Background/aim: Treatment of primary central nervous system lymphoma (PCNSL) includes high dose methotrexate-based polychemotherapy (HD-MTX). This study aimed to identify early predictive factors of methotrexate (MTX) delayed elimination.
Patients and methods: We prospectively included all patients with newly-diagnosed PCNSL. Daily serum and urinary creatinine and ionogram were collected. We generated two independent cohorts: a training cohort (TC) and a confirmatory cohort (CC).
Results: We included for analysis 64 cures of HD-MTX (20 patients) in the TC and 59 cures (22 patients) in the CC. Median elimination time of MTX was 95 h and 96 h in the TC and CC, respectively. In multivariate analysis, older age (p=0.004), low Karnofsky Performance Status (p=0.036) and high urinary K+ (p=0.001) were associated with delayed MTX elimination. An optimal cutoff for urinary K+ was defined. In the CC, we confirmed that high urinary K+ (p=0.004) remained associated with delayed MTX elimination.
Conclusion: High urinary K+ may be predictive of delayed MTX elimination in primary central nervous system lymphoma. Its relevance as a decision-making factor needs to be validated in additional prospective studies.
{"title":"Early Urinary Potassium Level Predicts High-dose Methotrexate Elimination Delay in Primary Central Nervous System Lymphoma.","authors":"Vincent Harlay, Alexandre Bertucci, Céline Boucard, Gregorio Petrirena, Chantal Campello, Maryline Barrié, Didier Autran, Olivier Chinot, Emeline Tabouret","doi":"10.21873/anticanres.17272","DOIUrl":"https://doi.org/10.21873/anticanres.17272","url":null,"abstract":"<p><strong>Background/aim: </strong>Treatment of primary central nervous system lymphoma (PCNSL) includes high dose methotrexate-based polychemotherapy (HD-MTX). This study aimed to identify early predictive factors of methotrexate (MTX) delayed elimination.</p><p><strong>Patients and methods: </strong>We prospectively included all patients with newly-diagnosed PCNSL. Daily serum and urinary creatinine and ionogram were collected. We generated two independent cohorts: a training cohort (TC) and a confirmatory cohort (CC).</p><p><strong>Results: </strong>We included for analysis 64 cures of HD-MTX (20 patients) in the TC and 59 cures (22 patients) in the CC. Median elimination time of MTX was 95 h and 96 h in the TC and CC, respectively. In multivariate analysis, older age (p=0.004), low Karnofsky Performance Status (p=0.036) and high urinary K<sup>+</sup> (p=0.001) were associated with delayed MTX elimination. An optimal cutoff for urinary K<sup>+</sup> was defined. In the CC, we confirmed that high urinary K<sup>+</sup> (p=0.004) remained associated with delayed MTX elimination.</p><p><strong>Conclusion: </strong>High urinary K<sup>+</sup> may be predictive of delayed MTX elimination in primary central nervous system lymphoma. Its relevance as a decision-making factor needs to be validated in additional prospective studies.</p>","PeriodicalId":8072,"journal":{"name":"Anticancer research","volume":null,"pages":null},"PeriodicalIF":1.6,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142339877","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Background/aim: The aim of the study was to develop a novel predictive scoring system based on the dynamics of serum inflammatory indicators in immune checkpoint inhibitor (ICI) treatment on non-small-cell lung cancer (NSCLC) with bone metastases.
Patients and methods: Sixty patients with NSCLC and bone metastases treated with ICIs between January 2016 and March 2021 were included in the development cohort. Serum neutrophil-to-lymphocyte ratio (NLR) and C-reactive protein (CRP) levels were assessed before (pre-value) and 6 weeks after (post-value) ICI treatment, and a novel predictive score was developed: pre-value ≥ post-value, 0 points; pre-value < post-value, 1 point; total score: 0-2 points. The associations of these dynamics and the score with clinical outcomes, including overall survival (OS), progression-free survival (PFS), response rate (RR) of bone metastases, and disease control rate (DCR), were evaluated. Furthermore, cross-validation was performed with 23 patients after April 2021 using the same inclusion criteria.
Results: The patients with decreased serum inflammation levels had significantly better OS, PFS, and RR than those with increased levels. Applying the developed score to the development cohort, the patients with 0 points had significantly better OS, PFS, and RR than others. In multivariable analysis, the score independently predicted treatment response to ICI for bone metastasis and prognosis. Cross-validation showed that OS, PFS, and RR were significantly better in the patients in the 0-point group.
Conclusion: The early NLR and CRP dynamics were associated with therapeutic responses to ICIs in NSCLC with bone metastases. Our novel scoring system based on these dynamics is simple and has a high predictive accuracy.
{"title":"Serum Inflammatory Dynamics as Novel Biomarkers for Immune Checkpoint Inhibitors in Non-small-cell Lung Cancer With Bone Metastases.","authors":"Yohei Asano, Norio Yamamoto, Katsuhiro Hayashi, Akihiko Takeuchi, Satoshi Kato, Shinji Miwa, Miho Okuda, Isao Matsumoto, Seiji Yano, Satoru Demura","doi":"10.21873/anticanres.17278","DOIUrl":"https://doi.org/10.21873/anticanres.17278","url":null,"abstract":"<p><strong>Background/aim: </strong>The aim of the study was to develop a novel predictive scoring system based on the dynamics of serum inflammatory indicators in immune checkpoint inhibitor (ICI) treatment on non-small-cell lung cancer (NSCLC) with bone metastases.</p><p><strong>Patients and methods: </strong>Sixty patients with NSCLC and bone metastases treated with ICIs between January 2016 and March 2021 were included in the development cohort. Serum neutrophil-to-lymphocyte ratio (NLR) and C-reactive protein (CRP) levels were assessed before (pre-value) and 6 weeks after (post-value) ICI treatment, and a novel predictive score was developed: pre-value ≥ post-value, 0 points; pre-value < post-value, 1 point; total score: 0-2 points. The associations of these dynamics and the score with clinical outcomes, including overall survival (OS), progression-free survival (PFS), response rate (RR) of bone metastases, and disease control rate (DCR), were evaluated. Furthermore, cross-validation was performed with 23 patients after April 2021 using the same inclusion criteria.</p><p><strong>Results: </strong>The patients with decreased serum inflammation levels had significantly better OS, PFS, and RR than those with increased levels. Applying the developed score to the development cohort, the patients with 0 points had significantly better OS, PFS, and RR than others. In multivariable analysis, the score independently predicted treatment response to ICI for bone metastasis and prognosis. Cross-validation showed that OS, PFS, and RR were significantly better in the patients in the 0-point group.</p><p><strong>Conclusion: </strong>The early NLR and CRP dynamics were associated with therapeutic responses to ICIs in NSCLC with bone metastases. Our novel scoring system based on these dynamics is simple and has a high predictive accuracy.</p>","PeriodicalId":8072,"journal":{"name":"Anticancer research","volume":null,"pages":null},"PeriodicalIF":1.6,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142339901","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-01DOI: 10.21873/anticanres.17245
Hirotaka Suto
Epithelioid hemangioendothelioma (EHE) is a rare malignant vascular tumor arising from vascular endothelial cells. This study delves into the molecular mechanisms underlying EHE, with a specific focus on the Hippo-YAP/TAZ pathway. EHE is characterized molecularly by transcriptional co-activator with a PDZ-motif (TAZ)-calmodulin binding transcription activator 1 (CAMTA1) or Yes-associated protein (YAP)-transcription factor E3 (TFE3) fusions. YAP/TAZ, a transcription co-activator, binds to transcription factors and regulates gene expression. The YAP/TAZ and its upstream Hippo pathway are involved in cell proliferation and cell contact inhibition, regulating organ size and carcinogenesis. In addition to oncogenic effects, dysfunction or gene duplication of the Hippo pathway results in a poor prognosis due to epithelial-mesenchymal transformation of epithelial cells, stem cell transformation, and increased drug resistance. Notably, the TAZ-CAMTA1 fusion is specific to EHE, and genetic alterations in the Hippo pathway other than this fusion gene are absent in EHE. The TAZ-CAMTA1 fusion is a promising therapeutic target. This review summarizes recent advances in EHE, focusing on the role of the Hippo-YAP/TAZ pathway in EHE and its potential as a therapeutic target for drug development.
{"title":"Role of the Hippo-YAP/TAZ Pathway in Epithelioid Hemangioendothelioma and its Potential as a Therapeutic Target.","authors":"Hirotaka Suto","doi":"10.21873/anticanres.17245","DOIUrl":"https://doi.org/10.21873/anticanres.17245","url":null,"abstract":"<p><p>Epithelioid hemangioendothelioma (EHE) is a rare malignant vascular tumor arising from vascular endothelial cells. This study delves into the molecular mechanisms underlying EHE, with a specific focus on the Hippo-YAP/TAZ pathway. EHE is characterized molecularly by transcriptional co-activator with a PDZ-motif (TAZ)-calmodulin binding transcription activator 1 (CAMTA1) or Yes-associated protein (YAP)-transcription factor E3 (TFE3) fusions. YAP/TAZ, a transcription co-activator, binds to transcription factors and regulates gene expression. The YAP/TAZ and its upstream Hippo pathway are involved in cell proliferation and cell contact inhibition, regulating organ size and carcinogenesis. In addition to oncogenic effects, dysfunction or gene duplication of the Hippo pathway results in a poor prognosis due to epithelial-mesenchymal transformation of epithelial cells, stem cell transformation, and increased drug resistance. Notably, the TAZ-CAMTA1 fusion is specific to EHE, and genetic alterations in the Hippo pathway other than this fusion gene are absent in EHE. The TAZ-CAMTA1 fusion is a promising therapeutic target. This review summarizes recent advances in EHE, focusing on the role of the Hippo-YAP/TAZ pathway in EHE and its potential as a therapeutic target for drug development.</p>","PeriodicalId":8072,"journal":{"name":"Anticancer research","volume":null,"pages":null},"PeriodicalIF":1.6,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142339899","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Background/aim: Patients with triple-negative breast cancer (TNBC) who obtain a pathological complete response (pCR) after neoadjuvant chemotherapy have an improved prognosis. Lymphocyte-predominant breast cancer is more likely to respond to neoadjuvant chemotherapy. Here, we investigated the correlation between tumor-infiltrating lymphocytes (TILs) in pre-treatment biopsy specimens from patients with TNBC in relation to response to NAC.
Patients and methods: The level of infiltration by immune cells expressing immune cell lineage surface markers (CD8, CD4, CD19, CD14, CD11c, and CD11b) in biopsy specimens from 52 patients with TNBC was examined using multispectral immunofluorescent labelling.
Results: The level of CD8-positive TILs was significantly higher in patients with a pCR (p=0.045). The Cox proportional hazard model confirmed that lymph node involvement was associated with poorer disease-free survival (p=0.008). A high level of CD8-positive TILs was related to significantly prolonged disease-free survival in patients with node-positive TNBC (p=0.018).
Conclusion: Assessing infiltration by CD8-positive TILs in the primary tumor is a useful biomarker to predict pCR and improved outcome in patients with node-positive TNBC.
{"title":"CD8-Positive T-Cells Are Key Immune Cells for Predicting the Therapeutic Effect of Neoadjuvant Chemotherapy in Triple-negative Breast Cancer.","authors":"Natsuki Uenaka, Eiichi Sato, Yoshiya Horimoto, Saori Kawai, Mariko Asaoka, Hiroshi Kaise, Kimito Yamada, Takashi Ishikawa","doi":"10.21873/anticanres.17281","DOIUrl":"https://doi.org/10.21873/anticanres.17281","url":null,"abstract":"<p><strong>Background/aim: </strong>Patients with triple-negative breast cancer (TNBC) who obtain a pathological complete response (pCR) after neoadjuvant chemotherapy have an improved prognosis. Lymphocyte-predominant breast cancer is more likely to respond to neoadjuvant chemotherapy. Here, we investigated the correlation between tumor-infiltrating lymphocytes (TILs) in pre-treatment biopsy specimens from patients with TNBC in relation to response to NAC.</p><p><strong>Patients and methods: </strong>The level of infiltration by immune cells expressing immune cell lineage surface markers (CD8, CD4, CD19, CD14, CD11c, and CD11b) in biopsy specimens from 52 patients with TNBC was examined using multispectral immunofluorescent labelling.</p><p><strong>Results: </strong>The level of CD8-positive TILs was significantly higher in patients with a pCR (p=0.045). The Cox proportional hazard model confirmed that lymph node involvement was associated with poorer disease-free survival (p=0.008). A high level of CD8-positive TILs was related to significantly prolonged disease-free survival in patients with node-positive TNBC (p=0.018).</p><p><strong>Conclusion: </strong>Assessing infiltration by CD8-positive TILs in the primary tumor is a useful biomarker to predict pCR and improved outcome in patients with node-positive TNBC.</p>","PeriodicalId":8072,"journal":{"name":"Anticancer research","volume":null,"pages":null},"PeriodicalIF":1.6,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142339840","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Background/aim: Pneumonitis during durvalumab consolidation therapy after chemoradiotherapy (CRT) is a major cause of treatment discontinuation. Although previous studies have revealed an association between antinuclear antibody (ANA) positivity and the safety and efficacy of immune checkpoint inhibitors in advanced non-small cell lung cancer (NSCLC), there are no reports on durvalumab consolidation therapy. This study investigated the safety and efficacy of durvalumab after CRT in ANA-positive patients.
Patients and methods: We retrospectively reviewed patients with unresectable NSCLC treated with durvalumab after CRT between August 2018 and July 2022 at our institution. We evaluated the association among ANA positivity, treatment-related adverse events (AEs), and survival outcomes.
Results: Overall, 80 patients were enrolled, 39 of whom were ANA-positive. Although there were no significant differences in the incidence of each AE of any grade, ANA-positive patients tended to have a higher frequency of pneumonitis of grade 3 to 5 than ANA-negative patients (12.8% vs. 2.4%, p=0.104). ANA-positive patients had a significantly shorter median progression-free survival (PFS) and overall survival (OS) than ANA-negative patients [14.9 months vs. not reached (NR), p=0.005; NR vs. NR, p=0.013]. Multivariate analysis revealed that ANA positivity was an independent predictor of shorter PFS (HR=2.23; 95% CI=1.16-4.29; p=0.016) and OS (HR=2.28; 95% CI=1.01-5.12; p=0.046).
Conclusion: ANA-positive patients receiving durvalumab after CRT tended to have a higher frequency of severe pneumonitis and significantly worse PFS and OS compared with ANA-negative patients.
背景/目的:在化放疗(CRT)后进行杜伐单抗巩固治疗期间出现肺炎是导致治疗中断的一个主要原因。尽管之前的研究显示抗核抗体(ANA)阳性与晚期非小细胞肺癌(NSCLC)免疫检查点抑制剂的安全性和疗效之间存在关联,但目前还没有关于durvalumab巩固治疗的报道。本研究调查了ANA阳性患者CRT后使用durvalumab的安全性和有效性:我们回顾性地回顾了2018年8月至2022年7月期间在我院接受CRT后使用度伐单抗治疗的不可切除NSCLC患者。我们评估了ANA阳性、治疗相关不良事件(AEs)和生存结果之间的关联:共有 80 名患者入组,其中 39 人 ANA 阳性。虽然各等级AE的发生率无明显差异,但ANA阳性患者发生3至5级肺炎的频率往往高于ANA阴性患者(12.8%对2.4%,P=0.104)。ANA阳性患者的中位无进展生存期(PFS)和总生存期(OS)明显短于ANA阴性患者[14.9个月 vs. 未达到(NR),p=0.005;NR vs. NR,p=0.013]。多变量分析显示,ANA阳性是较短PFS(HR=2.23;95% CI=1.16-4.29;P=0.016)和OS(HR=2.28;95% CI=1.01-5.12;P=0.046)的独立预测因素:结论:与ANA阴性患者相比,ANA阳性患者在CRT后接受度伐卢单抗治疗时,发生严重肺炎的频率更高,PFS和OS明显更差。
{"title":"Safety and Efficacy of Durvalumab After Chemoradiotherapy in Antinuclear Antibody-positive Patients With Non-small Cell Lung Cancer.","authors":"Akihiro Tsukaguchi, Akihiro Tamiya, Shoichi Fukuda, Yuki Iwahashi, Kensuke Kanaoka, Yuya Tanaka, Yuji Inagaki, Yoshihiko Taniguchi, Keiko Nakao, Tomoko Kagawa, Yoshinobu Matsuda, Kyoichi Okishio","doi":"10.21873/anticanres.17280","DOIUrl":"https://doi.org/10.21873/anticanres.17280","url":null,"abstract":"<p><strong>Background/aim: </strong>Pneumonitis during durvalumab consolidation therapy after chemoradiotherapy (CRT) is a major cause of treatment discontinuation. Although previous studies have revealed an association between antinuclear antibody (ANA) positivity and the safety and efficacy of immune checkpoint inhibitors in advanced non-small cell lung cancer (NSCLC), there are no reports on durvalumab consolidation therapy. This study investigated the safety and efficacy of durvalumab after CRT in ANA-positive patients.</p><p><strong>Patients and methods: </strong>We retrospectively reviewed patients with unresectable NSCLC treated with durvalumab after CRT between August 2018 and July 2022 at our institution. We evaluated the association among ANA positivity, treatment-related adverse events (AEs), and survival outcomes.</p><p><strong>Results: </strong>Overall, 80 patients were enrolled, 39 of whom were ANA-positive. Although there were no significant differences in the incidence of each AE of any grade, ANA-positive patients tended to have a higher frequency of pneumonitis of grade 3 to 5 than ANA-negative patients (12.8% vs. 2.4%, p=0.104). ANA-positive patients had a significantly shorter median progression-free survival (PFS) and overall survival (OS) than ANA-negative patients [14.9 months vs. not reached (NR), p=0.005; NR vs. NR, p=0.013]. Multivariate analysis revealed that ANA positivity was an independent predictor of shorter PFS (HR=2.23; 95% CI=1.16-4.29; p=0.016) and OS (HR=2.28; 95% CI=1.01-5.12; p=0.046).</p><p><strong>Conclusion: </strong>ANA-positive patients receiving durvalumab after CRT tended to have a higher frequency of severe pneumonitis and significantly worse PFS and OS compared with ANA-negative patients.</p>","PeriodicalId":8072,"journal":{"name":"Anticancer research","volume":null,"pages":null},"PeriodicalIF":1.6,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142339900","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-01DOI: 10.21873/anticanres.17275
Dirk Rades, Florian Cremers, Christian Ziemann, Laura Splettstösser, Carlos A Narvaez-Wolf, Ahmed Al-Salool, Michael VON Staden, Jan-Dirk Küter, Stefan Janssen, Carmen Timke
Background/aim: Patients irradiated for prostate cancer may experience urinary toxicity, particularly if the bladder volume is small. A mobile application (app) that reminds the patients to drink water prior to each radiation fraction may help avoid small volumes. This study investigating bladder volumes during a radiotherapy course is a prerequisite for a prospective trial testing such a reminder app.
Patients and methods: Frequency of bladder volumes <200 ml and seven potential risk factors were retrospectively evaluated in 72 patients receiving external beam radiotherapy for non-metastatic prostate cancer.
Results: The mean and median values of the numbers of radiation fractions with bladder volumes <200 ml were 17.8 (standard deviation=12.0) and 16.5 (interquartile range Q1-Q3=7.5-29.5) fractions, respectively. Higher numbers of fractions with volumes <200 ml were significantly associated with pre-radiotherapy bladder volumes <200 ml (p<0.001) and high-risk prostate cancer (p=0.014).
Conclusion: The proportion of bladder volumes <200 ml during the radiotherapy course was high and needs to be decreased. Pre-radiotherapy bladder volume and risk level of prostate cancer were significant risk factors for higher numbers of fractions with volumes <200 ml. These results are important for designing a prospective trial.
{"title":"Changes in Bladder Volume During Radiotherapy for Prostate Cancer.","authors":"Dirk Rades, Florian Cremers, Christian Ziemann, Laura Splettstösser, Carlos A Narvaez-Wolf, Ahmed Al-Salool, Michael VON Staden, Jan-Dirk Küter, Stefan Janssen, Carmen Timke","doi":"10.21873/anticanres.17275","DOIUrl":"https://doi.org/10.21873/anticanres.17275","url":null,"abstract":"<p><strong>Background/aim: </strong>Patients irradiated for prostate cancer may experience urinary toxicity, particularly if the bladder volume is small. A mobile application (app) that reminds the patients to drink water prior to each radiation fraction may help avoid small volumes. This study investigating bladder volumes during a radiotherapy course is a prerequisite for a prospective trial testing such a reminder app.</p><p><strong>Patients and methods: </strong>Frequency of bladder volumes <200 ml and seven potential risk factors were retrospectively evaluated in 72 patients receiving external beam radiotherapy for non-metastatic prostate cancer.</p><p><strong>Results: </strong>The mean and median values of the numbers of radiation fractions with bladder volumes <200 ml were 17.8 (standard deviation=12.0) and 16.5 (interquartile range Q1-Q3=7.5-29.5) fractions, respectively. Higher numbers of fractions with volumes <200 ml were significantly associated with pre-radiotherapy bladder volumes <200 ml (p<0.001) and high-risk prostate cancer (p=0.014).</p><p><strong>Conclusion: </strong>The proportion of bladder volumes <200 ml during the radiotherapy course was high and needs to be decreased. Pre-radiotherapy bladder volume and risk level of prostate cancer were significant risk factors for higher numbers of fractions with volumes <200 ml. These results are important for designing a prospective trial.</p>","PeriodicalId":8072,"journal":{"name":"Anticancer research","volume":null,"pages":null},"PeriodicalIF":1.6,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142339841","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-01DOI: 10.21873/anticanres.17244
Kozo Kuribayashi, Jun Hirano
In February 2004, the Food and Drug Administration (FDA) was the first to approve the combination of cisplatin (CDDP) and pemetrexed (PEM) as standard first-line chemotherapy for untreated, unresectable malignant pleural mesothelioma (MPM). However, after that approval, no progress was made in the standard first-line treatment of MPM for almost 15 years. Positive results from a phase 3 study (Mesothelioma Avastin Cisplatin Pemetrexed Study: MAPS) verifying the effect of bevacizumab, an anti-angiogenesis agent added to CDDP/PEM for unresectable MPM, were published in The Lancet in December 2015; however, this did not lead to approval by national drug regulatory agencies. Furthermore, no second-line treatment was established for cases refractory to CDDP/PEM. In August 2018, the Pharmaceuticals and Medical Devices Agency of Japan was the first in the world to approve monotherapy with nivolumab, an immune checkpoint inhibitor (ICI), for previously unresectable, advanced, or recurrent MPM. Following Japan, in October 2020, the FDA approved the combination of nivolumab and ipilimumab for the treatment of previously untreated, unresectable MPM. In this article, we review the transition of drug treatment for MPM, in light of the historical background, focusing on the benefits of ICIs.
{"title":"True Benefits of Immune Checkpoint Inhibitors in the Treatment of Malignant Pleural Mesothelioma in Japan.","authors":"Kozo Kuribayashi, Jun Hirano","doi":"10.21873/anticanres.17244","DOIUrl":"https://doi.org/10.21873/anticanres.17244","url":null,"abstract":"<p><p>In February 2004, the Food and Drug Administration (FDA) was the first to approve the combination of cisplatin (CDDP) and pemetrexed (PEM) as standard first-line chemotherapy for untreated, unresectable malignant pleural mesothelioma (MPM). However, after that approval, no progress was made in the standard first-line treatment of MPM for almost 15 years. Positive results from a phase 3 study (Mesothelioma Avastin Cisplatin Pemetrexed Study: MAPS) verifying the effect of bevacizumab, an anti-angiogenesis agent added to CDDP/PEM for unresectable MPM, were published in The Lancet in December 2015; however, this did not lead to approval by national drug regulatory agencies. Furthermore, no second-line treatment was established for cases refractory to CDDP/PEM. In August 2018, the Pharmaceuticals and Medical Devices Agency of Japan was the first in the world to approve monotherapy with nivolumab, an immune checkpoint inhibitor (ICI), for previously unresectable, advanced, or recurrent MPM. Following Japan, in October 2020, the FDA approved the combination of nivolumab and ipilimumab for the treatment of previously untreated, unresectable MPM. In this article, we review the transition of drug treatment for MPM, in light of the historical background, focusing on the benefits of ICIs.</p>","PeriodicalId":8072,"journal":{"name":"Anticancer research","volume":null,"pages":null},"PeriodicalIF":1.6,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142339928","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-01DOI: 10.21873/anticanres.17252
Katarzyna Unrug-Bielawska, David Earnshaw, Magdalena Cybulska-Lubak, Ewelina Kaniuga, Zuzanna Sandowska-Markiewicz, Malgorzata Statkiewicz, Izabela Rumienczyk, Michalina Dąbrowska, Justyna Kocik-Krol, Krzysztof Klimkiewicz, Magdalena Urbanowicz, Beata Naumczuk, Lech Kozerski, Marcin Krzykawski, Michal Mikula, Jerzy Ostrowski
Background/aim: SN-38, an active metabolite of irinotecan, exhibits toxicity to all proliferating cells, causing dose-limiting and potentially life-threatening side effects. Newly established water-soluble derivatives of SN-38, 7-ethyl-9-(N-morpholinyl)methyl-10-hydroxycamptothecin (BN-MOA) and 7-ethyl-9-(N-methylamino)methyl-10-hydroxycamptothecin (BN-NMe), exhibit a unique mechanism of spontaneous alkylation of aromatic bases in DNA and show greater in vitro activity on cancer cell lines than SN-38. The aim of this study was to compare the therapeutic responses to irinotecan, BN-MOA and BN-NMe in vivo and in vitro in 3D cultures using colorectal cancer (CRC) patient derived xenografts (PDX).
Materials and methods: Seven established PDX tissues were subcutaneously grown on the flanks of NSG or NSG-SGM3 mice and tumor diameters were measured with a caliper. Compounds were administrated intraperitoneally at 40 mg/kg every five days. 3D PDX cultures were performed on 96-well LifeGel plates and cell viability was determined with the CellTiter Glo 3D reagent.
Results: Treatment with irinotecan significantly delayed or stopped the growth of 5 out of 7 PDXs, with a greater level of inhibition from BN-MOA compared to irinotecan and BN-NMe. In vitro studies exhibited the same trends in SN-38 and BN-NMe but not in BN-MOA.
Conclusion: The new SN-38 derivatives, BN-MOA and BN-NMe, showed enhanced therapeutic effects compared to irinotecan in CRC models. BN-MOA demonstrated superior tumor inhibition in vivo, while BN-NMe had similar in vitro activity to SN-38. These findings highlight the potential of BN-MOA for greater antitumor efficacy in vivo, with BN-NMe showing comparable effectiveness to SN-38 in vitro. Future studies should optimize growth models to better predict anticancer drug responses.
{"title":"Therapeutic Responses to Two New SN-38 Derivatives in Colorectal Cancer Patient-Derived Xenografts and Respective 3D <i>In Vitro</i> Cultures.","authors":"Katarzyna Unrug-Bielawska, David Earnshaw, Magdalena Cybulska-Lubak, Ewelina Kaniuga, Zuzanna Sandowska-Markiewicz, Malgorzata Statkiewicz, Izabela Rumienczyk, Michalina Dąbrowska, Justyna Kocik-Krol, Krzysztof Klimkiewicz, Magdalena Urbanowicz, Beata Naumczuk, Lech Kozerski, Marcin Krzykawski, Michal Mikula, Jerzy Ostrowski","doi":"10.21873/anticanres.17252","DOIUrl":"https://doi.org/10.21873/anticanres.17252","url":null,"abstract":"<p><strong>Background/aim: </strong>SN-38, an active metabolite of irinotecan, exhibits toxicity to all proliferating cells, causing dose-limiting and potentially life-threatening side effects. Newly established water-soluble derivatives of SN-38, 7-ethyl-9-(N-morpholinyl)methyl-10-hydroxycamptothecin (BN-MOA) and 7-ethyl-9-(N-methylamino)methyl-10-hydroxycamptothecin (BN-NMe), exhibit a unique mechanism of spontaneous alkylation of aromatic bases in DNA and show greater in vitro activity on cancer cell lines than SN-38. The aim of this study was to compare the therapeutic responses to irinotecan, BN-MOA and BN-NMe in vivo and in vitro in 3D cultures using colorectal cancer (CRC) patient derived xenografts (PDX).</p><p><strong>Materials and methods: </strong>Seven established PDX tissues were subcutaneously grown on the flanks of NSG or NSG-SGM3 mice and tumor diameters were measured with a caliper. Compounds were administrated intraperitoneally at 40 mg/kg every five days. 3D PDX cultures were performed on 96-well LifeGel plates and cell viability was determined with the CellTiter Glo 3D reagent.</p><p><strong>Results: </strong>Treatment with irinotecan significantly delayed or stopped the growth of 5 out of 7 PDXs, with a greater level of inhibition from BN-MOA compared to irinotecan and BN-NMe. In vitro studies exhibited the same trends in SN-38 and BN-NMe but not in BN-MOA.</p><p><strong>Conclusion: </strong>The new SN-38 derivatives, BN-MOA and BN-NMe, showed enhanced therapeutic effects compared to irinotecan in CRC models. BN-MOA demonstrated superior tumor inhibition in vivo, while BN-NMe had similar in vitro activity to SN-38. These findings highlight the potential of BN-MOA for greater antitumor efficacy in vivo, with BN-NMe showing comparable effectiveness to SN-38 in vitro. Future studies should optimize growth models to better predict anticancer drug responses.</p>","PeriodicalId":8072,"journal":{"name":"Anticancer research","volume":null,"pages":null},"PeriodicalIF":1.6,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142339907","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-01DOI: 10.21873/anticanres.17273
Sun-Ju Byeon, Mee Soo Chang, Hye Eun Park, Doehee Kang, Yuting Wang, Dong-Seok Han, Hye Sung Ahn, Seung Chul Heo, Myong Seok Lee, Won Kim, Su Hwan Kim, Dong-Won Ahn, Kook Lae Lee
Background/aim: Predicting lymph node metastasis (LNM) in early gastric cancer (EGC) is crucial for making treatment decisions. This study aimed to confirm risk factors for LNM and identify novel auxiliary biomarkers for predicting LNM in EGC.
Patients and methods: We established a training set, comprising 63 patients with LNM-EGC and 274 patients with non-LNM EGC, and a test set, comprising 19 patients with LNM-EGC and 146 non-LNM EGC. Immunohistochemistry for lymphangiogenic and related pathway components (VEGF-C, TGF-β1, SMAD2/3, VEGF-D, pSTAT3, E-cadherin, CD44, c-MET, YAP, and HER2), in situ hybridization for Epstein-Barr virus-encoded small RNAs, and multiplex PCR for microsatellite instability were conducted.
Results: In the training set, Lauren's diffuse/mixed classification, stromal desmoplasia, submucosal invasion ≥500 μm, lymphatic invasion, and high VEGF-C and SMAD2/3 expression were independent risk factors for LNM (p<0.05). A large tumor size, mixed histology, submucosal invasion, perineural invasion, and ulceration were determined as risk factors using univariate analysis (p<0.05). The tumor cutoff size for predicting LNM was 2.65 cm, based on a ROC analysis. The test set study verified that stromal desmoplasia, submucosal invasion, and high VEGF-C expression were independent risk factors for LNM (p<0.05). Moreover, mixed histology, lymphatic invasion, ulceration, and high SMAD 2/3 expression were identified as additional risk factors using univariate analysis (p<0.05).
Conclusion: Stromal desmoplasia, submucosal invasion, and high VEGF-C expression are potential biomarkers for LNM in EGC. VEGF-C expression might serve as an adjunct biomarker for predicting LNM on forceps-biopsy tissue at initial diagnosis.
{"title":"Predictive Biomarkers of Lymph Node Metastasis in Early Gastric Cancer: A Reference of Clinicopathological Characteristics, Protein Expression, Epstein-Barr Virus Status, and Microsatellite Instability.","authors":"Sun-Ju Byeon, Mee Soo Chang, Hye Eun Park, Doehee Kang, Yuting Wang, Dong-Seok Han, Hye Sung Ahn, Seung Chul Heo, Myong Seok Lee, Won Kim, Su Hwan Kim, Dong-Won Ahn, Kook Lae Lee","doi":"10.21873/anticanres.17273","DOIUrl":"https://doi.org/10.21873/anticanres.17273","url":null,"abstract":"<p><strong>Background/aim: </strong>Predicting lymph node metastasis (LNM) in early gastric cancer (EGC) is crucial for making treatment decisions. This study aimed to confirm risk factors for LNM and identify novel auxiliary biomarkers for predicting LNM in EGC.</p><p><strong>Patients and methods: </strong>We established a training set, comprising 63 patients with LNM-EGC and 274 patients with non-LNM EGC, and a test set, comprising 19 patients with LNM-EGC and 146 non-LNM EGC. Immunohistochemistry for lymphangiogenic and related pathway components (VEGF-C, TGF-β1, SMAD2/3, VEGF-D, pSTAT3, E-cadherin, CD44, c-MET, YAP, and HER2), in situ hybridization for Epstein-Barr virus-encoded small RNAs, and multiplex PCR for microsatellite instability were conducted.</p><p><strong>Results: </strong>In the training set, Lauren's diffuse/mixed classification, stromal desmoplasia, submucosal invasion ≥500 μm, lymphatic invasion, and high VEGF-C and SMAD2/3 expression were independent risk factors for LNM (p<0.05). A large tumor size, mixed histology, submucosal invasion, perineural invasion, and ulceration were determined as risk factors using univariate analysis (p<0.05). The tumor cutoff size for predicting LNM was 2.65 cm, based on a ROC analysis. The test set study verified that stromal desmoplasia, submucosal invasion, and high VEGF-C expression were independent risk factors for LNM (p<0.05). Moreover, mixed histology, lymphatic invasion, ulceration, and high SMAD 2/3 expression were identified as additional risk factors using univariate analysis (p<0.05).</p><p><strong>Conclusion: </strong>Stromal desmoplasia, submucosal invasion, and high VEGF-C expression are potential biomarkers for LNM in EGC. VEGF-C expression might serve as an adjunct biomarker for predicting LNM on forceps-biopsy tissue at initial diagnosis.</p>","PeriodicalId":8072,"journal":{"name":"Anticancer research","volume":null,"pages":null},"PeriodicalIF":1.6,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142339895","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-01DOI: 10.21873/anticanres.17274
Antti Kivivuori, Pekka Lammi, Matti Eskelinen, Tuomo Rantanen, Hannu Paajanen, Jukka Pulkkinen, Mika Ukkonen
Background/aim: Cholelithiasis (Chole) is one of the most common diseases needing operative management worldwide. However, there are few studies assessing the intraoperative bleeding (IOB) complications leading to blood transfusions (BloTs) in elderly patients with cholecystectomy (Ccy).
Patients and methods: Outcome after IOB complications and need for BloTs in a cohort of 17,412 patients with Ccys were assessed with special reference to elderly Ccy patients.
Results: A total of 17,412 patients underwent Ccy and 11% of Ccy patients (1,856/17,412) were aged ≥75 years. The Ccy patients ≥75 years underwent more often emergency/open Ccys. Red blood cell BloTs were administered five times more often to Ccy patients ≥75 years versus Ccy patients <75 years (13% versus 2.6%, p<0.001). In Ccys by emergency surgery indications, the need for BloTs was four times higher in Ccy patients ≥75 years versus Ccy patients <75 years (5.5% versus 1.3%, p<0.001).
Conclusion: The elderly Chole patients have a higher risk than younger Chole patients for perioperative IOB complications and thus are more likely to need BloTs.
{"title":"Intraoperative Bleeding Complications Leading to Blood Transfusions (BloTs) in 17,412 Cholecystectomies in Finland: A Study With Special Reference to Elderly Patients.","authors":"Antti Kivivuori, Pekka Lammi, Matti Eskelinen, Tuomo Rantanen, Hannu Paajanen, Jukka Pulkkinen, Mika Ukkonen","doi":"10.21873/anticanres.17274","DOIUrl":"https://doi.org/10.21873/anticanres.17274","url":null,"abstract":"<p><strong>Background/aim: </strong>Cholelithiasis (Chole) is one of the most common diseases needing operative management worldwide. However, there are few studies assessing the intraoperative bleeding (IOB) complications leading to blood transfusions (BloTs) in elderly patients with cholecystectomy (Ccy).</p><p><strong>Patients and methods: </strong>Outcome after IOB complications and need for BloTs in a cohort of 17,412 patients with Ccys were assessed with special reference to elderly Ccy patients.</p><p><strong>Results: </strong>A total of 17,412 patients underwent Ccy and 11% of Ccy patients (1,856/17,412) were aged ≥75 years. The Ccy patients ≥75 years underwent more often emergency/open Ccys. Red blood cell BloTs were administered five times more often to Ccy patients ≥75 years versus Ccy patients <75 years (13% versus 2.6%, p<0.001). In Ccys by emergency surgery indications, the need for BloTs was four times higher in Ccy patients ≥75 years versus Ccy patients <75 years (5.5% versus 1.3%, p<0.001).</p><p><strong>Conclusion: </strong>The elderly Chole patients have a higher risk than younger Chole patients for perioperative IOB complications and thus are more likely to need BloTs.</p>","PeriodicalId":8072,"journal":{"name":"Anticancer research","volume":null,"pages":null},"PeriodicalIF":1.6,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142339885","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}