Prognostic Value of Adjuvant Chemotherapy Following Pancreaticoduodenectomy in Elderly Patients With Pancreatic Cancer

Background/Aim: The aim of this study was to investigate the relationship between age and long-term survival among patients who underwent pancreaticoduodenectomy (PD) for pancreatic ductal adenocarcinoma (PDAC). Patients and Methods: A total of 916 patients who underwent PD for curative resection of PDAC were included in this study. Patients were divided into younger (n=726, <70 years) and older (n=190, ≥70 years), and the overall survival (OS) between the two groups was compared. Results: Median OS was significantly longer in the younger group (p<0.001). However, the survival advantage among younger patients was not significant when analyzing only patients who received adjuvant chemotherapy (p=0.548). Among patients who did not receive adjuvant chemotherapy, OS was significantly longer in the younger group (p=0.003). Among patients who received neither adjuvant chemotherapy nor treatment for recurrence, survival was not significantly different between the groups (p=0.629). Conclusion: Adjuvant chemotherapy should be recommended, and additional treatment for recurrence is effective even among elderly who have not received adjuvant chemotherapy.

http://bit.ly/2MMl0bz

Radiation Therapy for Extrapelvic Lymph Node Recurrence After Curative Treatment for Cervical Cancer

Background/Aim: To investigate outcomes of patients with cervical cancer who received radiation therapy for extrapelvic lymph node recurrence after initial pelvic radiotherapy. Patients and Methods: The treatment charts of 20 patients were retrospectively reviewed, and factors influencing patient's prognosis were statistically analyzed. Results: The three-year in-field tumor control rate was 55% and overall survival (OS) at 2, 3, and 5 years was 55%, 45%, and 37.5%, respectively. The rate of the three-year OS in patients with recurrence within and after 9 months was 20% and 70%, respectively (p=0.016). None of the 4 patients who were diagnosed with supraclavicular lymph node recurrence alone at more than 9 months after initial treatment experienced further recurrence. Five-year survival of the remaining 16 patients was only 21% (p=0.021). Conclusion: Time to recurrence significantly influenced survival in patients with cervical cancer who received radiotherapy for extra-pelvic lymph node recurrence. Supraclavicular lymph node recurrence alone had a favorable impact on patient's prognosis.

http://bit.ly/2DPS0wB

The Role of KRAS in Endometrial Cancer: A Mini-Review

Endometrial cancer (EC) is the most common cancer of the female genital tract, resulting annually in 76,000 related deaths worldwide. EC originates either from oestrogen-related proliferative endometrium (type I, endometrioid), or from atrophic endometrium (type II, non-endometrioid). Each type of EC is characterized by different molecular profile alterations. The Kirsten rat sarcoma viral oncogene homolog (KRAS) gene encodes a signalling protein which moderates response to various extracellular signals via down-regulation of the mitogen-activated protein kinase (MAPK) or phosphoinositide-3-kinase/v-akt murine thymoma viral oncogene (PI3K/AKT) pathways. This article reviews the role of KRAS in predicting transition from hyperplastic endometrium to early-stage well-differentiated EC, as well as further invasive proliferation of the tumour to advanced-stage disease. KRAS seems to be directly associated with type I EC, and most studies support its early involvement in carcinogenesis. Current evidence correlates KRAS mutations with increased cell proliferation and apoptosis, as well as up-regulation of endometrial cell oestrogen receptors. Tumours positive for KRAS mutation can harbour hypermethylation-related changes in genome expression, and this can be the cause of concurrent loss of DNA repair proteins. Despite some evidence that KRAS mutation status affects cancer progression, a consensus is yet to be reached. Based on the available evidence, we suggest that screening for KRAS mutations in patients with hyperplastic endometrium or early-stage type I EC, may provide important information for prognosis stratification, and further provision of personalised treatment options.

http://bit.ly/2MNXR8u

Crypts With Corrupted Shapes in Non-polypoid Adenomas

Background: Colonic crypts with normal epithelial lining exhibiting corrupted shapes (NECS) have been previously found beneath the adenomatous tissue of polypoid conventional adenomas, in both rats and humans. Aim: To assess the frequency of NECS in non-polypoid colonic flat adenomas (FAs) and lateral-spreading adenomas (LSAs). Materials and Methods: Histological hematoxylin and eosin-stained sections from 51 non-polypoid colonic adenomas were scrutinized over a 10-mm field of vision (FOV). FAs were regarded lesions encompassed within the FOV and LSAs as those surpassing that limit. The NECS/mm ratio was calculated in individual lesions as the number of NECS beneath the adenomatous tissue, divided by the length (mm) of the FA and LSA. Results: Out of the 51 non-polypoid adenomas, 27 were FAs and the remaining 24 LSAs. All 51 non-polypoid lesions were tubular adenomas. The mean number of NECS in FAs was 6.29 (range=2-10) and in LSAs was 15.29 (range=7-41) (p<0.05). On the other hand, the mean NECS/mm ratio in FAs was 0.94 (range=0.50-2.00) and in LSAs was 0.92 (range=0.40-2.93). Thus, no essential differences in the number of NECS/mm was found between FA and LSA. Conclusion: The accretion of NECS below the neoplastic canopy of FA and LSA contrasts with the rare occurrence of NECS in normal colonic mucosa. This finding emerges as a previously unaddressed major event, an event that might play an important role in the histogenesis of non-polypoid adenomas of the colon.

http://bit.ly/2DRyrnU

Integrin as a Molecular Target for Anti-cancer Approaches in Lung Cancer

Integrins are cell-matrix adhesion molecules providing both mechanical engagement of cell to extracellular matrix, and generation of cellular signals that are implicated in cancer malignancies. The concept that integrins play important roles in cell survival, proliferation, motility, differentiation, and ensuring appropriate cell localization, leads to the hypothesis that inhibition of certain integrins would benefit cancer therapy. In lung cancer, integrins αv, α5, β1, β3, and β5 have been shown to augment survival and metastatic potential of cancer cells. This review presents data suggesting integrins as molecular targets for anti-cancer approaches, and the mechanisms through which integrins confer resistance of lung cancer to chemotherapeutics and metastasis. The better understanding of these key molecules may benefit the discovery of anti-cancer drugs and strategies.

http://bit.ly/2MJuMuW

County Median Family Income Is an Independent Prognostic Factor for Stage IV Anaplastic Thyroid Cancer

Background/Aim: Advanced anaplastic thyroid cancer (ATC) is a rare, but highly aggressive malignancy, and its prognostic factors need to be further explored. We examined socioeconomic factors' predictive effect for survival performance in stage IV ATC patients. Materials and Methods: Using the Surveillance, Epidemiology, and End Results database, we collected 1,048 cases with stage IV anaplastic thyroid cancer (ATC) from 2004 to 2015. Demographic, clinical, and socioeconomic factors were evaluated using univariate and multivariate analyses. Results: Median family income showed a significant effect on overall survival (OS) and cancer-specific survival (CSS) in univariate analysis. Median family income level was found to be an independent prognostic factor for OS after multivariate adjustment Multivariate analysis for CSS showed similar results. Conclusion: Family income level is an independent prognostic factor for stage IV ATC.

http://bit.ly/2DP76Tl

A Potent CD1d-binding Glycolipid for iNKT-Cell-based Therapy Against Human Breast Cancer

Background/Aim: Invariant natural killer T-cells (iNKT) stimulated by CD1d-binding glycolipids have been shown to exert antitumor effects by a number of studies in a mouse model. Breast cancer is a devastating disease, with different types of breast cancer recurring locally or distant as metastatic/advanced disease following initial treatment. The aim of this study was to examine the tumoricidal effect of a CD1d-binding glycolipid, called 7DW8-5, against a highly invasive human breast cancer cell line both in vitro and in vivo. Materials and Methods: Parental MDA-MB-231 cells and MDA-MB-231 cells transduced with human CD1d were labeled with carboxyfluorescein diacetate succinimidyl ester (CFSE), followed by loading with glycolipids. After co-culturing with human iNKT cells, the cells were permeabilized and stained with Alexa Flour 647-conjugated antibody to active caspase-3, and analyzed using a BD LSR II. For the in vivo tumoricidal effect, MDA-MB-231 cells transduced with human CD1d and luciferase genes were injected into the mammary fat pad of female NOD/SCID/IL2rnull (NSG) mice, followed by the injection of human iNKT cells with or without 7DW8-5, and the levels of luminescence were analyzed with whole-body imaging. Results: Human iNKT cells could kill CD1d-expressing human breast cancer cells in vitro in the presence of 7DW8-5, but not α-GalCer. As for in vivo, the adoptive transfer of human iNKT cells into tumor-challenged NSG mice significantly inhibited the growth of CD1d+ MDA-MB-231 human breast cancer cells in the presence of 7DW8-5. Conclusion: CD1d-binding, glycolipid-based iNKT-cell therapy is suggested as a potent and effective treatment against breast cancer in humans.

http://bit.ly/2ML4NDy

Clinical Outcomes of 42 Renal Cell Carcinoma Patients With Metastases Solely to the Lung Who Received Sorafenib as Second-line Systemic Therapy

Background/Aim: In renal cell carcinoma (RCC), sorafenib was the first targeted agent demonstrating a definitive benefit in a large phase III clinical trial. The objective of this study was to assess the clinical outcomes of 42 consecutive RCC patients with metastases solely to the lung who received sorafenib as a second-line systemic agent. Patients and Methods: Of the 42 patients, 14 (33.3%) and 28 (66.7%) received cytokine therapy and sunitinib, respectively, prior to treatment with sorafenib. In this series, all patients initially received 400 mg of sorafenib twice daily on a continuous dosing schedule. The efficacy and safety of second-line sorafenib in these 42 patients were retrospectively evaluated. Results: As the best response to sorafenib, 2 (4.8%), 14 (33.3%), 22 (52.4%) and 4 (9.5%) patients were judged to show a complete response, partial response, stable disease and progressive disease, respectively. The median progression-free survival (PFS) and overall survival (OS) after the introduction of sorafenib was 10.6 and 30.2 months, respectively. Multivariate analyses of several parameters identified the following independent prognostic predictors: C-reactive protein (CRP) level for PFS, and International Renal Cell Carcinoma Database Consortium classification and CRP level for OS. The common adverse events associated with sorafenib were hand-foot syndrome, hypertension and diarrhea, which developed in 22 (52.4%), 17 (40.5%) and 13 (31.0%), respectively; however, any AEs corresponding to ≥grade 3 occurred in only 16 (38.1%). Conclusion: Favorable disease control with acceptable tolerability might be expected by introducing sorafenib as second-line therapy for RCC patients with metastases solely to the lung; therefore, sorafenib could be the optimal option for this category of patients.

http://bit.ly/2DSe0Hv

High miR-3687 Expression Affects Migratory and Invasive Ability of Oesophageal Carcinoma

Background/Aim: Basaloid squamous cell carcinoma of the oesophagus (BSCCE) is a variant of oesophageal squamous cell carcinoma (ESCC), that has a more aggressive biological behaviour than that of typical ESCC. miR-3687 has been previously identified to be highly expressed in BSCCE. This study aimed to evaluate the prognostic impact of miR-3687 in ESCC and determine the role of miR-3687 in ESCC motility. Materials and Methods: miR-3687 expression in human ESCC cell lines and in primary tumour samples obtained from patients with ESCC who underwent esophagectomy were analyzed via real-time polymerase chain reaction (PCR). Knockdown and over-expression experiments were conducted with miR-3687 siRNA and miRNA mimic, and the effect on cell proliferation, migration, and invasion was analyzed. Results: A total of 92 samples were analyzed. High miR-3687 expression was correlated with poor prognosis. miR-3687 upregulation promoted cell migration and invasion. Conclusion: miR-3687 expression negatively impacts the prognosis of patients with ESCC.

http://bit.ly/2MKIZYB

Age Adjusted Charlson Comorbidity Index Strongly Influences Survival, Irrespective of Performance Status and Age, in Patients With Advanced Prostatic Cancer Treated With Enzalutamide

Background/Aim: Enzalutamide is prescribed for advanced prostatic cancer patients, regardless of physical comorbidity. We hypothesized that comorbidity negatively affects survival regardless of age, performance status and prostate-specific antigen (PSA) response. Patients and Methods: All patients (n=106) treated at the ADRZ Medical Center with enzalutamide in the period 2015-2018 and who had undergone at least one PSA response evaluation were included in a multivariate analysis to test which variables independently affected Time to PSA progression (TPSAP) and/or overall survival (OS). Results: A poorer performance status appeared to relate to a two times increased risk of dying (HR=2.032, 95%CI=1.078-3.830). An older age did not appear to influence OS, whereas an ACCI of more than 9 points appeared to relate to a more than three times increased risk of dying (HR=3.538, 95%CI=1.466-8.538). Conclusion: Survival appeared to be strongly affected by comorbidity, irrespective of age and performance status in patients treated with enzalutamide.

http://bit.ly/2DQfCBq

Association of CD31 and p53 With Survival of Ovarian Cancer Patients

Background/Aim: New markers for ovarian cancer are needed. This study aimed to examine the expression of tumour cell p53 and endothelial cell CD31 proteins and correlate them to clinicopathological factors. Patients and Methods: Expression of proteins was immunohistochemically assessed using tissue sections from 585-599 ovarian cancer patients from the Danish MALOVA study. Results: High CD31 expression was found in poorly differentiated tumours (p=0.0006), and high p53 expression was found in poorly differentiated cancers (p<0.0001), high clinical stage (p<0.0001), non-radical surgery (p<0.0001) and high serum CA-125 values (p<0.0001). CD31 expression showed no prognostic survival value, but high hazard ratios were found for patients with high p53 expression (HR=2.313, p<0.0001). An interaction was found between p53 and stage of cancer, suggesting a prognostic impact of p53 in low-stage, but not in advanced-stage cancer. Conclusion: More than 5% of p53 tissue expression may predict shorter survival of ovarian cancer patients and may be useful for predicting the risk of disease progression in low-stage patients following primary surgery. CD31 has no strong prognostic value.

http://bit.ly/2MQD84c

Diagnostic Utility of Third-Look, Contrast-Enhanced Sonography Followed by Needle Biopsy for MRI, But Not Ultrasonography Breast Lesions

Background/Aim: To clarify the diagnostic utility of third-look, contrast-enhanced ultrasonography (CEUS) for MRI-detected breast lesions undetectable by unenhanced, second-look ultrasonography (MRI+/US– lesions). Patients and Methods: Clinical stage 0–IIA breast cancer patients who underwent CEUS for incidental MRI+/US– lesions (n=27; cohort 1) and patients with breast lesions detected only by MRI, to be examined by CEUS (n=15; cohort 2), were retrospectively analyzed. Results: Of the 42 MRI+/US– lesions, 23 (55%) were detected by CEUS and then examined by needle biopsy. Pathological examination showed that 10 of these 23 lesions were malignant. None of the 19 lesions undetected by CEUS were found to be histologically malignant or developed malignancy with a median follow-up of 18.5 months. The accuracy, sensitivity, and specificity of CEUS plus needle biopsy were 98%, 91%, and 100%, respectively. Conclusion: Third-look CEUS followed by needle biopsy is useful in the initial diagnosis of MRI+/US– lesions.

http://bit.ly/2DSTSor

Oligodendrocytes Up-regulate the Invasive Activity of Glioblastoma Cells via the Angiopoietin-2 Signaling Pathway

Background/Aim: Glioblastoma (GBM) is one of the most lethal solid cancers due to its highly invasive nature. The malignant potential of GBM cells might be partially regulated by surrounding normal cells, such as oligodendrocytes or fibroblasts. The aim of this study was to examine the interaction between stromal cells and GBM cells. Materials and Methods: Two GBM cell lines were used. The effect of stromal cells, oligodendrocytes or fibroblasts, on the invasive ability of GBM cells was examined by wound-healing assay and invasion assay. Results: Oligodendrocytes, in contrast to fibroblasts, significantly increased the migration and invasive ability of GBM cells. Angiopoietin-2 levels were high in the conditioned medium obtained from oligodendrocytes. Angiopoietin-2 significantly increased the motility of GBM, and the motility-stimulating activity of the oligodendrocytes-derived conditioned medium was significantly decreased by anti-angiopoietin-2-neutralizing antibody. Conclusion: Glioma stromal cells, oligodendrocytes, might up-regulate the invasiveness of GBM cells via angiopoietin-2 signaling.

http://bit.ly/2MNUNt9

Postoperative Pneumonia After Esophagectomy and Systemic Inflammatory Response Syndrome

Background/Aim: The aim of this study was to determine the association between post-esophagectomy pneumonia and the presence of pathogenic organisms in the sputum or pharynx and postoperative systemic inflammatory response syndrome (SIRS). Materials and Methods: This retrospective study included 98 patients diagnosed with esophageal cancer who had undergone esophagectomy. Results: Postoperative pneumonia was observed in 24 patients (24.5%). Of the total 98 patients, 45 (45.9%) were tested positive for pathogenic organisms preoperatively, and 16 of those (35.6%) developed postoperative pneumonia; postoperative pneumonia occurred at a higher rate in these patients compared to pathogenic organism-negative patients (p=0.019). Postoperative SIRS was observed in 62 patients (63.3%), and 21 of these (33.9%) developed postoperative pneumonia, a significantly higher rate compared to patients without SIRS (p=0.007). Conclusion: Postoperative pneumonia was significantly associated with the presence of pathogenic organisms in the sputum or pharynx and postoperative SIRS.

http://bit.ly/2DQ3gZV

Cytoplasmic Keap1 Expression Is Associated With Poor Prognosis in Endometrial Cancer

Background/Aim: Oxidative stress is involved in several carcinogenic pathways. Nuclear factor erythroid 2-related factor (Nrf2), Kelch-like ECH-associated protein 1 (Keap1) and Park7 (DJ-1) are the main regulators of antioxidant enzymes eliminating reactive oxidative species (ROS). The roles of these proteins were studied as potential prognostic factors in endometrial cancer. Materials and Methods: Nrf2, Keap1 and DJ-1 expression in endometrial carcinomas was analyzed immunohistochemically. Correlations between staining patterns and clinical prognostic variables were evaluated. Results: Extensive cytoplasmic Keap1 staining correlated to several factors associated with poor prognosis of endometrial cancer including advanced stage, poor histological differentiation, lymphovascular invasion, pelvic lymph node metastasis and deep myometrial invasion. In multivariate analysis, cytoplasmic Keap1 was a stronger predictor of poor progression-free survival than grade. Nuclear Nrf2 staining was seen in all patients with lymph node metastasis while DJ-1 staining was associated with clinically favourable disease types. Conclusion: Cytoplasmic Keap1 expression indicates poor prognosis in endometrial cancer.

http://bit.ly/2MLdVrK

Leptomeningeal Gliomatosis: A Single Institution Study of 31 Patients

Background/Aim: Secondary leptomeningeal gliomatosis (LG) is a rare and severe progression pattern of glioma. Our objective was to evaluate the characteristics and outcome of patients with LG. Patients and Methods: We retrospectively reviewed 31 patients diagnosed with secondary LG. At the time of LG diagnosis, the median age of patients was 45 years. The histological grade was IV in 20 patients and II to III in 11 patients. As a first-line of therapy for LG, 22 patients received an oncological treatment: i) BCNU-temozolomide (TMZ) (n=15), ii) other type of chemotherapy (n=7), and iii) no treatment (supportive care) (n=9). Results: Following LG diagnosis, the median progression-free survival (PFS) and overall survival (OS) were 1.8 months [95% confidence interval (CI)=0.9-2.7] and 2.1 months (95%CI=1.3-3), respectively. The univariate analyses showed an improved OS with age of less than 45 years (p<0.001), a prolonged interval from the initial glioma diagnosis (IGD) to LG diagnosis (p=0.003), BCNU–TMZ as the preferred first-line treatment for LG out of the three options (p=0.008), and Karnofsky performance status (KPS) ≥70 (p=0.012). Prolonged interval from IGD to LG diagnosis (HR=5.839) and BCNU–TMZ as the chosen first-line treatment for LG (HR=6.635) remained significant in the multivariate analyses as well. Among the 22 treated patients, the median OS was significantly higher (p=0.008) with the BCNU–TMZ treatment (5.7 months; 95%CI=4.2-7.1), compared to other types of treatment offered (2 months; 95%CI=1.1-2.9). Conclusion: The time interval from the IGD to the LG diagnosis is a potential prognostic factor for LG. BCNU–TMZ may be a therapeutic option in the present setting.

http://bit.ly/2DQKbHi

Isothiocyanate-induced Cell Cycle Arrest in a Novel In Vitro Exposure Protocol of Human Malignant Melanoma (A375) Cells

Background/Aim: Several studies have documented the effects of isothiocyanates (ITCs) on cancer prevention by inducing oxidative stress, activating apoptosis, affecting cell-cycle regulation, etc. Previously, we have shown that ITCs, administered at low concentrations by the means of double-bolus are capable of potentiating cytotoxicity in human malignant melanoma (A375) cells by inducing apoptosis. The aim of the present study was to further investigate the effect of the treatment of A375 cells with ITCs on cell-cycle progression and the levels of various cell cycle regulators. Materials and Methods: Cell-cycle analysis was performed by means of flow cytometry whereas western immunoblotting was used to determine the expression levels of these protein regulators. Results: Our data showed an increase in the number of cells in the G₂/M phase accompanied by a decrease in the G₀/G₁ phase, while several cell-cycle regulators were shown to be differentially expressed upon exposure to ITCs. Conclusion: ITCs induced cell-cycle arrest in A375 cells.

http://bit.ly/2MK63qz

MicroRNA-based Targeted Therapeutics in Pancreatic Cancer

The discovery during the last decade of microRNAs (miRs, miRNA) and their role in regulating normal physiological processes as well as in the pathogenesis of human tumors has been a revolutionary development in molecular oncology. miRNAs activating or inhibiting oncogenic molecular pathways that are involved in tumorigenesis, cell progression, invasion, angiogenesis and metastasis are now considered of major impact in many cancer types. miRNA-based therapeutics that inhibit the levels of oncogenic miRNAs (oncomiRs) or elevate tumor suppressor miRs have enormous potential as molecular therapeutic targets. Thus, the development of new targeted cancer therapies based on miRNAs promise to revolutionize cancer treatment due to their increased efficacy compared to conventional chemoradiation-based therapies and hopefully to lower levels of adverse effects.

http://bit.ly/2DQW1ku

Basic Gene Expression Characteristics of Glioma Stem Cells and Human Glioblastoma

Background: Glioma stem cells (GSCs) play important roles in the tumorigenesis of glioblastoma multiforme (GBM). Using a novel cellular bioinformatics pipeline, we aimed to characterize the differences in gene-expression profiles among GSCs, U251 (glioma cell line), and a human GBM tissue sample. Materials and Methods: Total RNA was extracted from GSCs, U251 and GBM and microarray analysis was performed; the data were then applied to the bioinformatics pipeline consisting of a principal component analysis (PCA) with factor loadings, an intracellular pathway analysis, and an immunopathway analysis. Results: The PCA clearly distinguished the three groups. The factor loadings of the PCA suggested that v-myc avian myelocytomatosis viral oncogene neuroblastoma derived homolog (MYCN), dipeptidyl-peptidase 4 (DPP4), and macrophage migration-inhibitory factor (MIF) contribute to the stemness of GSCs. The intracellular pathway and immunopathway analyses provided relevant information about the functions of representative genes in GSCs. Conclusion: The newly-developed cellular bioinformatics pipeline was a useful method to clarify the similarities and differences among samples.

http://bit.ly/2MT8tmV

Genetic Analysis Using a Gene Panel in 87 Caucasian Patients With Colorectal Cancer: Own Results and Review of Literature

Background/Aim: Colorectal cancer (CRC) is the third most common cancer worldwide. The prognosis between left- and right-sided CRC differs, partly due to baseline differences as vascular supply. The purpose of the present study was to investigate whether there are genetic differences between left- and right-sided CRC. Patients and Methods: Eighty-seven patients with CRC (mean age: 61 years) were retrospectively included in the study. Blood samples were used for genetic analysis, by applying the sequencing research panel Ion AmpliSeq Colon and Lung Cancer Research Panel V2. Statistical analyses included Chi-square tests, Kaplan-Meier survival curves, and univariate/multivariate Cox-regression analyses. Results: By testing the sequence of 22 genes included in the panel, a significant difference was detected between left- and right-sided CRC regarding the expression of BRAF and DDR2 genes, with mutations occurring more often in the right-sided CRC. In the multivariate setting, left-sided CRC only turned out as a significant positive prognostic parameter regarding progression-free survival, irrespective of the type of chemotherapy or BRAF and NRAS mutations. Conclusion: Tumour location was the only parameter proven to be an independent prognostic factor for CRC in the present study.

http://bit.ly/2DPM8Ue