Overall Disease-free Survival In Patients Research Articles

Hesperidin potentially interacts with the catalytic site of gamma-secretase and modifies notch sensitive genes and cancer stemness marker expression in colon cancer cells and colonosphere

Gamma secretase (GS) produces Notch Intracellular Domain (NICD) by trans-membrane cleavage of notch receptor. The NICD enters the nucleus and activates the notch signaling pathway (NSP) by activating notch-responsive gene transcription. Hyperactivation of NSP is related to cancer aggressiveness, therapy resistance, and poor therapy outcome, and decreased overall disease-free survival in patients. Till date, none of the GS inhibitors (GSI) has been clinically approved due to their toxicity in patients. Thus in the present study, we explored the GS catalytic site binding potential of hesperidin (natural flavone glycoside) and its effect on notch responsive gene expression in HCT-116 cells. Molecular docking, MM-GBSA binding energy calculations, and molecular dynamics (MD) simulation experiments were performed to study the GS catalytic site binding potential of hesperidin. The compound showed better GS catalytic site binding potential at the active site compared to experimentally validated GSI, N-N-(3, 5-Difluorophenacetyl)-L-alanyl-S-phenylglycine t-butyl ester (DAPT) in molecular docking and MM-GBSA experiments. MD simulation results showed that hesperidin forms stable and energetically favorable complex with gamma secretase in comparison to standard inhibitor (DAPT)-GS complex. Further, in vitro experiments showed that hesperidin inhibited cell growth and sphere formation potential in HCT-116 cells. Further, hesperidin treatment altered notch responsive genes (Hes1, Hey1, and E-cad) and cancer stemness/self-renewal markers expression at transcription levels. In conclusion, hesperidin produces toxicity in HCT-116 cells and decreases colonosphere formation by inhibiting transcription of notch signaling pathway target genes and stemness markers. Communicated by Ramaswamy H. Sarma

Immune System Profiling Following Autologous Stem Cell Transplant for High-Risk Neuroblastoma Predicts Disease-Free Survival

Objective: Neuroblastoma (NB) is the most common extra cranial solid tumor in childhood. It accounts for approximately 7% of pediatric cancer diagnoses each year in the United States yet is responsible for 15% of pediatric cancer deaths annually. Occurring overwhelmingly in patients with high-risk (HR) disease.Measurable immune surveillance correlates with improved overall disease-free survival in patients with a myriad of cancer subtypes, including NB. Current therapeutic strategies in HR-NB incorporate manipulation of the host immune response, including autologous stem cell transplantation (autoSCT), cis-retinoic acid, and chimeric antibody targeting the tumor-associated antigen disialoganglioside (GD2). Understanding how such therapies affect the immune system and its relation to clinical response is of critical importance. We speculate that patients with higher proportions of regulatory T cells (Tregs) and slower recovery of other lymphocyte subsets will have higher rates of progressive disease and/or relapse.Methods: We reviewed the records of all University of Chicago patients between 2009 and 2015 who received autoSCT as part of upfront therapy for HR neuroblastoma. Data included complete blood count and peripheral blood lymphocyte flow cytometric (FACS) subset monitoring. Our analysis aimed to determine the association between lymphocyte subset kinetics following autoSCT with pre-transplant treatment, transplant conditioning, and disease-free/overall survival. Patients who had a follow-up of greater than one-year post-transplantation were included in the analysis.Results: Thirty-four patients (59% male, median age 5.6 years) received autoSCT between 2009 and 2015 for HR neuroblastoma. Seventy-six percent (n = 26) received either carboplatin, etoposide, melphalan (CEM) or busulfan/melphalan (BuMel) for conditioning. Among those patients, twenty-seven percent received MIBG prior to their autoSCT. The other patients received BSO/melphalan or tandem transplantations. Sixty-eight percent of these patients went on to receive chimeric antibody after their autoSCT irrespective of their conditioning regimen. Antibody therapy with IL-2 or GM-CSF was initiated at a median of 101 days (mean 98.9) post-autoSCT. All patients had normal neutrophil counts at 100 days post transplant, while the total absolute lymphocyte count (ALC), CD8+ T cells, NK cells and CD19+ B cells, were below normal levels in the majority of patients, (100%, 89%, 79% and 94% of patients respectively). Patients who received MIBG prior to autoSCT had a higher proportion of CD3+CD4+CD25+ T cells, the subset containing Tregs, among their total CD3+ population at 100 days post-transplant, (79.8% versus 32.8% p-value = 0.02). Following single autoSCT, patients with higher ALC and CD4+ cells had increased disease free survival in evaluations after six months post transplant. (Figure 1) CD8+ cells, NK cells and CD19+ cell counts were not significant in this analysis.Conclusions: Patients with HR NB have differential immune cell recovery following autoSCT that is dependent on the type of therapy received prior to autoSCT. Specifically, patients who received MIBG had markedly higher proportion of CD3+CD4+CD25+ T cell recovery compared to patients not receiving pre-autoSCT MIBG. This is the subset containing Tregs, which may indicate suppression of an anti-NB immune response long-term. Immune reconstitution is globally poor in all patients at the time of chimeric antibody immunotherapy that is initiated around day 100-post autoSCT. There are features of immune reconstitution that appear to correlate with improved outcomes, including elevated ALC, CD8+ and CD4+ cell counts when evaluated at least six months post transplantation. Additional characterization of T cell subsets is currently being performed to quantify the number of Treg cells in the CD3+CD4+CD25+ T cell subset population. Prospective evaluation of both immune cell recovery and functional evaluation of cells is required to confirm these findings, which may have a profound impact on how immune modulatory therapy is scheduled for those patients with high-risk neuroblastoma. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Cytotoxic agents and radiation therapy: mechanisms of action and clinical applications

AbstractBackgroundThe combination of radiation therapy and chemotherapy is rooted in its ability to help achieve locoregional and systemic control, therefore increasing the overall disease-free survival of patients. Understanding the mechanistic actions of cytotoxic agents and their targets on the cell cycle, as well as the governing pharmacokinetic principles can improve treatment delivery. The adjuvant treatment setting can overcome barriers such as hypoxia and genetically driven treatment resistance.PurposeThe purpose of this review is to present theoretical frameworks behind the chemoradiation paradigm and to describe current chemoradiation practices in radiation oncology.MethodologyA review was conducted using the US National Library of Medicine, National Institutes of Health database (PubMed) using the following search keywords: chemoradiation, spatial cooperation, chemotherapeutic agents, pharmacokinetics, anti-vascular agents, tumour vasculature and tumour hypoxia.Results and conclusionsCurrent research has reported several rationales for the beneficial combination of radiation and chemotherapy to eradicate oncological diseases. Mechanisms of action and biological approaches are showing that concurrent treatments, as well as novel agents such as anti-vascular and anti-angiogenic agents may benefit improved treatment outcomes by reducing micro hypoxic environments in tumours. In addition, chemotherapy administered in tandem with radiation enhances cell-killing effects by targeting the cell cycle.

Surgical salvage for recurrent retropharyngeal lymph node metastasis in nasopharyngeal carcinoma

The purpose of this study was to analyze the surgical management of recurrent retropharyngeal lymph node metastasis after radiotherapy for nasopharyngeal carcinoma (NPC). We conducted a prospective analysis of preoperative imaging, surgical approach, and oncological results. Between 1990 and 2011, 82 patients were included. The mean size of the retropharyngeal lymph node on MRI was 1.6 cm, and the mean standardized uptake value maximum (SUVmax) on positron emission tomography (PET) scan was 6.8. All the retropharyngeal lymph nodes were resected via the maxillary swing approach. Among the resected retropharyngeal lymph nodes, 87.8% contained viable tumor cells. The rate of microscopic extracapsular spread was 30.6%. The mean follow-up duration was 38 months. The 5-year actuarial tumor control and the overall disease-free survival of patients who underwent surgeries for isolated recurrent retropharyngeal lymph node metastasis was 79.6% and 59%, respectively. A PET scan is potentially useful in diagnosing persistent or recurrent retropharyngeal lymph node after previous radiotherapy for NPC. The maxillary swing approach allows surgical resection with clear margins in order to achieve the best oncological outcome.

Hemoglobin level as the prognostic factor for patients with carcinoma cervix receiving radiation therapy

Objective. The primary objective was to assess the influence of the pre-treatment and mid-treatment haemoglobin (Hb) level on local control and pelvic disease-free and overall disease-free survival in patients with carcinoma of the cervix receiving radiation therapy. Material and methods. Seventy-two patients referred for radiation therapy for carcinoma of the cervix between January and December 2002 were entered into this prospective study. Forty-three patients (60%) had stage II and 29 (40%) stage III disease. Hb levels were checked before starting treatment and in the middle of treatment. The mean Hb levels at the start and mid-treatment were 12.8 g/dl and 12.1 g/dl, respectively. Results. Treatment failed in 13 patients (pelvic disease 9, distant 3 and pelvic and distant 1). Patients with midtreatment Hb levels ≥12 g/dl had significantly lower rates of pelvic failure (p=0.05) as well as overall failure (p=0.03) than patients with levels South African Journal of Obstetrics & Gynaecology Vol. 14 (2) 2008: pp. 76-80