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Saint-Jean A, Reguart N, Eixarch A, Adán A, Castellà C, Sánchez-Dalmau B, Sainz-de-la-Maza M. Ocular surface adverse events of systemic epidermal growth factor receptor inhibitors (EGFRi): A prospective trial. J Fr Ophtalmol 2018; 41:955-962. [PMID: 30473235 DOI: 10.1016/j.jfo.2018.07.005] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2018] [Accepted: 07/20/2018] [Indexed: 11/26/2022]
Abstract
PURPOSE Controversy exists regarding the safety of agents that systemically inhibit epidermal growth factor receptor (EGFRi) in oncologic patients in terms of toxicity to the ocular surface. We performed a prospective clinical study comparing the ocular surface toxicity of systemic EGFRi between a case and a control group. METHODS Patients with lung or colon cancer were divided in two groups: 25 patients treated with systemic EGFRi and 25 control patients without EGFRi treatment. Patients in both groups were chemotherapy naive. Four visits were scheduled in a one year period comparing signs and symptoms in terms of symptom questionnaires (SIDEQ, OSDI and AVS), corneal fluorescein staining (Oxford test), tear production (Schirmer's test) and a quantitative evaluation of conjunctival chemosis and hyperemia. Basal epithelial cell density (CEBD) and corneal subepithelial nerve fiber density (CNFD) were measured and compared using confocal microscopy (Heidelberg Engineering, Germany). The differences in each variable were compared with the analysis of variance (ANOVA). A P value<0.05 was considered significant for all comparisons. RESULTS No statistically significant differences were found between patients under EGFRi treatment and the age-matched controls in the variables analyzed. When cases and controls were evaluated separately, the case group showed a significantly worse progression of signs (chemosis score, CFS, Schirmer's) as well as in terms of CEBD and CNFD (all P<0.05). CONCLUSION Systemic EGFRi may increase dry eye signs as well as decrease CEBD and CNFD. This study may help us to understand the true toxicity of EGFRi to the ocular surface.
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Affiliation(s)
- A Saint-Jean
- University of Barcelona, Clinica Baviera, Barcelona, Spain.
| | - N Reguart
- Thoracic Oncology, Medical Oncology Department, Hospital Clinic, IDIBAPS, University of Barcelona, Barcelona, Spain
| | | | - A Adán
- Head Ophthalmology Department, Hospital Clinic, Barcelona, Spain
| | - C Castellà
- Head Glaucoma Department, Hospital Joan XXIII, Tarragona, Spain
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Kimura K, Takayanagi R, Fukushima T, Yamada Y. Theoretical method for evaluation of therapeutic effects and adverse effects of epidermal growth factor receptor tyrosine kinase inhibitors in clinical treatment. Med Oncol 2017; 34:178. [PMID: 28887613 DOI: 10.1007/s12032-017-1036-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2017] [Accepted: 09/05/2017] [Indexed: 01/08/2023]
Abstract
Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are used for non-small cell lung cancer patients with an EGFR gene mutation. However, skin disorders are known as adverse events. In the present study, we investigated whether EGFR-TK occupancy is useful as an index for assessing clinical efficacy and adverse events for the proper use and development of EGFR-TKIs. Average binding occupancies (Φ ss) of EGFR-TKIs, gefitinib and erlotinib, for the EGFR-TK of cancer or skin cells were calculated. The relationships of Φ ss with response rate (RR) or frequency of rash were analyzed using the ternary complex model. Then, the relationships between the dose of EGFR-TKIs and RR or frequency of rash were examined. Gefitinib showed a greater difference for Φ ss value for both wild-type and mutant EGFR as compared to erlotinib at usual dose. The RR increased in a nonlinear manner rapidly rising when Φ ss exceeded 95%. It was thought that a very high Φ ss value might be needed to obtain the therapeutic effect of EGFR-TKIs. Meanwhile, the frequency of rash increased in a linear manner along with elevation of Φ ss. It was shown that the K d ratio (K d for mutant/K d for wild type) was less than 0.001, when the high RR and low frequency of rash were obtained simultaneously. The results showed that the therapeutic effects and skin disorder can be assessed by using Φ ss. Furthermore, it is likely that a proper choice of drug and dose can be made by using Φ ss in EGFR-TKI therapy.
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Affiliation(s)
- Koji Kimura
- Department of Clinical Evaluation of Drug Efficacy, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo, 192-0392, Japan.
| | - Risa Takayanagi
- Department of Clinical Evaluation of Drug Efficacy, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo, 192-0392, Japan
| | - Tomoki Fukushima
- Department of Clinical Evaluation of Drug Efficacy, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo, 192-0392, Japan
| | - Yasuhiko Yamada
- Department of Clinical Evaluation of Drug Efficacy, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo, 192-0392, Japan
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Miyata K, Takemoto A, Okumura S, Nishio M, Fujita N. Podoplanin enhances lung cancer cell growth in vivo by inducing platelet aggregation. Sci Rep 2017. [PMID: 28642617 PMCID: PMC5481446 DOI: 10.1038/s41598-017-04324-1] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023] Open
Abstract
Podoplanin/Aggrus, known as a platelet aggregation-inducing factor, is frequently overexpressed in lung squamous cell carcinomas (LSCC) and glioblastomas among other tumours, and its expression has been reported to be correlated with poor prognosis. However, the contribution of podoplanin to malignant progression has been elusive. Here we demonstrate that in podoplanin-positive LSCC cells, their growth was abrogated by podoplanin knockout in vivo but not in vitro. Conversely, ectopic expression of podoplanin promoted cell growth in vivo and facilitated intratumoral platelet activation. Consistently, LSCC cells evoked podoplanin-mediated platelet aggregation (PMPA), and the releasates from platelets during PMPA promoted the growth of LSCC cells in vitro. Phospho-receptor-tyrosine-kinase array analysis revealed that epidermal growth factor receptor (EGFR) phosphorylation of LSCC cells was responsible for the growth promotion induced by platelet releasates. Treatment with an antiplatelet agent or podoplanin-neutralizing antibody depressed the growth of an LSCC tumour xenograft via suppression of EGFR phosphorylation. These results suggested that podoplanin in LSCC enhanced cell growth by inducing PMPA in vivo and contributed to malignant progression.
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Affiliation(s)
- Kenichi Miyata
- Division of Experimental Chemotherapy, The Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, 3-8-31, Ariake, Koto-ku, Tokyo, 135-8550, Japan.,Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, 5-1-5, Kashiwanoha, Kashiwa-shi, Chiba, 277-8561, Japan
| | - Ai Takemoto
- Division of Experimental Chemotherapy, The Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, 3-8-31, Ariake, Koto-ku, Tokyo, 135-8550, Japan
| | - Sakae Okumura
- Thoracic Oncology Center, Cancer Institute Hospital, Japanese Foundation for Cancer Research, 3-8-31, Ariake, Koto-ku, Tokyo, 1350-8550, Japan
| | - Makoto Nishio
- Thoracic Oncology Center, Cancer Institute Hospital, Japanese Foundation for Cancer Research, 3-8-31, Ariake, Koto-ku, Tokyo, 1350-8550, Japan
| | - Naoya Fujita
- Division of Experimental Chemotherapy, The Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, 3-8-31, Ariake, Koto-ku, Tokyo, 135-8550, Japan. .,Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, 5-1-5, Kashiwanoha, Kashiwa-shi, Chiba, 277-8561, Japan. .,The Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, 3-8-31, Ariake, Koto-ku, Tokyo, 135-8550, Japan.
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Haddad J, Slika S, Mahfouz R. Epidermal growth factor receptor (EGFR) in the era of Precision Medicine: The tale of a perfect example of targeted therapy. A review. Meta Gene 2017. [DOI: 10.1016/j.mgene.2016.08.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022] Open
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Silva APS, Coelho PV, Anazetti M, Simioni PU. Targeted therapies for the treatment of non-small-cell lung cancer: Monoclonal antibodies and biological inhibitors. Hum Vaccin Immunother 2016; 13:843-853. [PMID: 27831000 PMCID: PMC5404364 DOI: 10.1080/21645515.2016.1249551] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023] Open
Abstract
The usual treatments for patients with non-small-cell lung cancer (NSCLC), such as advanced lung adenocarcinoma, are unspecific and aggressive, and include lung resection, radiotherapy and chemotherapy. Recently, treatment with monoclonal antibodies and biological inhibitors has emerged as an effective alternative, generating effective results with few side effects. In recent years, several clinical trials using monoclonal antibodies presented potential benefits to NSCLC, and 4 of them are already approved for the treatment of NSCLC, such as cetuximab, bevacizumab, nivolumab and pembrolizumab. Also, biological inhibitors are attractive tolls for biological applications. Among the approved inhibitors are crizotinib, erlotinib, afatinib and gefitinib, and side effects are usually mild to intense. Nevertheless, biological molecule treatments are under development, and several new monoclonal antibodies and biological inhibitors are in trial to treat NSCLC. Also under trial study are as follows: anti-epidermal growth factor receptor (EGFR) antibodies (nimotuzumab and ficlatuzumab), anti-IGF 1 receptor (IGF-1R) monoclonal antibody (figitumumab), anti-NR-LU-10 monoclonal antibody (nofetumomab) as well as antibodies directly affecting the cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) molecule (ipilimumab and tremelimumab), to receptor activator of nuclear factor-kappa B ligand (RANKL) (denosumab) or to polymerase enzyme (veliparib and olaparib). Among new inhibitors under investigation are poly-ADP ribose polymerase (PARP) inhibitors (veliparib and olaparib) and phosphatidylinositol 3-kinase (PI3K) inhibitor (buparlisib). However, the success of immunotherapies still requires extensive research and additional controlled trials to evaluate the long-term benefits and side effects.
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Affiliation(s)
- Ana P S Silva
- a Department of Biomedical Science , Faculty of Americana , Americana , SP , Brazil
| | - Priscila V Coelho
- a Department of Biomedical Science , Faculty of Americana , Americana , SP , Brazil
| | - Maristella Anazetti
- a Department of Biomedical Science , Faculty of Americana , Americana , SP , Brazil.,b Department of Health Science , Faculty DeVry Metrocamp , Campinas , SP , Brazil
| | - Patricia U Simioni
- a Department of Biomedical Science , Faculty of Americana , Americana , SP , Brazil.,c Department of Genetics , Evolution and Bioagents, Institute of Biology, University of Campinas (UNICAMP) , Campinas , SP , Brazil.,d Department of Biochemistry and Microbiology , Institute of Biosciences, Universidade Estadual Paulista, UNESP , Rio Claro , SP , Brazil
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Shinoda M, Akutsu H, Ohtani T, Tamura T, Satoh H. Lower limb lymphedema in lung adenocarcinoma: Two case reports. Mol Clin Oncol 2016; 5:478-479. [PMID: 27699046 DOI: 10.3892/mco.2016.988] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2016] [Accepted: 07/04/2016] [Indexed: 12/25/2022] Open
Abstract
Breast and gynecological cancers and their treatment may cause lymphedema of the upper and lower extremities, respectively. We herein report the cases of two patients with lung adenocarcinoma who developed lymphedema of the lower extremities. One patient harbored an epidermal growth factor receptor mutation and the other patient harbored an anaplastic lymphoma kinase fusion gene. The patients had developed intra-abdominal lymph node metastases and received several lines of chemotherapy. In both patients, lymphedema in the lower extremities developed >30 months after the initiation of first-line chemotherapy. To the best of our knowledge, these are the first reported cases of lung cancer patients who developed lymphedema in the lower extremities. Although rarely, lymphedema of the lower extremities may develop long after successful therapy with molecular-targeted therapy in advanced lung adenocarcinoma patients with a specific genetic etiological background.
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Affiliation(s)
- Misae Shinoda
- Division of Nursing, Mito Medical Center, University of Tsukuba, Mito, Ibaraki 310-0015, Japan
| | - Haruka Akutsu
- Division of Nursing, Mito Medical Center, University of Tsukuba, Mito, Ibaraki 310-0015, Japan
| | - Toshihiro Ohtani
- Division of Pharmacy, Mito Medical Center, University of Tsukuba, Mito, Ibaraki 310-0015, Japan
| | - Tomohiro Tamura
- Division of Respiratory Medicine, Mito Medical Center, University of Tsukuba, Mito, Ibaraki 310-0015, Japan
| | - Hiroaki Satoh
- Division of Respiratory Medicine, Mito Medical Center, University of Tsukuba, Mito, Ibaraki 310-0015, Japan
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Abdel-Rahman O, Elhalawani H. Risk of fatal pulmonary events in patients with advanced non-small-cell lung cancer treated with EGF receptor tyrosine kinase inhibitors: a comparative meta-analysis. Future Oncol 2016; 11:1109-22. [PMID: 25804125 DOI: 10.2217/fon.15.16] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023] Open
Abstract
We performed a meta-analysis of fatal pulmonary events associated with erlotinib, gefitinib or afatinib in patients with non-small-cell lung cancer (NSCLC). Eligible studies included randomized trials of patients with NSCLC on the three drugs describing events of high-grade pulmonary events. The relative risk of high-grade interstitial lung disease, pneumonitis, pneumonia, pulmonary embolism and hemoptysis were 4.18 (95% CI: 2.49-7.01; p < 0.00001), 1.94 (95% CI: 0.93-4.06; p = 0.08), 1.28 (95% CI: 0.92-1.77; p = 0.14), 1.6 (95% CI: 0.81-3.18 p = 0.17), 1.00 (95% CI: 0.14-7.08 p = 0.35), respectively. Our meta-analysis has demonstrated that erlotinib, gefitinib and afatinib are associated with an increased risk of high-grade interstitial lung disease in patients with NSCLC.
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Affiliation(s)
- Omar Abdel-Rahman
- Clinical Oncology Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt
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Matsuoka T, Yashiro M. Molecular targets for the treatment of pancreatic cancer: Clinical and experimental studies. World J Gastroenterol 2016; 22:776-789. [PMID: 26811624 PMCID: PMC4716076 DOI: 10.3748/wjg.v22.i2.776] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2015] [Revised: 08/13/2015] [Accepted: 09/30/2015] [Indexed: 02/06/2023] Open
Abstract
Pancreatic cancer is the fourth most common cause of cancer deaths worldwide. Although recent therapeutic developments for patients with pancreatic cancer have provided survival benefits, the outcomes for patients with pancreatic cancer remain unsatisfactory. Molecularly targeted cancer therapy has advanced in the past decade with the use of a number of pathways as candidates of therapeutic targets. This review summarizes the molecular features of this refractory disease while focusing on the recent clinical and experimental findings on pancreatic cancer. It also discusses the data supporting current standard clinical outcomes, and offers conclusions that may improve the management of pancreatic cancer in the future.
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Abdel-Rahman O, Fouad M. Risk of selected gastrointestinal toxicities in patients with advanced non-small cell lung cancer receiving erlotinib: a systematic review and meta-analysis. Expert Rev Anticancer Ther 2015; 15:465-475. [DOI: 10.1586/14737140.2015.1014035] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/30/2023]
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