bluuebunny/crossref_metadata_2025 huggingface dataset:
Combining immune checkpoint inhibitors and molecular-targeted agents with hepatic arterial infusion chemotherapy for hepatocellular carcinoma with inferior vena cava and/or right atrium tumor thrombus.
Authors: Zhong Suixing , Lyu Ning , Zhao Ming
Published: July 2024

e16177

Background: Patients with hepatocellular carcinoma and inferior vena cava and/or right atrium tumor thrombus (HCC-IVC/RATT) have a poor prognosis and lack evidence for standard first-line systemic treatment due to its low incidence. This study aims to evaluate the effectiveness and safety of three treatments in HCC-IVC/RATT patients: immune checkpoint inhibitors plus molecular-targeted agents (ICI-MTA), hepatic arterial infusion chemotherapy (HAIC), and their combination (ICI-MTA-HAIC). Methods: This multicenter retrospective cohort study included consecutive HCC-IVC/RATT patients who received ICI-MTA, HAIC, or ICI-MTA-HAIC from June 1, 2014, to December 31, 2022. The propensity score matching (PSM) was used to balance baseline characteristics. Survival analysis was conducted using Kaplan-Meier curves and compared using the log-rank test. Results: A total of 243 HCC-IVC/RATT patients were included, with 144 receiving ICI-MTA-HAIC, 29 receiving ICI-MTA, and 70 receiving HAIC. Before PSM, the ICI-MTA-HAIC group had significantly superior median overall survival (OS) of 16.5 months, progression-free survival (PFS) of 8.0 months, and objective response rate (ORR) of 47.9%, in comparison to both the ICI-MTA (OS: 7.7 months, P < 0.001; PFS: 3.5 months, P = 0.001; ORR: 24.1%, P = 0.019) and HAIC groups (OS: 9.1 months, P = 0.003; PFS: 4.9 months, P = 0.007; ORR: 25.7%, P = 0.002) among HCC-IVC/RATT patients based on RECIST v1.1 criteria. The ICI-MTA and HAIC groups didn’t exhibit significant differences in OS, PFS, or ORR ( P = 0.061, 0.043, 0.869, respectively). After PSM, similar results were obtained across the three groups. All adverse reactions were manageable, and no unexpected adverse reactions or treatment-related deaths were observed among the three groups. Conclusions: ICI-MTA-HAIC was a safe and effective therapy that prolonged the survival of HCC-IVC/RATT patients compared to ICI-MTA or HAIC.
Comparative efficacy of systemic sequential regorafenib after TACE combined with first-line targeted drugs (donafenib, sorafenib, or lenvatinib) after treatment failure for advanced hepatocellular carcinoma: A retrospective, single-center, real-world study.
Authors: Wei Ning , Lu Dong , Zhou Chunze , Cheng Delei , Zhang Zhengfeng , Zhang Xingming , Xiao Jingkun , Lv Weifu
Published: July 2024

e16190

Background: Donafenib is a novel multikinase inhibitor, which is a 1st-line systemic treatment for advanced hepatocellular carcinoma (HCC) in China. Regorafenib is an oral multikinase inhibitor and has been approved as the 2nd-line systemic treatment for advanced HCC based on the RESORCE trial. However, the efficacy of systemic sequential regorafenib after donafenib treatment failure in advanced HCC patients(pts) remains unclear. Methods: A retrospective analysis was conducted on the clinical data of advanced HCC pts treated with donafenib combined with TACE (Dona-TACE), sorafenib combined with TACE (Sora-TACE) or lenvatinib combined with TACE (Lenva-TACE) at The First Affiliated Hospital of USTC from January 2018 to December 2023. A total of 87 of these pts with advanced HCC who received regorafenib as the 2nd-line treatment. The 1st-line targeted drugs, disease control rate (DCR) (defined by the mRECIST), progression-free survival (PFS) and adverse events (AEs) (defined by the CTCAE version 5.0) were recorded and compared. Results: After screening, 27 pts in the Dona-TACE group ,35 pts in the Sora-TACE group and 31 pts in the Lenva-TACE group were included in this study. The baseline characteristics of the three groups were similar. The median treatment duration of regorafenib was 5.2 months in the Dona-TACE group, 4.8 months in the Sora-TACE group and 3.7 months in the Lenva-TACE group. The overall DCRs of sequential regorafenib after donafenib, sorafenib or lenvatinib treatment failed were 79%, 75% and 71%(P>0.05). There was no significant difference in median PFS of regorafenib (4.8, 3.9, 4.1m) in the Dona-TACE, Sora-TACE and Lenva-TACE groups. Compared with other groups, the Dona-TACE group received regorafenib sequentially had a lowest incidence of grade 3-4 AEs (39.1%, P<0.05). All groups had no treatment-related deaths from regorafenib. Multivariate analysis showed that ECOG PS score, up-to-seven criteria, tumor blood supply and Extrahepatic metastasis were independent prognostic factors affecting PFS (HR, 3.220, 3.019, 2.753, 3.142; P < 0.05). No survival differences were observed between the patients who received 1st-line treatment with or without a combination of immune checkpoint inhibitor(ICI) reagents. Conclusions: This retrospective, single-center, real-world study demonstrated that when donafenib failed the regorafenib could still improve the prognosis of advanced HCC pts with fewer AEs. The study will continue to focus on overall survival(OS) and whether combined ICIs or not in the 1st-line/ 2nd-line treatment could have a positive effect on OS.
A machine learning–based radiomics approach to predict MUC4 mutation and response to immunotherapy in cholangiocarcinoma.
Authors: Jia Yunlu , Luo Xiao , Wang Junli , Ruan Jian
Published: July 2024

e16203

Background: The immunogenicity of MUC4 made it a tumor antigen for immunotherapeutic interventions in cholangiocarcinoma (CCA). Identifying CCA patients with elevated MUC4 expression would be crucial for MUC4-targeted immunotherapies and the prediction response to immunotherapy. Methods: In this retrospective study, 55 CCA patients who received first-line treatment with pembrolizumab in combination with gemcitabine plus cisplatin (GP) chemotherapy were enrolled. Enrolled patients underwent surgery before, and their postoperative specimens were subjected to whole exome sequencing and proteomic sequencing, and matched magnetic resonance imaging (MRI) data were collected. We employed a random forest classifier based on radiomic features to predict the status of key genes mutation including MUC4 and tested it on an internal and an external validation CCA cohort. Odds ratio of MUC4 expression for objective response to pembrolizumab plus GP was tested with logistic regression analysis. Association of MUC4 expression with progression-free survival (PFS) and overall survival (OS) was analyzed with a Cox proportional hazard regression. Results: A radiomics nomogram that incorporates radiomics signature and MUC4 mutation showed good calibration and discrimination in the training cohort (AUC = 0.762), internal validation cohort (AUC = 0.812) and external validation cohort (AUC = 0.801). The radiomics nomogram was an independent preoperative predictor of overall and recurrence-free survival. High expression of MUC4 portended significantly lower overall and recurrence-free survival than decreased MUC4 expression levels (P < 0.001). Findings from cell experiments revealed targeting MUC4 with bosutinib showed inhibitory effects on cell proliferation and promoted apoptosis. Additionally, the combination of bosutinib with a PD-1 inhibitor increased the inhibitory effect. Investigating the feasibility of translating these findings into clinical trials for patients with CCA is an important next step. Conclusions: The integration of MUC4-based immunotherapy and incorporating radiomics-based biomarkers could significantly advance personalized medicine and contribute to more effective treatment strategies for CCA patients.
Utility of an amplicon-based ctDNA platform for advanced cholangiocarcinomas (CCA) in Asia.
Authors: Kwok Gin Wai , Poh Jonathan , Cher Chae Yin , Pinweha Pannapa
Published: July 2024

e16206

Background: Cholangiocarcinoma represents a major cause of cancer mortality in Asia. While clinical outcomes have improved with the addition of anti-PD1/PDL1 agents to standard-of-care chemotherapy for advanced disease, recent data suggests that novel agents against IDH1 mutations, FGFR2 and NTRK rearrangements, BRAF V600E mutations, and microsatellite instability (MSI) are effective. Tumor-based next generation sequencing (NGS) is routinely recommended by guidelines but is limited by tissue availability and quality in patients with unresectable disease. A comprehensive circulating tumor DNA-based (ctDNA) NGS platform offers an acceptable alternative, but its clinical utility and pickup rate for oncogenic drivers remain unknown. Methods: In our multi-national cohort of advanced CCA across 5 countries, we explored the utility of Lucence LiquidHALLMARK (LHM), a Medicare-reimbursed, amplicon-based NGS ctDNA platform targeting 80 cancer related genes, 10 fusions, and MSI. Performance of LHM has been previously reported. Data was retrieved in-house by a de-identified centralized database and pooled for analysis. Here, we report the demographic and genomic findings of our cohort and highlight the impact of testing on actionable molecular alteration discovery. Results: Between Jan 2020 and Dec 2023, 60 samples from 56 patients (62.5% male) with advanced CCA in Hong Kong SAR (50.0%), Singapore (41.1%), Thailand (3.6%), Philippines (3.6%), and Malaysia (1.8%) underwent LHM testing. Metastatic disease accounted for 83.9% and 8.9% had locally advanced disease. Median age was 67 years (range 33-88), with 34% and 30% of tests obtained during first-line therapy and at diagnosis respectively. Only 6 cases had available tissue NGS results. Analysis on 56 baseline samples showed an 80.4% discovery rate (45/56 patients) for ≥1 molecular alterations. A median of 2 variants (mean 3.27) was detected per sample, with variant allele fraction ranging from 0.05% to 66.5%. Importantly, 8.9% (5/56) of patients harbored ≥1 actionable variants, including 3 with FGFR2 rearrangements ( FGFR2- WAC, FGFR2- ACTR1A, FGFR2- CAMK2D) and 2 with BRAF V600E drivers. A further 3 patients had potentially druggable variants in IDH2 and FGFR3 and 12 harbored BRCA1/2 variants, of which 4 were deleterious. None of the samples had MSI. Top 10 mutated genes were TP53 (48%), KRAS (21%), BRCA2 (18%), PIK3CA (11%), TERT (9%), CDKN2A (9%), SMAD4 (9%), FGFR2 (7%), BRAF (7%), and CDK6 (5%). Limited histopathological and treatment outcomes are available in the current dataset. Conclusions: Our advanced cholangiocarcinoma cohort of 56 patients from 5 Asian countries showed that an amplicon based ctDNA liquid biopsy platform overcomes the tissue-related challenges of genomic profiling specific to unresectable biliary tumors. We showed an 80.4% discovery rate for any molecular alterations and a 8.9% pickup rate for variants with strong actionability.
Phase I study of ProAgio, an αvβ3 integrin cytotoxin, in patients with previously treated advanced pancreatic cancer and other solid tumors.
Authors: Skorupan Nebojsa , Schmidt Keith Thomas , Koehler Eve , Lee Min-Jung , Steinberg Seth M. , Figg William Douglas , Liu Zhi-Ren , Alewine Christine
Published: July 2024

e16336

Background: The limited clinical benefit of combination chemotherapy in patients with advanced pancreatic cancer is in part attributed to the tumor’s dense, hypoxic stroma that is largely composed of extracellular matrix, cancer-associated fibroblasts (CAFs), and myeloid cells. ProAgio is a pegylated peptide drug that targets and kills cells expressing integrin αvβ3, such as CAFs and endothelial cells. Preclinical activity of ProAgio was demonstrated in murine pancreatic cancer models. Here we describe the dose escalation arm of the first-in-human Phase 1 trial of ProAgio in patients with advanced solid malignancies, including pancreatic cancer. Methods: The dose escalation arm of this single institution study of ProAgio monotherapy enrolled adults with previously treated, histologically confirmed advanced solid tumors for which no curative therapy exists. Participants were required to have evaluable disease. The primary objective was to determine the recommended Phase 2 dose (RP2D) of ProAgio. Secondary objectives assessed the safety (CTCAE v. 4.03), pharmacokinetics, and objective response rate. ProAgio was administered as an intravenous infusion every 1-2 weeks depending on the dose level. Response was determined by serial imaging (CT or MRI) or serum tumor marker assessment. Results: Twenty-eight participants (26 with pancreatic adenocarcinoma and 2 with other gastrointestinal malignancies) were treated as of January 30, 2024, completing enrollment to all 6 planned dose levels. ProAgio has been remarkably well tolerated with only transient grade 1 or 2 treatment-related adverse events observed in most participants. Two participants had grade 2 infusion related reaction but were able to continue treatment with increased dose of diphenhydramine pre-medication. Isolated serious adverse events of hyperglycemia, acute kidney injury, or anemia (all grade 3) considered at least possibly related to ProAgio were observed in 3 separate participants. Five participants with pancreatic cancer receiving weekly dosing of ProAgio had stable disease, 2 of which had interval stabilization in CA 19-9 tumor markers. RP2D determination is pending completion of pharmacokinetic analyses. Conclusions: ProAgio is safe and well-tolerated at all dose levels. A dose expansion phase of 15 participants will begin enrolling once RP2D is determined. Clinical trial information: NCT05085548 .
Clinical characteristics and treatment outcomes of advanced penile squamous cell carcinoma: Real-world evidence from a tertiary cancer center in Brazil.
Authors: Parrela Vinicius Cruz , Polho Gabriel Berlingieri , Andrade Matheus de Oliveira , Almeida Moreno Santos Rogerio , Alves Gustavo Luis , Arneiro Matheus Henrique Juliani , Felix Vitor Hugo , Hidalgo Filho Cassio Murilo , Cazellato Pacheco de Mello Murilo , Mota Jose Mauricio
Published: July 2024

e17025

Background: Penile cancer is a rare disease worldwide. However, Brazil has an annual incidence of 1.5 cases per 100,000 inhabitants, representing 2% of male cancers. This study aims to evaluate clinical characteristics and treatment outcomes of patients (pts) with advanced penile squamous cell carcinoma (SCC) in a large tertiary cancer center in Brazil. Methods: We performed a retrospective database analysis of pts with advanced penile squamous cell carcinoma (SCC) treated at Instituto do Cancer do Estado de Sao Paulo between January 2008 and October 2023. Medical records were reviewed for demographic, clinicopathological features and treatment outcomes data. Cumulative survival probabilities were computed using the Kaplan-Meier method. Prognostic factors associated with survival were evaluated through univariate analyses, using the Cox regression model. Results: We identified 91 pts with advanced penile SCC eligible for analysis. Median age was 62 years (IQR 44.5-64.5), most were married (53.8%), diagnosed with stage T3/T4 (60.4%), and N2/N3 (64.9%) SCC. At diagnosis, 65% were classified as stage IV (T4, N3, or M1 disease). De novo metastasis occurred in 35% pts. Neoadjuvant chemotherapy was given to 30.8%, mainly ITP regimen containing paclitaxel, ifosfamide, and cisplatin (46.4%). First-line palliative chemotherapy was given to 50.5%, being carboplatin and paclitaxel the predominant choice (47.8%). Disease progression occurred in 54% pts, after a median follow-up of 21.8 months. At the last follow-up, 61.5% had nodal disease. Most common sites of metastasis were lung (50.5%) and liver (19.8%). Overall survival (OS) was 12.9 months (95% CI 9.8 - 18.3). Prognostic factors significantly correlated with OS were ECOG 0-1 (HR 0.40, 95% CI 0.21 - 0.74, p=0.003) and complete response post-chemotherapy (HR 0.14; 95% CI 0.02 - 0.80, p=0.02). No association with survival was found for region/state of origin, distance from patient’s home to the hospital, marital status, education level, and age. Conclusions: Advanced penile squamous cell carcinoma (SCC) presents significant challenges in Brazil, with high rates of advanced disease at diagnosis. OS correlated with complete response to chemotherapy and performance status.
Utidelone for heavily pretreated metastatic castration-resistant prostate cancer after failing docetaxel treatment: An open-label, single-arm, phase II trial.
Authors: Chen Meiting , An Xin , Xue Cong , Li Haifeng , Yang Wei , Huang Riqing , Peng Jing , Tang Li , Wang Jun , Li Yonghong , Shi Yanxia
Published: July 2024

e17036

Background: The appropriate chemotherapy for metastatic castration-resistant prostate cancer (mCRPC) that progressed after docetaxel treatment remains unmet medical needs. Utidelone (UTD1) is a genetically engineered epothilone analog with antitumor activity in taxane-resistant cancers. UTD1 was approved for advanced breast cancer in 2021. This study was designed to evaluate the safety and efficacy of UTD1 in mCRPC. Methods: In this perspective, phase II clinical trial, men with progressive mCRPC after docetaxel and abiraterone, and/or enzalutamide, and/or apalutamide received UTD1 monotherapy treatment at a total dose of 150 mg/m2 for five days intravenous, every three weeks until disease progression, or intolerable toxicity, or death. We reported the preliminary results for potential benefits in this new treatment. The primary endpoint was prostate specific antigen (PSA) response rate, defined as a 50% or greater reduction in serum PSA. The secondary endpoint included investigators-assessed objective response rate (ORR) and disease control rate (DCR) according to RECIST v1.1, radiographic progression-free survival (rPFS) according to PCWG3 criteria, overall survival (OS), and safety. The trial was registered at Chinese Clinical Trial Registry (No. ChiCTR2200061635). Results: By January 31st, 2024, twenty-five mCRPC patients with a median age of 67 years were enrolled in this study at Sun Yat-sen University Cancer Center since March 23rd, 2022. Patients received an average of 4.2 lines of prior anticancer treatments: 100% of them received docetaxel, 96.0% of them received abiraterone, and 80.0% progressed after enzalutamide, and/or apalutamide. 28.0% of patients had visceral metastases, and 88.0% patients had bone metastases. At of the cut-off date, the PSA response rate was 16.0%. The median rPFS and OS were 4.9 months and 7.1 months, respectively. One patient had a durable response for 19.2 months and had been remaining on study treatment to date. One PR and four SD were observed in ten patients with measurable lesions, resulting in an overall ORR and DCR of 10.0% and 50.0%, respectively. The most common treatment-related adverse events (TRAEs) including peripheral sensory neuropathy (76.0%), dyspepsia (72.0%), anemia (64.0%), constipation (60.0%), fatigue (64.0%), nausea (36.0%), leukocytopenia (32.0%), arthralgia (32.0%), dizziness (32.0%), vomiting (20.0%), and diarrhea (20.0%) were manageable. The 3/4 grade TRAEs included anemia (16.0%), and diarrhea (4%). No treatment-related death occurred. Conclusions: UTD1 has demonstrated promising efficacy and favorable tolerance in heavily pretreated mCRPC patients after progression on docetaxel in the preliminary analyses. Additional randomized trials are warranted for this new regimen. Clinical trial information: ChiCTR2200061635.
Effect of ionizing radiation on JAK/STAT pathway and immune microenvironment in cervical cancer.
Authors: Zhang Yongchun , Jiang Yuqi , Wu Yaping , Zhang Lei , Chen Zhiying , Qi Yingxue , Yin Xiangyu
Published: July 2024

e17516

Background: STAT proteins play an important role in the development and progression of cervical cancer, and inhibition of the JAK/STAT pathway may be critical for enhancing tumor cell death. Delivering a certain dose of ionizing radiation (IR) directly to the lesion is one of the conventional treatments for cervical cancer. Whether IR will trigger changes in the JAK/STAT pathway and tumor immune microenvironment (TIME) is unknown and continues to be explored. Methods: We collected 30 patients received IR therapy with locally advanced cervical cancer (LACC) at the Affiliated Hospital of Qingdao University. Matched pre-IR and post-IR tumor tissue samples were collected from all patients, and the samples underwent RNA sequencing based on the nCounter platform (NanoString Technologies, Seattle, USA) and protein testing based on immunohistochemistry (IHC) staining. All tumor TIME cell infiltration scores were calculated as arithmetic mean of the constituent genes. P-values were calculated via the T Test. Results: RNA sequencing of tumor tissue from LACC patients before and after IR showed 35 differential genes. The results of GSEA pathway enrichment analysis of differential genes showed that compared with before IR, the IFN-α response pathway, IFN-γ response pathway and epithelial mesenchymal transition pathway were significantly up-regulated and enriched after IR. These three pathways collectively affect changes in the downstream JAK/STAT pathway. Moreover, compared with before IR, the cell infiltration abundance of overall macrophages (P=0.0087) and M2 macrophages (P=0.0043) increased significantly after IR. M1 macrophages also showed an increasing trend, but there was no statistically significant difference. In addition, further verification of changes in several proteins on the JAK/STAT pathway by IHC. The results showed that overall macrophages (P=0.0087) and M1 macrophages (P=0.026), PD-L1 (p=0.003), JAK1 (p=0.021) and STAT3 (p=0.018) were significantly increased after IR compared with before IR. M2 macrophages and STAT1 (p=0.734) also showed an increasing trend, but there was no statistically significant difference. It is worth noting that Kendall's tau-b correlation analysis was used to study the correlation of protein changes. The results found that the changes in PD-L1 expression before and after radiotherapy were related to STAT3 (Kendall's tau-b=0.487, P=0.02), JAK1 (Kendall's tau-b=0.513, P=0.015), there is a strong positive correlation. Conclusions: This study found that IR affects changes in cervical cancer TIME and these changes may promote the transition to an immunosuppressive phenotype. In addition, IR may affect changes in PD-L1 levels through the JAK1/STAT3 pathway. This needs to be further verified by designing large prospective clinical trials in the future.
Safety and clinical activity of cadonilimab, an anti PD-1/CTLA-4 bispecific antibody, for patients with persistent, recurrent, or metastatic cervical cancer (R/M CC): A retrospective, real-world study.
Authors: Fan Shi , Wang Tao , Zhang Qiying , Wang Juan , Su Jin , Liu Zi
Published: July 2024

e17522

Background: Recurrent, metastatic or persistent cervical cancer (R/M cc) patients have limited treatment options. Immune chechpoint inhibitors targeting PD-1 or CTLA-4 individually have shown substantial clinical benefits in the treatment of malignancies, cadonilimab monotherapy has shown promising efficacy and tolerable toxicity in pre-treated R/M CC (NCT04380805).We aimed to assess the safety and clinical activity of Cadonilimab combination therapy(including chemotherapy, radiotherapy, targeted therapy, or immunotherapy) in patients with advanced r/m CC. Methods: Pts (FIGO stage IIIc2r-IVb CC) previously treated with or not candidates for standard therapy, aged ≥ 18 years, with ECOG PS ≤ 2, and measurable (RECIST 1.1) or evaluable disease, were enrolled.All patients received at least one dose of Cadonilimab (10mg/kg, Q3W or 6mg/kg Q2W), 32 patients received concurrent radiotherapy, 66 patients received concurrent chemotherapy, 57patients received targeted therapy, and 4 patients received local injections of oncolytic virus.Immune-related adverse events (irAEs), objective response rate (ORR) and disease control rate (DCR) were evaluated. Results: 82 pts were enrolled from Jul 13, 2022, to Dec 20, 2023. As of Jan 10, 2024, we assessed safety in all pts and efficacy in pts with at least one tumor assessment result. IrAEs of any grade occurred in 46 (56.1%) pts. Grade ≥ 3 irAE occurred in 15 (18.3%) pts. The most frequent were irAEs hypothyroidism (28,34%), Rash (5,6%), infusion reaction (3,3.7%), hepatitis (2,2.4%), there were no toxic deaths reported. The ORR was 70.4% (57/81,95% CI:60.2%-80.5%) with 23 (28.4%) CR,34 PR, 5 SD, and the DCR was 76.5% (62/81,95% CI:67.1%-86.0%). Especially, 6 Pts had previously received immunotherapy, and 2 of them achieved PR. mPFS and mOS data are not mature by cut-off date. Conclusions: Cadonilimab combined with standard therapy (including radiotherapy, chemotherapy and targeted therapy) was well tolerated, with encouraging antitumor activity in pts with R/M CC. Pts who had failed checkpoint inhibitor therapy may still benefit from cardonilimab. Meanwhile, long-term safety and activity evaluation still needs following up.
Single-cell sequencing to elucidate the disparities in the immune microenvironment between PIK3CA mutants and wild types.
Authors: Xu Qin , Zhu Fei , Liu Jing , Chang Lele , Li Li , Zhu Mingxuan , Zhang Huiqi , Luo Lan , Zang Lele
Published: July 2024

e17524

Background: In patients with cervical cancer, PIK3CA exhibits the highest mutation rate, with the predominant oncogenic alteration reported to occur in 40% of cases. Recent studies in cervical cancer have indicated that the mutation status of PIK3CA is prominently associated with a diminished overall survival. Nevertheless, in our preceding study entitled 'Efficacy and Safety of Sintilimab Plus Anlotinib for PD-L1–Positive Recurrent or Metastatic Cervical Cancer: A Multicenter, Single-Arm, Prospective Phase II Trial', the prognosis for the mutant group surpassed that of the non-mutant group. Therefore, distinguishing the differences in the immune microenvironment between PIK3CA mutant and wild-type cervical cancer patients is of great significance. Methods: We used Single-cell RNA sequencing (scRNA-seq) to analyze the tissue samples of 7 cervical cancer patients with PIK3CA mutations and 9 with wild-type. Results: We partitioned cells from both the mutated and wild-type forms of cervical cancer into nine distinct clusters. To better understand the transcriptional heterogeneity of tumor-infiltrating T lymphocytes, we re-clustered 45,574 NK/T cells into 9 clusters. A specific cell cluster, designated as CD8+ ISG15, exhibited a significant enrichment in interferon-induced genes, including ISG15, IFIT3, IFIT1, RSAD2, and IFI6. To explore intergroup differences, we performed differential analysis on the proportions of mutations and non-mutations in different subgroups. We found significant differences in CD8+ ISG15 between the mutant group and the widegroup. ISG15 plays a pivotal role in antiviral responses, and as research advances, it has been identified as a potential prognostic biomarker and therapeutic target for cancer, beyond its antiviral function. A growing body of studies indicates that ISG15 is overexpressed in the majority of tumors, however, the influence of high ISG15 expression on the overall survival of cancer patients is dependent on the cancer type. In our single-cell analysis of cervical cancer, we observed that the CD8+ ISG15 subgroup specifically expresses ISG15, and the prevalence of this subgroup is significantly greater in the PIK3CA wild-type group compared to the mutant group. Consequently, the CD8+ ISG15 subgroup is perceived as a significant subset within the cervical cancer immune microenvironment for regulating anti-tumor responses. Conclusions: We defined the CD8+ ISG15 cell cluster present in the cervical cancer immune microenvironment using scRNA-seq, and found that its proportion is significantly lower in the PIK3CA mutant group than in the wild-type group. Combined with existing research, this suggests that this subgroup plays an important role in immune regulation within the cervical cancer immune microenvironment.
Sintilimab and anlotinib combination therapy in PD-L1-positive recurrent/metastatic cervical carcinoma: A 3-year follow-up of ALTER-C201 study.
Authors: Xu Qin , Liu Jing , Chang Lele , Zhu Fei , Zhu Mingxuan , Zhang Huiqi
Published: July 2024

e17526

Background: Sintilimab plus Anlotinib has been shown to be effective in advanced cervical cancer in the ALTER-C201 Study. Here, we report an updated, post-hoc analysis of overall survival from ALTER-C201 Study, after 3 years of follow-up. Methods: ALTER-C201 study was a multicenter, single-arm, prospective phase II trial. Patients with PD-L1–positive (Combined Positive Score ≥ 1) R/M CA who progressed after at least one prior systemic chemotherapeutic regimen or could not tolerate chemotherapy were eligible for the phase II trial. The patients received 200 mg sintilimab once on day 1 and 10 mg anlotinib once daily on days 1-14 every 3 weeks. The second endpoint was OS. The post-hoc analysis included Duration of Response (DoR), second progression-free survival (PFS2), as well as the efficacy of other treatments received by patients after disease progression. Results: Between December 2019 and December 2020, 42 patients were enrolled. We followed up for 38.0 (range, 0.6 - 44.0) months. The median overall survival was 17.59 months (95% CI, 12.831-36.163). Through multivariable analysis, it was found that PIK3CA (HR 3.430; 95%CI 1.040 - 11.310; P = 0.043) and KMT2C (HR 0.236; 95%CI 0.056 - 0.998; P = 0.049) are independent prognostic factors associated with overall survival (OS). In post-hoc analysis, the median DoR was 19 months (95%CI, 8.66 - not reach). Thirteen patients who experienced disease progression were subsequently treated with other anti-tumor therapies. Among them, nine received chemotherapy, three received radiotherapy, four received combination therapy with immune checkpoint inhibitors. The median PFS2 was 23.56 months (95%CI, 14.045 - not reach). The overall response rate (ORR) was 53.84%, with 2 patients (15.38%) achieving complete response (CR) and 5 patients (38.46%) achieving partial response (PR), Among the 4 patients who received immune checkpoint inhibitors, 3 of them achieved a partial response (PR). Conclusions: Sintilimab plus Anlotinib showed durable antitumor activity in patients with heavily pre-treated, PD-L1-positive advanced cervical cancer. PIK3CA and KMT2C may serve as potential prognostic biomarkers, but further studies are needed to validate their effectiveness. Patients who experience progression after treatment with the sintilimab plus anlotinib may still benefit from treatment with chemotherapy or combination therapy of other immune checkpoint inhibitors. Clinical trial information: ChiCTR1900023015.
Weekly BH009 in patients with squamous cell carcinoma of the head and neck (SCCHN) and ovarian cancer: Interim phase I results.
Authors: Wang Jing , Han Yaqian , Wang Ruoyu , Li Xiang , Kang Yu , Cheng Xiaobo , Chai Ranran , Jin Guanqin , Wei Xiaohua , Sun Qun
Published: July 2024

e17545

Background: BH009 is a novel polysorbate 80-free formulation of docetaxel that will eliminate hypersensitivity reactions associated with polysorbate 80. BH009 has completed a bioavailability study compared to Taxotere and was found to have a better safety profile to Taxotere with the potential for higher doses. As a result, we conducted a phase I dose escalation study to determine the maximum tolerated dose (MTD), and the safety profile of a weekly BH009 regimen in the treatment of patients with advanced SCCHN and Ovarian cancer. Methods: This phase I study assessed safety of BH009 in patients with advanced SCCHN and Ovarian cancer. BH009 was administered at escalating doses (starting dose 40 mg/m2) as a 1-h i.v. infusion for three consecutive weeks every 28 days without dexamethasone premedication. Results: Up to January 2024, 11 patients were treated with BH009 (4 at 40 mg/m2, 7 at 50 mg/m2). 2 patients with SCCHN, and 9 patients with ovarian cancer. 100% of ovarian cancer patients were recurrent platinum-resistant ovarian cancer (PROC) patients. 82% (9/11) of patients had received prior taxanes, of whom 33% (3/9) had received prior docetaxel. There were no DLT observed in 40 mg/m2 dose groups, and one DLT was observed in the 50 mg/m2 group (grade 3 febrile neutropenia). The MTD for BH009 is expected to exceed 50 mg/m2, which would be higher than that of Taxotere under the same dosing regimen (≥50mg/m2 vs 42mg/m2*), and the overall tolerability was better than Taxotere. In this study, treatment-related adverse events (TRAEs) occurred in 100% (11/11) patients. The most common grade 3/4 TRAEs were Leukopenia (36%, n=4), Anaemia (36%, n=4), and Neutropenia (55%, n=6). Non-hematologic toxicities were generally mild with no grade 4 toxicity observed. No AEs that led to death were related to BH009. Up to January 2024, the DCR is 50% (3/6) after 2 courses of treatment. The ORR in 6 evaluable patients was 33% (2/6, 1 patient with SCCHN at 40 mg/m2, 1 patient with ovarian cancer at 50 mg/m2). One patient (17%, 1/6) with ovarian cancer at 50 mg/m2 dose group received a complete response to the target lesion and the non-target lesion was partially responded after 2 courses of BH009, and this patient had been previously treated with docetaxel, carboplatin, and bevacizumab. Conclusions: The weekly BH009 for three consecutive weeks every 28 days is a feasible schedule with a favorable toxicity profile, and the overall tolerability is better than Taxotere. BH009 has the potential to increase the dose of administration and improve the clinical efficacy. Dose escalation is ongoing. Clinical trial information: NCT06232863 . [Table: see text]
Analysis of glycemia during olaparib therapy in patients with ovarian cancer.
Authors: Stanislawiak-Rudowicz Joanna , Szalek Edyta , Czyrski Andrzej , Grzeskowiak Edmund , Madry Radoslaw
Published: July 2024

e17559

Background: Olaparib (poly(ADP-ribose) polymerase inhibitor) is a relatively new anticancer drug and some of its metabolic side effects, such as its effect on blood glucose, are not yet well defined. The aim of the study was a retrospective analysis to investigate olaparib-induced changes in glucose levels in patients with ovarian cancer (OC). Methods: The study was conducted on 32 OC patients with normoglycemia (3.9–5.5 mmol/l) confirmed before olaparib treatment. The fasting glucose (FG) levels were estimated after I (one month), II (two months), and III (three months) courses of olaparib treatment. The severity of hyperglycemia was graded according to the Common Terminology Criteria for Adverse Events (CTCAE v5.0). Results: During treatment with olaparib, grade 1 hyperglycemia was found in 18 patients (56.2%), therefore hemoglobin A1C level measurement was recommended. The number of patients with impaired fasting glucose (5.6–6.9 mmol/l), characteristic of a pre-diabetic state, was 17 (53.1%), while glycemia indicative of diabetes (≥7.0 mmol/l) were found in 1 patient (3.1%). The statistically significant increase in glycemia was observed after I course of treatment (p< 0.0001), then after the second (p=0.0003), and III course (p=0.0025). Conclusions: During olaparib therapy, hyperglycemia was observed in 56.2% of the analyzed OC patients, implying the need for glycemic monitoring during monthly routine check-ups to implement effective behavioral and therapeutic management.
Efficacy of compound pholcodine syrup and compound codeine phosphate oral solution on lung cancer cough.
Authors: Yu Huiqing , Chen Mengting , Zhang Junhui , Yang Hong
Published: July 2024

e20548

Background: To assess the therapeutic effect of compound pholcodine syrup and compound codeine phosphate oral solution on lung cancer cough. Methods: A total of 60 patients with diagnosed middle-advanced stage lung cancer accompanied with lung cancer cough from Jan, 2022 to May, 2022 were enrolled . According to the method of random number table, the patients were divided into two groups: observation group and control group. Observation group received compound pholcodine syrup treatment, while control group received compound codeine phosphate oral solution treatment. The dosage of the two drugs was 15 ml each time, 3 times a day, and the treatment course was 5 days. The antitussive effectiveness, cough severity and quality of life , were observed and compared between the two groups before and after the 3 days and 5 days treatment, respectively. Results: All 60 patients completed the treatment. Both two groups were effective in controlling lung cancer cough. After the 3 days treatment, the antitussive effective rates of the observation group and the control group were 83.3% (25/30) and 73.3% (22/30), respectively, with no statistical significance ( P= 0.347). After the 5 days treatment, the antitussive effective rates of observation group and control group were 90.0% (27/30) and 86.6% (26/30), respectively, with no statistical significance ( P= 0.687). There was no significant difference in the composition of patient cough severity between observation group[moderate and severe cough, 56.7% (17/30) ] and control group [moderate and severe cough, 67.7% (20/30) ]. After 3 days treatment, cough symptoms were relieved in both groups. Patients with mild cough accounted for 73.3% (22/30) in the observation group and 56.7% (17/30) in the control group, the difference was not statistically significant ( P= 0.331). What's more, after 5 dyas treatment, there was also no significant difference( P= 0.067)between observation group[mild cough, 86.7%(26/30)] and control group [mild cough, 66.7%(20/30)] . In the meantime, there were no significant differences in the physiological score, psychological score, social score and total score of the Leicester Cough Questionnaire in Mandarin-Chinese scale before the treatment, after 3 days and 5 days treatment between the two groups (all P > 0.05). Patients in the observation group had a lower incidence of xerostomia (0.0% vs 20.0 %, P= 0.024) and constipation (0.0% vs 20.0 %, P= 0.024) than control group. Conclusions: Compound pholcodine syrup and compound codeine phosphate oral solution are effective in treating lung cancer cough with similar antitussive effectiveness. Compound pholcodine syrup has a lower incidence of xerostomia and constipation than control group, which indicates that the security may be better. Clinical trial information: ChiCTR2300076684.
Predictors of immediate and delayed cutaneous hypersensitivity reactions to paclitaxel.
Authors: Trager Megan Hannah , Kuo Alyce Mei-Shiuan , Dusza Stephen W. , Park Vivian , Geskin Larisa J. , Guyer Autumn , Abuhadra Nour , Gucalp Ayca , Lacouture Mario E.
Published: July 2024

e24101

Background: Paclitaxel is one of the first-line treatments for breast, ovarian, and lung cancers. However, its use is limited by the high frequency of hypersensitivity reactions. The purpose of the current study was to assess clinical factors associated with immediate and delayed hypersensitivity reactions to paclitaxel and characterize delayed hypersensitivity reactions to paclitaxel in patients with breast cancer. Methods: We conducted a retrospective chart review of patients who received paclitaxel (Taxol) or nab-paclitaxel (Abraxane) between 1/1/2017 and 1/1/2022 at Memorial Sloan Kettering Cancer Center. Results: In total, 12,274 patients were identified who were treated with paclitaxel. Of these, 6,165 had breast cancer and 1,233 were seen by a dermatologist. 734 patients (11.9%) developed an immediate hypersensitivity reaction to paclitaxel. Age (p < 0.001), race (p < 0.001), and prior history of allergy based on prior ICD-10 code (p = 0.05) were significantly associated with immediate hypersensitivity reactions. Patients who developed an immediate HSR (mean 52.5 ± 12.5 years versus 54.8 ± 12.9 years) tended to be younger, on average, than those who did not experience a reaction. Compared to White patients, Black patients were 37% less likely (OR = 0.63; 95% 0.48 – 0.83) and Asian patients were 70% more likely (OR = 1.70; 95% 1.37 – 2.12) to experience a hypersensitivity reaction. 147 patients (4.0%) had a delayed hypersensitivity reaction (cutaneous rash). Delayed hypersensitivity reaction included toxic erythema of chemotherapy, urticaria, morbilliform, maculopapular, and pruritus phenotypes. The most common phenotypes were maculopapular (52%) and urticaria (36%). The majority had not been treated with nab-paclitaxel prior to rash (86%). Race (p < 0.001) and history of allergy (p < 0.001) were associated with development of a cutaneous reaction. Asian patients were almost twice as likely (OR = 1.99; 95% CI: 1.51 - 2.61, P < 0.001) as White patients to present with a delayed HSR to paclitaxel. Patients with an immediate hypersensitivity reaction were more likely to develop a delayed cutaneous reaction (OR = 1.80; 95% confidence interval: 1.27-2.55) than those who did not get an immediate HSR, controlling for breast cancer stage and patient race. Conclusions: In conclusion, risk factors identified for development of immediate hypersensitivity reactions in this study were younger age, Asian race, and history of allergy. Patients who developed an immediate hypersensitivity reaction were more likely to develop a delayed hypersensitivity reaction. Risk factors for development of the rash included Asian race and history of allergy. Awareness of these clinical factors which are associated with development of a rash could guide providers in choosing treatment with paclitaxel or nab-paclitaxel.
Real world data of safety of immune-checkpoint inhibitors in patient with cancer at tertiary care hospital in Saudi Arabia.
Authors: Alanazi Ahmed , Alzaharani Iman , Bashir Mohammed Salman , AlNajjar Fouad H.
Published: July 2024

e24104

Background: Immune checkpoint inhibitors (ICIs) become an integral part of many cancer therapies, such as melanoma, esophageal carcinoma, breast cancer and other malignancies. Immune checkpoint inhibitors work by activation the immune system that blocks negative regulators expressed on immune or tumor cells. Accordingly, the mechanism of action of ICI may cause autoimmunity-like symptoms called immune-related adverse events (irAEs) that affect many organs in body like skin, liver, lung, endocrine and gastrointestinal tract. These irAEs may reduce the organ function, quality of life and it may cause death. The present work addressed the knowledge gap in understanding real-world outcomes of irAEs associated with ICIs. Real-world patients are more diverse than clinical trial. Methods: This retrospective cohort study investigated the use of immune checkpoint inhibitor (ICI) therapy in an oncology and hematology patients treated at King Fahad Medical City (KFMC) comprehensive cancer center between February 2021 and February 2023. Adult patients (≥ 18 years old) diagnosed with any malignancy or hematological disorder who received at least one dose of ICI therapy during the study period have been included. Patients younger than 18 years old have been excluded. Demographic, clinical, and treatment data have been extracted from the electronic medical records (EMR). The study protocol has been reviewed and approved by the KFMC Institutional Review Board (IRB). The trial still undergoing not yet finished. Results: A total of 44 patients were included by the time preliminary data analysis was conducted on January 1st, 2024. All Patient included were receiving Pembrolizumab 44 patients. In regards to demographics, 27 (61.4%) of the patients were female. Breast cancer was the most common diagnosis (34.1%), followed by non-small cell lung cancer (22.7%). Among patients undergoing ICI, 34.1% had at least one Emergency Room (ER) visit. Notably, 25% of these patients had 1-2 ER visits. The most common reason for ER visits was patient complaints of GI toxicity related to ICI, including nausea, vomiting, and diarrhea (colitis). 12 (26.8%) patients required hospitalization, and 9 (20.5%) stayed for more than seven days.The time to first adverse event of ICI therapy was most commonly seen after nine weeks in 8 (18.2%) patients. Hypothyroidism was the most common adverse event (11.4%), followed by gastrointestinal toxicity (6.8%). Skin, grade 2 hepatotoxicity, and renal toxicity were also reported in 1 (2.3%) patient respectively. Conclusions: Overall, this initial analysis suggests that while ICI known to offers promising potential, it also carries the risk of various adverse events, including a significant rate of ER visits and hospitalizations. Further investigation with larger patient cohorts is warranted to confirm these findings and optimize IO therapy management.
Acute pancreatitis secondary to tamoxifen-induced hypertriglyceridemia: A systematic review.
Authors: Hussain Ali , Zareef Sumaira , Isaac Sangeetha , Arora Aakriti , Valasapalli Srijan , Paracha Munizay , Tasleem Azka , Mainkar Nayan , Muzaffar Mahvish
Published: July 2024

e24105

Background: Tamoxifen can cause paradoxical effects on lipid metabolism and increase triglyceride levels. Acute pancreatitis (AP) can culminate in increased severity and morbidity. A multitude of secondary etiologies may lead to hypertriglyceridemia (HTG), including alcohol, pregnancy, diabetes mellitus, or medications. Tamoxifen is known to cause HTG, but AP as a sequel to this complication remains exceedingly rare. Methods: We performed a systematic search of MEDLINE, Cochrane, Embase, and Google Scholar by using MeSH terms and keywords "tamoxifen," "acute pancreatitis," and "hypertriglyceridemia" from tamoxifen approval in 1977 to December 2023. A total of 26 cases were identified. The diagnosis of AP was established on meeting two of the three Revised Atlanta Classification criteria. Results: A total of 17 case reports fulfilled our inclusion criteria. The mean age of included patients was 35.84 ± 5.99 years. Clinical presentation was mainly related to vomiting (65%), abdominal pain (59%), nausea (47%), and epigastric discomfort (18%). HTG (55%), diabetes mellitus (27%), and hypertension (18%) were major comorbid conditions. The mean onset delay was 11.81 ± 14.75 months, and the tamoxifen dose was 20 mg per day. AP was categorized into mild (35%), moderate (35%), or severe (30%) forms. Treatment mainly consisted of conservative measures, but intravenous insulin (24%) and plasmapheresis (6%) were used in severe cases. The overall mortality rate was 6%. Conclusions: Tamoxifen-induced hypertriglyceridemic pancreatitis is a potential complication of tamoxifen therapy. The findings underscore the need for regular monitoring of serum lipids in these patient patients, especially those with pre-existing HTG or other comorbid conditions that increase their risk of developing hypertriglyceridemic pancreatitis. By implementing these recommendations, clinicians can help reduce morbidity and mortality associated with this condition. [Table: see text]