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Cancers
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Emerging Therapies in Management of Gastrointestinal Malignancies
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Emerging Therapies in Management of Gastrointestinal Malignancies

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Therapy".

Deadline for manuscript submissions: closed (15 November 2023) | Viewed by 12223

Special Issue Editor

Dr. Amir A. Rahnemai Azar

E-Mail Website
Guest Editor
Division of Surgical Oncology and Hepatopancreatobiliary Surgery, Arrowhead Regional Academic Comprehensive Cancer Center, California University of Science and Medicine, Colton, CA 92324, USA
Interests: cholangiocarcinoma; biliary malignancies; primary liver cancers; metastatic liver malignancies; minimally invasive surgery

Special Issue Information

Dear Colleagues,

Gastrointestinal cancer is the leading cause of cancer related death globally. In recent decades, the paradigm of management of gastrointestinal malignancies has shifted from conventional cytotoxic chemotherapy regimens with limited benefit to more selective and efficient, mechanism-based therapeutics. Better understanding of genomic profiling and molecular pathogenesis of tumors has resulted in development of novel targeted therapies and precision medicine. Boosting host antitumor reaction via Immunotherapy has also revolutionized the landscape for treatment of some gastrointestinal cancers.

The management strategy of esophageal, gastric, and colorectal cancers has changed remarkably in the past decade, and there are promising developments in treatment of cancers with high fatality rate such as pancreas cancers and cholangiocarcinoma. In this special issue, we sincerely hope to gather experts to discuss the latest scientific developments in the field.

Dr. Amir A. Rahnemai Azar
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Published Papers (6 papers)

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Research

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14 pages, 2055 KiB  
Article
Prognosis and Treatment Outcomes of Bone Metastasis in Gallbladder Adenocarcinoma: A SEER-Based Study
by Kriti Gera, Doga Kahramangil, Graeme A. Fenton, Daniela Martir, Diana N. Rodriguez, Zohaib Ijaz, Rick Y. Lin, Sherise C. Rogers, Brian H. Ramnaraign, Thomas J. George, Young-Rock Hong, Steven J. Hughes, Ibrahim Nassour and Ilyas Sahin
Cancers 2023, 15(20), 5055; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers15205055 - 19 Oct 2023
Cited by 1 | Viewed by 1893
Abstract
Background: Gallbladder carcinoma (GBC) is a rare, aggressive malignancy comprising 0.5% of gastrointestinal cancers. It has poor survival outcomes due to its insidious onset, lack of standardized screening, and limited therapies. Advanced-stage diagnosis with liver, lymph node, and peritoneal metastasis is common, while [...] Read more.
Background: Gallbladder carcinoma (GBC) is a rare, aggressive malignancy comprising 0.5% of gastrointestinal cancers. It has poor survival outcomes due to its insidious onset, lack of standardized screening, and limited therapies. Advanced-stage diagnosis with liver, lymph node, and peritoneal metastasis is common, while bone metastasis is rare. The knowledge on bone metastasis in GBC is limited to case reports and small series, and its clinical significance is largely unexplored. Methods: The study extracted the demographic and clinical variables of patients with metastatic (M1) gallbladder adenocarcinoma from the Surveillance, Epidemiology, and End Results (SEER) database between 2011 and 2020. Descriptive statistics were used to analyze the demographic characteristics. The multivariate Cox regression analysis was used to calculate the hazard ratio. The overall survival (OS) was assessed using the Kaplan–Meier method, and the log-rank test was utilized to compare the survival between the groups. Results: A total of 2724 patients were included in the study. A total of 69% of the patients were female, and the median age was 68 (range 24–90+). A total of 7.4% of the patients had bone metastasis on diagnosis. The multivariate Cox analysis identified bone metastasis as an independent mortality risk factor in metastatic GBC (HR 1.50, p < 0.001). The patients were divided into two age groups: a younger age group (18–74 years) and an older age group (75+ years). In the younger group, the median OS with and without bone metastasis was 3 and 5 months, respectively (p < 0.0001). In the older age group, there was no significant difference in the OS between the patients with and without bone metastasis (p = 0.35). In the younger group who were treated with chemotherapy, the patients with bone metastasis had a significantly worse OS (median OS 5 months vs. 8 months, p < 0.0001). In the untreated group, the patients with bone metastasis in the younger age group had a significantly worse OS (median OS 1 month vs. 2 months, p = 0.014). In the patients with bone metastasis, those who did not receive chemotherapy had a significantly worse OS than those who were treated with chemotherapy in both age groups (younger age group: median OS 1 month vs. 5 months, p < 0.0001 and older age group: median OS 1 month vs. 5 months, p = 0.041). Conclusions: Our findings suggest that the presence of bone metastasis in gallbladder adenocarcinoma is an independent prognostic factor associated with unfavorable survival outcomes in the younger age group (18–74 years). However, in the older age group (75+ years), the presence of bone metastasis did not impact the survival. Treatment with chemotherapy was associated with extended survival in all patients. Thus, early detection and aggressive management of bone metastasis, including the consideration of chemotherapy, may be crucial in improving the OS and quality of life for individuals with gallbladder adenocarcinoma. Full article
(This article belongs to the Special Issue Emerging Therapies in Management of Gastrointestinal Malignancies)
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17 pages, 3683 KiB  
Article
The Anti-Tumor Effect of the Newly Developed LAT1 Inhibitor JPH203 in Colorectal Carcinoma, According to a Comprehensive Analysis
by Rina Otani, Hidehiko Takigawa, Ryo Yuge, Daisuke Shimizu, Misa Ariyoshi, Ryo Miyamoto, Hiroki Kadota, Yuichi Hiyama, Ryohei Hayashi, Yuji Urabe, Akira Ishikawa, Naohide Oue, Yasuhiko Kitadai, Shiro Oka and Shinji Tanaka
Cancers 2023, 15(5), 1383; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers15051383 - 22 Feb 2023
Cited by 2 | Viewed by 2117
Abstract
A novel large neutral amino acid transporter 1 (LAT1)-specific inhibitor, JPH203, is expected to cause cancer-specific starvation and possess anti-tumor effects; however, its anti-tumor mechanism for colorectal cancer (CRC) remains unclear. We analyzed LAT family gene expressions in public databases using UCSC Xena [...] Read more.
A novel large neutral amino acid transporter 1 (LAT1)-specific inhibitor, JPH203, is expected to cause cancer-specific starvation and possess anti-tumor effects; however, its anti-tumor mechanism for colorectal cancer (CRC) remains unclear. We analyzed LAT family gene expressions in public databases using UCSC Xena and evaluated LAT1 protein expression using immunohistochemistry in 154 cases of surgically resected CRC. We also evaluated mRNA expression using polymerase chain reaction in 10 CRC cell lines. Furthermore, JPH203 treatment experiments were conducted in vitro and in vivo using an allogeneic immune-responsive mouse model with abundant stroma created via the orthotopic transplantation of the mouse-derived CRC cell line CT26 and mesenchymal stem cells. The treatment experiments were followed by comprehensive gene expression analyses with RNA sequencing. Database analyses and immunohistochemistry research on clinical specimens revealed that LAT1 expression was cancer-dominant, and its increase was accompanied by tumor progression. In vitro, JPH203 was effective in an LAT1 expression-dependent manner. In vivo, JPH203 treatment considerably reduced tumor size and metastasis, and RNA sequencing-based pathway analysis showed that not only tumor growth and amino acid metabolism pathways, but also stromal activation-related pathways were suppressed. The results of the RNA sequencing were validated in the clinical specimens, as well as both in vitro and in vivo. LAT1 expression in CRC plays an important role in tumor progression. JPH203 may inhibit the progression of CRC and tumor stromal activity. Full article
(This article belongs to the Special Issue Emerging Therapies in Management of Gastrointestinal Malignancies)
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Review

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17 pages, 833 KiB  
Review
Emerging Therapies in Management of Cholangiocarcinoma
by Jessica Speckart, Veronica Rasmusen, Zohray Talib, Dev A. GnanaDev and Amir A. Rahnemai-Azar
Cancers 2024, 16(3), 613; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers16030613 - 31 Jan 2024
Viewed by 1692
Abstract
Cholangiocarcinoma is a heterogeneous group of biliary tract cancers that has a poor prognosis and globally increasing incidence and mortality. While surgical resection remains the only curative option for the treatment of cholangiocarcinoma, the majority of cancers are unresectable at the time of [...] Read more.
Cholangiocarcinoma is a heterogeneous group of biliary tract cancers that has a poor prognosis and globally increasing incidence and mortality. While surgical resection remains the only curative option for the treatment of cholangiocarcinoma, the majority of cancers are unresectable at the time of diagnosis. Additionally, the prognosis of cholangiocarcinoma remains poor even with the current first-line systemic therapy regimens, highlighting the difficulty of treating locally advanced, metastatic, or unresectable cholangiocarcinoma. Through recent developments, targetable oncogenic driver mutations have been identified in the pathogenesis of cholangiocarcinoma, leading to the utilization of molecular targeted therapeutics. In this review, we comprehensively discuss the latest molecular therapeutics for the treatment of cholangiocarcinoma, including emerging immunotherapies, highlighting promising developments and strategies. Full article
(This article belongs to the Special Issue Emerging Therapies in Management of Gastrointestinal Malignancies)
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20 pages, 1370 KiB  
Review
Mutational Landscape and Precision Medicine in Hepatocellular Carcinoma
by Leva Gorji, Zachary J. Brown and Timothy M. Pawlik
Cancers 2023, 15(17), 4221; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers15174221 - 23 Aug 2023
Cited by 1 | Viewed by 1524
Abstract
Hepatocellular carcinoma (HCC) is the fourth most common malignancy worldwide and exhibits a universal burden as the incidence of the disease continues to rise. In addition to curative-intent therapies such as liver resection and transplantation, locoregional and systemic therapy options also exist. However, [...] Read more.
Hepatocellular carcinoma (HCC) is the fourth most common malignancy worldwide and exhibits a universal burden as the incidence of the disease continues to rise. In addition to curative-intent therapies such as liver resection and transplantation, locoregional and systemic therapy options also exist. However, existing treatments carry a dismal prognosis, often plagued with high recurrence and mortality. For this reason, understanding the tumor microenvironment and mutational pathophysiology has become the center of investigation for disease control. The use of precision medicine and genetic analysis can supplement current treatment modalities to promote individualized management of HCC. In the search for personalized medicine, tools such as next-generation sequencing have been used to identify unique tumor mutations and improve targeted therapies. Furthermore, investigations are underway for specific HCC biomarkers to augment the diagnosis of malignancy, the prediction of whether the tumor environment is amenable to available therapies, the surveillance of treatment response, the monitoring for disease recurrence, and even the identification of novel therapeutic opportunities. Understanding the mutational landscape and biomarkers of the disease is imperative for tailored management of the malignancy. In this review, we summarize the molecular targets of HCC and discuss the current role of precision medicine in the treatment of HCC. Full article
(This article belongs to the Special Issue Emerging Therapies in Management of Gastrointestinal Malignancies)
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16 pages, 1008 KiB  
Review
The Present and Future of Neoadjuvant and Adjuvant Therapy for Locally Advanced Gastric Cancer
by Anna S. Koerner, Ryan H. Moy, Sandra W. Ryeom and Sam S. Yoon
Cancers 2023, 15(16), 4114; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers15164114 - 15 Aug 2023
Cited by 4 | Viewed by 1964
Abstract
Gastric cancer is a highly prevalent and lethal disease worldwide. Given the insidious nature of the presenting symptoms, patients are frequently diagnosed with advanced, unresectable disease. However, many patients will present with locally advanced gastric cancer (LAGC), which is often defined as the [...] Read more.
Gastric cancer is a highly prevalent and lethal disease worldwide. Given the insidious nature of the presenting symptoms, patients are frequently diagnosed with advanced, unresectable disease. However, many patients will present with locally advanced gastric cancer (LAGC), which is often defined as the primary tumor extending beyond the muscularis propria (cT3-T4) or having nodal metastases (cN+) disease and without distant metastases (cM0). LAGC is typically treated with surgical resection and perioperative chemotherapy. The treatment of LAGC remains a challenge, given the heterogeneity of this disease, and the optimal multimodal treatment regimen may be different for different LAGC subtypes. However, many promising treatments are on the horizon based on knowledge of molecular subtypes and key biomarkers of LAGC, such as microsatellite instability, HER2, Claudin 18.2, FGFR2, and PD-L1. This review will expand upon the discussion of current standard neoadjuvant and adjuvant therapies for LAGC and explore the ongoing and future clinical trials for novel therapies, with information obtained from searches in PubMed and ClinicalTrials.gov. Full article
(This article belongs to the Special Issue Emerging Therapies in Management of Gastrointestinal Malignancies)
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26 pages, 635 KiB  
Review
State of the Art: ctDNA in Upper Gastrointestinal Malignancies
by Ibone Labiano, Ana Elsa Huerta, Virginia Arrazubi, Irene Hernandez-Garcia, Elena Mata, David Gomez, Hugo Arasanz, Ruth Vera and Maria Alsina
Cancers 2023, 15(5), 1379; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers15051379 - 21 Feb 2023
Cited by 4 | Viewed by 2399
Abstract
Circulating tumor DNA (ctDNA) has emerged as a promising non-invasive source to characterize genetic alterations related to the tumor. Upper gastrointestinal cancers, including gastroesophageal adenocarcinoma (GEC), biliary tract cancer (BTC) and pancreatic ductal adenocarcinoma (PADC) are poor prognostic malignancies, usually diagnosed at advanced [...] Read more.
Circulating tumor DNA (ctDNA) has emerged as a promising non-invasive source to characterize genetic alterations related to the tumor. Upper gastrointestinal cancers, including gastroesophageal adenocarcinoma (GEC), biliary tract cancer (BTC) and pancreatic ductal adenocarcinoma (PADC) are poor prognostic malignancies, usually diagnosed at advanced stages when no longer amenable to surgical resection and show a poor prognosis even for resected patients. In this sense, ctDNA has emerged as a promising non-invasive tool with different applications, from early diagnosis to molecular characterization and follow-up of tumor genomic evolution. In this manuscript, novel advances in the field of ctDNA analysis in upper gastrointestinal tumors are presented and discussed. Overall, ctDNA analyses can help in early diagnosis, outperforming current diagnostic approaches. Detection of ctDNA prior to surgery or active treatment is also a prognostic marker that associates with worse survival, while ctDNA detection after surgery is indicative of minimal residual disease, anticipating in some cases the imaging-based detection of progression. In the advanced setting, ctDNA analyses characterize the genetic landscape of the tumor and identify patients for targeted-therapy approaches, and studies show variable concordance levels with tissue-based genetic testing. In this line, several studies also show that ctDNA serves to follow responses to active therapy, especially in targeted approaches, where it can detect multiple resistance mechanisms. Unfortunately, current studies are still limited and observational. Future prospective multi-center and interventional studies, carefully designed to assess the value of ctDNA to help clinical decision-making, will shed light on the real applicability of ctDNA in upper gastrointestinal tumor management. This manuscript presents a review of the evidence available in this field up to date. Full article
(This article belongs to the Special Issue Emerging Therapies in Management of Gastrointestinal Malignancies)
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