{"title":"Correction to \"miR-203 inhibits augmented proliferation and metastasis of hepatocellular carcinoma residual in the promoted regenerating liver\".","authors":"","doi":"10.1111/cas.16361","DOIUrl":"https://doi.org/10.1111/cas.16361","url":null,"abstract":"","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142548476","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Retraction: C. Di Stefano, G. Marfe, M. M. Trawinska, P. Sinibaldi-Salimei, R. Silvestri, S. Amadori and E. Abruzzese, "Pyrrolo[1,2-b][1,2,5]benzothiadiazepines (PBTDs) Exert Their Anti-proliferative Activity by Interfering With Akt-mTOR Signaling and bax:bcl-2 Ratio Modulation in Cells From Chronic Myeloid Leukemic Patients," Cancer Science 101, no. 4 (2010): 991-1000, https://doi.org/10.1111/j.1349-7006.2010.01490.x. The above article, published online on 07 January 2010 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the journal Editor-in-Chief, Masanori Hatakeyama; the Japanese Cancer Association; and John Wiley & Sons Australia, Ltd. The retraction has been agreed due to several instances of duplications of western blot bands observed in Figures 3, 4, 5 and 8. Furthermore, splicing and deletion of bands was uncovered in Figures 4 and 7 respectively. Finally, western blot bands presented in Figure 4 was also found published earlier in another article. The authors provided partial raw data but the inconsistencies found could not be resolved on this basis. Due to the extent and nature of the duplications, the editors consider the results and conclusions of this study invalid.
撤回:C. Di Stefano、G. Marfe、M. M. Trawinska、P. Sinibaldi-Salimei、R. Silvestri、S. Amadori 和 E. Abruzzese,"吡咯并[1,2-b][1,2,5]苯并噻二氮卓(PBTDs)发挥抗增殖作用"。Abruzzese, "Pyrrolo[1,2-b][1,2,5]benzothiadiazepines (PBTDs) Exert Their Anti-proliferative Activity by Interfering With Akt-mTOR Signaling and bax:bcl-2 Ratio Modulation in Cells from Chronic Myeloid Leukemic Patients," Cancer Science 101, no.4 (2010):991-1000,https://doi.org/10.1111/j.1349-7006.2010.01490.x。上述文章于 2010 年 1 月 7 日在线发表于 Wiley Online Library (wileyonlinelibrary.com),经杂志主编 Masanori Hatakeyama、日本癌症协会和 John Wiley & Sons Australia, Ltd.协商,该文章已被撤回。同意撤稿的原因是在图 3、图 4、图 5 和图 8 中观察到多处 Western 印迹条带重复。此外,图 4 和图 7 分别发现了条带的拼接和删除。最后,图 4 中显示的 Western 印迹条带也是早先在另一篇文章中发现的。作者提供了部分原始数据,但发现的不一致之处无法据此解决。由于重复的程度和性质,编辑认为这项研究的结果和结论无效。
{"title":"RETRACTION: Pyrrolo[1,2-b][1,2,5]benzothiadiazepines (PBTDs) Exert Their Anti-proliferative Activity by Interfering With Akt-mTOR Signaling and bax:bcl-2 Ratio Modulation in Cells From Chronic Myeloid Leukemic Patients.","authors":"","doi":"10.1111/cas.16390","DOIUrl":"https://doi.org/10.1111/cas.16390","url":null,"abstract":"<p><strong>Retraction: </strong>C. Di Stefano, G. Marfe, M. M. Trawinska, P. Sinibaldi-Salimei, R. Silvestri, S. Amadori and E. Abruzzese, \"Pyrrolo[1,2-b][1,2,5]benzothiadiazepines (PBTDs) Exert Their Anti-proliferative Activity by Interfering With Akt-mTOR Signaling and bax:bcl-2 Ratio Modulation in Cells From Chronic Myeloid Leukemic Patients,\" Cancer Science 101, no. 4 (2010): 991-1000, https://doi.org/10.1111/j.1349-7006.2010.01490.x. The above article, published online on 07 January 2010 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the journal Editor-in-Chief, Masanori Hatakeyama; the Japanese Cancer Association; and John Wiley & Sons Australia, Ltd. The retraction has been agreed due to several instances of duplications of western blot bands observed in Figures 3, 4, 5 and 8. Furthermore, splicing and deletion of bands was uncovered in Figures 4 and 7 respectively. Finally, western blot bands presented in Figure 4 was also found published earlier in another article. The authors provided partial raw data but the inconsistencies found could not be resolved on this basis. Due to the extent and nature of the duplications, the editors consider the results and conclusions of this study invalid.</p>","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142548478","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Tumor stiffness is drawing attention as a novel axis that is orthogonal to existing parameters such as pathological examination. We developed a new diagnostic method that focuses on differences in stiffness between tumor and normal tissue. This study comprised a clinical application of laser resonance frequency analysis (L-RFA) for diagnosing gastric cancer. L-RFA allows for precise and contactless evaluation of tissue stiffness. We used a laser to create vibrations on a sample's surface that were then measured using a vibrometer. The data were averaged and analyzed to enhance accuracy. In the agarose phantom experiments, a clear linear correlation was observed between the Young's modulus of the phantoms (0.34-0.71 MPa) and the summation of normalized vibration peaks (Score) in the 1950-4050 Hz range (R2 = 0.93145). Higher Young's moduli also resulted in lower vibration peaks at the excitation frequency, signal-to-noise (S/N) ratios, and harmonic peaks. We also conducted L-RFA measurements on gastric cancer specimens from two patients who underwent robot-assisted distal gastrectomy. Our results revealed significant waveform differences between tumor and normal regions, similar to the findings in agarose phantoms, with tumor regions exhibiting lower vibration peaks at the excitation frequency, S/N ratios, and harmonic peaks. Statistical analysis confirmed significant differences in the score between normal and tumor regions (p = 0.00354). L-RFA was able to assess tumor stiffness and holds great promise as a noninvasive diagnostic tool for gastric cancer.
{"title":"Evaluating stiffness of gastric wall using laser resonance frequency analysis for gastric cancer.","authors":"Tasuku Furube, Daisuke Nakashima, Satoru Matsuda, Katsuhiro Mikami, Takuto Hatakeyama, Masashi Takeuchi, Kazumasa Fukuda, Akihisa Ueno, Hajime Okita, Hirofumi Kawakubo, Masaya Nakamura, Takeo Nagura, Yuko Kitagawa","doi":"10.1111/cas.16383","DOIUrl":"https://doi.org/10.1111/cas.16383","url":null,"abstract":"<p><p>Tumor stiffness is drawing attention as a novel axis that is orthogonal to existing parameters such as pathological examination. We developed a new diagnostic method that focuses on differences in stiffness between tumor and normal tissue. This study comprised a clinical application of laser resonance frequency analysis (L-RFA) for diagnosing gastric cancer. L-RFA allows for precise and contactless evaluation of tissue stiffness. We used a laser to create vibrations on a sample's surface that were then measured using a vibrometer. The data were averaged and analyzed to enhance accuracy. In the agarose phantom experiments, a clear linear correlation was observed between the Young's modulus of the phantoms (0.34-0.71 MPa) and the summation of normalized vibration peaks (Score) in the 1950-4050 Hz range (R<sup>2</sup> = 0.93145). Higher Young's moduli also resulted in lower vibration peaks at the excitation frequency, signal-to-noise (S/N) ratios, and harmonic peaks. We also conducted L-RFA measurements on gastric cancer specimens from two patients who underwent robot-assisted distal gastrectomy. Our results revealed significant waveform differences between tumor and normal regions, similar to the findings in agarose phantoms, with tumor regions exhibiting lower vibration peaks at the excitation frequency, S/N ratios, and harmonic peaks. Statistical analysis confirmed significant differences in the score between normal and tumor regions (p = 0.00354). L-RFA was able to assess tumor stiffness and holds great promise as a noninvasive diagnostic tool for gastric cancer.</p>","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142523445","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Fudong Xu, Chong Wang, Hongxia Li, Bo Yu, Luyuan Chang, Feng Wang, Chaolian Long, Ling Bai, Hanqing Zhao, Nanying Che
Lung cancer is one of the most prevalent cancers worldwide, yet only approximately 16% of patients are diagnosed in early stage, highlighting the urgent need for novel, highly accurate detection models. In our study, patients with suspected lung cancer or lung disease, as identified through radiographic imaging, along with healthy individuals, were consecutively recruited from Beijing Chest Hospital. Circulating free DNA (cfDNA) was extracted from plasma samples, and low-depth whole-genome sequencing was performed to identify fragmentomic features for model construction. A total of 265 participants were prospectively enrolled, comprising 124 lung cancer patients and 141 noncancer individuals. The model we developed was based on four cfDNA fragmentation characteristics, including 20-bp breakpoint nucleotides motif, fragmentation size coverage, fragmentation size distribution, and copy number variation. In an independent test cohort, the model achieved an area under the curve (AUC) of 0.861 (95% CI: 0.781-0.942) and demonstrated a sensitivity of 70% (95% CI: 53.5%-83.4%) at a specificity of 89.4% (95% CI: 76.9%-96.5%). Notably, the model was also effective in detecting early-stage cancer, with an AUC of 0.808 (95% CI: 0.69-0.925). In summary, our lung cancer detection model shows strong screening capabilities by leveraging four cfDNA fragmentation characteristics, exhibiting robust performance in early cancer diagnosis.
{"title":"Evaluation of cfDNA fragmentation characteristics in plasma for the diagnosis of lung cancer: A prospective cohort study.","authors":"Fudong Xu, Chong Wang, Hongxia Li, Bo Yu, Luyuan Chang, Feng Wang, Chaolian Long, Ling Bai, Hanqing Zhao, Nanying Che","doi":"10.1111/cas.16360","DOIUrl":"https://doi.org/10.1111/cas.16360","url":null,"abstract":"<p><p>Lung cancer is one of the most prevalent cancers worldwide, yet only approximately 16% of patients are diagnosed in early stage, highlighting the urgent need for novel, highly accurate detection models. In our study, patients with suspected lung cancer or lung disease, as identified through radiographic imaging, along with healthy individuals, were consecutively recruited from Beijing Chest Hospital. Circulating free DNA (cfDNA) was extracted from plasma samples, and low-depth whole-genome sequencing was performed to identify fragmentomic features for model construction. A total of 265 participants were prospectively enrolled, comprising 124 lung cancer patients and 141 noncancer individuals. The model we developed was based on four cfDNA fragmentation characteristics, including 20-bp breakpoint nucleotides motif, fragmentation size coverage, fragmentation size distribution, and copy number variation. In an independent test cohort, the model achieved an area under the curve (AUC) of 0.861 (95% CI: 0.781-0.942) and demonstrated a sensitivity of 70% (95% CI: 53.5%-83.4%) at a specificity of 89.4% (95% CI: 76.9%-96.5%). Notably, the model was also effective in detecting early-stage cancer, with an AUC of 0.808 (95% CI: 0.69-0.925). In summary, our lung cancer detection model shows strong screening capabilities by leveraging four cfDNA fragmentation characteristics, exhibiting robust performance in early cancer diagnosis.</p>","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142511151","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Fibroblast growth factor receptors (FGFRs) are a highly conserved family of transmembrane receptor tyrosine kinases with multiple roles in the regulation of key cellular processes. Specific FGFR mutations have been observed in several types of cancers, including gastric carcinoma and cholangiocarcinoma. Dose escalation data of 24 Japanese patients with solid tumors treated with Tasurgratinib (previously known as E7090), a potent, selective FGFR1-3 inhibitor, was reported in a phase I, first-in-human, single-center study. Based on the safety, pharmacokinetic, and pharmacodynamic profiles observed in this study, the recommended dose of 140 mg once daily was selected for the expansion part (Part 2), a multicenter expansion of the dose-finding study restricted to patients with tumors harboring FGFR gene alterations. Safety and preliminary efficacy were assessed in Part 2. Pharmacodynamic pharmacogenomic markers (serum phosphate, FGF23, and 1,25-(OH)2-vitamin D, circulating tumor DNA) and pharmacokinetic profiles were also evaluated. A total of 16 patients were enrolled in Part 2, six with cholangiocarcinoma and 10 with gastric cancer. The most common treatment-emergent adverse events were hyperphosphatemia, palmar-plantar erythrodysesthesia syndrome, and paronychia. Five partial responses (83.3%) in cholangiocarcinoma patients and one partial response (11.1%) in gastric cancer patients were observed; median progression-free survival was 8.26 months (95% confidence interval [CI] 3.84, not evaluable [NE]) and 3.25 months (95% CI 0.95, 4.86), and overall survival was 22.49 months (95% CI 6.37, NE) and 4.27 months (95% CI 2.23, 7.95), respectively, in the two groups. In conclusion, Tasurgratinib 140 mg has a tolerable safety profile with good clinical efficacy in patients with cholangiocarcinoma harboring FGFR2 gene rearrangements.
成纤维细胞生长因子受体(FGFR)是一个高度保守的跨膜受体酪氨酸激酶家族,在调控关键细胞过程中发挥着多种作用。在胃癌和胆管癌等几种癌症中都观察到了特定的 FGFR 突变。Tasurgratinib 是一种强效、选择性的 FGFR1-3 抑制剂,在一项 I 期、首次进入人体的单中心研究中,报告了 24 名日本实体瘤患者接受 Tasurgratinib(以前称为 E7090)治疗的剂量升级数据。根据该研究中观察到的安全性、药代动力学和药效学特征,该研究选择了每日一次 140 毫克的推荐剂量作为扩展部分(第二部分)的剂量,这是一项多中心扩展剂量探索研究,仅限于携带 FGFR 基因改变的肿瘤患者。第二部分对安全性和初步疗效进行了评估。此外,还评估了药效学药物基因组标记物(血清磷酸盐、FGF23 和 1,25-(OH)2-维生素 D、循环肿瘤 DNA)和药代动力学特征。共有 16 名患者参加了第二部分的研究,其中 6 人患有胆管癌,10 人患有胃癌。治疗过程中最常见的不良反应是高磷血症、掌跖红斑综合征和副癣。在胆管癌患者中观察到5例部分反应(83.3%),在胃癌患者中观察到1例部分反应(11.1%);两组患者的中位无进展生存期分别为8.26个月(95%置信区间[CI] 3.84,不可评估[NE])和3.25个月(95% CI 0.95,4.86),总生存期分别为22.49个月(95% CI 6.37,NE)和4.27个月(95% CI 2.23,7.95)。总之,对于携带FGFR2基因重排的胆管癌患者,塔舒瑞替尼140毫克具有可耐受的安全性和良好的临床疗效。
{"title":"Tasurgratinib in patients with cholangiocarcinoma or gastric cancer: Expansion part of the first-in-human phase I study.","authors":"Chigusa Morizane, Makoto Ueno, Tatsuya Ioka, Masahiro Tajika, Masafumi Ikeda, Kensei Yamaguchi, Hiroki Hara, Hiroshi Yabusaki, Atsushi Miyamoto, Satoru Iwasa, Manabu Muto, Tsutomu Takashima, Keiko Minashi, Yoshito Komatsu, Tomohiro Nishina, Takako Eguchi Nakajima, Atsuchi Takeno, Toshikazu Moriwaki, Masayuki Furukawa, Takatoshi Sahara, Hiroki Ikezawa, Maiko Nomoto, Shuya Takashima, Taisuke Uehara, Setsuo Funasaka, Masakazu Yashiro, Junji Furuse","doi":"10.1111/cas.16354","DOIUrl":"https://doi.org/10.1111/cas.16354","url":null,"abstract":"<p><p>Fibroblast growth factor receptors (FGFRs) are a highly conserved family of transmembrane receptor tyrosine kinases with multiple roles in the regulation of key cellular processes. Specific FGFR mutations have been observed in several types of cancers, including gastric carcinoma and cholangiocarcinoma. Dose escalation data of 24 Japanese patients with solid tumors treated with Tasurgratinib (previously known as E7090), a potent, selective FGFR1-3 inhibitor, was reported in a phase I, first-in-human, single-center study. Based on the safety, pharmacokinetic, and pharmacodynamic profiles observed in this study, the recommended dose of 140 mg once daily was selected for the expansion part (Part 2), a multicenter expansion of the dose-finding study restricted to patients with tumors harboring FGFR gene alterations. Safety and preliminary efficacy were assessed in Part 2. Pharmacodynamic pharmacogenomic markers (serum phosphate, FGF23, and 1,25-(OH)<sub>2</sub>-vitamin D, circulating tumor DNA) and pharmacokinetic profiles were also evaluated. A total of 16 patients were enrolled in Part 2, six with cholangiocarcinoma and 10 with gastric cancer. The most common treatment-emergent adverse events were hyperphosphatemia, palmar-plantar erythrodysesthesia syndrome, and paronychia. Five partial responses (83.3%) in cholangiocarcinoma patients and one partial response (11.1%) in gastric cancer patients were observed; median progression-free survival was 8.26 months (95% confidence interval [CI] 3.84, not evaluable [NE]) and 3.25 months (95% CI 0.95, 4.86), and overall survival was 22.49 months (95% CI 6.37, NE) and 4.27 months (95% CI 2.23, 7.95), respectively, in the two groups. In conclusion, Tasurgratinib 140 mg has a tolerable safety profile with good clinical efficacy in patients with cholangiocarcinoma harboring FGFR2 gene rearrangements.</p>","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2024-10-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142511156","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The progression of hepatocellular carcinoma (HCC) is coincident with aberrant splicing of numerous tumor-related genes. Identification of the tumor-specific splice variants that facilitate HCC metastasis may provide a more comprehensive insight into the mechanisms of HCC metastasis. Through RNA sequencing and bioinformatic analyses, PPM1G was identified as a biomarker associated with HCC metastasis. Our data mapped a transcriptome-wide landscape of alternative splicing events modulated by PPM1G in HCC. Notably, we characterized the exon six-skipping transcript of TBL1X as an onco-splice variant regulated by PPM1G. Experimental validation revealed the enrichment of TBL1X-S in response to PPM1G overexpression. Moreover, mRNA stability analyses revealed that PPM1G prolonged the half-life of the TBL1X-S transcript. Both PPM1G and TBL1X-S exhibited metastasis-promoting phenotypes, with PPM1G-driven metastasis in HCC being partially dependent on TBL1X-S. Mechanistically, different TBL1X splice variants showed varying affinities for ZEB1, with TBL1X-S significantly enhancing ZEB1 activation and repressing CDH1 transcription, potentially accelerating the epithelial-mesenchymal transition (EMT) process. In conclusion, our study highlights the biological role of PPM1G and TBL1X-S in tumor metastasis. The PPM1G/TBL1X-S signaling axis presents a new view for investigating liver cancer metastasis mechanisms.
{"title":"PPM1G-mediated TBL1X mRNA splicing promotes cell migration in hepatocellular carcinoma.","authors":"Liling Hu, Xinyu Shi, Xiaoyi Yuan, Danya Liu, Dandan Zheng, Yuying Li, Fujin Shi, Meifang Zhang, Shu-Guang Su, Chris Zhiyi Zhang","doi":"10.1111/cas.16372","DOIUrl":"https://doi.org/10.1111/cas.16372","url":null,"abstract":"<p><p>The progression of hepatocellular carcinoma (HCC) is coincident with aberrant splicing of numerous tumor-related genes. Identification of the tumor-specific splice variants that facilitate HCC metastasis may provide a more comprehensive insight into the mechanisms of HCC metastasis. Through RNA sequencing and bioinformatic analyses, PPM1G was identified as a biomarker associated with HCC metastasis. Our data mapped a transcriptome-wide landscape of alternative splicing events modulated by PPM1G in HCC. Notably, we characterized the exon six-skipping transcript of TBL1X as an onco-splice variant regulated by PPM1G. Experimental validation revealed the enrichment of TBL1X-S in response to PPM1G overexpression. Moreover, mRNA stability analyses revealed that PPM1G prolonged the half-life of the TBL1X-S transcript. Both PPM1G and TBL1X-S exhibited metastasis-promoting phenotypes, with PPM1G-driven metastasis in HCC being partially dependent on TBL1X-S. Mechanistically, different TBL1X splice variants showed varying affinities for ZEB1, with TBL1X-S significantly enhancing ZEB1 activation and repressing CDH1 transcription, potentially accelerating the epithelial-mesenchymal transition (EMT) process. In conclusion, our study highlights the biological role of PPM1G and TBL1X-S in tumor metastasis. The PPM1G/TBL1X-S signaling axis presents a new view for investigating liver cancer metastasis mechanisms.</p>","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2024-10-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142511155","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
A glioblastoma (GBM) patient with a high tumor mutation burden (TMB-high) and mismatch repair deficiency (dMMR) exhibited a significant response to pembrolizumab, an immune checkpoint inhibitor (ICI), despite prior treatment with temozolomide (TMZ), known to induce hypermutation and potential resistance to ICIs. The rapid disease progression, indicated by 80% Ki67 positivity, was markedly countered by the positive outcome of pembrolizumab treatment. This case challenges traditional GBM treatment paradigms, demonstrating the potential of precision oncology in patients with significant TMB and dMMR, and underscores the importance of comprehensive genomic profiling in guiding clinical decisions in GBM management.
{"title":"Pembrolizumab efficacy in a tumor mutation burden-high glioblastoma patient: A case study and implications for precision oncology.","authors":"Akihiro Nishiyama, Shigeki Sato, Hiroyuki Sakaguchi, Hiroshi Kotani, Kaname Yamashita, Koushiro Ohtsubo, Tomoko Sekiya, Atsushi Watanabe, Atsushi Tajima, Chie Shimaguchi, Keishi Mizuguchi, Hiroko Ikeda, Masashi Kinoshita, Mitsutoshi Nakada, Shinji Takeuchi","doi":"10.1111/cas.16370","DOIUrl":"https://doi.org/10.1111/cas.16370","url":null,"abstract":"<p><p>A glioblastoma (GBM) patient with a high tumor mutation burden (TMB-high) and mismatch repair deficiency (dMMR) exhibited a significant response to pembrolizumab, an immune checkpoint inhibitor (ICI), despite prior treatment with temozolomide (TMZ), known to induce hypermutation and potential resistance to ICIs. The rapid disease progression, indicated by 80% Ki67 positivity, was markedly countered by the positive outcome of pembrolizumab treatment. This case challenges traditional GBM treatment paradigms, demonstrating the potential of precision oncology in patients with significant TMB and dMMR, and underscores the importance of comprehensive genomic profiling in guiding clinical decisions in GBM management.</p>","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142511154","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
An increase in cervical cancer incidence has been reported in Japan. The Ministry of Health, Labor, and Welfare of Japan has resumed the active recommendation of regular HPV vaccines in 2022. In Japan, the preventive effect of CIN3+ in the real world has not yet been demonstrated in age-adjusted cohort or case-control studies. This study aimed to estimate the effect of the HPV vaccine against CIN3+ in Japanese women. This nationwide case-control study from April 2013 to March 2020 targeted women aged 20-26 years old at the time of cervical screening. We compared HPV vaccination exposure between those with abnormal and those with normal cytology. Abnormal cytology was classified into cervical intraepithelial neoplasia (CIN)1+, CIN2+, and CIN3+. We calculated the odds ratio (OR) and 95% confidence interval (CI) of the above endpoints and vaccination exposure using the conditional logistic regression model and estimated vaccine effectiveness using the formula (1 -OR) × 100. A total of 2790 cases and 13,990 controls (one-to-five matching) were eligible in 37 municipalities in Japan. In this study, 61 CIN3 (2.2%) and 10 squamous cell carcinomas (SCC) (0.4%) were found. The OR for CIN3+ versus controls was 0.14 (95% CI, 0.03-0.75), equating to a vaccine effectiveness of 86%. Of the 10 patients who had SCC none were vaccinated. This nationwide case-control study in Japan demonstrated a substantial risk reduction in CIN3+ among women who did versus those who did not receive HPV vaccination.
{"title":"Human papillomavirus vaccine to prevent CIN3 or worse (CIN3+): A nationwide case-control study in Japan.","authors":"Sayaka Ikeda, Yutaka Ueda, Asami Yagi, Taichi Mizushima, Akiko Sukegawa, Risa Kudoh, Manako Yamaguchi, Megumi Kurosawa, Etsuko Miyagi, Masayuki Sekine, Takayuki Enomoto","doi":"10.1111/cas.16375","DOIUrl":"https://doi.org/10.1111/cas.16375","url":null,"abstract":"<p><p>An increase in cervical cancer incidence has been reported in Japan. The Ministry of Health, Labor, and Welfare of Japan has resumed the active recommendation of regular HPV vaccines in 2022. In Japan, the preventive effect of CIN3+ in the real world has not yet been demonstrated in age-adjusted cohort or case-control studies. This study aimed to estimate the effect of the HPV vaccine against CIN3+ in Japanese women. This nationwide case-control study from April 2013 to March 2020 targeted women aged 20-26 years old at the time of cervical screening. We compared HPV vaccination exposure between those with abnormal and those with normal cytology. Abnormal cytology was classified into cervical intraepithelial neoplasia (CIN)1+, CIN2+, and CIN3+. We calculated the odds ratio (OR) and 95% confidence interval (CI) of the above endpoints and vaccination exposure using the conditional logistic regression model and estimated vaccine effectiveness using the formula (1 -OR) × 100. A total of 2790 cases and 13,990 controls (one-to-five matching) were eligible in 37 municipalities in Japan. In this study, 61 CIN3 (2.2%) and 10 squamous cell carcinomas (SCC) (0.4%) were found. The OR for CIN3+ versus controls was 0.14 (95% CI, 0.03-0.75), equating to a vaccine effectiveness of 86%. Of the 10 patients who had SCC none were vaccinated. This nationwide case-control study in Japan demonstrated a substantial risk reduction in CIN3+ among women who did versus those who did not receive HPV vaccination.</p>","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142511153","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The tumor immune microenvironment is increasingly becoming a key consideration in developing treatment regimens for aggressive cancers, with evidence that regulatory T cells (Tregs) attenuate the antitumor response by interrupting cytotoxic T cells (CD8+). Here, we hypothesized the prognostic relevance of the proportions of Tregs (marked by forkhead box protein 3 [FOXP3]) and CD8+ cells in diffuse, non-Epstein-Barr virus (EBV)/non-microsatellite instability (MSI)-high gastroesophageal adenocarcinomas (GEAs), which are clinically characterized as more aggressive, immunologically inactive tumors as compared with their intestinal counterparts. Cell-count ratios of FOXP3+/CD8+ expression were calculated at the intratumoral region and invasive margin discretely on digital images from 303 chemo-naive non-EBV/non-MSI-high esophagogastric junction (EGJ) adenocarcinomas. A significant modifying prognostic effect of tumor histology was observed between 5-year EGJ cancer-specific survival and the FOXP3+/CD8+ ratio at the invasive margin in pStage I-III tumors (p for interaction = 0.022; hazard ratio [HR] = 8.47 and 95% confidence interval [CI], 2.04-35.19 for high ratio [vs. low] for diffuse; HR = 1.57 and 95% CI, 0.88-2.83 for high ratio [vs. low] for intestinal). A high FOXP3+/CD8+ ratio at the invasive margin was associated with RUNX3 methylation (p = 0.035) and poor prognosis in RUNX3-methylated diffuse histological subtype (5-year EGJ cancer-specific survival, 52.3% for high and 100% for low, p = 0.015). Multiomics data from The Cancer Genome Atlas linked CCL28 with RUNX3-suppressed diffuse histological subtypes of non-EBV/non-MSI-high GEA. Our data suggest that a high FOXP3+/CD8+ ratio at the invasive margin might indicate tumor immune escape via CCL28, particularly in the RUNX3-methylated diffuse histological subtype.
有证据表明,调节性 T 细胞(Tregs)通过干扰细胞毒性 T 细胞(CD8+)而减弱抗肿瘤反应,因此肿瘤免疫微环境正日益成为开发侵袭性癌症治疗方案的关键考虑因素。在这里,我们假设在弥漫性、非爱伯斯坦-巴尔病毒(EBV)/非微卫星不稳定性(MSI)高的胃食管腺癌(GEA)中,调节性 T 细胞(以叉头盒蛋白 3 [FOXP3]为标志)和 CD8+ 细胞的比例与预后有关。在303例化疗无效的非EBV/非MSI-高食管胃交界处(EGJ)腺癌的数字图像上离散计算了瘤内区域和侵袭边缘的FOXP3+/CD8+表达的细胞计数比。在 p 阶段 I-III 肿瘤中,肿瘤组织学对 5 年 EGJ 癌症特异性生存率和浸润边缘的 FOXP3+/CD8+ 比值有明显的预后调节作用(交互作用 p = 0.022;弥漫型高比值[与低比值]的危险比 [HR] = 8.47,95% 置信区间 [CI]为 2.04-35.19;肠型高比值[与低比值]的危险比 [HR] = 1.57,95% CI 为 0.88-2.83)。浸润边缘的高 FOXP3+/CD8+ 比值与 RUNX3 甲基化(p = 0.035)和 RUNX3 甲基化弥漫组织学亚型的不良预后有关(5 年 EGJ 癌特异性生存率,高比值为 52.3%,低比值为 100%,p = 0.015)。癌症基因组图谱》(The Cancer Genome Atlas)的多组学数据将CCL28与非EBV/非MSI-高GEA的RUNX3抑制弥漫组织学亚型联系起来。我们的数据表明,浸润边缘的高FOXP3+/CD8+比值可能表明肿瘤通过CCL28逃避免疫,尤其是在RUNX3甲基化的弥漫组织学亚型中。
{"title":"FOXP3+/CD8+ ratio associated with aggressive behavior in RUNX3-methylated diffuse esophagogastric junction tumor.","authors":"Suguru Maruyama, Yu Imamura, Tasuku Toihata, Ikumi Haraguchi, Manabu Takamatsu, Makiko Yamashita, Yuichiro Nakashima, Eiji Oki, Kenichi Taguchi, Manabu Yamamoto, Shinji Mine, Akihiko Okamura, Jun Kanamori, Souya Nunobe, Takeshi Sano, Shigehisa Kitano, Tetsuo Noda, Masayuki Watanabe","doi":"10.1111/cas.16373","DOIUrl":"https://doi.org/10.1111/cas.16373","url":null,"abstract":"<p><p>The tumor immune microenvironment is increasingly becoming a key consideration in developing treatment regimens for aggressive cancers, with evidence that regulatory T cells (Tregs) attenuate the antitumor response by interrupting cytotoxic T cells (CD8+). Here, we hypothesized the prognostic relevance of the proportions of Tregs (marked by forkhead box protein 3 [FOXP3]) and CD8+ cells in diffuse, non-Epstein-Barr virus (EBV)/non-microsatellite instability (MSI)-high gastroesophageal adenocarcinomas (GEAs), which are clinically characterized as more aggressive, immunologically inactive tumors as compared with their intestinal counterparts. Cell-count ratios of FOXP3+/CD8+ expression were calculated at the intratumoral region and invasive margin discretely on digital images from 303 chemo-naive non-EBV/non-MSI-high esophagogastric junction (EGJ) adenocarcinomas. A significant modifying prognostic effect of tumor histology was observed between 5-year EGJ cancer-specific survival and the FOXP3+/CD8+ ratio at the invasive margin in pStage I-III tumors (p for interaction = 0.022; hazard ratio [HR] = 8.47 and 95% confidence interval [CI], 2.04-35.19 for high ratio [vs. low] for diffuse; HR = 1.57 and 95% CI, 0.88-2.83 for high ratio [vs. low] for intestinal). A high FOXP3+/CD8+ ratio at the invasive margin was associated with RUNX3 methylation (p = 0.035) and poor prognosis in RUNX3-methylated diffuse histological subtype (5-year EGJ cancer-specific survival, 52.3% for high and 100% for low, p = 0.015). Multiomics data from The Cancer Genome Atlas linked CCL28 with RUNX3-suppressed diffuse histological subtypes of non-EBV/non-MSI-high GEA. Our data suggest that a high FOXP3+/CD8+ ratio at the invasive margin might indicate tumor immune escape via CCL28, particularly in the RUNX3-methylated diffuse histological subtype.</p>","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142511152","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Peng Xu, Tanglin Liu, Zile Yang, Kai Zang, Xiaoxuan Gao, Yuling Shi, Xiyun Ye, Yongyan Dang
Our previous research has demonstrated that P2RY6 functions as an oncogene in DMBA/TPA-induced two-stage chemical skin carcinogenesis in mice. However, considering that human skin cancer is predominantly attributed to UV radiation from sunlight, additional investigations are needed to elucidate the role of P2RY6 in UVB-induced skin carcinogenesis. Surprisingly, we found that P2ry6-deficient mice exhibited marked promotion to UVB-induced skin papilloma formation compared with wild-type mice, suggesting its tumor-suppressive role in UVB-induced skin cancer. Additionally, a P2ry6 gene knockout promoted skin hyperplasia induced by short-term UVB irradiation, while UDP, the ligand of P2RY6, could inhibit the short-term UVB-induced increase of epiderma thickness in mouse skin. Furthermore, UVB irradiation could significantly upregulate P2RY6 expression in human and mouse skin cells. These results indicated that P2RY6 may play a crucial protective role in resisting the UVB-induced formation of skin tumors. At the molecular level, the loss of the P2RY6 gene inhibits the ubiquitination modification and expression of XPC after UVB irradiation in skin keratinocytes, resulting in the accumulation of CPDs (cyclobutane pyrimidine dimers). We have also demonstrated that P2RY6 deletion activates the PI3K/AKT signaling pathway both in vitro and in vivo. The CPD accumulation and acute inflammatory response enhanced by the loss of the P2RY6 gene can be reversed by an AKT inhibitor. These findings suggest that P2RY6 may act as a tumor suppressor in UVB-induced skin cancer by regulating the PI3K/AKT signaling pathway.
{"title":"P2RY6 deletion promotes UVB-induced skin carcinogenesis by activating the PI3K/AKT signal pathway.","authors":"Peng Xu, Tanglin Liu, Zile Yang, Kai Zang, Xiaoxuan Gao, Yuling Shi, Xiyun Ye, Yongyan Dang","doi":"10.1111/cas.16378","DOIUrl":"10.1111/cas.16378","url":null,"abstract":"<p><p>Our previous research has demonstrated that P2RY6 functions as an oncogene in DMBA/TPA-induced two-stage chemical skin carcinogenesis in mice. However, considering that human skin cancer is predominantly attributed to UV radiation from sunlight, additional investigations are needed to elucidate the role of P2RY6 in UVB-induced skin carcinogenesis. Surprisingly, we found that P2ry6-deficient mice exhibited marked promotion to UVB-induced skin papilloma formation compared with wild-type mice, suggesting its tumor-suppressive role in UVB-induced skin cancer. Additionally, a P2ry6 gene knockout promoted skin hyperplasia induced by short-term UVB irradiation, while UDP, the ligand of P2RY6, could inhibit the short-term UVB-induced increase of epiderma thickness in mouse skin. Furthermore, UVB irradiation could significantly upregulate P2RY6 expression in human and mouse skin cells. These results indicated that P2RY6 may play a crucial protective role in resisting the UVB-induced formation of skin tumors. At the molecular level, the loss of the P2RY6 gene inhibits the ubiquitination modification and expression of XPC after UVB irradiation in skin keratinocytes, resulting in the accumulation of CPDs (cyclobutane pyrimidine dimers). We have also demonstrated that P2RY6 deletion activates the PI3K/AKT signaling pathway both in vitro and in vivo. The CPD accumulation and acute inflammatory response enhanced by the loss of the P2RY6 gene can be reversed by an AKT inhibitor. These findings suggest that P2RY6 may act as a tumor suppressor in UVB-induced skin cancer by regulating the PI3K/AKT signaling pathway.</p>","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142478523","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}