate logistic regression analyses were conducted to identify characteristics associated with RASI prescription.
RESULTS
A total of 35090 CKD patients were included, with 10043 (28.6%) RASI prescriptions. Among these patients, 18919 (53.9%) met the criteria for RASI treatments based on the 2012 kidney disease: Improving global outcomes guidelines. Of these, 7246 (38.3%) patients received RASI prescriptions. RASI prescriptions showed an initial rapid increase from 2011 to 2012, reached its peak around 2015 and 2016, and then exhibited a subsequent slight decreasing trend. Both bivariate and multivariate analyses showed that several characteristics, including the male gender, age < 60-year-old, nephrology department admission, lower CKD stage, history of hypertension or diabetes, proteinuria, glomerulonephritis as the CKD etiology, and non-acute kidney injury were associated with RASI prescriptions.
CONCLUSION
The frequency of RASI prescriptions showed an initial increase but a slight decreasing trend in more recent years. CKD patients with certain characteristics such as elderly age, advanced disease stage, surgery department admission, or acute kidney injury were less likely to receive RASI prescriptions. In the application of RASI in hospitalized CKD patients is insufficient. The actual clinical practice needs to be improved. The development of related research is helpful to guide the correct choice of clinical treatment strategy.