bluuebunny/crossref_metadata_2025_split huggingface dataset:
Differential therapeutic benefit of platinum-doublet chemotherapies with ICIs based on smoking status plus PD-L1 expression in advanced NSCLC patients.
Authors: Fukuda Akito , Yoshida Tatsuya , Masuda Ken , Shinno Yuki , Okuma Yusuke , Goto Yasushi , Horinouchi Hidehito , Yamamoto Noboru , Ohe Yuichiro 
Published: August 2023

148 Background: Chemotherapy combined with immune checkpoint inhibitors (Chemo-ICIs) has been the standard of care for advanced NSCLC patients. Smoking status is associated with PD-L1 expression and the TILs within tumor microenvironment, which leads to the efficacy of ICIs. It remains unclear how the combined with PD-L1 expression and smoking status affect the efficacy of Chemo-ICIs. Methods: We retrospectively reviewed advanced NSCLC patients without driver mutation (EGFR, ALK, ROS-1, BRAF) who received Chemo-ICIs from January 2019 to June 2021, and Chemo from January 2014 to December 2016 as a first-line therapy at the National Cancer Center Hospital, Tokyo, Japan. The additional benefit of ICIs to chemotherapy were evaluated by comparing the Chemo-ICIs group with Chemo group. Results: During study period, 225 patients received Chemo-ICIs and 133 received Chemo as a first line therapy. Overall response rate (ORR) and progression free survival (PFS) was significantly better in the Chemo-ICIs group than the Chemo group (ORR: 44.9% vs. 40.2%, p=0.01, and median PFS: 8.2 months vs. 6.2 months, P<0.001). The median overall survival was 27.9 months in Chemo-ICIs and 20.4 months in chemo (P=0.14). In the subgroup analysis of PFS, the benefit of Chemo-ICIs compared to Chemo was not observed in never-smoker patients (8.9months vs 8.8months; HR 0.72; 95% CI, 0.49 to 1.28; P=0.27). In contrast, among smoker patients, Chemo-ICIs showed significant longer PFS compared to Chemo (7.5 months vs 5.7 months, P<0.001). Next, patients received Chemo-ICIs were classified into six groups, based on the smoking status (never smoker or smoker) and PD-L1 expression (TPS: 0%, 1-49%, or 50%) (Table). Chemo-ICIs showed better PFS rate at 12 months in the smoker/ TPS ≥50% group (42.2% vs 25.0%, p=0.03), and the never smoker/TPS ≥50% group (75.0% vs 27.3%, p=0.05) compared with Chemo (Table). In patients with 1-49% TPS, compared to the Chemo group, significant PFS benefit of ICIs was observed only in smoker patients (42.2% vs 25.0%, p=0.003), not in never smoker patients (46.2% vs 27.3%, p=0.13). In patients with 0% TPS, although the additional benefit of ICIs to Chemo was not observed both in never smoker (13.3% vs 27.3%, p=0.47) and smoker patients (26.6% vs 25.0%, p=0.13), PFS rate at 12 months in never smoker (13.3%) was lowest among all six groups. Conclusions: Our study suggested that additional benefit of ICIs to chemotherapy could be predicted by combined with smoking status and PD-L1 expression. [Table: see text]
Retrospective observational study of outcomes in HER2-positive metastatic breast cancer patients treated with trastuzumab emtansine in single center.
Authors: Hsieh WanChen , Chang Chia lun 
Published: August 2023

15 Background: Trastuzumab emtansine (T-DM1) was established as a standard second line treatment option for metastatic HER2 positive breast cancer (mBC). However, the EMILIA study did not include disease progression patients who received pertuzumab plus trastuzumab previously. After CLEOPATRA study, the dual blockade treatment was indicated for advanced breast cancer as first line treatment. In this study, we attempted to build the T-DM1 predictive model and to evaluate the association between dual blockade and T-DM1 for metastatic HER2-positive breast cancer. Methods: This retrospective cohort study was conducted in Taiwan. Consecutive patients with metastatic HER2-positive breast cancer who had received T-DM1 between January 2013 and December 2022 were enrolled. Those patients were divided to two groups based on strategy of trastuzumab only or dual-blockade as prior therapy. Demographic, clinical, and pre- and post-T-DM1 treatment characteristics were described. The swimmer plots were used to estimate time to treatment discontinuation (TTD) and overall survival (OS). Results: Of 32 patients treated with T-DM1, 12 (38%) had prior treatment with pertuzumab plus trastuzumab. The median age was 60 years. Most patients had visceral disease and 59% had two or more prior treatments for mBC before T-DM1 (range 1–8 lines). Most patients (63%) stopped T-DM1 due to disease progressed and followed by financial problem (22%). In dual-blockade group, median TTD with T-DM1 was 4.5 months; median OS from diagnosis day was 68.2 months (8 patients still alive in the end of study). In trastuzumab only group, median TTD with T-DM1 was 3.8 months; median OS from diagnosis day was 73.2 months (5 patients still alive in the end of study). In our swimmer plots we found a trend that the shorter interval between trastuzumab +/- pertuzumab and T-DM1 the longer TTD with T-DM1. Conclusions: Patients treated with T-DM1 in this study appeared to have more advanced disease than patients in clinical trials and were treated in later lines of therapy. We should prescribe T-DM1 once trastuzumab with or without pertuzumab failure for the longer TTD. The small patient number was a major limitation in our study. A multi-center analysis is needed and it will help us for treatment suggestion under the Taiwan’s National Health Insurance clinical practice.
Furmonertinib as adjuvant therapy in postoperative EGFR-mutated stage IA2-IIIA non-small cell lung cancer (NSCLC) with high-risk pathological factors.
Authors: Wu Ziheng , Zhang Qingyi , Ke Lei , He Tianyu , Lv Wang , Hu Jian 
Published: August 2023

150 Background: NSCLC patients with high-risk pathological factors such as micropapillary (MP), solid (S), spread through air spaces (STAS), and visceral pleural invasion (VPI) have shown poor prognosis in previous studies. Furmonertinib (AST2818) is a novel, promising oral third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), which has demonstrated efficacy in tumours harbouring sensitive EGFR mutations and T790M resistance mutation. Here, we investigated the efficacy and safety of furmonertinib as adjuvant therapy in postoperative EGFR-mutated NSCLC patients with high-risk pathological factors. Methods: Patients who underwent radical lung cancer surgery with both EGFR mutations and MP/S/STAS/VPI were enrolled and received furmonertinib 80mg daily. The adjuvant therapy time (6-36months) depended on patients’ pathologic stage and physical conditions. The disease-free survival (DFS), safety and tolerability were evaluated. Results: This study retrospectively analyzed 69 patients who were pathologically confirmed adenocarcinoma, EGFR mutation positive (exon 19 deletion/L858R/exon 20ins), stage IA2-IIIA NSCLC. All of them had at least one high-risk pathological factor. There were 44 (63.8%) patients with MP, 14 (20.3%) with S, 10 (14.5%) with STAS and 33 (47.8%) with VPI. All patients were followed at least 13 months, and 24 (34.8%) of them have been followed up for over 21 months, median follow-up time was 18.5 months. By the cut-off date of March 1, 2023, all patients were alive and with no radiographic recurrence, including 3 (4.3%) with exon 20ins. During therapy, 26 (37.7%) patients had treatment-related adverse events (TRAEs) of any grade. The most common TRAEs were rash (12/69, 17.4%), mouth ulcer (6/69, 8.7%), diarrhea (5/69, 7.2%) and transaminase elevation (4/69, 5.8%). Only 2 (2.9%) patients had TRAEs of grade 3 or higher and 1(1.4%) of the two discontinued therapy. Conclusions: This is the first study to demonstrate that furmonertinib has good efficacy and a tolerable safety profile as adjuvant therapy in EGFR-mutated NSCLC patients with high-risk pathological factors who underwent radical lung cancer surgery.[Table: see text]
Second chance for cure: Stereotactic ablative radiotherapy in oligometastatic disease.
Authors: Salim Nidal , Tumanova Kristina , Popodko Alexey , Libson Eugene 
Published: August 2023

154 Background: Local ablative therapy, such as radiation therapy or surgery plays a key role in treatment of patients with oligometastatic disease. Stereotactic ablative radiotherapy (SABR) comes to the fore as a safe and effective treatment option for patients with a limited number of metastases, even those located in hard-to-reach body sites. Many researchers have suggested that metastatic direct therapy (MDT) could improve long-term progression-free and overall survival (PFS and OS) in patients with 1-5 metastatic lesions. Methods: This was a retrospective, single-arm, observational, evaluation study between July 2015 to February 2022. In our institute 60 patients with controlled primary tumors and 1-5 metastases were treated with SABR.We did not exclude patients who subsequently had intracranial metastases from the analysis (n 3). Prescribed radiation doses ranged from 24 to 60 Gy administered in one to seven fractions. Primary endpoint was PFS and the secondary endpoints were OS and toxicity. Results: The most common primary malignancy types were prostate cancer (n 14), colon (n 10), lung (n 7), breast (n 6), melanoma (n 6) and gynecology malignancies (n 6). Median follow-up was 30 months, ranging from 9 to 79. The 1, 3 and 5-year OS rate was 98,3%, 84,4% and 73,8% respectively, the median time to first progression was 15 (range 2 - 32) months. 36 (60%) patients have no recurrence. Two of three patients with intracranial metastases were alive at the end of the study. There were no grade 3-5 adverse events related to specific treatment of SABR. In our analysis, neither the number of metastases nor the primary site were independent prognostic factors. Conclusions: In our retrospective analysis, SABR was associated with high levels of PFS and OS in patients with oligometastatic disease. The limitations of our study were lacking high-level evidence, randomized studies to compare SABR and palliative standard-of-care are mandatory.
Hypoxia-related genes and PD-L1 inhibitor resistance in hepatocellular carcinoma.
Authors: Mohan Huang , Chan Wing Chi 
Published: August 2023

158 Background: PD-L1 inhibitor in combination with anti-angiogenic drug has become the first-line treatment strategy for unresectable hepatocellular carcinoma (HCC). However, PD-L1 inhibitor resistance remains an essential issue in treating HCC. It has been proved in the tumor microenvironment that hypoxia-induced increase in PD-L1 expression makes a significant impact on drug resistance. Methods: Two public datasets of gene expression profiles (GSE 14520 and GSE 41666) from the Gene Expression Omnibus (GEO) database were analyzed using bioinformatics: (1) HCC tumor versus adjacent normal tissue (N = 214) and (2) normoxia versus anoxia of HepG2 cells (N = 6). HCC-signature and hypoxia-related genes were identified as the differentially expressed genes (DEGs). Gene set enrichment analyses (GSEA) were performed on the DEGs. Furthermore, multiple regression analysis on the TCGA-LIHC dataset (N=371) and construction of the protein-protein interaction (PPI) network were performed to investigate potential PD-L1 regulatory genes and hub genes. Results: A total of 52 genes overlapped in HCC-signature and hypoxia-related DEGs. Five genes were identified by GSEA as being concurrently associated with the PD-L1 expression pathways. Multiple regression analysis results showed 14 potential PD-L1 regulatory genes. Ten hub genes were identified in the PPI network. Finally, three genes (DLGAP5, KIF20A, and TPX2) were found in common and may be regulatory genes affecting PD-L1 expression. Conclusions: In conclusion, our study provides new insights into the potential hypoxia-related mechanisms of PD-L1 inhibitor resistance and contributes to exploring new therapeutic strategies for treating unresectable HCC.
Comparison of the initial presentation and long-term outcome of differentiated thyroid carcinoma (DTC) between children and adults: A single institution experience in Taiwan.
Authors: Chang Yen Hsiang 
Published: August 2023

163 Background: Differentiated thyroid carcinoma (DTC) in children is known to be more aggressive than in adults. However, there are no cohort studies in Asia that have compared the presentation and long-term outcomes of pediatric DTC with adult DTC. In this study, we aimed to compare the clinical characteristics and outcomes of pediatric DTC with a comparison cohort of adult DTC patients. Methods: We reviewed the data of 46 pediatric DTC patients who underwent total thyroidectomy from January 1991 to December 2021, along with a comparison cohort of 350 adult DTC patients at our hospital. All patients received postoperative radioiodine therapy. Clinicopathologic features and surgical outcomes were analyzed retrospectively, and patients were stratified according to the American Thyroid Association (ATA) risk stratification system. Clinical outcomes were classified according to Dynamic Risk Stratification (DRS) at the end of follow-up. Results: Children with DTC had less common papillary thyroid carcinoma (80 vs. 93%) but had larger primary tumors, more multifocal disease, and more lymph node and distant metastasis at presentation compared to adults. Thus, at initial risk stratification, more children had intermediate-to-high risk (62 vs. 49%) than adults. At the end of follow-up, fewer children were classified as having excellent response (no evidence of disease) than adults (48 vs. 79%). Based on the ATA risk stratification system, a higher percentage of high-risk children had structural-persistent disease (60%) compared to high-risk adults (29%), and a lower percentage of low-risk children became no evidence of disease (76%) compared to low-risk adults (93%). Conclusions: Children with DTC present with more extensive disease and have worse outcomes compared to adults. The ATA initial risk stratification system can predict long-term outcomes in both children and adult DTC patients and guide personalized management and follow-up strategies.
Comparison of treatment discontinuation rates between CDK4/6 inhibitors.
Authors: Kosaka Maya , Tanioka Maki , Nishina Takuya , Takata Kenji , Shoko Otsuka , Tsukioki Takahiro , Takahashi Yuko , Iwatani Tsuguo , Kawasaki Kensuke , Shien Tadahiko 
Published: August 2023

2 Background: Abemaciclib and Palbociclib are both CDK4/6 inhibitors and its combination use with hormone drugs prolonged progression-free survival in estrogen receptor positive metastatic breast cancer. Both are not yet directly compared in terms of efficacy, adverse events, and discontinuation rates due to the adverse events. MonarchE trial evaluated adverse events of Abemaciclib as follows; 81.3% had diarrhea and 41.3% had neutropenia, whereas PALOMA-3 trial showed 92% of neutropenia (74% had Grade3 neutropenia) in patients receiving Palbociclib. Of the patients who received CDK4/6 inhibitors in our institutions, we compared the difference of rates in adverse events, and we discussed the importance of acknowledging the risks between the two drugs. Methods: We reviewed a total of 169 patients comprising 53 with Abemaciclib and 116 with Palbociclib from 2017 to 2023 at two institutions as 1st – 3rd line treatments. The year of prescription, treatment line, age and the adverse event which led to treatment discontinuation was analyzed. Results: All patients were women, and the median age was 57 (29-84). The patients who received treatment as 1st, 2nd, 3rd lines were 98, 49, and 22, respectively. Twenty-six patients received cytotoxic chemotherapy before CDK4/6 inhibitors. Patients diagnosed as de-novo stage IV patients were 108, while 61 had recurrent tumors. Treatment discontinuation due to adverse events of CDK4/6 inhibitors were 41 (24%) in which 14 (8.3%) had diarrhea and 20 (12%) had neutropenia. We conducted a multivariate analysis setting the endpoint as any adverse events resulting to treatment discontinuation. Abemaciclib (HR=1.20 p=0.01), the first prescription date (2017-19 vs 2020-23, HR:0.84 p=0.02), and patients with metastatic breast cancer at first diagnosis (HR:1.15 p=0.039) significantly affected adverse events leading to treatment discontinuation. Patients receiving Abemaciclib discontinuedecause of diarrhea more than patients receiving Palbociclib (p<0.001 HR:1.28), whereas patients receiving Palbociclib discontinued treatment because of neutropenia more than patients receiving Abemaciclib (HR=1.13 p=0.036). Conclusions: The type of CDK4/6 inhibitor, de-novo Stage IV or recurrent breast cancer, and the year of treatment initiation led to differences in safety of CDK4/6 inhibitor treatment. Abemaciclib leads to treatment discontinuation more than Palbociclib with the most reported adverse event; diarrhea. In addition, the risk of adverse events differs from the year of treatment initiation, which suggests that management of adverse events is improving over time. Thus, it is crucial to accomplish the management of adverse events when starting Abemaciclib which has higher treatment discontinuation rates due to adverse events.
HYbrid DegRAding Copolymer (HYDRAC): Heterobifunctional polymers for targeted degradation of undruggable proteins.
Authors: Wang Max Mu , Truica Mihai Ioan , Abdulkadir Sarki , Gianneschi Nathan 
Published: August 2023

22 Background: Of the ~20,000 proteins encoded by the human genome, only a small subset can be modulated via traditional pharmacological approaches. Included in the list of “undruggable” proteins are ones with pivotal roles in cancer. We aim to expand the arsenal of compounds able to affect the activity of these therapeutically relevant targets by introducing a modular proteomimetic platform technology designed to carry side chains consisting of targeting warheads and recruiters of cellular protein degradation machinery. We term these compounds HYbrid DegRAding Copolymers (HYDRACs) in reference to the multiplexing of different protein binders and degradation inducing sequences. Peptides arranged as HYDRACs exhibit favorable emergent properties including resistance to proteolysis, high levels of cell uptake, and payload-specific activity. Initial studies were conducted focusing on a undruggable transcription factor MYC, which is widely dysregulated in human cancers. Methods: A library of HYDRACs and control polymers were synthesized and were cell-penetrating with antiproliferative effects at sub-micromolar IC50s in a formulation- and MYC-dependent manner across multiple cell lines. Results: HYDRAC treatment resulted in significant decreases in MYC protein levels, which was rescued by proteasome inhibitor MG132 and neddylation inhibitor MLN4924, without changes in mRNA levels. RNAseq showed selective overexpression of MYC pathway genes only in HYDRAC treated cells, confirming on-target effects. Circular dichroism showed strong HYDRAC-MYC interactions, which was supported by the presence of MYC following pull-down of biotin-terminated HYDRACs. Removal of the RRRG degron, scrambling the H1 sequence, and disassociation of the two domains on separate polymers all abrogated MYC-degradation. Mice bearing transplanted Myc-CaP tumors showed delayed tumor growth and reduced tumor cell proliferation following HYDRAC treatment. Mice bearing luminescent Luc-MV-411 tumors treated with Cy5.5-labeled HDRACs showed selective tumor accumulation with detectable fluorescent signal in the tumor up to 72 hours following a single IP administration. The versatility of the platform was demonstrated by substituting the degron for recruiters of three different E3 ligases (VHL, KEAP1, and CRBN), which all maintained ability to degrade MYC. HYDRACs were also able to selectively degrade other protein targets including alpha-syn and RAS. Conclusions: We present a platform technology that addresses challenges inherent to small molecule drug design. HYDRACs have the potential to dramatically alter the drug discovery landscape, allowing for development of modulators of "undruggable" targets. We envision the HYDRAC platform as a generalizable approach to designing degraders of proteins of interest, greatly expanding the therapeutic armamentarium for target protein degradation.
A novel approach for the treatment of advanced hepatocellular carcinoma (HCC).
Authors: Fishman Pnina , Lencioni Riccardo , Stemmer Salomon M , Farbstein Motti , Harpaz Zivit , Bareket-Samish Avital , Silverman Michael H. , Ciurescu Ioana Adriana 
Published: August 2023

35 Background: No established treatments for patients with advanced HCC and moderate hepatic dysfunction (Child-Pugh B; CPB) are available. Namodenoson is an A3 adenosine-receptor agonist currently under clinical development as a treatment for advanced HCC with CPB. Methods: Wereport the results of a prospective placebo-controlled randomized (2:1) phase 2 trial investigating namodenoson (25 mg BID) as a second-line therapy in HCC with CPB and focus on a case of a long-term complete response (CR). Results: The study included 78 patients (50 namodenoson-treated, 28 placebo-treated). Namodenoson was well-tolerated and no treatment-related deaths were reported. Median overall survival (OS, the primary endpoint) was not statistically significantly different between the namodenoson and placebo arms (4.1 and 4.3 months, respectively, hazard ratio [HR], 0.82; 95% confidence interval [CI], 0.49‒1.38; p=.46). The difference in 12-month OS was statistically significant (44% vs 18%, respectively, p=.028). Pre-planned analysis of patients with CPB7 (34 namodenoson-treated, 22 placebo-treated) showed nonsignificant improvements in OS and progression-free survival (PFS). OS: 6.9 vs 4.3 months; HR, 0.81; 95% CI: 0.45‒1.43; p=.46. PFS: 3.5 vs 1.9 months; HR, 0.89; 95% CI: 0.51‒1.55; p=.67. Of the patients with ≥1 assessment post-baseline, partial response (PR) was reported in 3 of 34 (8.8%) namodenoson-treated patients and none of the 21 placebo-treated patients. One of 3 the patients who achieved a PR (a 61-year old woman with CPB7, Barcelona Clinic Liver Cancer stage C, and Eastern Cooperative Oncology Group performance status 2) continued treatment with namodenoson under an open-label extension program (treatment is ongoing for >6 years). The patient achieved a CR (determined via CT scans) 4 years after treatment initiation. Furthermore, the patient's baseline ALT and AST levels which were elevated at baseline (68 U/L and 44 U/L, respectively) normalized after 4 weeks, and her serum α-fetoprotein level, which was 47 ng/ml at baseline, declined to normal levels after 20 weeks of treatment and reached 1.3 ng/mL at time of CR. The patient experienced no treatment-related adverse events. At present (6 years from treatment initiation), the response is ongoing as shown by liver function evaluation and imaging studies. Conclusions: Treatment with namodenoson can result in a complete and long-term response. The findings support the clinical development of namodenoson as a treatment for HCC with CPB7. Clinical trial information: NCT02128958 .