Biomarkers for Early Detection, Prognosis, and Therapeutics of Esophageal Cancers.

Esophageal cancer (EC) is the deadliest cancer worldwide, with a 92% annual mortality rate per incidence. Esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC) are the two major types of ECs, with EAC having one of the worst prognoses in oncology. Limited screening techniques and a lack of molecular analysis of diseased tissues have led to late-stage presentation and very low survival durations. The five-year survival rate of EC is less than 20%. Thus, early diagnosis of EC may prolong survival and improve clinical outcomes. Cellular and molecular biomarkers are used for diagnosis. At present, esophageal biopsy during upper endoscopy and histopathological analysis is the standard screening modality for both ESCC and EAC. However, this is an invasive method that fails to yield a molecular profile of the diseased compartment. To decrease the invasiveness of the procedures for diagnosis, researchers are proposing non-invasive biomarkers for early diagnosis and point-of-care screening options. Liquid biopsy involves the collection of body fluids (blood, urine, and saliva) non-invasively or with minimal invasiveness. In this review, we have critically discussed various biomarkers and specimen retrieval techniques for ESCC and EAC.

Current state of prognostication, therapy and prospective innovations for Barrett's-related esophageal adenocarcinoma: a literature review.

OBJECTIVE: Barrett's esophagus (BE) is the only known precursor to esophageal adenocarcinoma (EAC), which has one of the lowest 5-year survival rates in oncology. The reasons for poor survival are twofold: the large majority of diagnoses are in advanced stages (~80%) and limited treatment options, with a deficit of biology-guided therapies. As a rapidly growing public health concern with poor prognosis, research into the molecular progression for BE and novel therapeutics for EAC currently has high clinical utility. Review of the literature reveals that innovative analysis of metaplastic progression from BE to EAC at a molecular level can shed light on the underlying transformative probabilities of BE into malignant pathologies and may impact current of future therapeutic modalities for management of these diseases. BACKGROUND: EAC is the fastest increasing cancer in the United States with a 600% increase over the past 25 years. This cancer arises from dysplastic tissue of BE, a complication of gastroesophageal reflux disease (GERD). Chronic acid and bile reflux in the distal esophagus initiates a metaplastic conversion of normal squamous epithelium to premalignant intestinalized columnar epithelium. Patients with BE have a 125-fold higher risk of cancer compared to the general population. METHODS: We critically reviewed the current status of BE monitoring, and subsequent therapeutic strategies being used in patients who have progressed to cancer. Also, new diagnostic tools and therapeutic candidates for BE-related EAC are discussed. Highly-targeted searches of databases containing recent original peer-reviewed papers were utilized for this review. CONCLUSIONS: Novel and well-described biomarkers analyzed in the patient's diseased tissue will provide for more powerful diagnostics, but also possess the potential to develop strategies for personalized management and identify targets for intervention to either cease disease progression or treat BE and/or EAC. Since millions of Americans develop BE without progressing to cancer, there is a critical need to identify the small percentage of Barrett's patients who possess hallmarks of disease progression or carcinogenesis with novel screening techniques. Incorporation of such tools into standard screening protocols for BE surveillance and/or therapy would be critical to detect malignant transformations before clinically obvious cancer ever develops.

Corrigendum: Discovery of Novel and Clinically Relevant Markers in Formalin-Fixed Paraffin-Embedded Esophageal Cancer Specimen.

[This corrects the article DOI: 10.3389/fonc.2018.00157.].

Discovery of Novel and Clinically Relevant Markers in Formalin-Fixed Paraffin-Embedded Esophageal Cancer Specimen.

Due to the ineffectiveness of chemoradiation and targeted therapy in esophageal anticancer care and the subsequent low survival rates, we constructed a high throughput method to discover and investigate new markers with prognostic, diagnostic, and therapeutic clinical utility. This was accomplished by developing a quick, inexpensive, and dependable platform to simultaneously quantify thousands of proteins which subsequently revealed novel markers involved in the pathogenesis of esophageal adenocarcinoma (EAC) via discovery mass spectrometry paired with conservative biostatistics. Our method uncovered a perfect storm of tumor suppressors being downregulated, proliferation markers ramped up, and chemoresistance markers overexpressed-many of which could serve as new therapy targets for EAC. The 12 markers discovered by this method are novel regarding their involvement in the pathogenesis of EAC. The molecular oncology arena now has a dozen new proteomic targets suitable for validation and elucidation of their clinical utility via gene knockdown in cellular and animal models. This new method can be replicated and applied to other cancers or disease states for research and development and discovery-based investigations. Our findings, which serve as a proof of concept, will hopefully motivate research groups to further expound on the molecular processes involved in the aggressiveness of EAC and other solid tumor diseases, ultimately leading to improved patient management strategies.

Immunotherapy Plus Cryotherapy: Potential Augmented Abscopal Effect for Advanced Cancers.

Since the 1920s the gold standard for treating cancer has been surgery, which is typically preceded or followed with chemotherapy and/or radiation, a process that perhaps contributes to the destruction of a patient's immune defense system. Cryosurgery ablation of a solid tumor is mechanistically similar to a vaccination where hundreds of unique antigens from a heterogeneous population of tumor cells derived from the invading cancer are released. However, releasing tumor-derived self-antigens into circulation may not be sufficient enough to overcome the checkpoint escape mechanisms some cancers have evolved to avoid immune responses. The potentiated immune response caused by blocking tumor checkpoints designed to prevent programmed cell death may be the optimal treatment method for the immune system to recognize these new circulating cryoablated self-antigens. Preclinical and clinical evidence exists for the complementary roles for Cytotoxic T-lymphocyte-associated protein (CTLA-4) and PD-1 antagonists in regulating adaptive immunity, demonstrating that combination immunotherapy followed by cryosurgery provides a more targeted immune response to distant lesions, a phenomenon known as the abscopal effect. We propose that when the host's immune system has been "primed" with combined anti-CTLA-4 and anti-PD-1 adjuvants prior to cryosurgery, the preserved cryoablated tumor antigens will be presented and processed by the host's immune system resulting in a robust cytotoxic CD8+ T-cell response. Based on recent investigations and well-described biochemical mechanisms presented herein, a polyvalent autoinoculation of many tumor-specific antigens, derived from a heterogeneous population of tumor cancer cells, would present to an unhindered yet pre-sensitized immune system yielding a superior advantage in locating, recognizing, and destroying tumor cells throughout the body.

Cellular and molecular targets for the immunotherapy of hepatocellular carcinoma.

Liver cancer is the sixth most common cancer worldwide and 3rd most common cause of cancer-related death. Hepatocellular carcinoma (HCC) represents more than 90% of primary liver cancer and is a major public health problem. Due to the advanced stages of HCC at the time of diagnosis, utilizing the conventional treatment for solid tumors frequently ends with treatment failure, recurrence, or poor survival. HCC is highly refractory to chemotherapy and other systemic treatments, and locoregional therapies or selective internal radiation therapies are largely palliative. Considering how the pathogenesis of HCC often induces an immunosuppressed state which is further amplified by post-treatment recurrence and reactivation, immunostimulation provides a potential novel approach for the treatment of HCC. Immune response(s) of the body may be potentiated by immunomodulation of various effector cells such as B-cells, T-cells, Treg cells, natural killer cells, dendritic cells, cytotoxic T-lymphocytes, and other antigen-presenting cells; cellular components such as genes and microRNA; and molecules such as proteins, proteoglycans, surface receptors, chemokines, and cytokines. Targeting these effectors individually has helped in the development of newer therapeutic approaches; however, combinational therapies targeting multi-faceted biomarkers have yielded better results. Still, there is a need for further research to develop novel therapeutic strategies which may act as either complementary or an alternative treatment to the standard therapy protocols of HCC. This review focuses on potential cellular and molecular targets, as well as the role of virotherapy and combinational therapy in the treatment of HCC.

Neoadjuvant Therapy for Esophageal Adenocarcinoma in the Community Setting-Practice and Outcomes.

There has been an alarming rise in the incidence of esophageal adenocarcinoma which continues to have poor survival rates primarily due to lack of effective chemotherapy and presentation at advanced stages. Over a dozen chemotherapeutic agents are FDA approved for esophageal cancer (EC), and a two or three-drug combination is typically prescribed as first-line therapy for the majority of EC patients, administered either pre or post-operatively with esophageal resection. We have noticed significant variability in adjuvant and neoadjuvant regimens used in the community setting. The aim of this study was to review the various drug regimens used in the neoadjuvant setting for EC patients with adenocarcinoma undergoing resection at a single tertiary referral center in the Midwest. A total of 123 patients (stage II-III) underwent esophageal resection after neoadjuvant treatment at the center. Overall, 18 distinct drug regimens were used in 123 patients including two patients who received targeted therapy. Median survival post-surgery for this group was 11.2 months with no single regimen offering a survival advantage. These results reveal an unclear algorithm of how accepted regimens are prescribed in the community setting as well as a dire need for agents that are more effective. Additionally, it was noted that although proteomic markers have been found to predict drug response to 92% of the FDA-approved drugs in EC (12 of 13), according to pathology reports, molecular diagnostic testing was not used to direct treatment in this cohort. We therefore propose potential strategies to improve clinical outcomes including the use of a robust molecular oncology diagnostic panel and discuss the potential role for targeted chemotherapy and/or immunotherapy in the management of EC patients.

Vitamin D Receptor Polymorphism and Cancer: An Update.

BACKGROUND: Vitamin D mediates its action via vitamin D receptor (VDR) and is involved in a wide variety of biological processes including regulation of cell proliferation and differentiation in normal tissue and apoptosis, and cell adhesion in tumor cells. The study of genetic variations in VDR may elucidate the association of vitamin D levels, its metabolism, and VDR polymorphism with various diseases and cancer. The association of VDR polymorphism with cancer has been reported; however, the literature lacks critical analyses of the studies in last 3 years. MATERIALS AND METHODS: A systematic search of PubMed database (2015 through mid-2017) was conducted to provide a comprehensive overview of this clinical arena. RESULTS: Studies on the association of VDR polymorphisms FokI, BsmI, TaqI, and ApaI and cancer have suggested the involvement of VDR polymorphism in tumorigenesis. CONCLUSION: The inconsistent results and lack of the studies in some cancer types warrant additional research.

Interplay of Immunity and Vitamin D: Interactions and Implications with Current IBD Therapy.

Crohn's disease (CD) and ulcerative colitis (UC) are classified under inflammatory bowel disease (IBD) which has been linked to a multifaceted etiology involving both environmental and genetic factors that intersect with the vitamin D pathway. Dysfunctions in innate immune defense mechanisms in the epithelial compartment of the intestine play a crucial role in the pathogenesis of IBD. Symptoms of IBD are caused by excessive immune responses to luminal bacteria, and vitamin D has been shown to play a role in intestinal defense by aiding in the suppression of microbial invasion into the epithelium. Vitamin D, as an immunomodulator, can modify the innate immune response of the body. Vitamin D attenuates the transcription of pro-inflammatory cytokines that are upregulated in the event of epithelial stress common in patients with IBD. Vitamin D deficiency was identified in 82% of IBD patients compared to the 31% national average and has been linked to defective epithelial processes at both genomic and proteomic levels. Mucosal damage and an impaired immune response are at the center of IBD, and vitamin D aids in sustaining the structural integrity of epithelial cells while enhancing innate immune responses in the mucosa. Here we provide a systematic review of the pathophysiological effects of cytokines in IBD in the presence of vitamin D deficiency. Also, analysis of the immunomodulatory effect of vitamin D in regulating immunopathogenic factors like chemokines, growth factors, and human defensins will enhance knowledge of the underlying molecular mechanisms of the therapeutic role of vitamin D in IBD and thus aid in the development of better patient management strategies.

Basis for molecular diagnostics and immunotherapy for esophageal cancer.

INTRODUCTION: Esophageal cancer (EC) is an extremely aggressive neoplasm, diagnosed in about 17,000 Americans every year with a mortality rate of more than 80% within five years and a median overall survival of just 13 months. For decades, the go-to regimen for esophageal cancer patients has been the use of taxane and platinum-based chemotherapy regimens, which has yielded the field's most dire survival statistics. Areas covered: Combination immunotherapy and a more robust molecular diagnostic platform for esophageal tumors could improve patient management strategies and potentially extend lives beyond the current survival figures. Analyzing a panel of biomarkers including those affiliated with taxane and platinum resistance (ERCC1 and TUBB3) as well as immunotherapy effectiveness (PD-L1) would provide oncologists more information on how to optimize first-line therapy for EC. Expert commentary: Of the 12 FDA-approved therapies in EC, zero target the genome. A majority of the approved drugs either target or are effected by proteomic expression. Therefore, a broader understanding of diagnostic biomarkers could give more clarity and direction in treating esophageal cancer in concert with a greater use of immunotherapy.