Jesse Yu, Xiaolin Xu, J. I. Griffin, Qingxin Mu, Rodney J Y Ho
Early diagnosis, intervention, and therapeutic advancements have extended the lives of breast cancer patients; however, even with molecularly targeted therapies, many patients eventually progress to metastatic cancer. Recent data suggest that residual breast cancer cells often reside in the lymphatic system before rapidly spreading through the bloodstream. To address this challenge, an effective drug combination composed of gemcitabine (G) and paclitaxel (T) is administered intravenously in sequence at the metastatic stage, but intravenous GT infusion may limit lymphatic GT drug accessibility and asynchronous drug exposure in cancer cells within the lymph. To determine whether co-localization of intracellular gemcitabine and paclitaxel (referred to as GT) could overcome these limitations and enhance the efficacy of GT, we have evaluated a previously reported GT drug-combination formulated in nanoparticle (referred to as GT-in-DcNP) evaluated in an orthotopic breast tumor model. Previously, with indocyanine green-labeled nanoparticles, we reported that GT-in-DcNP particles after subcutaneous dosing were taken up rapidly and preferentially into the lymph instead of blood vessels. The pharmacokinetic study showed enhanced co-localization of GT within the tumors and likely through lymphatic access, before drug apparency in the plasma leading to apparent long-acting plasma time-course. The mechanisms may be related to significantly greater inhibitions of tumor growth—by 100 to 140 times—in both sub-iliac and axillary regions compared to the equivalent dosing with free-and-soluble GT formulation. Furthermore, GT-in-DcNP exhibited dose-dependent effects with significant tumor regression. In contrast, even at the highest dose of free GT combination, only a modest tumor growth reduction was notable. Preliminary studies with MDA-231-HM human breast cancer in an orthotopic xenograft model indicated that GT-in-DcNP may be effective in suppressing human breast tumor growth. Taken together, the synchronized delivery of GT-in-DcNP to mammary tumors through the lymphatic system offers enhanced cellular retention and greater efficacy.
{"title":"Drug Combination Nanoparticles Containing Gemcitabine and Paclitaxel Enable Orthotopic 4T1 Breast Tumor Regression","authors":"Jesse Yu, Xiaolin Xu, J. I. Griffin, Qingxin Mu, Rodney J Y Ho","doi":"10.3390/cancers16162792","DOIUrl":"https://doi.org/10.3390/cancers16162792","url":null,"abstract":"Early diagnosis, intervention, and therapeutic advancements have extended the lives of breast cancer patients; however, even with molecularly targeted therapies, many patients eventually progress to metastatic cancer. Recent data suggest that residual breast cancer cells often reside in the lymphatic system before rapidly spreading through the bloodstream. To address this challenge, an effective drug combination composed of gemcitabine (G) and paclitaxel (T) is administered intravenously in sequence at the metastatic stage, but intravenous GT infusion may limit lymphatic GT drug accessibility and asynchronous drug exposure in cancer cells within the lymph. To determine whether co-localization of intracellular gemcitabine and paclitaxel (referred to as GT) could overcome these limitations and enhance the efficacy of GT, we have evaluated a previously reported GT drug-combination formulated in nanoparticle (referred to as GT-in-DcNP) evaluated in an orthotopic breast tumor model. Previously, with indocyanine green-labeled nanoparticles, we reported that GT-in-DcNP particles after subcutaneous dosing were taken up rapidly and preferentially into the lymph instead of blood vessels. The pharmacokinetic study showed enhanced co-localization of GT within the tumors and likely through lymphatic access, before drug apparency in the plasma leading to apparent long-acting plasma time-course. The mechanisms may be related to significantly greater inhibitions of tumor growth—by 100 to 140 times—in both sub-iliac and axillary regions compared to the equivalent dosing with free-and-soluble GT formulation. Furthermore, GT-in-DcNP exhibited dose-dependent effects with significant tumor regression. In contrast, even at the highest dose of free GT combination, only a modest tumor growth reduction was notable. Preliminary studies with MDA-231-HM human breast cancer in an orthotopic xenograft model indicated that GT-in-DcNP may be effective in suppressing human breast tumor growth. Taken together, the synchronized delivery of GT-in-DcNP to mammary tumors through the lymphatic system offers enhanced cellular retention and greater efficacy.","PeriodicalId":504676,"journal":{"name":"Cancers","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141925493","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Osteosarcoma (OS) is the most common primary bone tumor in children and adolescents. Prognosis is improving with advances in multidisciplinary treatment strategies, but the development of new anticancer agents has not, and improvement in prognosis for patients with pulmonary metastases has stalled. In recent years, the tumor microenvironment (TME) has gained attention as a therapeutic target for cancer. The immune component of OS TME consists mainly of tumor-associated macrophages (TAMs). They exhibit remarkable plasticity, and their phenotype is influenced by the TME. In general, surface markers such as CD68 and CD80 show anti-tumor effects, while CD163 and CD204 show tumor-promoting effects. Surface markers have potential value as diagnostic and prognostic biomarkers. The cytokines and chemokines produced by TAMs promote tumor growth and metastasis. However, the role of TAMs in OS remains unclear to date. In this review, we describe the role of TAMs in OS by focusing on TAM surface markers and the TAM-produced cytokines and chemokines in the TME, and by comparing their behaviors in other carcinomas. We found contrary results from different studies. These findings highlight the urgency for further research in this field to improve the stalled OS prognosis percentages.
骨肉瘤（Osteosarcoma，OS）是儿童和青少年最常见的原发性骨肿瘤。随着多学科治疗策略的进步，骨肉瘤的预后正在得到改善，但新抗癌药物的开发却没有取得进展，肺转移患者的预后改善也停滞不前。近年来，肿瘤微环境（TME）作为癌症的治疗靶点备受关注。OS TME 的免疫成分主要包括肿瘤相关巨噬细胞（TAMs）。它们表现出显著的可塑性，其表型受到 TME 的影响。一般来说，CD68 和 CD80 等表面标记物具有抗肿瘤作用，而 CD163 和 CD204 则具有促肿瘤作用。表面标志物具有诊断和预后生物标志物的潜在价值。TAMs 产生的细胞因子和趋化因子可促进肿瘤生长和转移。然而，迄今为止，TAMs 在 OS 中的作用仍不明确。在这篇综述中，我们通过聚焦 TAM 表面标志物和 TAM 在 TME 中产生的细胞因子和趋化因子，并比较它们在其他癌症中的行为，来描述 TAM 在 OS 中的作用。我们发现不同的研究得出了相反的结果。这些发现凸显了在这一领域开展进一步研究以改善停滞不前的 OS 预后百分比的紧迫性。
{"title":"Surface Markers and Chemokines/Cytokines of Tumor-Associated Macrophages in Osteosarcoma and Other Carcinoma Microenviornments—Contradictions and Comparisons","authors":"Rikito Tatsuno, Yoshihiro Komohara, Cheng Pan, Tomonori Kawasaki, Atsushi Enomoto, Takahiro Jubashi, Hiroyuki Kono, M. Wako, Tomoyuki Ashizawa, Hirotaka Haro, Jiro Ichikawa","doi":"10.3390/cancers16162801","DOIUrl":"https://doi.org/10.3390/cancers16162801","url":null,"abstract":"Osteosarcoma (OS) is the most common primary bone tumor in children and adolescents. Prognosis is improving with advances in multidisciplinary treatment strategies, but the development of new anticancer agents has not, and improvement in prognosis for patients with pulmonary metastases has stalled. In recent years, the tumor microenvironment (TME) has gained attention as a therapeutic target for cancer. The immune component of OS TME consists mainly of tumor-associated macrophages (TAMs). They exhibit remarkable plasticity, and their phenotype is influenced by the TME. In general, surface markers such as CD68 and CD80 show anti-tumor effects, while CD163 and CD204 show tumor-promoting effects. Surface markers have potential value as diagnostic and prognostic biomarkers. The cytokines and chemokines produced by TAMs promote tumor growth and metastasis. However, the role of TAMs in OS remains unclear to date. In this review, we describe the role of TAMs in OS by focusing on TAM surface markers and the TAM-produced cytokines and chemokines in the TME, and by comparing their behaviors in other carcinomas. We found contrary results from different studies. These findings highlight the urgency for further research in this field to improve the stalled OS prognosis percentages.","PeriodicalId":504676,"journal":{"name":"Cancers","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141925916","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Karam Ashouri, Alexandra Wong, Pooja Mittal, Lesly Torres-Gonzalez, Jae Ho Lo, S. Soni, S. Algaze, Taline Khoukaz, Wu Zhang, Yan Yang, J. Millstein, H. Lenz, F. Battaglin
Colorectal cancer (CRC) remains the second leading cause of cancer-related mortality worldwide. While immune checkpoint inhibitors have significantly improved patient outcomes, their effectiveness is mostly limited to tumors with microsatellite instability (MSI-H/dMMR) or an increased tumor mutational burden, which comprise 10% of cases. Advancing personalized medicine in CRC hinges on identifying predictive biomarkers to guide treatment decisions. This comprehensive review examines established tissue markers such as KRAS and HER2, highlighting their roles in resistance to anti-EGFR agents and discussing advances in targeted therapies for these markers. Additionally, this review summarizes encouraging data on promising therapeutic targets and highlights the clinical utility of liquid biopsies. By synthesizing current evidence and identifying knowledge gaps, this review provides clinicians and researchers with a contemporary understanding of the biomarker landscape in CRC. Finally, the review examines future directions and challenges in translating promising biomarkers into clinical practice, with the goal of enhancing personalized medicine approaches for colorectal cancer patients.
{"title":"Exploring Predictive and Prognostic Biomarkers in Colorectal Cancer: A Comprehensive Review","authors":"Karam Ashouri, Alexandra Wong, Pooja Mittal, Lesly Torres-Gonzalez, Jae Ho Lo, S. Soni, S. Algaze, Taline Khoukaz, Wu Zhang, Yan Yang, J. Millstein, H. Lenz, F. Battaglin","doi":"10.3390/cancers16162796","DOIUrl":"https://doi.org/10.3390/cancers16162796","url":null,"abstract":"Colorectal cancer (CRC) remains the second leading cause of cancer-related mortality worldwide. While immune checkpoint inhibitors have significantly improved patient outcomes, their effectiveness is mostly limited to tumors with microsatellite instability (MSI-H/dMMR) or an increased tumor mutational burden, which comprise 10% of cases. Advancing personalized medicine in CRC hinges on identifying predictive biomarkers to guide treatment decisions. This comprehensive review examines established tissue markers such as KRAS and HER2, highlighting their roles in resistance to anti-EGFR agents and discussing advances in targeted therapies for these markers. Additionally, this review summarizes encouraging data on promising therapeutic targets and highlights the clinical utility of liquid biopsies. By synthesizing current evidence and identifying knowledge gaps, this review provides clinicians and researchers with a contemporary understanding of the biomarker landscape in CRC. Finally, the review examines future directions and challenges in translating promising biomarkers into clinical practice, with the goal of enhancing personalized medicine approaches for colorectal cancer patients.","PeriodicalId":504676,"journal":{"name":"Cancers","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141929444","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Alejandro Heredia-Ciuró, Florencio Quero-Valenzuela, Javier Martín-Núñez, A. Calvache-Mateo, G. Valenza-Peña, L. López-López, M. Valenza
Background. Lung resection represents the main curative treatment modality for lung cancer. These patients present with physical deterioration that has been studied previously using objective variables; however, no previous studies have evaluated the self-perceived physical fitness of these patients. For these reasons, to increase the current knowledge on lung cancer patients’ impairment, the aim of this study was to characterize the self-perceived physical deconditioning of lung cancer patients undergoing lung resection in the short and medium term after surgery. Methods. A longitudinal, observational, prospective cohort study was performed in the Thoracic Surgery Service of the Hospital Virgen de las Nieves (Granada). Symptoms (pain, fatigue, cough and dyspnea) and physical fitness (upper and lower limbs) were assessed before surgery, at discharge and at one month after discharge. Results. Among the total of 88 patients that we included in our study, significant differences were found at discharge in symptoms (p < 0.05) and physical fitness (p < 0.05). One month after surgery, higher levels of pain (p = 0,002) and dyspnea (p = 0.007) were observed, as well as poorer results in the upper (p = 0.023) and lower limbs’ physical fitness, with regard to the initial values. Conclusions. Patients undergoing lung resection present an increase in symptoms and physical fitness deterioration at discharge, which is maintained one month after surgery.
背景。肺切除术是治疗肺癌的主要方法。以前曾使用客观变量对这些患者的体能衰退情况进行过研究；但是，以前没有研究对这些患者的自我感觉体能进行过评估。因此，为了增加目前对肺癌患者体能损伤的了解，本研究旨在描述接受肺切除术的肺癌患者在术后中短期内自我感觉的体能下降情况。研究方法在格拉纳达 Virgen de las Nieves 医院胸外科开展了一项纵向、观察性、前瞻性队列研究。在手术前、出院时和出院后一个月对患者的症状（疼痛、疲劳、咳嗽和呼吸困难）和体能（上肢和下肢）进行了评估。结果在纳入研究的 88 名患者中，出院时的症状（P < 0.05）和体能（P < 0.05）存在显著差异。术后一个月，疼痛（p = 0.002）和呼吸困难（p = 0.007）程度较高，上肢（p = 0.023）和下肢体能与初始值相比也较差。结论接受肺切除术的患者出院时症状加重，体能下降，术后一个月症状依然存在。
{"title":"Physical Deconditioning in Lung Cancer Patients Who Underwent Lung Resection Surgery in Spain: A Prospective Observational Study","authors":"Alejandro Heredia-Ciuró, Florencio Quero-Valenzuela, Javier Martín-Núñez, A. Calvache-Mateo, G. Valenza-Peña, L. López-López, M. Valenza","doi":"10.3390/cancers16162790","DOIUrl":"https://doi.org/10.3390/cancers16162790","url":null,"abstract":"Background. Lung resection represents the main curative treatment modality for lung cancer. These patients present with physical deterioration that has been studied previously using objective variables; however, no previous studies have evaluated the self-perceived physical fitness of these patients. For these reasons, to increase the current knowledge on lung cancer patients’ impairment, the aim of this study was to characterize the self-perceived physical deconditioning of lung cancer patients undergoing lung resection in the short and medium term after surgery. Methods. A longitudinal, observational, prospective cohort study was performed in the Thoracic Surgery Service of the Hospital Virgen de las Nieves (Granada). Symptoms (pain, fatigue, cough and dyspnea) and physical fitness (upper and lower limbs) were assessed before surgery, at discharge and at one month after discharge. Results. Among the total of 88 patients that we included in our study, significant differences were found at discharge in symptoms (p < 0.05) and physical fitness (p < 0.05). One month after surgery, higher levels of pain (p = 0,002) and dyspnea (p = 0.007) were observed, as well as poorer results in the upper (p = 0.023) and lower limbs’ physical fitness, with regard to the initial values. Conclusions. Patients undergoing lung resection present an increase in symptoms and physical fitness deterioration at discharge, which is maintained one month after surgery.","PeriodicalId":504676,"journal":{"name":"Cancers","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141927190","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
A. Asakawa, Ryoto Yoshimoto, Maki Kobayashi, Nanae Izumi, Takanori Maejima, Tsuneo Deguchi, K. Kubota, H. Takahashi, Miyuki Yamada, S. Ishibashi, Iichiroh Onishi, Yuko Kinowaki, Morita Kurata, Masashi Kobayashi, H. Ishibashi, Kenichi Okubo, Kenichi Ohashi, Masanobu Kitagawa, Kouhei Yamamoto
Lung squamous cell carcinoma (LSCC) is refractory to various therapies for non-small cell cancer; therefore, new therapeutic approaches are required to improve the prognosis of LSCC. Although immunotherapies targeting B7 family molecules were explored as treatments for several cancer types, the expression and significance of B7-H3 in the tumor microenvironment (TME) and its relationship with other immune checkpoint molecules have not yet been investigated in detail. We used high-throughput quantitative multiplex immunohistochemistry to examine B7-H3 expression in the TME. We investigated the relationship between B7-H3 expression and prognosis as well as changes in the TME with B7-H3 expression using 110 surgically resected pathological specimens retrospectively. We examined the correlation between B7-H3 and programmed cell death-ligand 1 (PD-L1) expression in single cells. High B7-H3 expression in tumor cells was associated with a better prognosis and a significant increase in the number of CD163+PD-L1+ macrophages. Quantitative analysis revealed that there is a positive correlation between B7-H3 and PD-L1 expression in tumor and stromal cells, as well as in intratumoral tumor-infiltrating lymphocytes and tumor-associated macrophages in the same cells. CD68+, CD163+, and CK+ cells with PD-L1+ phenotypes had higher B7-H3 expression compared to PD-L1− cells. Our findings demonstrate a correlation between B7-H3 and PD-L1 expression in the same cells, indicating that therapies targeting B7-H3 could provide additional efficacy in patients refractory to PD-L1-targeting therapies.
{"title":"The Comprehensive Characterization of B7-H3 Expression in the Tumor Microenvironment of Lung Squamous Cell Carcinoma: A Retrospective Study","authors":"A. Asakawa, Ryoto Yoshimoto, Maki Kobayashi, Nanae Izumi, Takanori Maejima, Tsuneo Deguchi, K. Kubota, H. Takahashi, Miyuki Yamada, S. Ishibashi, Iichiroh Onishi, Yuko Kinowaki, Morita Kurata, Masashi Kobayashi, H. Ishibashi, Kenichi Okubo, Kenichi Ohashi, Masanobu Kitagawa, Kouhei Yamamoto","doi":"10.3390/cancers16112140","DOIUrl":"https://doi.org/10.3390/cancers16112140","url":null,"abstract":"Lung squamous cell carcinoma (LSCC) is refractory to various therapies for non-small cell cancer; therefore, new therapeutic approaches are required to improve the prognosis of LSCC. Although immunotherapies targeting B7 family molecules were explored as treatments for several cancer types, the expression and significance of B7-H3 in the tumor microenvironment (TME) and its relationship with other immune checkpoint molecules have not yet been investigated in detail. We used high-throughput quantitative multiplex immunohistochemistry to examine B7-H3 expression in the TME. We investigated the relationship between B7-H3 expression and prognosis as well as changes in the TME with B7-H3 expression using 110 surgically resected pathological specimens retrospectively. We examined the correlation between B7-H3 and programmed cell death-ligand 1 (PD-L1) expression in single cells. High B7-H3 expression in tumor cells was associated with a better prognosis and a significant increase in the number of CD163+PD-L1+ macrophages. Quantitative analysis revealed that there is a positive correlation between B7-H3 and PD-L1 expression in tumor and stromal cells, as well as in intratumoral tumor-infiltrating lymphocytes and tumor-associated macrophages in the same cells. CD68+, CD163+, and CK+ cells with PD-L1+ phenotypes had higher B7-H3 expression compared to PD-L1− cells. Our findings demonstrate a correlation between B7-H3 and PD-L1 expression in the same cells, indicating that therapies targeting B7-H3 could provide additional efficacy in patients refractory to PD-L1-targeting therapies.","PeriodicalId":504676,"journal":{"name":"Cancers","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141267872","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Lauren Julia Brown, J. Ahn, Bo Gao, Harriet Gee, Adnan Nagrial, Eric Hau, Inês Pires da Silva
Patients with advanced NSCLC have heterogenous responses to immune checkpoint inhibitors (ICIs) with or without chemotherapy. In NSCLC, the impact of the distribution of metastatic sites and the response to systemic therapy combinations remain poorly understood. In a retrospective cohort study of patients with unresectable stage III/IV NSCLC who received first-line systemic therapy, we sought to assess the association between the site of metastases with patterns of response and progression. Data regarding demographics, tumour characteristics (including site, size, and volume of metastases), treatment, and outcomes were examined at two cancer care centres. The endpoints included organ site-specific response rate, objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). Two-hundred and eighty-five patients were included in the analysis. In a multivariate analysis, patients with bone metastases had a reduced ORR, PFS, and OS. Primary resistance was also more likely in patients with bone metastases. Patients with bone or liver metastases had a shorter OS when receiving ICIs with or without chemotherapy, but not with chemotherapy alone, suggesting an immunological basis for therapeutic resistance. A directed assessment of the tumour microenvironment in these locations and a deeper understanding of the drivers of organ-specific resistance to immunotherapy are critical to optimise novel combination therapies and sequencing in these patients.
{"title":"Site-Specific Response and Resistance Patterns in Patients with Advanced Non-Small-Cell Lung Cancer Treated with First-Line Systemic Therapy","authors":"Lauren Julia Brown, J. Ahn, Bo Gao, Harriet Gee, Adnan Nagrial, Eric Hau, Inês Pires da Silva","doi":"10.3390/cancers16112136","DOIUrl":"https://doi.org/10.3390/cancers16112136","url":null,"abstract":"Patients with advanced NSCLC have heterogenous responses to immune checkpoint inhibitors (ICIs) with or without chemotherapy. In NSCLC, the impact of the distribution of metastatic sites and the response to systemic therapy combinations remain poorly understood. In a retrospective cohort study of patients with unresectable stage III/IV NSCLC who received first-line systemic therapy, we sought to assess the association between the site of metastases with patterns of response and progression. Data regarding demographics, tumour characteristics (including site, size, and volume of metastases), treatment, and outcomes were examined at two cancer care centres. The endpoints included organ site-specific response rate, objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). Two-hundred and eighty-five patients were included in the analysis. In a multivariate analysis, patients with bone metastases had a reduced ORR, PFS, and OS. Primary resistance was also more likely in patients with bone metastases. Patients with bone or liver metastases had a shorter OS when receiving ICIs with or without chemotherapy, but not with chemotherapy alone, suggesting an immunological basis for therapeutic resistance. A directed assessment of the tumour microenvironment in these locations and a deeper understanding of the drivers of organ-specific resistance to immunotherapy are critical to optimise novel combination therapies and sequencing in these patients.","PeriodicalId":504676,"journal":{"name":"Cancers","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141267407","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
A. Fernández‐Galván, P. Rodríguez‐Jiménez, Beatriz González-Sixto, M. Abalde-Pintos, B. Butrón‐Bris
Basal Cell Carcinoma (BCC) is the most common type of cancer among the white population. Individuals with fair skin have an average lifetime risk of around 30% for developing BCC, and there is a noticeable upward trend in its incidence rate. The principal treatment objectives for BCC involve achieving the total excision of the tumor while maximizing the preservation of function and cosmesis. Surgery is considered the treatment of choice for BCC for two main reasons: it allows for the highest cure rates and facilitates histological control of resection margins. However, in the subgroup of patients with low-risk recurrence or medical contraindications for surgery, new non-surgical treatment alternatives can provide an excellent oncological and cosmetic outcome. An evident and justified instance of these local therapies occurred during the COVID-19 pandemic, a period when surgical interventions carried out in hospital settings were not a viable option.
{"title":"Topical and Intralesional Immunotherapy for the Management of Basal Cell Carcinoma","authors":"A. Fernández‐Galván, P. Rodríguez‐Jiménez, Beatriz González-Sixto, M. Abalde-Pintos, B. Butrón‐Bris","doi":"10.3390/cancers16112135","DOIUrl":"https://doi.org/10.3390/cancers16112135","url":null,"abstract":"Basal Cell Carcinoma (BCC) is the most common type of cancer among the white population. Individuals with fair skin have an average lifetime risk of around 30% for developing BCC, and there is a noticeable upward trend in its incidence rate. The principal treatment objectives for BCC involve achieving the total excision of the tumor while maximizing the preservation of function and cosmesis. Surgery is considered the treatment of choice for BCC for two main reasons: it allows for the highest cure rates and facilitates histological control of resection margins. However, in the subgroup of patients with low-risk recurrence or medical contraindications for surgery, new non-surgical treatment alternatives can provide an excellent oncological and cosmetic outcome. An evident and justified instance of these local therapies occurred during the COVID-19 pandemic, a period when surgical interventions carried out in hospital settings were not a viable option.","PeriodicalId":504676,"journal":{"name":"Cancers","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141266584","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Sofia Catalina Heredia-Guerrero, Marietheres Evers, S. Keppler, Marlene Schwarzfischer, Viktoria Fuhr, Hilka Rauert-Wunderlich, Anne Krügl, T. Nedeva, T. Grieb, Julia Pickert, Hanna Koch, Torsten Steinbrunn, Otto-Jonas Bayrhof, R. Bargou, Andreas Rosenwald, T. Stühmer, E. Leich
High expression of the receptor tyrosine kinase (RTK) insulin-like growth factor-1 receptor (IGF1R) and RTK mutations are associated with high-risk/worse prognosis in multiple myeloma (MM). Combining the pIGF1R/pINSR inhibitor linsitinib with the proteasome inhibitor (PI) bortezomib seemed promising in a clinical trial, but IGF1R expression was not associated with therapy response. Because the oncogenic impact of IGF1R mutations is so far unknown, we investigated the functional impact of IGF1R mutations on survival signaling, viability/proliferation and survival response to therapy. We transfected four human myeloma cell lines (HMCLs) with IGF1RWT, IGF1RD1146N and IGF1RN1129S (Sleeping Beauty), generated CRISPR-Cas9 IGF1R knockouts in the HMCLs U-266 (IGF1RWT) and L-363 (IGF1RD1146N) and tested the anti-MM activity of linsitinib alone and in combination with the second-generation PI carfilzomib in seven HMCLs. IGF1R knockout entailed reduced proliferation. Upon IGF1R overexpression, survival signaling was moderately increased in all HCMLs and slightly affected by IGF1RN1129S in one HMCL, whereby the viability remained unaffected. Expression of IGF1RD1146N reduced pIGF1R-Y1135, especially under serum reduction, but did not impact downstream signaling. Linsitinib and carfilzomib showed enhanced anti-myeloma activity in six out of seven HMCL irrespective of the IGF1R mutation status. In conclusion, IGF1R mutations can impact IGF1R activation and/or downstream signaling, and a combination of linsitinib with carfilzomib might be a suitable therapeutic approach for MM patients potentially responsive to IGF1R blockade.
{"title":"Functional Investigation of IGF1R Mutations in Multiple Myeloma","authors":"Sofia Catalina Heredia-Guerrero, Marietheres Evers, S. Keppler, Marlene Schwarzfischer, Viktoria Fuhr, Hilka Rauert-Wunderlich, Anne Krügl, T. Nedeva, T. Grieb, Julia Pickert, Hanna Koch, Torsten Steinbrunn, Otto-Jonas Bayrhof, R. Bargou, Andreas Rosenwald, T. Stühmer, E. Leich","doi":"10.3390/cancers16112139","DOIUrl":"https://doi.org/10.3390/cancers16112139","url":null,"abstract":"High expression of the receptor tyrosine kinase (RTK) insulin-like growth factor-1 receptor (IGF1R) and RTK mutations are associated with high-risk/worse prognosis in multiple myeloma (MM). Combining the pIGF1R/pINSR inhibitor linsitinib with the proteasome inhibitor (PI) bortezomib seemed promising in a clinical trial, but IGF1R expression was not associated with therapy response. Because the oncogenic impact of IGF1R mutations is so far unknown, we investigated the functional impact of IGF1R mutations on survival signaling, viability/proliferation and survival response to therapy. We transfected four human myeloma cell lines (HMCLs) with IGF1RWT, IGF1RD1146N and IGF1RN1129S (Sleeping Beauty), generated CRISPR-Cas9 IGF1R knockouts in the HMCLs U-266 (IGF1RWT) and L-363 (IGF1RD1146N) and tested the anti-MM activity of linsitinib alone and in combination with the second-generation PI carfilzomib in seven HMCLs. IGF1R knockout entailed reduced proliferation. Upon IGF1R overexpression, survival signaling was moderately increased in all HCMLs and slightly affected by IGF1RN1129S in one HMCL, whereby the viability remained unaffected. Expression of IGF1RD1146N reduced pIGF1R-Y1135, especially under serum reduction, but did not impact downstream signaling. Linsitinib and carfilzomib showed enhanced anti-myeloma activity in six out of seven HMCL irrespective of the IGF1R mutation status. In conclusion, IGF1R mutations can impact IGF1R activation and/or downstream signaling, and a combination of linsitinib with carfilzomib might be a suitable therapeutic approach for MM patients potentially responsive to IGF1R blockade.","PeriodicalId":504676,"journal":{"name":"Cancers","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141267828","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
A. Porcaro, A. Bianchi, S. Gallina, A. Panunzio, A. Tafuri, E. Serafin, R. Orlando, Giovanni Mazzucato, P. Ornaghi, Francesco Cianflone, Francesca Montanaro, Francesco Artoni, Alberto Baielli, Francesco Ditonno, Filippo Migliorini, Matteo Brunelli, Salvatore Siracusano, M. Cerruto, Alessandro Antonelli
Objectives: To assess the prognostic impact and predictors of adverse tumor grade in very favorable low- and intermediate-risk prostate cancer (PCa) patients treated with robot-assisted radical prostatectomy (RARP). Methods: Data of low- and intermediate PCa risk-class patients were retrieved from a prospectively maintained institutional database. Adverse tumor grade was defined as pathology ISUP grade group > 2. Disease progression was defined as a biochemical recurrence event and/or local recurrence and/or distant metastases. Associations were assessed by Cox’s proportional hazards and logistic regression model. Results: Between January 2013 and October 2020, the study evaluated a population of 289 patients, including 178 low-risk cases (61.1%) and 111 intermediate-risk subjects (38.4%); unfavorable tumor grade was detected in 82 cases (28.4%). PCa progression, which occurred in 29 patients (10%), was independently predicted by adverse tumor grade and biopsy ISUP grade group 2, with the former showing stronger associations (hazard ratio, HR = 4.478; 95% CI: 1.840–10.895; p = 0.001) than the latter (HR = 2.336; 95% CI: 1.057–5.164; p = 0.036). Older age and biopsy ISUP grade group 2 were independent clinical predictors of adverse tumor grade, associated with larger tumors that eventually presented non-organ-confined disease. Conclusions: In a very favorable PCa patient population, adverse tumor grade was an unfavorable prognostic factor for disease progression. Active surveillance in very favorable intermediate-risk patients is still a hazard, so molecular and genetic testing of biopsy specimens is needed.
{"title":"Prognostic Impact and Clinical Implications of Adverse Tumor Grade in Very Favorable Low- and Intermediate-Risk Prostate Cancer Patients Treated with Robot-Assisted Radical Prostatectomy: Experience of a Single Tertiary Referral Center","authors":"A. Porcaro, A. Bianchi, S. Gallina, A. Panunzio, A. Tafuri, E. Serafin, R. Orlando, Giovanni Mazzucato, P. Ornaghi, Francesco Cianflone, Francesca Montanaro, Francesco Artoni, Alberto Baielli, Francesco Ditonno, Filippo Migliorini, Matteo Brunelli, Salvatore Siracusano, M. Cerruto, Alessandro Antonelli","doi":"10.3390/cancers16112137","DOIUrl":"https://doi.org/10.3390/cancers16112137","url":null,"abstract":"Objectives: To assess the prognostic impact and predictors of adverse tumor grade in very favorable low- and intermediate-risk prostate cancer (PCa) patients treated with robot-assisted radical prostatectomy (RARP). Methods: Data of low- and intermediate PCa risk-class patients were retrieved from a prospectively maintained institutional database. Adverse tumor grade was defined as pathology ISUP grade group > 2. Disease progression was defined as a biochemical recurrence event and/or local recurrence and/or distant metastases. Associations were assessed by Cox’s proportional hazards and logistic regression model. Results: Between January 2013 and October 2020, the study evaluated a population of 289 patients, including 178 low-risk cases (61.1%) and 111 intermediate-risk subjects (38.4%); unfavorable tumor grade was detected in 82 cases (28.4%). PCa progression, which occurred in 29 patients (10%), was independently predicted by adverse tumor grade and biopsy ISUP grade group 2, with the former showing stronger associations (hazard ratio, HR = 4.478; 95% CI: 1.840–10.895; p = 0.001) than the latter (HR = 2.336; 95% CI: 1.057–5.164; p = 0.036). Older age and biopsy ISUP grade group 2 were independent clinical predictors of adverse tumor grade, associated with larger tumors that eventually presented non-organ-confined disease. Conclusions: In a very favorable PCa patient population, adverse tumor grade was an unfavorable prognostic factor for disease progression. Active surveillance in very favorable intermediate-risk patients is still a hazard, so molecular and genetic testing of biopsy specimens is needed.","PeriodicalId":504676,"journal":{"name":"Cancers","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141267382","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
A. Pellerino, Tara Marie Davidson, Shreyas Bellur, M. Ahluwalia, Hussein A Tawbi, R. Rudà, Riccardo Soffietti
This review discusses the topic of prevention of brain metastases from the most frequent solid tumor types, i.e., lung cancer, breast cancer and melanoma. Within each tumor type, the risk of brain metastasis is related to disease status and molecular subtype (i.e., EGFR-mutant non-small cell lung cancer, HER2-positive and triple-negative breast cancer, BRAF and NRAF-mutant melanoma). Prophylactic cranial irradiation is the standard of care in patients in small cell lung cancer responsive to chemotherapy but at the price of late neurocognitive decline. More recently, several molecular agents with the capability to target molecular alterations driving tumor growth have proven as effective in the prevention of secondary relapse into the brain in clinical trials. This is the case for EGFR-mutant or ALK-rearranged non-small cell lung cancer inhibitors, tucatinib and trastuzumab–deruxtecan for HER2-positive breast cancer and BRAF inhibitors for melanoma. The need for screening with an MRI in asymptomatic patients at risk of brain metastases is emphasized.
{"title":"Prevention of Brain Metastases: A New Frontier","authors":"A. Pellerino, Tara Marie Davidson, Shreyas Bellur, M. Ahluwalia, Hussein A Tawbi, R. Rudà, Riccardo Soffietti","doi":"10.3390/cancers16112134","DOIUrl":"https://doi.org/10.3390/cancers16112134","url":null,"abstract":"This review discusses the topic of prevention of brain metastases from the most frequent solid tumor types, i.e., lung cancer, breast cancer and melanoma. Within each tumor type, the risk of brain metastasis is related to disease status and molecular subtype (i.e., EGFR-mutant non-small cell lung cancer, HER2-positive and triple-negative breast cancer, BRAF and NRAF-mutant melanoma). Prophylactic cranial irradiation is the standard of care in patients in small cell lung cancer responsive to chemotherapy but at the price of late neurocognitive decline. More recently, several molecular agents with the capability to target molecular alterations driving tumor growth have proven as effective in the prevention of secondary relapse into the brain in clinical trials. This is the case for EGFR-mutant or ALK-rearranged non-small cell lung cancer inhibitors, tucatinib and trastuzumab–deruxtecan for HER2-positive breast cancer and BRAF inhibitors for melanoma. The need for screening with an MRI in asymptomatic patients at risk of brain metastases is emphasized.","PeriodicalId":504676,"journal":{"name":"Cancers","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141268288","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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