bluuebunny/crossref_metadata_2025 huggingface dataset:
Hospitalization outcome of patients with lung cancer with COVID-19 infection: NIS 2020 analysis.
Authors: Suenghataiphorn Thanathip , Srikulmontri Thitiphan , Kulthamrongsri Narathorn , Tribuddharat Narisara , Naunsilp Piengpitch , Saowapa Sakditad , Xanthavanij Nutchapon
Published: August 2024

212

Background: Lung cancer is the most commonly diagnosed cancer and the leading cause of cancer-related deaths globally. Recent data showed the detrimental effects of COVID-19 infection on other neoplasm conditions, causing increased mortality rates and complications. However, data on the precise effects of COVID-19 on hospitalized individuals with lung cancer are scarce. Methods: We analyzed the 2020 U.S. National Inpatient Sample (NIS) to investigate the effects of COVID-19 infection on cases primarily admitted due to lung and bronchus cancer. Adjusted odds ratios (aORs) for specified outcomes were calculated through multivariable logistic and linear regression analyses. The primary outcome was inpatient mortality, with secondary outcomes including system-based complications. Statistical significance was established at a p-value of 0.05. Results: We identified 103,334 patients with a primary discharge diagnosis of lung and bronchus cancer. The mean age was 68.9 years; 50.5% were female. In the non-COVID group, Caucasians accounted for 75%, followed by Hispanics (12%). Of these, 0.36% (374/103,334) had a concurrent diagnosis of COVID-19 infection. In a survey multivariable logistic and linear regression model adjusting for patient and hospital factors, COVID-19 infection was associated with higher in-hospital mortality (aOR 5.39; 95% CI (3.01, 9.64), p < 0.001), higher mean length of stay (b 5.51; 95% CI (2.59, 8.43) p < 0.001), mean total hospital cost (b 10,683; 95% CI (784.32, 20,581.93) p = 0.034), shock (aOR 4.37; 95% CI (1.96, 9.91), p < 0.001), acute respiratory failure (aOR 2.23; 95% CI (1.30, 3.85), p = 0.004), mechanical ventilation usage (aOR 3.12; 95% CI (1.46, 6.66), p = 0.003) and acute kidney injury (aOR 2.71; 95% CI (1.54, 4.74), p < 0.001). We observed non-significant, but increased, risks of sepsis, SIRS, and coagulopathy in COVID-19-positive patients. Conclusions: In conclusion, our study underscores that COVID-19 infection is associated with higher in-hospital mortality and other major clinical outcomes in lung cancer, as well as increased economic burden and cost of stay. To definitively establish causal relationships between the observed factors and the reported clinical outcomes in this population, further longitudinal research is necessary.
Efficacy and safety of 1L selpercatinib in RET fusion-positive NSCLC: LIBRETTO-431 East Asian subgroup analysis.
Authors: Cheng Ying , Loong Herbert H. , Zhou Caicun , Nishino Kazumi , Lee Dae Ho , Lee Se-Hoon , Yang James Chih-Hsin , Liu Dan , Rajakumar Deborah , Han Hongmei , Puri Tarun , Lin Aimee Bence , Goto Koichi
Published: August 2024

214

Background: In prior studies, the efficacy and safety of selpercatinib, a selective RET inhibitor, was consistent in RET+ NSCLC pts across geographies. As previously reported, LIBRETTO-431 met its primary endpoint of improved PFS by blinded independent central review (BICR) at the pre-planned interim analysis. Here we report the efficacy and safety from LIBRETTO-431 in pts from East Asia, a majority of the study population. Methods: LIBRETTO-431 (NCT04194944) is a randomized, open-label phase 3 trial comparing 1L selpercatinib vs control (platinum/pemetrexed +/- pembrolizumab). Geography (East Asia vs non-East Asia) was a stratification factor. BICR-assessed PFS, ORR and DOR were examined in pts from East Asia randomized with investigator’s intent to treat with pembrolizumab (ITT-pembro) if assigned to control. AE data were collected for all pts from East Asia who received at least one dose of selpercatinib or control (n=140). Results: Of 142 randomized pts from East Asia, 116 were included in the ITT-pembro population (selpercatinib: n=75, control: n=41). Baseline characteristics were well balanced, however the selpercatinib arm had slightly more pts from East Asia vs the control arm (58% vs 49%). In ITT-pembro pts from East Asia, with a median follow up of 19.4 mo and 21.2 mo in the selpercatinib and control arms respectively, the median PFS was not yet reached with selpercatinib (95% CI: 16.4-NE) vs 11.1 mo (95% CI: 7.0-16.8) with control. At 12 mo the PFS rate was 72.8% with selpercatinib vs. 41.7% with control. The ORR was 86.7% (95% CI: 76.8-93.4) with selpercatinib vs 61.0% (95% CI: 44.5-75.8) with control. Similar results were observed in pts from East Asia in the overall ITT population. The most common AEs reported in pts from East Asia on selpercatinib included elevated AST (73.6%), elevated ALT (70.3%), hypertension (60.4%), increased blood bilirubin (52.7%) and diarrhea (44.0%) while those reported with control included anemia (61.2%), elevated AST (49.0%), leukopenia (49.0%), neutropenia (44.9%) and elevated ALT (42.9%). A summary of safety data for selpercatinib vs control in pts from East Asia is presented in the table. Conclusions: LIBRETTO-431 is the first randomized study to report efficacy and safety of a RET inhibitor in pts from East Asia. Consistent with the results in the overall population, selpercatinib demonstrated superior PFS compared to chemotherapy + pembrolizumab in 1L pts from East Asia. These data support early comprehensive genomic testing and the use of selpercatinib as the preferred 1L regimen in RET+ NSCLC pts across geographies. Clinical trial information: NCT04194944 . [Table: see text]
Early circulating tumor DNA (ctDNA) changes during treatment with immune checkpoint inhibitors (ICI) as a predictor of clinical outcomes in patients (pts) with advanced stage melanoma/skin cancer.
Authors: Ma Vincent T. , Park Yeonhee , Patel Janmesh. D , Harris Madison S. , Mannino Matthew C. , Schehr Jennifer L. , Birbrair Alexander , Zhao Shuang , Lang Joshua Michael
Published: August 2024

225

Background: ctDNA monitoring has shown promising results in predicting relapse in resected solid tumors. Its role in treatment response assessment and predicting survival outcomes in the unresectable or metastatic disease setting merits further investigation. In our study, we attempt to assess the role of early ctDNA changes in predicting disease response, progression, and overall survival outcomes in pts with advanced stage melanoma/skin cancer treated with ICI therapy. Methods: A retrospective analysis using a personalized, tumor-informed ctDNA assay (Natera) on prospectively collected plasma samples from pts with unresectable stage III/IV melanoma/skin cancer treated with anti-PD-1 based therapy at the University of Wisconsin (Madison) was performed. Baseline ctDNA levels were assessed prior to the start of treatment and at 3-4 weeks (i.e. prior to the second treatment dose). A logistic regression model was used to evaluate the odds of overall disease control [complete response + partial response + stable disease, per RECIST version 1.1] based on the change in ctDNA levels (decrease vs increase) between both time points. Cox proportional hazard models were used to investigate the effects of ctDNA level change on progression free survival (PFS) and overall survival (OS). Results: 46 pts were evaluated. 82% melanoma, 14% Merkel cell carcinoma, 2% skin adenocarcinoma and 2% squamous cell carcinoma. 77% were treated with dual ICI (anti-PD-1 based) therapy and 23% with anti-PD-1 monotherapy. Median follow up was 12.1 months. Median change in ctDNA levels from baseline were -4.83 MTM/mL among pts with ctDNA decrease and +37.39 MTM/mL among pts with ctDNA increase. A qualitative decrease in ctDNA level was associated with overall disease control (OR 65.00, 95% CI 11.88-587.89, p<0.0001), longer PFS (HR 0.08, 95% CI 0.03-0.22, p<0.0001), and longer OS (HR 0.17, 95% CI 0.05-0.54, p=0.0008) compared to an increase in ctDNA level from baseline to 3-4 weeks after starting ICI therapy. Median PFS was not reached (NR) and 1.63 months; and median OS was NR and 5.57 months among pts with ctDNA decrease and ctDNA increase, respectively. Conclusions: We found that early ctDNA dynamics after 3-4 weeks of ICI initiation in pts with advanced melanoma/skin cancer appears to be a candidate strategy to predict treatment response, risk of progression, and potentially long-term survival. Larger prospective studies are warranted to validate the utility of ctDNA in treatment monitoring.
Factors predicting long-term survival of hepatocellular carcinoma in developing country.
Authors: Neesanun Sunee
Published: August 2024

231

Background: Hepatocellular carcinoma (HCC) is a common cancer globally, especially in Asian Pacific countries with survival time limit. Previous data on long-term survival (LS) in HCC patients has been limited. This study aims identifying factors that predict LS for HCC patients treated in hospitals with restricted access to advanced therapies. Methods: This study utilized a retrospective cohort design, analyzing electronic medical records of patients diagnosed with HCC at Sawanpracharak Hospital from October 2018 to September 2022. LS for HCC was defined as survival for two years or more. Univariable and multivariable with stepwise backward regression analyses were employed to identify independent prognostic factors. Results: The analysis included 398 HCC patients, with 75 (18.84%) classified as long-term survivors (LS HCC). Stepwise backward regression identified that ALP levels <172 U/L were associated with a significantly increased likelihood of LS (OR = 3.667, 95% CI 1.443-9.317, p=0.006). Additionally, curative surgery/RFA treatment (OR = 1.941, 95% CI 1.128-3.342, p=0.017) and Albumin >3.5 g/dL (OR = 9.898, 95% CI 1.160- 84.438, p=0.036) were significant positive predictors. ECOG performance status (3-4 vs 2 vs 0-1) and AJCC stage (early vs locally vs advance) also emerged as significant factors, with better performance status (OR = 8.723, 95% CI 1.046-72.741, p=0.045) and AJCC stage 3 and 4 (OR 0.200 95% CI= 0.075-0.532, P= 0.001 and OR = 0.204, 95% CI 0.0547-0.760, p=0.018 respectively) associated with LS. Notably, alcohol consumption was associated with a decreased likelihood of LS (OR = 0.399, 95% CI 0.171-0.929, p=0.033). The model demonstrated good discriminative ability with an AUC of 0.912. Conclusions: Lower ALP levels, curative treatment, higher albumin levels, better ECOG performance status, earlier AJCC stage, and abstinence from alcohol consumption were all associated with a significantly increased likelihood of LS HCC. The high AUC of the model suggests its potential for predicting long-term survival in this patient population. [Table: see text]
The single cell transcriptional landscape of fibrosarcoma.
Authors: Wang Juan , Li Zhenfeng , Zhang Ning
Published: August 2024

235

Background: Fibrosarcoma (FS) is a relatively uncommon subtype of soft tissue sarcoma, which predominantly occurs in the extremities and girdles of elderly individuals. FS are famous for its high recurrence and metastasis rate. However, the current treatment regimens have shown poor efficacy in treating these progressive lesions. Therefore, a deep understanding of the tumor microenvironment characteristics of fibrosarcoma is needed to develop more effective drugs.Therefore, a deeper understanding of the tumor microenvironment characteristics of fibrosarcoma is needed for further development of therapeutic drugs. Methods: We performed single-cell transcriptome sequencing for the first time on 6 patients bearing with FS. Bulk-seq data of soft tissue sarcoma was downloaded from public database including TCGA and GEO for prognostic analysis. What' s more, a cohort of 54 FS patients was retrospectively collected for protein detection. Results: The tumor microenvironment landscape was characterized by the presence of malignant fibroblast, diverse macrophages, limited T-cell presence, and high levels of vascular infiltration. The expression of siglec15 was significantly upregulated in the malignant cells. And the prognostic significance of siglec15 was confirmed by the TCGA public database. What’s more, the high expression of siglec15 protein was negatively related to overall survival of fibrosarcoma patients from our institution. We also explored the interactions among different cell subtypes, especially the interactions between malignant cells and endothelial cells, as well as macrophages and endothelial cells, which not only promote tumor progression but also inhibit T-cell infiltration and function. Conclusions: In total, our work has uncovered the low T cell infiltration landscape of FS. The primary reason of insufficient immune infiltration may be due to the blockage of T cell extravasation caused by the interaction between endothelial cells, malignant cells and macrophages.
The candidate novel markers PIV and PILE score to predict survival outcomes and therapeutic response in patients with primary central nervous system lymphoma.
Authors: Duan Ling , Li Wenbin , Chen Feng
Published: August 2024

24

Background: Recent studies highlighted the predictive value of easily measurable blood-based biomarkers, such as the neutrophil-to-lymphocyte ratio (NLR), the monocyte-to-lymphocyte ratio (MLR), the platelet-to-lymphocyte ratio (PLR), and the systemic immune-inflammation index (SII). Recently, a novel comprehensive marker that represents the pan-immune-inflammation value (PIV) has been proposed as a more reliable predictor of clinical outcomes. We aimed to investigate the prognostic significance of PIV and PILE score (a score based on PIV, lactate dehydrogenase (LDH), and Eastern Cooperative Oncology Group Performance Status (ECOG PS)), in patients with PCNSL. Methods: A total of 109 patients were enrolled. PIV was calculated as follows: (neutrophil count × platelet count × monocyte count)/lymphocyte count. The PILE score was calculated with the sum of individual values (for PIV < median = 0, ≥ median = 1; for LDH ≤ upper limit of normal (ULN) = 0, > ULN = 1; for ECOG PS < 2 = 0, ≥ 2 = 1). The Kaplan–Meier method and Cox hazards regression models were used for survival analyses. The relationship between PIV, PILE, and therapeutic response was examined. Results: Pretreatment high PIV was confirmed to be an independent significant factor for overall survival (OS) in univariate (HR 3.990, 95%CI 1.778-8.954, p < 0.001) and multivariate (HR 3.047, 95%CI 1.175-7.897, p = 0.022) analyses. Baseline PIV was also associated with worse progression-free survival (PFS). Regarding OS, PIV showed a better predictive performance than other widely used systemic inflammation parameters. Significantly shorter OS and PFS were observed in the high PILE group (median OS: 25.60, 95% CI 15.60-NR vs. NR months, 95% CI 26.10-NR, p = 0.008; median PFS: 26.13, 95% CI 23.30-NR vs. 7.13 months, 95% CI 4.87-NR, p < 0.001). High PILE was associated with primary resistance to therapy (high PILE group: 21/42 patients, 50.00%; low PILE group: 5/45 patients, 11.11%; p < 0.001). A significantly lower response rate to initial treatment was found in patients in the high PILE group (23/42, 54.76%) as compared to patients in the low PILE group (7/45, 15.56%; p < 0.001). PILE was independently associated with therapeutic response to initial treatment (OR 0.17, 95% CI 0.05–0.46; p < 0.001). Conclusions: High PIV and high PILE were correlated with worse clinical outcomes in PCNSL patients, indicating that PIV and PILE might be a powerful predictor of prognosis and a potential predictive indicator for treatment response in PCNSL.
The use of adjuvant radiotherapy in resected adult intracranial atypical meningioma in United States: A SEER analysis.
Authors: Co Jayson L.
Published: August 2024

27

Background: It is unclear whether adjuvant external beam radiotherapy (EBRT) in atypical meningiomas after surgical resection provided overall survival advantage. Although meta-analysis were previously reported, there is heterogeneity in the included studies. With lack of prospective trial, we rely on observational data for management. This project aims to determine if the addition of adjuvant EBRT after resection compared to resection alone in atypical meningioma is associated with better prolonged survival among patients within United States. Methods: The National Cancer Institute Surveillance, Epidemiology and End Results database was queried for list of patients diagnosed with atypical meningioma from 2000 to 2020 according to International Classification of Disease (ICD) for Oncology, third edition with morphology codes 9539/0 and 9539/1.This was limited to intracranial location. Rate of dying among those receiving adjuvant EBRT after surgery for atypical meningiomas was compared to the rate of dying of those who had resection alone without adjuvant EBRT postoperatively. Other covariates included, age at diagnosis, gender, marital status, race, tumor laterality, tumor site, tumor, extent of resection and household median income. Chi-squared test was used to test the association between institution of adjuvant EBRT and other co-variates for categorical variable. Cox-proportional analysis was used to test the association between adjuvant EBRT and death. Observed survival was estimated using Kaplan-Meyer method. Survival curves were generated for both cohorts and log rank test was performed. Results: A total of 3,328 patients were included in analysis.1,004(30.17%) patients received adjuvant EBRT and 767(23.05%) died in the entire cohort. Rate of dying in the entire cohort is 43.84 per 1,000 person-years. Death rate for patients receiving adjuvant EBRT is 44.95 per 1,000 person-years, while patients who did not receive adjuvant EBRT had a death rate of 40.95 per 1,000 person-years. Patients aged 80 years or older, divorced and separated tend not to receive adjuvant EBRT, while patients with tumor size of 51-100mm and 101-200mm are more likely to receive adjuvant RT. Crude rate ratio among those patients receiving RT compared to the rate of those who did not receive adjuvant RT is 0.91 (95% CI: 0.76-1.07). Adjusting for possible confounders did not change the rate ratio between adjuvant EBRT compared to resection alone. Extent of resection did not modify the effect of adjuvant RT to death (likelihood ratio test-0.363). Survival analysis using Kaplan Meier curve showed no difference whether a patient received adjuvant EBRT or not (log rank test-0.238). Conclusions: There is no clear evidence on the survival benefit for use of adjuvant EBRT in resected atypical meningioma compared resection alone. This is true both in incomplete and completely resected atypical meningiomas.
Bruton's tyrosine kinase inhibitor zanubrutinib-based regimens in relapsed/refractory primary diffuse large B-cell lymphoma of central nervous system.
Authors: Wang Yali , Chen Feng , Li Wenbin
Published: August 2024

30

Background: Patients with relapsed/refractory primary central nervous system lymphoma (R/R PCNSL) usually have a poor prognosis. Ibrutinib-based regimens revealed promising efficacy but showed off-target effects and drug resistance in some cases. Here, we conducted a retrospective study to evaluate the efficacy and safety of regimens based on second-generation bruton's tyrosine kinase (BTK) inhibitor zanubrutinib in R/R PCNSL. Methods: We respectively reviewed 23 patients with R/R PCNSL treated with zanubrutinib in our center from Apr. 2021 to Jan. 2024. The primary end points were overall response rate (ORR) and progression-free survival (PFS). Secondary end points included complete response rate (CRR), disease control rate (DCR), overall survival (OS) and adverse events (AEs). Response was assessed according to International Primary CNS Lymphoma Collaborative Group criteria. The severity of AEs was graded using the NCI Common Toxicity Criteria, version 5.0. Validated next-generation sequencing (NGS) panels were used to analyze the mutational status of the BCR pathway genes or other solid tumor-related genes. Results: The median follow-up at the cutoff date (15 Jan 2024) was 17.0 months (range, 2-33 months). The ORR, CRR and DCR were 78.3%, 39.1% and 91.3%. The median PFS was 31.0 months, but the median OS was not reached. Compared to germinal center B-cell like (GCB) group, non-GCB group showed a better ORR (76.9% vs 66.7%) and CRR (46.2% VS 33.3%). Multivariate analysis revealed that overall response (vs. no response, HR=0.20, P=0.027), long duration of zanubrutinib (≥6months vs. 2-5 months, HR=0.07, P=0.009) and refractory disease status (vs. relapse disease status, HR=0.12, P=0.014) were independent factors for longer PFS. The most commonly mutated genes are MYD88(15/17,88.2%), PIM1(9/17 52.9%), CD79B (8/17,47.1%), ETV6(7/17,41.2%), BTG1(5/17,29.4%) and GNA13(5/17,29.41%). The mutational status of MYD88/CD79B did not lead to any difference in PFS and OS. We obtained the Tumor Mutational Burden (TMB) information from 11 patients. The median TMB was 15.96 (range: 3.82-28.11) muts/Mb. Kaplan-Meier analysis demonstrated that PFS was significantly longer in patients with higher TMB (≥15.96 muts/Mb) after zanubrutinib-based treatment(P=0.005). Grade ≥3 and serious treatment-emergent AEs (TEAEs) were not found. The most commonly TEAEs were hematologic toxicity (8/23,34.8%) and skin rash (5/23,21.7%). Conclusions: Our study demonstrates that zanubrutinib-based therapy is effective and safe for the treatment of R/R PCNSL. We advocate for the prolonged administration of zanubrutinib to maintain treatment response. Patients with higher TMB derive greater benefits from zanubrutinib-based regimens.
Efficacy of combination of immune checkpoint inhibitors, chemotherapy, and targeted therapy in advanced/refractory cancer.
Authors: Salem Philip A. , Gensini Lorenzo , McCallum William G.B. , Hanna John , Wheeler Thomas M. , Stenoien Randall A. , Jabboury Khaled W.
Published: August 2024

41

Background: The treatment of advanced/refractory malignancies continues to pose a major challenge, and it is associated with poor outcome. It has been shown that in some cancers, the combination of chemotherapy (CT) with immune checkpoint inhibitors (ICIs), or CT with targeted therapy (TT), are superior to chemotherapy alone. Consequently, in our treatment program (ICTriplex), TT was added to CT plus ICIs. These three modalities have convergent efficacy with divergent toxicity. Our prior data were previously reported (1-3). Methods: Treatment with ICTriplex was highly personalized and was tailored to the individual patient and their specific cancer. It was designed based on diagnosis, prior therapy, and genomic profiling. Between March 2017 and January 2024, 56 patients (pts) with advanced malignancies were treated: 31 females and 25 males, with a median age of 58. Tumor types included: lung (12), pancreas (8), colorectal (8), biliary tract (5), breast (4), stomach (4), melanoma (3), ovary (3), sarcoma (3), cervix (2), glioblastoma (2), Hodgkin’s (1), and thymoma (1). 43 pts received prior therapy: 14 received ICIs, 23 TT, and 42 CT. The agents used in ICTriplex were: 6 ICIs primarily nivolumab and pembrolizumab, 12 CT primarily taxanes, gemcitabine, and platinum, and 23 TT, primarily bevacizumab and erlotinib. Response was evaluated by both PET/CT and CT scans. A complete remission was achieved when metabolic activity completely resolved on PET/CT. Progression-free survival (PFS) and overall survival (OS) were calculated using the Kaplan-Meier estimator. Results: The overall response rate (ORR) was 88%. A complete remission (CR) occurred in 29 pts (52%), and a partial remission (PR) in 20 pts (36%). Of the 12 pts with lung cancer, 9 (75%) achieved CR and of these, 4 pts had brain metastases that completely resolved without radiation. Of the 8 pts with pancreatic cancer, 4 (50%) achieved CR. 4 of 5 pts with biliary tract cancer achieved CR. Toxicity was reasonable in all pts except for 3 who died from complications possibly related to ICIs. The median PFS was 11 months, and the median OS was 15 months. The achievement of CR and the PD-L1 + status, resulted in a statistically significant better PFS (p= 0.00; p= 0.02) and OS (p=0.00; p= 0.005). Patients with lung cancer showed a better PFS (p= 0.02) with the median at 19 months, and the median OS was 36 months. Potential predictors of unfavorable prognosis, such as receiving prior treatment, did not impact patients' clinical outcome. Conclusions: ICTriplex is a very effective treatment for advanced cancer that has become resistant to conventional therapy or with no available standard therapy. We strongly recommend this therapeutic approach for the treatment of such patients. 1. ASCO 2019 (e14254) 2. ASCO 2020 (e15150) 3. ASCO 2022 (e14590).
Targeted degradation of undruggable proteins using a novel heterobifunctional proteomimetic platform.
Authors: Wang Max Mu
Published: August 2024

47

Background: Of the ~20,000 proteins in the human genome, only a subset can be modulated via traditional pharmacological approaches. “Undruggable” targets currently include proteins with pivotal roles in cancer pathogenesis. Our work aims to introduce a new paradigm for engaging these clinically relevant proteins using a modular platform we term the HYbrid DegRAding Copolymers (HYDRACs). HYDRACs multiplex targeting warheads with degradation inducers and have long circulation times plus high cell uptake. Preliminary studies on MYC and RAS, targets of great pharmaceutical interest, highlight the potential of this platform to revolutionize drug design. Methods: HYDRACs containing MYC or RAS targeting peptides randomly copolymerized with degrons were synthesized using ROMP. Fluorescent and biotin-tags were incorporated for use in uptake and pull-down assays. Viability following treatment with MYC-HYDRACs was performed in multiple cell lines with both cellular (MYC-independent lines) and polymer composition controls. Target engagement was assessed via immunoprecipitation and circular dichroism with protein degradation monitored by WB. Unbiased whole proteome analysis and RNAseq were done to confirm observed effects were selectively on-target. In vivo efficacy and biodistribution was assessed in tumor-bearing mice. Results: HYDRACs show high levels of cell uptake and antiproliferative effects at sub-micromolar concentrations in a formulation- and target-dependent manner. Cells treated with MYC-HYDRACs displayed reduced MYC protein levels, which were rescued by proteasome or neddylation inhibition. Swapping out the degron for various validated E3 ligase recruiters maintained MYC degradation, highlighting the “plug-and-play” nature of this approach. On-target activity was confirmed via RNAseq. Biophysical analysis showed strong HYDRAC-protein interactions, orthogonally supported by the presence of target protein following pull-down of biotin-terminated HYDRACs. Target protein degradation only occurred following treatment with an intact HYDRAC compound. Mice bearing MYC-CaP tumors showed delayed tumor growth following treatment with MYC-HYDRACs, with compound accumulation in the tumor for up to 72 h following a single injection. Generalizability was demonstrated against RAS, with RAS-HYDRACs capable of degrading KRAS across multiple different alleles, acting as a pan-KRAS degrader. Conclusions: We present a novel platform technology that addresses the challenges inherent to peptide delivery approaches. HYDRACs have the potential to dramatically alter the drug discovery landscape, allowing for the development of cancer-relevant target modulators for which there are no current viable therapies. We envision the HYDRAC platform as a generalizable approach to designing degraders of proteins of interest, greatly expanding the therapeutic armamentarium for TPD.
Multiinstitutional cohort study of patient outcomes in Child-Pugh (CP) B liver function treated with atezolizumab plus bevacizumab (A+B) for hepatocellular carcinoma (HCC).
Authors: Mahipal Amit , Zemla Tyler J. , Patell Kanchi , Naleid Nikolas , Gile Jennifer , Jin Zhaohui , Tran Nguyen H. , Borad Mitesh , Chakrabarti Sakti , Storandt Michael H.
Published: August 2024

50

Background: A+B is commonly used as first line systemic therapy in HCC patients with CP-B liver function, although in the IMbrave150 clinical trial, its efficacy was only assessed in patients with CP-A liver function. We evaluated outcomes in patients with CP-B liver function and compared to those with CP-A. Methods: We completed a multi-institution, retrospective review of patients with HCC from Mayo Clinic and University Hospitals Seidman Cancer Center, who had received A+B in the first line setting between March 2018 and November 2023. CP score was calculated at time of treatment, response was assessed, and progression free (PFS) and overall (OS) survival were determined using the Kaplan Meier method. Results: Among 322 patients with HCC, median age was 66.5 years, 78.6% were male, and 82.6% were white. Eighty-six patients (27%) had CP-B liver function, while 226 (70%) had CP-A and 10 (3%) had CP-C. Etiology of liver disease in patients with CP-B included hepatitis B in 7.0%, hepatitis C in 38.4%, alcohol use in 30.2%, and metabolic associated steatohepatitis in 20.9%. Median OS in patients with CP-B liver function was 6.4 months, while mOS was 21.6 months for those with CP-A ( p<0.0001). Further stratifying, mOS in those with CP-B7 was 9.1 months, CP-B8 was 5.5 months, and CP-B9 was 4.0 months. 12-month OS in patients with CP-B was 32.4%, compared to 69.3% in CP-A. Median PFS was 4.8 months in those with CP-B and 8.9 months in those with CP-A. Median PFS in those with CP-B7, -B8, and -B9 was 6.4 months, 2.7 months, and 2.7 months, respectively. Among those with CP-B, 1 patient had a complete response, 17 (19.8%) had a partial response, 29 (33.7%) had stable disease, and 37 (43.0%) had progressive disease. Adverse events in CP-B patients included hypertension in 14.0% (grade 3 in 1 patient), bleeding in 16.3% (grade 3 or greater in 11.6%), fatigue in 38.4%, and an immune-related adverse event in 17.4% (grade 3 in 5.8%). Conclusions: Patients with advanced HCC and CP-B7 liver function may still benefit from A+B. Importantly, no additional safety risks were identified in this subgroup. Those with CP-B8 and CP-B9 have significantly worse survival than those with CP-B7 and the likelihood of benefit from systemic therapy is minimal. It is important for providers to address the impact of baseline liver function on expected outcomes in patient with HCC.
Cryoablation versus transcatheter arterial chemoembolization for unresectable hepatocellular carcinoma with lenvatinib from a real-world study.
Authors: Chang Xiujuan , Wang Di , Zhang Wei , Huang Jiagan , Zeng Zhen
Published: August 2024

54

Background: Hepatocellular carcinoma (HCC) is characterized by hypovascularity, the efficacy of transcatheter arterial chemoembolization (TACE) has been suboptimal. This study sought to evaluate and compare the efficacy and safety profiles of cryoablation (CRYO) plus lenvatinib (LEN) against TACE plus LEN for unresectable hepatocellular carcinoma (u-HCC) patients within a real-world clinical practice. Methods: A prospective study was conducted involving 234 patients with u-HCC who underwent treatment with LEN plus either CRYO or TACE at the Fifth Medical Center of the Chinese PLA General Hospital from October 2018 to May 2023. Treatment selection was determined through multidisciplinary discussions among a liver cancer board, weighing the pros and cons. The final decision was made by the patients and clinicians based on consensus. Clinical characteristics were balanced using propensity score matching (PSM). The primary endpoint was overall survival (OS), while secondary endpoints included progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and adverse events (AEs). Tumor response was based on RECIST v1.1 and mRECIST by blinded independent imaging review, AEs by CTCAE v5.0. Results: In this study, 212 (90.6%) were male, with an average age of 56 years. 206 (88%) patients were infected with hepatitis B virus (HBV), and 178 (76.1%) and 77 (32.9%) patients were classified as Child-Pugh A and BCLC B. After PSM, the clinical characteristics were comparable between the CRYO plus LEN and the TACE plus LEN group. Over a median follow-up of 31.8 months, 124 patients (53%) died. The CRYO plus LEN group demonstrated similar OS (24.2 vs. 22.0 months, P = 0.64), PFS (8.7 vs. 11.9 months, P = 0.48), ORR (53.1% vs. 53.1%, P = 1.00), and DCR (86.5% vs. 78.1%, P = 0.19) compared to the TACE plus LEN group after PSM, with consistent results observed before PSM. The two groups exhibited comparable AEs. In addition to similar LEN-related AEs, the most common CRYO-related AEs included 50% elevated ALT, 50% elevated AST, and 38.5% fever, which were consistent with the TACE related AEs. Notably, the incidence of abdominal pain was higher in the TACE plus LEN group compared to the CRYO plus LEN group (7.5% vs. 0.8%, P = 0.021), while pleural effusion was more prevalent in the CRYO plus LEN group than that in the TACE plus LEN group (6.2% vs. 0, P = 0.038). Conclusions: The CRYO plus LEN group exhibited comparable efficacy and well-tolerated safety with TACE plus LEN for u-HCC patients within a real-world clinical setting. It offers a viable alternative for HCC characterized by hypovascularity, presenting a promising therapeutic approach in the clinical management of u-HCC. Clinical trial information: ChiCTR2200058643 .
Clinical determinants of survival in patients with stage II-III pancreatic cancer.
Authors: Itakura Haruka , Xu Qinmei , Toesca Diego , Vitzthum Lucas , Jamalian Arash , Schueler Emil , Alkim Emel , Baclay J Richelcyn , Chang Daniel Tandel , Fisher George A.
Published: August 2024

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Background: We sought to identify the clinical determinants of overall survival (OS) in patients diagnosed with stage II-III pancreatic cancer not undergoing surgery. We curated a relatively homogenous cohort of patients who did not undergo surgical resection, but instead underwent chemotherapy in sequence with stereotactic body radiation therapy (SBRT) to examine the features that differentiated those with poor OS. Methods: In a retrospective study, we examined a cohort of 259 patients with stage II-III pancreatic cancer who underwent chemotherapy in sequence with SBRT without surgery at a single institution (Stanford Health Care). We conducted both univariate and multivariate Cox regression analyses to assess the relationships between OS and individual clinical and tumoral variables, including: age, sex, stage, Karnofsky performance status (KPS), body mass index, vessel involvement, tumor location, and biological equivalent dose [BED] of SBRT as potential determinants. Results: The study cohort consisted of 136 men (52.5%) and 123 women (47.5%) with a median age of 69 (range 38-94). Tumor histology was predominantly ductal adenocarcinoma (n=249, 96.1%), with tumor sites of involvement spanning: uncinate (n=35, 13.5%), head (n=160, 61.8%), body (n=59, 22.8%), and tail (n=5,1.9%). More patients had stage III (n=171, 66%) than stage II (n=88, 34%) disease, and their tumor resectability by NCCN criteria were rated as: unresectable (n=145, 56%), borderline (n=28, 10.8%), resectable (n=11, 4.2%), or unrecorded (n=75, 29%). Tumor progression was observed in local (n=71, 27.4%), regional (n=29, 11.2%), and distant (n=150, 57.9%) sites during the median follow up period of 17 months (range 15-18 months) from diagnosis and 12 months (10-13 months) from SBRT. Death (n=213, 82.2%) during this period was more common than survival (n=46, 17.8%). In univariate analyses, clinical features impacting OS included: KPS (hazard ratio [HR] 0.14, p=0.007); male sex (HR 1.44, p=0.01), pancreatic head tumors (HR 1.44, p=0.011), BED (HR 1.33, p=0.035), and age (HR 1.013, p=0.044). In the multivariate analysis, which incorporated only features significant in the univariate analyses, tumor location at the pancreatic head (HR 1.412, p=0.021) and male sex (HR 1.360, p=0.03) conferred the highest risks for poor OS, with BED bordering on significance (p=0.059) (Table). Conclusions: Among patients with stage II-III pancreatic cancer who underwent chemotherapy in sequence with SBRT, but not surgery, the most significant clinical determinants of poor OS were location of the tumor in the pancreatic head and male sex. Prioritizing additional disease monitoring and alternative therapies for this subset of patients at higher risk of poor survival may be warranted. [Table: see text]
Effect of impaired autophagic flux on breast carcinogenesis through the enhanced LC3-p62-NRF2 feedback loop.
Authors: Aftab Mehreen , Waidha Kamran , Gopas Jacob , Hussain Showket
Published: August 2024

6

Background: Breast cancer affects more women worldwide than any other type of cancer. Although some genes have been identified as potential causes, the exact molecular mechanism of the disease is still unknown. In our study, we aimed to investigate the role of NRF2 and the autophagy markers p62 and LC3 in breast cancer cell lines that have different Tp53 status using a new compound called 6,6'dihydroxythiobinupharidine (DTBN). In our previous research, we have shown that DTBN modulates key cellular signal transduction pathways that are relevant to disease biology, including cancer. Furthermore, we analyzed online databases to determine the correlation between NRF2, p62, LC3, and Tp53 in breast cancer patients. Methods: To evaluate the effect of DTBN on NRF2, p62 and LC3 in different types of breast cancer cell lines with varying TP53 status, we conducted molecular studies by inhibiting NRF2 activity. We synthesized the correlation between NRF2, p62, LC3 and TP53 expression and clinical parameters by analyzing TCGA and GEO datasets. Results: Our findings suggest that DTBN induces cell death and autophagy in all breast cancer cell lines, regardless of their Tp53 status. However, they also led us to hypothesize that NRF2 may hinder the sensitivity of cancer cells to DTBN-induced cell death and autophagy. To test this hypothesis, we inhibited NRF2 activity using an NRF2 inhibitor called brusatol. The results of the study indicate that the inhibition of NRF2 significantly increased cell death and autophagy in DTBN-treated cells. We observed a decrease in the expression of the autophagy marker p62, while an increase in the expression of another autophagy marker LC3. These findings suggest that the interaction between NRF2, LC3 and p62, which is activated in response to DTBN treatment, may serve as a potential anticancer drug target. We have validated the positive correlation between NRF2 and the autophagic gene p62 and LC3, in different Tp53 status breast cancer cell lines by analyzing TCGA and GEO data. Conclusions: Our study shows that high levels of Nrf2, LC3 and p62 expression are significantly associated with increased breast cancer cell proliferation and migration. This implies that patients with breast cancer have lower overall survival and a higher rate of recurrence. Our findings highlight the role of DTBN-induced NRF2 and LC3 expression and reduced p62 expression in breast cancer cells with varying Tp53 status. These results may represent a paradigm for better understanding the cancer cell response to therapies and designing more efficient combined anticancer therapies targeting NRF2, LC3 p62, and Tp53.
68Ga-FAPI-04 positron emission tomography/computed tomography (PET/CT) for detecting occult peritoneal metastasis in locally advanced gastric cancer: A single-center prospective cohort study.
Authors: Hu Qiancheng , Zhang Shunyu , Su Ming Gang , Yang Kun , Gou Hongfeng , Hu Jiankun
Published: August 2024

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Background: Occult peritoneal metastasis (OPM) is a common finding in patients diagnosed with advanced gastric cancer. Preoperative diagnosis of OPM is crucial for developing treatment strategies and for evaluating the prognosis of patients with locally advanced gastric cancer. To evaluate the accuracy of 68Ga-FAPI-04 PET/CT in diagnosing OPM in locally advanced gastric cancer. Methods: This was a prospective, observational, single-center, single-blind, cohort study. Patients with histologically proven locally advanced gastric or gastroesophageal junction adenocarcinoma on initial staging evaluation were recruited. Laparoscopic staging and cytological analysis of peritoneal washing served as reference standards for the final diagnosis. The primary outcome was the proportion of participants changing treatment strategy from curative to palliative treatment. Results: A total of 49 patients were recruited between November 2022 and July 2023 . Nine of the 49 patients were diagnosed with OPM following 68Ga-FAPI-04 PET/CT examinations. A total of 18.4% (n=9) of patients with locally advanced disease on initial staging evaluation by contrast-enhanced CT were upstaged to stage IV for peritoneal metastasis on 68Ga-FAPI-04 PET/CT. The sensitivity of 68Ga-FAPI-04 PET/CT in detecting OPM was 85.7%, and the specificity was 92.3%. The overall diagnostic accuracy of 68Ga-FAPI-04 PET/CT was 91.8%. Based on ROC curve analysis, the area under the curve (AUC) was 0.893 (95% CI: 0.734–1). Conclusions: The findings of this study suggest a significantly additional value of 68Ga-FAPI-04 PET/CT in detecting OPM. Thus, it would be useful to include 68Ga-FAPI-04 PET/CT in the guidelines for staging locally advanced gastric cancer, instead of laparoscopic staging. Clinical trial information: ChiCTR2300067591 .
Safety analysis by treatment periods from EMERALD-1: A phase 3, randomized, placebo-controlled study of transarterial chemoembolization with durvalumab with/without bevacizumab in participants with embolization-eligible unresectable hepatocellular carcinoma.
Authors: Kudo Masatoshi , Chan Stephen Lam , Sangro Bruno , Erinjeri Joseph P. , Qin Shukui , Ren Zhenggang , Arai Yasuaki , Breder Valeriy Vladimirovich , Lin Shi-Ming , Peron Jean-Marie , Nguyen Tien Quang , Yan Lunan , Chiu Chang-Fang , Santos Florinda A. , Veluvolu Anil , Thungappa Satheesh Chiradoni , Morgan Claire , Parsons Kerry , Xynos Ioannis , Lencioni Riccardo
Published: August 2024

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Background: The global Phase 3 EMERALD-1 study (NCT03778957) primary endpoint was met: durvalumab (D) + bevacizumab (B) + transarterial chemoembolization (TACE) significantly improved progression-free survival vs placebos (pbos) + TACE (median 15.0 vs 8.2 mo; HR, 0.77; 95% CI, 0.61–0.98; p=0.032 [threshold 0.0435]) in participants (pts) with embolization-eligible unresectable hepatocellular carcinoma (uHCC) with a manageable safety profile. This post hoc, exploratory analysis assessed safety in the study’s two treatment (tx) periods (pds): D-TACE (D-T) and D-B. Methods: Pts were randomized 1:1:1 to D+TACE, D+B+TACE, or pbos+TACE. In the D-T pd, pts received 1–4 TACE (cTACE or DEB-TACE [investigator choice]) plus D (1500 mg Q4W) or pbo for D. In the D-B pd, post-last TACE, pts received D (1120 mg Q3W) plus pbo for B, D (1120 mg Q3W) plus B (15 mg/kg Q3W), or pbos for D and B. Adverse events (AEs), start/end date, maximum/change in CTCAE grade, and causality were assessed in the D-T and D-B pds in pts who received any study tx in the arm to which they were randomized, until end of follow-up. Results: The Table shows duration of exposure (DoE). In the D+TACE, D+B+TACE, and pbos+TACE arms, AEs were reported by 144 (74.6%), 139 (72.0%), and 148 (74.0%) pts in the D-T pd and 133 (68.9%), 147 (76.2%), and 132 (66.0%) pts in the D-B pd; were possibly related (pos rel) to study tx in 59 (30.6%), 56 (29.0%), and 41 (20.5%) pts in the D-T pd and 76 (39.4%), 114 (59.1%), and 69 (34.5%) pts in the D-B pd; and were provoked by TACE in 72 (37.3%), 90 (46.6%), and 85 (42.5%) pts in the D-T pd and 16 (8.3%), 18 (9.3%), and 21 (10.5%) pts in the D-B pd, respectively. Conclusions: D+B+TACE had a manageable safety profile across the D-T and D-B pds, consistent with the individual agents and underlying disease. These data further support D+B+TACE as a new potential standard of care in embolization-eligible uHCC. Clinical trial information: NCT03778957 . [Table: see text]
Utility of radiomic features in predicting clinical outcomes in stage II-III pancreatic cancer.
Authors: Itakura Haruka , Xu Qinmei , Toesca Diego , Vitzthum Lucas , Jamalian Arash , Schueler Emil , Alkim Emel , Baclay J Richelcyn , Chang Daniel Tandel , Fisher George A.
Published: August 2024

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Background: We identified computed tomography (CT)-derived radiomic features predictive of tumor progression within three months, then examined their ability to prognosticate overall survival (OS) along with clinical features in pancreatic cancer. We evaluated these features in patients with unresected pancreatic cancer who underwent stereotactic body radiation therapy (SBRT) in sequence with chemotherapy, but not surgery. Methods: In this retrospective study, we examined a cohort of 101 patients with stage II-III pancreatic cancer who underwent SBRT with sequential chemotherapy at a single institution (Stanford Health Care) between 1999-2020. From their pre-SBRT contrast-enhanced CT images with segmented tumors, delineating regions-of-interest, we extracted 900 radiomic (quantitative pixel-level imaging characteristic) features. In the first phase, we identified radiomic features that predicted rapid tumor progression within three months following SBRT. We divided the dataset into a training set (n = 53) for model development and a test set (n = 48) for evaluation. Using logistic regression with the Least Absolute Shrinkage and Selection Operator algorithm for feature selection and classification, we built a binary prediction model on the training set to identify patients at risk of progression within three months of SBRT. To fine-tune parameters, we performed five-fold cross-validation (CV) on the training set, repeating each set of parameters five times. We assessed model performance on the test set using the area under the curve (AUC). We selected the model with the best AUC, generating the predictive radiomic feature set. In the second phase, we conducted univariate and multivariate Cox regression analyses to assess the relationship between OS and individual clinical variables (age, sex, stage, vessel involvement, tumor location, performance status, body mass index, biological equivalent dose of radiation) and the radiomic feature set as high versus low risk. Results: Our cohort consisted of 48 men (mean age, 70 years ± 11 [SD]) and 53 women (mean age, 67 years ± 13 [SD]). From the first phase, 32 textural features comprised the radiomic feature set that best predicted rapid tumor progression, with mean AUCs of 0.852 (CV, n=53) and 0.814 (test, n=48). In the univariate Cox model, only the radiomic feature set was predictive of OS (hazard ratio, HR, 1.724, p=0.011). In the multivariate Cox model, radiomic features and age were significant predictors of OS, with HR of 1.819 (p=0.007) and 1.024 (p=0.024), respectively. Conclusions: CT-derived radiomic features predict rapid tumor progression following SBRT, confer nearly a twofold increase in mortality risk, and, along with patient age, enhance the identification of patients with stage II-III pancreatic cancer with poor OS. [Table: see text]