Gastrointestinal cancer : targets and therapy最新文献

{"title":"Evidence for improvements to risk stratification in high-risk gastrointestinal stromal tumor patients","authors":"A. Greco, S. Rossi, C. Ruffolo, B. Pauletti, A. D. Dei Tos, G. Morana, M. Massani","doi":"10.2147/GICTT.S145037","DOIUrl":"https://doi.org/10.2147/GICTT.S145037","url":null,"abstract":": Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. Significant prognostic heterogeneity has been described with GISTs, which can range from clinically benign to frankly malignant tumors. Although several GISTs classification systems have been established to identify tumors with high risk of relapse, there is a sample of patients who still do not receive an appropriate treatment. The classification scores by Fletcher et al and Miettinen and Lasota are the most widely clinically accepted, while the Memorial Sloan Kettering Cancer Center prognostic nomogram is considered the most feasible. There are several studies about new prognostic factors in radiological, biological, and surgical fields. Tumors with mixed growth pattern, enlarged vessels feeding, or draining the mass on computed tomography or with high standardized uptake values on positron emission tomography/ computed tomography should be considered as high-grade GISTs. Among biological markers, the most relevant are programmed cell death ligand 1, Pfetin, SETD2, SLITRK3, mir-215-5p, and monoglyceride lipase. These factors need to be further investigated in order to validate their use in risk stratification. Laparoscopy and open surgery can have the same oncological outcomes even for larger gastric tumors, up to 10 cm. Laparoscopy should be considered the best surgical approach when executed by skilled surgeons and for tumor localized in reachable sites. Adjuvant chemotherapy with imatinib is recommended for high-grade GIST, but the optimal duration of this therapy is still debated. Some authors advocated that imatinib treatment should last for 5 years. A subgroup of GIST is represented by small GISTs, lesions < 2 cm in diameter, which need a radical surgical treatment in the presence of symptoms or when high-risk factors such as irregular borders, cystic spaces, ulceration, echogenic foci, internal heterogeneity, tumor progression during follow-up, small intestinal or colorectal localization are present.","PeriodicalId":90503,"journal":{"name":"Gastrointestinal cancer : targets and therapy","volume":"31 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2018-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86984353","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}

{"title":"Emerging treatment options for <i>BRAF</i>-mutant colorectal cancer.","authors":"Carling Ursem,&nbsp;Chloe E Atreya,&nbsp;Katherine Van Loon","doi":"10.2147/GICTT.S125940","DOIUrl":"10.2147/GICTT.S125940","url":null,"abstract":"<p><p>The personalization of cancer care is rooted in the premise that there are subsets of patients with tumors harboring clinically relevant targets for patient-specific treatments. Colorectal cancer (CRC) is a disease that has historically been notable for its dearth of biomarkers that are predictive of response to targeted therapies. In recent years, <i>BRAF</i>^V600E-mutated CRC has emerged as a distinct biologic entity, typically refractory to standard chemotherapy regimens approved for the treatment of metastatic CRC and associated with a dismal prognosis. Multiple clinical trials sought to replicate the successes of targeted therapies seen in <i>BRAF</i>^V600E-mutated melanoma without success; metastatic <i>BRAF</i>^V600E-mutated CRC is clearly a distinct biologic entity. We review a number of recent studies demonstrating the evidence of modest responses to combinations of BRAF, EGFR, and/or MEK inhibition in patients with metastatic <i>BRAF</i>^V600E-mutated CRC; however, despite advances, overall survival remains far inferior for these patients compared to their <i>BRAF</i>-wild-type counterparts. Development of combination therapies to impede signaling through the <i>MAPK</i> pathway through alternate targets remains an area of active investigation. Reflecting the rapid evolution of efforts for this small subset of CRC patients, the first-ever Phase III study is now underway evaluating the combination of <i>BRAF</i>, <i>EGFR</i>, and <i>MEK</i> inhibition. Immunotherapies are also an area of active research, particularly for the subset of patients with tumors that are also microsatellite instability (MSI) high. Here, we summarize the current landscape and emerging data on the molecular, clinical, and therapeutic aspects of <i>BRAF</i>-mutant CRC.</p>","PeriodicalId":90503,"journal":{"name":"Gastrointestinal cancer : targets and therapy","volume":"8 ","pages":"13-23"},"PeriodicalIF":0.0,"publicationDate":"2018-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2147/GICTT.S125940","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35985737","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PD-1 and PD-L1 as emerging therapeutic targets in gastric cancer: current evidence.","authors":"Phu N Tran,&nbsp;Sarmen Sarkissian,&nbsp;Joseph Chao,&nbsp;Samuel J Klempner","doi":"10.2147/GICTT.S113525","DOIUrl":"https://doi.org/10.2147/GICTT.S113525","url":null,"abstract":"<p><p>Gastric adenocarcinoma is a leading cause of global cancer-related morbidity and mortality, and new therapeutic approaches are needed. Despite the improved outcomes with monoclonal antibodies targeting human epidermal growth factor receptor 2 and vascular endothelial growth factor receptor 2, durable responses are uncommon. Targeting immune checkpoints including PD-1, PD-L1 and CTLA-4 have led to improved survival across several tumor types, frequently characterized by prolonged benefit in responding patients. Tumoral and lymphocyte-derived immunohistochemical staining for PD-1, PD-L1, and tumor mutational burden have shown potential as predictive response biomarkers in several tumor types. Optimal incorporation of immune-mediated therapies into gastric cancer (GC) is an area of intense ongoing investigation and benefit has been demonstrated in smaller studies of advanced patients. Important questions of biomarker selection, roles for molecular characterization, optimal combinatorial approaches, and therapeutic sequencing remain. In this study, current data are reviewed for immune checkpoint inhibitors in GC, and putative biomarkers, ongoing trials, and future considerations are discussed.</p>","PeriodicalId":90503,"journal":{"name":"Gastrointestinal cancer : targets and therapy","volume":"7 ","pages":"1-11"},"PeriodicalIF":0.0,"publicationDate":"2017-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2147/GICTT.S113525","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35365699","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Spotlight on bevacizumab in metastatic colorectal cancer: patient selection and perspectives","authors":"M. Bupathi, D. Ahn, T. Bekaii-Saab","doi":"10.2147/GICTT.S97740","DOIUrl":"https://doi.org/10.2147/GICTT.S97740","url":null,"abstract":"Metastatic colorectal cancer (mCRC) is a prevalent disease for which combination cytotoxic chemotherapy is the mainstay of treatment. With the use of targeted therapy, including anti-angiogenic agents, there have been significant improvements in overall outcome of patients with mCRC. Bevacizumab, a monoclonal antibody targeting the vascular endothelial growth factor ligand A, is approved for use in mCRC patients in both the first and second lines of therapy. With a better understanding of the disease through molecular profiling, identification of prognostic biomarkers may lead to better patient selection with improved outcomes for those affected by this disease.","PeriodicalId":90503,"journal":{"name":"Gastrointestinal cancer : targets and therapy","volume":"6 1","pages":"21 - 30"},"PeriodicalIF":0.0,"publicationDate":"2016-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2147/GICTT.S97740","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"68359915","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}

{"title":"Von Hippel-Lindau status influences phenotype of liver cancers arising from PTEN loss.","authors":"Adam B Sendor,&nbsp;Kathryn E Hacker,&nbsp;Shufen Chen,&nbsp;Armando L Corona,&nbsp;Oishee Sen,&nbsp;Derek Y Chiang,&nbsp;Anna Snavely,&nbsp;Arlin B Rogers,&nbsp;Stephanie A Montgomery,&nbsp;W Kimryn Rathmell,&nbsp;Autumn J McRee","doi":"10.2147/GICTT.S72274","DOIUrl":"https://doi.org/10.2147/GICTT.S72274","url":null,"abstract":"<p><strong>Background: </strong><i>PTEN</i> loss contributes to the development of liver diseases including hepatic steatosis and both hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC). The factors that influence the penetrance of these conditions are unclear. We explored the influence of sustained hypoxia signaling through co-deletion of <i>Pten</i> and <i>Vhl</i> in a murine model.</p><p><strong>Methods: </strong>We used a CreER-linked Keratin 18 mouse model to conditionally delete <i>Pten</i>, <i>Vhl</i> or both in somatic cells of adult mice, evaluating the resultant tumors by histology and gene expression microarray. Existing sets of gene expression data for human HCC and CC were examined for pathways related to those observed in the murine tumors, and a cohort of human CC samples was evaluated for relationships between HIF-1α expression and clinical outcomes.</p><p><strong>Results: </strong>Both <i>Pten</i> deletion genotypes developed liver tumors, but with differing phenotypes. <i>Pten</i> deletion alone led to large hepatic tumors with widespread hepatosteatosis. Co-deletion of <i>Pten</i> and <i>Vhl</i> with the Keratin 18 promoter resulted in reduced steatosis and a reduced tumor burden that was characterized by a trabecular architecture similar to CC. Genes associated with hepatic steatosis were coordinately expressed in the human HCC dataset, while genes involved in hypoxia response were upregulated in tumors from the human CC dataset. HIF-1α expression and overall survival were examined in an independent cohort of human CC tumors with no statistical differences uncovered.</p><p><strong>Conclusion: </strong><i>Pten</i> deletion in Keratin 18 expressing cells leads to aggressive tumor formation and widespread steatosis in mouse livers. Co-deletion of <i>Vhl</i> and <i>Pten</i> results in lower tumor burden with gene expression profiling suggesting a switch from a profile of lipid deposition to an expression profile more consistent with upregulation of the hypoxia response pathway. A relationship between tumor hypoxia signaling and altered hepatic steatotic response suggests that competing influences may alter tumor phenotypes.</p>","PeriodicalId":90503,"journal":{"name":"Gastrointestinal cancer : targets and therapy","volume":"5 ","pages":"61-71"},"PeriodicalIF":0.0,"publicationDate":"2015-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2147/GICTT.S72274","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33192566","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Esophageal cancer-related gene 4 at the interface of injury, inflammation, infection, and malignancy.","authors":"Andrew Baird,&nbsp;Jisook Lee,&nbsp;Sonia Podvin,&nbsp;Arwa Kurabi,&nbsp;Xitong Dang,&nbsp;Raul Coimbra,&nbsp;Todd Costantini,&nbsp;Vishal Bansal,&nbsp;Brian P Eliceiri","doi":"10.2147/GICTT.S49085","DOIUrl":"https://doi.org/10.2147/GICTT.S49085","url":null,"abstract":"<p><p>In humans, esophageal cancer-related gene 4 (ECRG4) is encoded by four exons in the c2orf40 locus of chromosome 2. Translation of ECRG4 messenger ribonucleic acid produces a 148 amino acid-secreted 17 KDa protein that is then processed to 14, ten, eight, six, four, and two KDa peptides, depending on the cell in which the gene is expressed. As hypermethylation at the c2orf40 locus inhibits ECRG4 gene expression in many epithelial cancers, several investigators have speculated that ECRG4 is a candidate tumor suppressor. Indeed, overexpression of ECRG4 inhibits cell proliferation in vitro, but it also has a wide range of effects in vivo beyond its antitumor activity. ECRG4 overexpression affects apoptosis, senescence, cell migration, inflammation, injury, and infection responsiveness. ECRG4 activities also depend on its cellular localization, secretion, and post-translational processing. These cytokine/chemokine-like characteristics argue that ECRG4 is not a traditional candidate tumor suppressor gene, as originally predicted by its downregulation in cancer. We review how insights into the regulation of ECRG4 gene expression, knowledge of its primary structure, and the study of its emerging physiological functions come together to support a much more complex role for ECRG4 at the interface of inflammation, infection, and malignancy.</p>","PeriodicalId":90503,"journal":{"name":"Gastrointestinal cancer : targets and therapy","volume":"2014 4","pages":"131-142"},"PeriodicalIF":0.0,"publicationDate":"2014-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2147/GICTT.S49085","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"32967362","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}