bluuebunny/crossref_metadata_2025_split huggingface dataset:
Detailed pathological characteristics and survival prognosis of patients with penile cancer from a high-capacity tertiary referral centre over a 20-year period.
Authors: Liu Zhicheng , Tan Xingliang , Wang Yanjun , Wei Wensu , Zhou Qianghua , Yuan Gangjun , Yao Kai 
Published: August 2024

120 Background: Penile cancer is a rare cancer that affects 0.1-1 per 100,000 men in developed countries. However, data on this cancer in developing countries, particularly in Asian populations, are lacking. A retrospective study is needed to determine the characteristics of penile cancer patients, tumor-related treatments, and prognosis. The objective of our study was to present statistical results that are applicable to an Asian population under the most recent staging system. Additionally, we aimed to report on the pathological characteristics and prognosis of a large sample of patients with penile cancer who underwent long-term follow-up with the standard extent of radical dissection. Methods: This study retrospectively analyzed clinical and pathological data from 1017 patients who were diagnosed with penile cancer at Sun Yat-sen University Cancer Center between October 2001 and October 2023. The primary study endpoint was overall survival (OS), and the secondary endpoint was progression-free survival (PFS). Survival curves were plotted using the Kaplan‒Meier method, and differences were compared using the log-rank test. Univariate and multivariate Cox proportional risk models were used to analyze the factors associated with tumor survival. Results: The average follow-up time was 50 months (range: 0.6-232.8 months). The 5- and 10-year OS rates were 67.3% and 62.7%, respectively, and the 5- and 10-year PFS rates were 63.9% and 61.1%, respectively. After excluding 127 Tx patients and 23 TIS stage patients, the 10-year OS rates of pTa stage (29 patients), pT1 (305 patients), pT2 stage (217 patients), pT3 stage (271 patients), and pT4 stage (45 patients) patients were 96.3%, 80.1%, 61.7%, 55.4%, and 14.2%, respectively. A total of 690 patients underwent standard lymph node dissection. The 10-year OS rates of pN0 (376 patients), pN1 (111 patients), pN2 (78 patients), and pN3 (125 patients) patients were 92.7%, 62.5%, 48.1% and 31.3%, respectively. The results of the multifactorial analysis revealed that T stage (T4 stage versus Ta-T1 stage: HR=2.38, 95% CI: 1.00~5.66, P=0.05), pathological grade (G3~4 grade versus G1~2 grade: HR=1.63, 95% CI: 1.05~2.53, P=0.027), N stage (pN+ versus pN0: HR=14.11, 95% CI: 7.83~25.43, P<0.001), and white blood cell count (WBC>8.5: HR=1.71, 95% CI: 1.17~2.51, P=0.006) were independent prognostic factors in penile cancer patients. Conclusions: Patients with penile cancer had better long-term OS after standard lymph node dissection. The adverse factors were T stage, pathological grade, extent of lymph node metastasis, and preoperative WBC count. Identifying high-risk patients through preoperative evaluation can improve long-term survival rates. Radical lymph node dissection in the early stage has more curative value, and adjuvant therapy should be provided in patients with advanced-stage disease after surgery.
Effect of ZCRB1 on the glycolysis via PKM2-HIF1α axis and promotion of immune tolerance in nasopharyngeal carcinoma.
Authors: Hong Gengde , Wang Meng-Yao , Chen Dong-ping 
Published: August 2024

130 Background: Nasopharyngeal carcinoma (NPC) is characterized by abundant lymphocyte infiltration. The failure of immune checkpoint inhibitors in NPC may be related to immune tolerance. Methods: Bioinformatics analysis was performed to identify the correlation between the ZCRB1 mRNA level and immune cell infiltration in NPC tissues. Quantitative real time PCR and immunoblotting were used to determine the mRNA and protein expression, respectively. Functional experiments (CCK8, colony formation assay, cell migration assay and tumor xenograft) were used to explore the effect of ZCRB1 on the malignant phenotype in NPC cells. Glucose and lactate measurement assays as well as Seahorse XF glycolysis stress assay, were conducted to investigate the effects of ZCRB1 on glycolysis in NPC cells. RNA sequencing, QPCR and minigene analysis were used to confirm the splicing switch between PKM1 and PKM2. Luciferase assay was performed to detect the transcription activity of HIF1-α. Finally, correlation analysis between the ZCRB1 expression and glycolysis level was performed to in NPC samples. Results: The expression of ZCRB1 was negatively correlated with checkpoint-related genes and immune regulation-related gene sets in head and neck cancer. Likewise, in NPC, the expression of ZCRB1 was negatively correlated with lymphocyte infiltration, tumor immune microenvironment score and tumor-infiltrating CD4+ T cells, CD8+ T cells, and dendritic cells. Low expression of ZCRB1 was associated with better prognosis. Functional assays demonstrated that ZCRB1 significantly promoted NPC cells growth, clonogenicity, migratory capacity and glycolysis. Mechanistically, ZCRB1 was mainly involved in the hypoxic signaling pathway. Cells with ZCRB1 downregulation downregulated glycolysis-related genes and significantly reduced the transcriptional activity of HIF-1α. Moreover, minigene assays showed that the intron 9 region spliced by PKM in cells with ZCRB1 downregulation. Finally, bioinformatics analysis showed that the mRNA expression of ZCRB1 was positively correlated with the immune infiltration score significantly during glycolysis. Conclusions: ZCRB1 promotes the growth and migration of nasopharyngeal carcinoma cells and is associated with immune tolerance. Further, ZCRB1 accelerates the glycolysis via enhancing the transcriptional activity of HIF-1α through increasing PKM2 isoform splicing, providing a scientific basis for tumor metabolic reprogramming to reshape the immune microenvironment.
Effect of tumor-immune microenvironment (TIME) on disparate ascending (A) and descending (D) subtypes of nasopharyngeal carcinoma (NPC).
Authors: Yeo Eugenia Li Ling , Ong Enya , Hong Boon Hao , Lim Darren Wan-Teck , Yeong Joe , Tan Sze Huey , Chua Melvin L.K. , Hwang Jacqueline Siok Gek , Lu Tianzhu 
Published: August 2024

145 Background: Endemic NPC is invariably linked to Epstein-Barr virus infection, and often presents as locoregionally-advanced (LA-) disease. Nonetheless, it is acknowledged that LA-NPC is clinically heterogeneous, with disparate clinical presentations of ascending (A) and descending (D) subtypes that are characterized by T3-4N0-1 and T1-2N2-3 disease, respectively. Here, we investigated the TIME between these distinct NPC phenotypes using whole transcriptome sequencing and digital pathology. Methods: We utilized a cohort of 111 patients with NPC from 2 institutions – NCCS (n=68) and JXCH (n=43) as test and validation datasets, respectively. Whole transcriptome profiling using RNAseq (Illumina, CA) was performed in the NCCS cohort, while spatial analyses of hematoxylin and eosin-stained whole slide images (WSIs) were undertaken in the NCCS cohort (35 A- and 33 D-subtypes), and validated in the JXCH cohort (26 A- and 17 D-subtypes). A customized pipeline was developed to analyze the spatial relationships between tumor-rich and immune-rich regions (tiles) within the WSIs. Mean distances between each tumor-rich and its nearest immune-rich tiles were computed for each WSI. Highest and lowest quartiles of the mean distances in the test cohort were used as thresholds to classify NPC tumors into 3 immune classes of differing immune cell density. Results: Transcriptomic profiling revealed an enrichment of immune-related genesets and differentially expressed genes in D- relative to A-subtype tumors. This corresponded to observations of higher overall immune, T and B cell scores in D- than A-subtypes by deconvolution analyses (ESTIMATE and CIBERSORT). Through spatial analyses of our WSIs, we defined three immune classes – immune-dense, -sparse, and -desert, which corresponded to mean distances of <88 μm, 88-208 μm, and >208 μm between tumour- to immune-rich tiles, respectively. D-subtype NPC had significantly more immune-rich regions compared with A-subtypes in both NCCS and JXCH cohorts ( P=0.02 [NCCS]; P=0.01 [JXCH]). This corresponded to shorter median distances between tumor-rich to immune-rich tiles in D- than A-subtypes (103 μm vs 200 μm, P=0.01 [NCCS]; 123 μm vs250 μm, P=0.01 [JXCH]). Based on our novel spatial-based classification, we observed a higher proportion of immune dense tumors in D- than A-subtypes in the NCCS cohort, with only 3/33 (9%) D-subtypes being classified as immune desert. Using the same distance thresholds, we derived a consistent trend in the JXCH cohort, where a higher proportion of D-subtypes were classified as immune dense and sparse than A-subtypes (59% vs 31%, P=0.01). Conclusions: Our results support a model where the TIME delineates the biology underpinning the disparate clinical presentations of distinct A- and D-subtypes of LA-NPC.
Cost-effectiveness of liquid biopsy for molecular profiling of newly diagnosed advanced non-squamous NSCLC in an Asian population.
Authors: Tan Aaron C. , Liu Sibo , Graves Nicholas 
Published: August 2024

178 Background: Liquid biopsy is complementary to tissue biopsy for lung cancer profiling, yet evidence of the cost-effectiveness is limited. This could retard implementation and reimbursement in clinical practice. The aim of this study is to estimate the cost-effectiveness of profiling strategies that include liquid biopsy and to identify the optimal profiling approach for newly diagnosed advanced non-squamous non-small cell lung cancer (NSCLC) in an Asian population using Singapore as an example. Methods: A decision tree and partitioned-survival model was developed from the Singapore healthcare system’s perspective to evaluate the cost-effectiveness of five molecular profiling strategies: either tissue or plasma next-generation sequencing (NGS) alone, a concurrent, and two sequential approaches. Model inputs were informed by local data or published literature. Sensitivity analyses and scenario analyses were undertaken to understand the robustness of the conclusions for decision making. The optimal strategy at different willingness-to-pay (WTP) thresholds was presented by cost-effectiveness acceptability frontier and the expected loss curve. Results: The sequential tissue-plasma NGS approach revealed an additional 0.0981 quality adjusted life years (QALYs) for an extra cost of S$3,074 over a 20-year time horizon compared to tissue NGS alone, resulting in an incremental cost-effectiveness ratio (ICER) of S$31,318/QALY and an incremental net monetary benefit of S$1,343 per patient. The findings were sensitive to the costs of pembrolizumab and osimertinib and the probabilities of re-biopsy after tissue NGS. Sequential plasma-tissue NGS and plasma NGS alone were more costly and less effective than alternatives. Conclusions: The sequential tissue-plasma NGS approach generated the highest net monetary benefit and was the optimal testing strategy when WTP was S$45,000/QALY. It retained superiority but understandably with a higher ICER when expensive, non-first line treatments were included. Overall, its routine clinical practice should be proactively considered for newly diagnosed advanced non-squamous NSCLC in an Asian population.
Addressing ovarian cancer research gaps in under-resourced settings using individual initiatives: The OVANORDEST pilot project in Morocco.
Authors: El Bairi Khalid 
Published: August 2024

183 Background: In Morocco, ovarian cancer (OC) is a neglected women’s cancer. To bridge this gap, early-career cancer researchers might develop and engage in individual initiatives to enhance research outcomes. In this perspective, I recently launched the OVANORDEST project as an individual initiative. This plan outlines a three-step strategy designed to promote OC research, highlighting specific milestones. This abstract presents the findings from the initial feasibility study, which focuses on real-world evidence, implementing inexpensive precision medicine approaches, supporting women in oncology, and enhancing meta-research. Methods: Initially, a bibliometric study was conducted to find research gaps in the field of OC in Morocco. A 16-year real-world retrospective study was conducted at the Hassan II Oncology Center (October 2005-June 2020). To implement precision medicine approaches, quality evidence on several potentially inexpensive blood-based biomarkers such as Pan-Immune Inflammation-Value (PIIV) were explored using a PROSPERO-registered umbrella systematic review and then investigated in an original cohort. Cox regression analyses were applied to identify the effects of different biomarkers on survival outcomes. Meta-research was developed by publishing two special thematic issues and one edited book on OC biomarkers. The project also included a mentorship program designed to empower women oncologists. Results: A total of 258 patients with OC were included. Most patients had advanced FIGO stages at diagnosis. The median overall survival (OS) for the entire cohort was 32 months, with a median progression-free survival (PFS) of 14.6 months. CA-125 positivity, advanced disease stage, and presence of residual disease after surgery were prognostic factors that adversely affected survival. In the multivariable analysis after adjustment for the FIGO stage, high PIIV was an independent predictive factor of OS (HR= 1.83; 95% CI: 1.18-2.84, p=0.007). Two specialized thematic issues were published alongside a book dedicated to ovarian cancer biomarkers. Additionally, careers of a group of women oncologists were boosted and a local patient advocacy group was supported in adopting supportive strategies for patients. Conclusions: Engaging early-career cancer researchers through individual initiatives in under-resourced settings may considerably improve research outcomes. In this context, I propose that sharing this experience, which has been successfully applied in Morocco, could empower health systems and facilitate the generation of research outputs in low- and middle-income countries.
A phase 2, open-label, single-arm study evaluating the combination of pembrolizumab (pembro), lenvatinib, and chemotherapy in patients (pts) with metastatic non-small cell lung cancer (NSCLC) harbouring a targetable mutation who experienced disease progression on standard tyrosine kinase inhibitors (TKIs).
Authors: Chan Hoi Wai , Tse Chris Chun Long , Li Yu-Chung , Leung Roland Ching-Yu , Wong Jeffrey Sum Lung , Kwok Gin Wai , Li Hoi Lam , Tsang Wing Yan Josephine , Li Cho Wing , Lo Jenny WY , Tang Vikki , Hui Rina , Yau Thomas , Ho James CM , Chiu Joanne W 
Published: August 2024

198 Background: Pts with metastatic NSCLC harbouring a targetable mutation who progressed on standard TKIs often receive chemotherapy as the next line of treatment. We report efficacy and safety of a novel combination of pembro, lenvatinib and chemotherapy for these pts. Methods: This was a phase 2, open-label, single-centre, single-arm study enrolling pts with metastatic NSCLC with sensitizing EGFR, ALK or ROS1 mutation who progressed on standard TKIs. Eligible pts had measurable disease, no untreated brain metastasis and ECOG PS ≤1. Pts received pembro 200 mg, pemetrexed 500 mg/m2 and carboplatin AUC 5 every 3 weeks for 4 cycles plus lenvatinib 8 mg QD. The maintenance regimen without carboplatin was continued as tolerated for up to 2 years. The primary endpoint was objective response rate (ORR) by independent radiology review (IRR) as per RECIST 1.1. The secondary endpoints were PFS, overall survival (OS) and safety. Results: At the data cutoff date (2nd February 2024), 24 pts were screened and 19 were enrolled: median age 64 years (range 29–77); 10 (53%) female. Four pts were excluded at screening due to untreated brain metastasis. All enrolled pts were evaluated for safety while 15 pts were evaluable for response. All pts had adenocarcinoma with targetable mutation: EGFR mutation in 18 (95%) pts and ALK fusion in 1 (5%) pt. The median follow-up time was 11.3 months. Treatment was ongoing in 8 pts on the date of analysis, while 6 pts permanently discontinued due to disease progression and 1 pt permanently discontinued due to a treatment-related adverse event (TRAE). The ORR was 40% (6/15, 95% CI 19.8%–64.3%). All responses were partial responses. The median PFS was 11.9 months (range 3.5–20.3). The OS was not reached. TRAEs of any grade (Gr) occurred in 74% (14/19) of the pts. Most of the TRAEs were Gr 1–2, which occurred in 63% (12/19) of the pts. The most common TRAEs were hypothyroidism (31.6%), nausea (26.3%), neutropenia (26.3%), thrombocytopenia (26.3%), anorexia (21.1%), hypertension (15.8%), anaemia (10.5%), pruritus (10.5%) and rash (10.5%). G1 diarrhoea was reported in 1 pt (5.3%) and G1 adrenal insufficiency in 1 pt (5.3%). Gr 3 TRAEs were neutropenia in 2 pts, anaemia in 1 pt and thrombocytopenia in 1 pt. The only Gr 4 TRAE was thrombocytopenia. No treatment related death was observed. Conclusions: The combination of pembro, lenvatinib and chemotherapy demonstrated a favourable ORR and safety in treating metastatic NSCLC pts with a targetable mutation who progressed on standard TKIs. Clinical trial information: NCT04989322 .
Effect of heterozygosity loss of HLA-I on immune evasion and promotion of non-small cell lung cancer brain metastasis and immunotherapy resistance.
Authors: Han Jiefei , Lin Yi , Li Wenbin 
Published: August 2024

209 Background: HLA-I play a crucial role in T cell recognition and killing of tumor cells as well as in PD-1/PD-L1 immunotherapy. Loss of heterozygosity (LOH) of HLA-I alleles has been found to be common in lung cancer patients and influences immune escape during tumor evolution. This study aims to explore the incidence of HLA-I LOH in intracranial metastases of advanced non-small cell lung cancer patients with brain metastasis and its impact on the efficacy of immunotherapy. Methods: A total of 29 patients with non-small cell lung cancer brain metastasis were included in this study. All enrolled patients underwent either percutaneous biopsy or surgical resection of intracranial metastases and had tissue specimens from the primary lung lesions. Whole-exome sequencing was performed on all primary/metastatic lesions to determine HLA-I typing/LOH and calculate tumor mutation burden (TMB). Additionally, we assessed the expression levels of CD8 T cells in the tumor immune microenvironment. Among the enrolled patients, 20 received PD-1/PD-L1 treatment. Results: Among the enrolled patients, 82.8% (24/29) had heterozygous HLA-I typing, with HLA-I LOH present in 25% (6/24) of patients' primary lesions and 58.3% (14/24) in brain metastatic lesions. Analysis of TMB in different lesions revealed a median TMB of 7.8 mut/Mb in lesions with intact HLA-I and 11.4 mut/Mb in lesions with HLA-I LOH. Notably, the median TMB in brain metastatic lesions with HLA-I LOH was 13.2 mut/Mb, higher than that in HLA-I LOH primary lung lesions (10.1 mut/Mb). Immunohistochemistry demonstrated that CD8 T cell expression levels were lowest in brain metastatic lesions with HLA-I LOH and highest in intact HLA-I primary lung lesions. Among patients who received immunotherapy, four cases exhibited inconsistent lesion responses, with stable or regressing primary lesions but progressive intracranial metastases. Survival analysis revealed that patients with HLA-I LOH in brain metastases had significantly lower PFS compared to those without (4.1 months vs. 6.9 months, P < 0.05), with no significant difference in OS. Conclusions: This study indicates that the incidence of HLA-I LOH in brain metastases of lung cancer is higher than that in primary lung lesions, accompanied by higher TMB, possibly due to the ineffective presentation of tumor antigens resulting in the accumulation of mutations in lost HLA-I. Moreover, tumors with HLA-I LOH have reduced levels of CD8 T cell infiltration, suggesting impaired tumor antigen presentation impedes immune cytotoxicity. These phenomena contribute to the poorer efficacy of immunotherapy in such patients. In conclusion, HLA-I LOH may be one of the important mechanisms of immune escape in lung cancer brain metastases.
Racial impact of secondary metastasis in patients with lung cancer: Evidence of US hospitals in 2020.
Authors: Suenghataiphorn Thanathip , Kulthamrongsri Narathorn , Saowapa Sakditad , Naunsilp Piengpitch , Xanthavanij Nutchapon , Osataphan Soravis Alm 
Published: August 2024

213 Background: Lung cancer patient often encounter disparities in health outcomes, especially in difference racial and ethnic groups. Metastasis is the primary cause of cancer morbidity and mortality. However, data on the metastasis risks and clinical outcomes on hospitalized individuals with lung cancer is still limited. Therefore, we aim to assess the association between metastatic lung cancer and racial differences. Methods: We analyzed the 2020 U.S. National Inpatient Sample (NIS) to explore patients who have lung cancer as the primary diagnosis. Additionally, we identified evidence of metastasis, as recorded by ICD-10-CM. Adjusted odds ratios (aORs) for specified outcomes were calculated through multivariable logistic and linear regression analyses. The primary outcome was racial differences in organ metastasis and secondary outcomes included mortality and length of stay. Statistical significance was established at p-value of 0.05. Results: We identified 103,335 patients with primary diagnosis of lung and bronchus cancer at discharge. The mean age was 68.9 years; 50.5% were female. Caucasians accounted for 74.3%, with African Americans at 12.1% and Hispanics at 4.6%. 10% of the patients had brain metastasis, whereas 14% had bone metastasis. In a multivariate analysis adjusting for patient, COVID-19, chemotherapy usage and hospital factors, African Americans had higher risk of brain metastasis (aOR 1.18; 95%CI (1.02, 1.37), p = 0.002), higher risk of bone metastasis (aOR 1.16; 95%CI (1.02, 1.33), p = 0.025), higher risk of mortality (aOR 1.21; 95% CI (1.01, 1.45), p = 0.039) and longer length of stay (b = 0.85; 95%CI (0.55, 1.16), p = 0.001). Hispanics also had higher risk of brain (aOR 1.36, p < 0.05) and prolonged length of stay (b 0.79, p < 0.005). We observed an increase in risk of metastasis and mortality but non-statistically significant in some parameters and races, as shown in table provided. Conclusions: In conclusion, our study revealed that racial difference is associated with higher risk of metastasis, as well as other outcomes. Further longitudinal research is necessary to establish a causal relationship between races, metastasis, and mortality in patients with lung cancer. [Table: see text]