Mutations in codons 12/13 of K-ras exon 2 are associated with reduced benefit from anti-epidermal growth factor receptor antibody treatment for metastatic colorectal cancer (CRC). Here, we evaluated the frequency of K-ras mutations and their relationship with clinicopathological features and treatment outcomes in Saudi Arabian patients with CRC. The genetic status of K-ras was determined in 300 patients diagnosed with CRC. Clinical information was collected retrospectively. K-ras was wild-type in 58% and mutated in 42% of the tumors. Most mutations were at codon 12 (89%) and were associated with metastasis [odds ratio (OR) = 1.38 (95%CI = 1.14-1.67] and occurrence of >40 µg/L carcinoembryonic antigen (CEA) [OR = 1.33 (1.1-1.74)] during diagnosis. Patients in stages I-III of the disease with wild-type K-ras tumors had a median relapse free survival (RFS) of 29 months in contrast to 22 months for those with the mutated K-ras tumor (P = 0.0357). In multivariate analysis, only the stage of the disease significantly predicted RFS (P = 0.001). Patients in stage IV of CRC with the wild-type K-ras tumor did not reach the median overall survival (OS), whereas patients with the mutated K-ras tumor survived for 23.5 months (P = 0.044). CEA level >40 µg/L (P = 0.004) and status of K-ras (P = 0.044) were independent predictors of OS. This is the largest study investigating K-ras mutations in patients with CRC in the Middle East. Mutations were associated with advanced stage of CRC, higher serum CEA, shorter RFS and OS.

Treatment of patients with triple-negative breast cancer (TNBC) is challenging due to the absence of well- defined molecular targets and the heterogeneity of such disease. In our endeavor to develop potent isatin-based anti-proliferative agents, we utilized the hybrid-pharmacophore approach to synthesize three series of novel isatin-based hybrids 5a-h, 10a-h and 13a-c, with the prime goal of developing potent anti-proliferative agents toward TNBC MDA-MB-231 cell line. In particular, compounds 5e and 10g were the most active hybrids against MDA-MB-231 cells (IC50 = 12.35 ± 0.12 and 12.00 ± 0.13 μM), with 2.37- and 2.44-fold increased activity than 5-fluorouracil (5-FU) (IC50 = 29.38 ± 1.24 μM). Compounds 5e and 10g induced the intrinsic apoptotic mitochondrial pathway in MDA-MB-231; evidenced by the reduced expression of the anti-apoptotic protein Bcl-2, the enhanced expression of the pro-apoptotic protein Bax and the up-regulated active caspase-9 and caspase-3 levels. Furthermore, 10g showed significant increase in the percent of annexin V-FITC positive apoptotic cells from 3.88 to 31.21% (8.4 folds compared to control).

We investigated the association of the Osteopontin (OPN) (rs9138 and rs1126616) polymorphisms with colorectal cancer (CRC). One hundred CRC patients and 112 healthy individuals were subjected to OPN (rs9138 and rs1126616) genotyping and measurement of OPN protein plasma level. The C allele of OPN rs1126616 and the CC haplotype were significantly higher in CRC patient (p = 0.036, 0.003, respectively). In females, the C allele of OPN rs9318 (A/C) polymorphism was significantly associated with increased CRC risk (p = 0.036). The plasma OPN level >104.35 ng/mL was significantly associated with CRC. Our findings suggest a significant role played by OPN (rs9138 and rs1126616) in colorectal carcinogenesis.

BACKGROUND: At experienced centers, laparoscopic partial nephrectomy (LPN) can achieve similar results to those of open surgery (OPN). However, the role of LPN for complex tumors and imperative indications is under debate.
PATIENTS AND METHODS: A total of 356 cases (186 LPN and 170 OPN) between 2005-2012 were reviewed. Clinical, surgical, pathological and radiological data, including PADUA classification were analyzed.
RESULTS: In overall analysis, OPN was associated with higher tumor complexity (p≤0.03). Subgroup analysis of PADUA >8 tumors (n=85) showed no significant difference between LPN and OPN. In patients with unfavorable treatment characteristics (imperative indication/multifocal tumors, n=71) LPN was beneficial. In this subgroup, LPN led to better perioperative (p≤0.02) and postoperative (p≤0.04) outcome.
CONCLUSION: Use of LPN is associated with favorable tumor characteristics. Although no advantage was shown for LPN for tumors with higher complexity (PADUA>8), this large series confirmed the superiority of LPN for imperative indication or multifocal tumors.

OBJECTIVES: To detect FMS-like tyrosine kinase-3 internal tandem duplicate (FLT3 ITD) mutation, Myeloproliferative leukemia virus oncogene (cMPL) and Ephrin A 4 receptor (EphA4) expressions in Acute myeloid leukemia (AML) and their correlation to patient's clinicopathological characteristics and survival.
METHODS: RNA was extracted from blood samples of 58 AML patients (39 adults and 19 children) and 20 age and sex matched controls. FLT3 ITD mutation, cMPL and EphA4 expression was studied using RT-PCR and correlated to the clinical and survival data of the patients.
RESULTS: FLT3 ITD mutation, cMPL and EphA4 expression was positive in 35.9%, 76.9% and 56.4% of adult AML patients respectively and in 15.8%, 47.4% and 36.8% of pediatric AML patients respectively. 76.9% of adult and 89.5% of pediatric patients expressed CD33. 64.1 % of adults and 42.1% of children expressed CD34. CD34 expression was significantly associated with both FLT3 ITD mutation and cMPL expression. CD34, FLT3 and cMPL negative cases have significantly higher overall survival than positive cases.
CONCLUSION: CD34 expression is significantly associated with both FLT3 ITD mutation and cMPL expression which could be used as a marker for low survival. Normal FLT3 and negative expression of CD34 and cMPL may predict a longer overall survival. Further studies are needed to investigate the mechanism that may correlate CD34 to both markers.

BACKGROUND: mTOR inhibitors are widely used in different malignancies with several trials testing their efficacy and safety in gynecological malignancies. We aimed to review the current evidence that support the expansion of using such drugs in the treatment of advanced gynecological cancers.
METHODS: A comprehensive systematic review of literature has been conducted to include prospective trials that used everolimus, temsirolimus or ridaforolimus in the management of gynecological cancers and have available efficacy and toxicity results.
RESULTS: A total of 23 studies including 980 patients were considered eligible for our review. Our review included 16 phase II and 7 phase I studies with the majority of patients having uterine cancers. Regarding Endometrial cancer, the CBR ranged from 21% to 60% and median PFS from 2.8 months to 7.3 months. In Ovarian cancers, CBR ranged from 24% to 50% and median PFS from 3.2 months to 5.9 months. In the single phase II study in cervical cancer the CBR was 61% and median PFS was 3.5 months. The toxicity profile was consistent with what was observed previously in other malignancies with fatigue, mucositis, and hematological toxicities being the most common adverse events observed.
CONCLUSION: mTOR inhibitors seem to be a promising option in the second line management of advanced gynecological cancers with best safety and efficacy outcomes when given as a single agent or in combination with hormonal treatment. More research is needed for better patient selection.

OBJECTIVE There is a paucity of literature regarding the learning curve associated with performing endoscopic endonasal cranial base surgery. The purpose of this study was to determine to what extent a learning curve might exist for endoscopic endonasal resection in cases of craniopharyngiomas. METHODS A retrospective review was performed for all endoscopic endonasal craniopharyngioma resections performed at Thomas Jefferson University from 2005 to 2015. To assess for a learning curve effect, patients were divided into an early cohort (2005-2009, n = 20) and a late cohort (2010-2015, n = 23). Preoperative demographics, clinical presentation, imaging characteristics, extent of resection, complications, tumor control, and visual and endocrine outcomes were obtained. Categorical variables and continuous variables were compared using a 2-sided Fisher's exact test and t-test, respectively. RESULTS Only the index operation performed at the authors' institution was included. There were no statistically significant differences between early and late cohorts in terms of patient age, sex, presenting symptoms, history of surgical or radiation treatment, tumor size or consistency, hypothalamic involvement, or histological subtype. The rate of gross-total resection (GTR) increased over time from 20% to 65% (p = 0.005), and the rate of subtotal resection decreased over time from 40% to 13% (p = 0.078). Major neurological complications, including new hydrocephalus, meningitis, carotid artery injury, or stroke, occurred in 6 patients (15%) (8 complications) in the early cohort compared with only 1 (4%) in the late cohort (p = 0.037). CSF leak decreased from 40% to 4% (p = 0.007). Discharge to home increased from 64% to 95% (p = 0.024). Visual improvement was high in both cohorts (88% [early cohort] and 81% [late cohort]). Rate of postoperative panhypopituitarism and permanent diabetes insipidus both increased from 50% to 91% (p = 0.005) and 32% to 78% (p = 0.004), which correlated with a significant increase in intentional stalk sacrifice in the late cohort (from 0% to 70%, p < 0.001). CONCLUSIONS High rates of near- or total resection and visual improvement can be achieved using an endoscopic endonasal approach for craniopharyngiomas. However, the authors did find evidence for a learning curve. After 20 cases, they found a significant decrease in major neurological complications and significant increases in the rates of GTR rate and discharge to home. Although there was a large decrease in the rate of postoperative CSF leak over time, this was largely attributable to the inclusion of very early cases prior to the routine use of vascularized nasoseptal flaps. There was a significant increase in new panhypopituitarism and diabetes insipidus, which is attributable to increase rates of intentional stalk sacrifice.

The role of heavy metals and trace elements (HMTE) in the development of some cancers has been previously reported. Bladder carcinoma is a frequent malignancy of the urinary tract. The most common risk factors for bladder cancer are exposure to industrial carcinogens, cigarette smoking, gender, and possibly diet. The aim of this study was to evaluate HTME concentrations in the cancerous and adjacent non-cancerous tissues and compare them with those of normal cadaveric bladder. This prospective study included 102 paired samples of full-thickness cancer and adjacent non-cancerous bladder tissues of radical cystectomy (RC) specimens that were histologically proven as invasive bladder cancer (MIBC). We used 17 matched controls of non-malignant bladder tissue samples from cadavers. All samples were processed and evaluated for the concentration of 22 HMTE by using Inductively Coupled Plasma Optical Emission Spectrometry (ICP-OES). Outcome analysis was made by the Mann-Whitney U, chi-square, Kruskal-Wallis, and Wilcoxon signed ranks tests. When compared with cadaveric control or cancerous, the adjacent non-cancerous tissue had higher levels of six elements (arsenic, lead, selenium, strontium, zinc, and aluminum), and when compared with the control alone, it had a higher concentration of calcium, cadmium, chromium, potassium, magnesium, and nickel. The cancerous tissue had a higher concentration of cadmium, lead, chromium, calcium, potassium, phosphorous, magnesium, nickel, selenium, strontium, and zinc than cadaveric control. Boron level was higher in cadaveric control than cancerous and adjacent non-cancerous tissue. Cadmium level was higher in cancerous tissue with node-positive than node-negative cases. The high concentrations of cadmium, lead, chromium, nickel, and zinc, in the cancerous together with arsenic in the adjacent non-cancerous tissues of RC specimens suggest a pathogenic role of these elements in BC. However, further work-up is needed to support this conclusion by the application of these HMTE on BC cell lines.

We aimed to investigate any association between hepatitis C virus (HCV) infection and non-Hodgkin's lymphoma (NHL) in the view of cytokines that control in ammation/angiogenesis and their correlation with certain CD markers. NHL patients with or without HCV infection were studied. CD5, CD30, CD3, CD20 and CD45 were immunohistochemically evaluated. Plasma levels of vascular endothelial and platelet derived growth factors (VEGF, and PDGF), tumor necrosis factor (TNF-α), transforming growth factor (TGF-β), interleukin-6 (IL-6), IL-8, IL-4, IL-12 and interferon gamma (IFN-γ) were detected by enzyme-linked immunosorbent assay (ELISA). HCV+ve NHL patients showed a signi cant reduction in VEGF, PDGF, IFN-γ, CD5 and CD45 and a signi cant increase in IL-12 and IL-8. In conclusion, there was a signi cant change in cytokine secretion and expression of CD markers in HCV+ve NHL patients. Based on our results, HCV infection in NHL patients requires more in-depth investigations to explore any role in lymphoma progression.

BACKGROUND: Surgery is the corner stone for the management of rectal cancer. The purpose of this study was to demonstrate the optimal time of surgical resection after the completion of neoadjuvant chemo-radiotherapy (CRT) in treatment of locally advanced rectal cancer.
MATERIALS AND METHODS: This study compared 2 groups of patients with locally advanced rectal cancer, treated with neoadjuvant CRT followed by surgical resection either 6-8 weeks or 9-14 weeks after the completion of chemo-radiotherapy. The impact of delaying surgery was tested in comparison to early surgical resection after completion of chemo-radiotherapy.
RESULTS: The total significant response rate that could result in functional preservation was estimated to be 3.85% in group I and 15.4% in group II. Some 9.62% of our patients had residual malignant cells at one cm surgical margin. All those patients with positive margins at one cm were in group I (19.23%). There was less operative time in group II, but the difference between both groups was statistically insignificant (P=0.845). The difference between both groups regarding operative blood loss and intra operative blood transfusion was significantly less in group II (P=0.044). There was no statistically significant difference between both groups regarding the intra operative complications (P=0.609). The current study showed significantly less post-operative hospital stay period, and less post-operative wound infection in group II (P=0.012 and 0.017). The current study showed more tumor regression and necrosis in group II with a highly significant main effect of time F=61.7 (P<0.001). Pathological TN stage indicated better pathological tumor response in group II (P=0.04). The current study showed recurrence free survival for all cases at 18 months of 84.2%. In group I, survival rate at the same duration was 73.8%, however none of group II cases had local recurrence (censored) (P=0.031). Disease free survival (DFS) during the same duration (18 months) was 69.4 % for patients in group I and 82.3% for group II (P=0.429).
CONCLUSIONS: Surgical resection delay up to 9-14 weeks after chemo-radiation was associated with better outcome and better recurrence free survival.

Small cell lung cancer (SCLC) is one of the most malignant neoplasms in common human cancers. The tumor is composed of small immature-looking cells with a round or fusiform shape, which possesses weak adhesion features among them, suggesting that SCLC shows the morphological characteristics of epithelial to mesenchymal transition (EMT). SCLC is characterized by high metastatic and recurrent rates, sensitivity to the initial chemotherapy, and easy acquirement of chemoresistance afterwards. These characters may be related to the EMT phenotype of SCLC. Notch signaling is an important signaling pathway, and could have roles in regulating neuroendocrine differentiation, proliferation, cell adhesion, EMT, and chemoresistance. Notch1 is usually absent in SCLC in vivo, but could appear after chemotherapy. Notch1 can enhance cell adhesion by induction of E-cadherin in SCLC, which indicates mesenchymal to epithelial transition. On the other hand, achaete-scute complex homologue 1 (ASCL1), negatively regulated by Notch signaling, is a lineage-specific gene of SCLC, and functions to promote neuroendocrine differentiation as well as EMT. ASCL1-transfected adenocarcinoma cell lines induced neuroendocrine phenotypes and lost epithelial cell features. SCLC is characterized by neuroendocrine differentiation and EMT-like features, which could be produced by inactive Notch signaling and ASCL1 expression. In addition, chemical and radiation treatments can activate Notch signaling, which suppress neuroendocrine differentiation and induces chemoradioresistance, accompanied by secession from EMT. Thus, the status of Notch signaling and ASCL1 expression may determine the cell behaviors of SCLC partly through modifying EMT phenotypes.

Conflicting results for circulating glypican-3 (GPC3) were reported in hepatocellular carcinoma (HCC) diagnosis. We aimed to improve the diagnostic power of GPC3 by developing a GPC-HCC model for diagnosing HCC. GPC3 was tested for HCC (138), liver cirrhosis (56), and fibrosis (62) patients by ELISA. Data from patient groups were retrospectively analyzed. A novel score, GPC-HCC, based on combination of GPC3 and routine laboratory tests, was developed for HCC diagnosis. The GPC-HCC model values produced a significant 1.7-fold increase in liver cirrhosis and 3.2-fold increase in HCC, in comparison with liver fibrosis. In contrast to GPC3 and alpha fetoprotein (AFP), the GPC-HCC model showed high HCC diagnostic power with area under the curve (AUC) of 0.939, sensitivity 93 %, specificity 93 %, positive predictive value 89 %, negative predictive value 95 %, and efficiency 93 %. GPC-HCC AUC in HCC with single tumor, absent vascular invasion, and tumor size ≤3 cm were 0.93, 0.92, and 0.92, respectively, compared with 0.63, 0.63, and 0.64, respectively, for GPC3 and 0.69, 0.70, 0.55, respectively, for AFP. In conclusion, owing to these promising findings, the combination of GPC3 with other laboratory simple routine tests (GPC-HCC model) could improve the diagnostic power of GPC3 in HCC screening and follow up of cirrhotic patients.

Epithelial-mesenchymal transition (EMT) is an essential process in breast cancer metastasis. The aim of the present study was to determine the role of secretions of tumor-associated leukocytes (TALs) isolated from negative and positive lymph nodes (nLNs and pLNs, respectively) breast cancer patients in regulating EMT mechanism and the associated signaling pathways. We found an increased infiltration of TALs, which was associated with downregulation of E-cadherin and over-expression of vimentin in the breast carcinoma tissues of pLNs as compared to nLNs patients and normal breast tissues obtained from healthy volunteers during mammoplasty. Furthermore, TALs isolated from pLNs breast cancer patients secreted an elevated panel of cytokines by up to 2-5-fold when compared with those isolated from nLNs patients. Secretome of TALs of pLNs possessed higher TARC, IGF-1, IL-3, TNF-β, IL-5, G-CSF, IL-4, and IL-1α with more than a fivefold compared to those of nLNs. Using the human breast cancer cell lines MCF-7 and MDA-MB-231, we found that cytokines secreted by TALs isolated from nLNs and pLNs breast cancer patients promoted EMT via upregulation of TGF-β and vimentin and downregulation of E-cadherin at messenger RNA (mRNA) levels in both cell lines and at protein level in MCF-7. While TGF-β is over-expressed by MDA-MB-231 seeded in media conditioned by secretome of TALs isolated from nLNs and pLNs breast cancer patients. The downstream TGF-β signaling transcription factors, Snail, Slug, and Twist, known to be associated with EMT mechanism were over-expressed by MCF-7 and MDA-MB-231 seeded in media conditioned by secretome of TALs isolated from nLNs and pLNs breast cancer patients. Acquisition of EMT in MCF-7 cells is mechanistically attributed to the activation of EGFR((Tyr845)) and NF-κB/p65((Ser276)) signaling which are significantly highly expressed by MCF-7 cells seeded in media conditioned by secretome of TALs isolated from pLNs compared to nLNs patients. Overall, this study provides implications of secretome of TALs and activated EGFR((Tyr845)) and NF-κB/p65((Ser276)) in EMT process that may be considered a therapeutic strategy to inhibit lymph node metastasis in breast cancer patients.

The identification of new high-sensitivity and high-specificity markers for hepatocellular carcinoma (HCC) is essential. We aimed at identifying serum microRNAs (miRNAs) as potential biomarkers for early detection of HCC on top hepatitis C virus (HCV) infection. We investigated serum expression of 13 miRNAs in 384 patients with HCV-related chronic liver disease (192 with HCC, 96 with liver cirrhosis (LC), and 96 with chronic hepatitis C (CHC)) in addition to 96 healthy participants enrolled as a control group. The miRNA expression was performed using real-time quantitative PCR-based SYBR Green custom miRNA arrays. The area under the receiver operating characteristic curve (AUC) was used to evaluate the diagnostic performance of miRNA panels for early detection of HCC. Using miRNA panel of miR-122, miR-885-5p, and miR-29b with alpha fetoprotein (AFP) provided high diagnostic accuracy (AUC = 1) for early detection of HCC in normal population while using miRNA panel of miR-122, miR-885-5p, miR-221, and miR-22 with AFP provided high diagnostic accuracy (AUC = 0.982) for early detection of HCC in LC patients. However, using miRNA panel of miR-22 and miR-199a-3p with AFP provided high diagnostic accuracy (AUC = 0.988) for early detection of HCC in CHC patients. We identified serum miRNA panels that could have a considerable clinical use in early detection of HCC in both normal population and high-risk patients.

BACKGROUND AND STUDY AIMS: Polymorphisms in the DNA repair genes may influence individual capacity to repair DNA damage, which may be associated with increased genetic instability and carcinogenesis. Our aim was to evaluate the relation of genetic polymorphisms in 2 DNA repair genes, XPD Lys751Gln and XRCC1 (A399G), with colorectal cancer (CRC) susceptibility. We further investigated the potential effect of these DNA repair variants on clinicopathological parameters of CRC patients.
PATIENTS AND METHODS: Both XPD and XRCC1 polymorphisms were characterised in one hundred CRC patients and one hundred healthy controls who had no history of any malignancy by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) method and PCR with confronting two-pair primers (PCR-CTPP), using DNA from peripheral blood in a case control study.
RESULTS: Our results revealed that the frequencies of GG genotype of XRCC1 399 polymorphism were significantly higher in the CRC patients than in the normal individuals (p⩽0.03), and did not observe any association between the XPD Lys751Gln polymorphism and CRC risk. We found association between both XRCC1 A399G polymorphisms and histological grading of disease.
CONCLUSION: Our results suggested that, XRCC1 gene is an important candidate gene for susceptibility to colorectal carcinoma.

Plasmonic photothermal therapy (PPTT) is a cancer therapy in which gold nanorods are injected at the site of a tumor before near-infrared light is transiently applied to the tumor causing localized cell death. Previously, PPTT studies have been carried out on xenograft mice models. Herein, we report a study showing the feasibility of PPTT as applied to natural tumors in the mammary glands of dogs and cats, which more realistically represent their human equivalents at the molecular level. We optimized a regime of three low PPTT doses at 2-week intervals that ablated tumors mainly via apoptosis in 13 natural mammary gland tumors from seven animals. Histopathology, X-ray, blood profiles, and comprehensive examinations were used for both the diagnosis and the evaluation of tumor statuses before and after treatment. Histopathology results showed an obvious reduction in the cancer grade shortly after the first treatment and a complete regression after the third treatment. Blood tests showed no obvious change in liver and kidney functions. Similarly, X-ray diffraction showed no metastasis after 1 year of treatment. In conclusion, our study suggests the feasibility of applying the gold nanorods-PPTT on natural tumors in dogs and cats without any relapse or toxicity effects after 1 year of treatment.

Recently, research has progressively highlighted on clues from conventional use of herbal medicines to introduce new anticancer drugs. Aloe-emodin (AE) is a herbal drug with promising anticancer activity. Nevertheless, its clinical utility is handicapped by its low solubility. For the first time, this study aims to the fabrication of surface-functionalized polyethylene glycol liquid crystalline nanoparticles (PEG-LCNPs) of AE to enhance its water solubility and enable its anticancer use. Developed AE-PEG-LCNPs were optimized via particle size and zeta potential measurements. Phase behavior, solid state characteristics, hemocompatibility, and serum stability of LCNPs were assessed. Sterile formulations were developed using various sterilization technologies. Furthermore, the potential of the formulations was investigated using cell culture, pharmacokinetics, biodistribution, and toxicity studies. AE-PEG-LCNPs showed particle size of 190 nm and zeta potential of -49.9, and PEGylation approach reduced the monoolein hemolytic tendency to 3% and increased the serum stability of the nanoparticles. Sterilization of liquid and lyophilized AE-PEG-LCNPs via autoclaving and γ-radiations, respectively, insignificantly affected the physicochemical properties of the nanoparticles. Half maximal inhibitory concentration of AE-PEG-LCNPs was 3.6-fold lower than free AE after 48 hours and their cellular uptake was threefold higher than free AE after 24-hour incubation. AE-PEG-LCNPs presented 5.4-fold increase in t1/2 compared with free AE. Biodistribution and toxicity studies showed reduced AE-PEG-LCNP uptake by reticuloendothelial system organs and good safety profile. PEGylated LCNPs could serve as a promising nanocarrier for efficient delivery of AE to cancerous cells.

OBJECTIVE: The purpose of this study is to retrospectively evaluate local tumor control, time to tumor progression, and survival rates among patients with lung metastatic colorectal cancer who have undergone ablation therapy performed using laser-induced thermotherapy (LITT), radiofrequency ablation (RFA), or microwave ablation (MWA).
MATERIALS AND METHODS: Data for this retrospective study were collected from 231 CT-guided ablation sessions performed for 109 patients (71 men and 38 women; mean [± SD] age, 68.6 ± 11.2 years; range, 34-94 years) from May 2000 to May 2014. Twenty-one patients underwent LITT (31 ablations), 41 patients underwent RFA (75 ablations), and 47 patients underwent MWA (125 ablations). CT scans were acquired 24 hours after each therapy session and at follow-up visits occurring at 3, 6, 12, 18, and 24 months after ablation. Survival rates were calculated from the time of the first ablation session, with the use of Kaplan-Meier and log-rank tests. Changes in the volume of the ablated lesions were measured using the Kruskal-Wallis method.
RESULTS: Local tumor control was achieved in 17 of 25 lesions (68.0%) treated with LITT, 45 of 65 lesions (69.2%) treated with RFA, and 91 of 103 lesions (88.3%) treated with MWA. Statistically significant differences were noted when MWA was compared with LITT at 18 months after ablation (p = 0.01) and when MWA was compared with RFA at 6 months (p = 0.004) and 18 months (p = 0.01) after ablation. The overall median time to local tumor progression was 7.6 months. The median time to local tumor progression was 10.4 months for lesions treated with LITT, 7.2 months for lesions treated with RFA, and 7.5 months for lesions treated with MWA, with no statistically significant difference noted. New pulmonary metastases developed in 47.6% of patients treated with LITT, in 51.2% of patients treated with RFA, and in 53.2% of patients treated with MWA. According to the Kaplan-Meier test, median survival was 22.1 months for patients who underwent LITT, 24.2 months for those receiving RFA, and 32.8 months for those who underwent MWA. The overall survival rate at 1, 2, and 4 years was 95.2%, 47.6%, and 23.8%, respectively, for patients treated with LITT; 76.9%, 50.8%, and 8.0%, respectively, for patients treated with RFA; and 82.7%, 67.5%, and 16.6%, respectively, for patients treated with MWA. The log-rank test revealed no statistically significant difference among LITT, RFA, and MWA. The progression-free survival rate at 1, 2, 3, and 4 years was 96.8%, 52.7%, 24.0%, and 19.1%, respectively, for patients who underwent LITT; 77.3%, 50.2%, 30.8%, and 16.4%, respectively, for patients who underwent RFA; and 54.6%, 29.1%, 10.0%, and 1.0%, respectively, for patients who underwent MWA, with no statistically significant difference noted among the three ablation methods.
CONCLUSION: LITT, RFA, and MWA can be used as therapeutic options for lung metastases resulting from colorectal cancer. Statistically significant differences in local tumor control revealed a potential advantage in using MWA. No differences in time to tumor progression or survival rates were detected when the three different ablation methods were compared.

Inflammasome complexes function as key innate immune effectors that trigger inflammation in response to pathogen- and danger-associated signals. Here, we report that germline mutations in the inflammasome sensor NLRP1 cause two overlapping skin disorders: multiple self-healing palmoplantar carcinoma (MSPC) and familial keratosis lichenoides chronica (FKLC). We find that NLRP1 is the most prominent inflammasome sensor in human skin, and all pathogenic NLRP1 mutations are gain-of-function alleles that predispose to inflammasome activation. Mechanistically, NLRP1 mutations lead to increased self-oligomerization by disrupting the PYD and LRR domains, which are essential in maintaining NLRP1 as an inactive monomer. Primary keratinocytes from patients experience spontaneous inflammasome activation and paracrine IL-1 signaling, which is sufficient to cause skin inflammation and epidermal hyperplasia. Our findings establish a group of non-fever inflammasome disorders, uncover an unexpected auto-inhibitory function for the pyrin domain, and provide the first genetic evidence linking NLRP1 to skin inflammatory syndromes and skin cancer predisposition.

The process of angiogenesis is quite well-known nowadays. Some medicines and extracts affecting this process are already used routinely in supporting the conventional treatment of many diseases that are considered angiogenic such as cancer. However, we must be aware that the area of currently used drugs of this type is much narrower than the theoretical possibilities existing in therapeutic angiogenesis. Plant substances are a large and diverse group of compounds that are found naturally in fruits, vegetables, spices, and medicinal plants. They also have different anticancer properties. The aim of this literature review article is to present the current state of knowledge concerning the molecular targets of tumor angiogenesis and the active substances (polyphenols, alkaloids, phytohormones, carbohydrates, and terpenes) derived from natural sources, whose activity against cancer angiogenesis has been confirmed.

BACKGROUND: Hepatocellular carcinoma (HCC) is a dreadful complication of end stage liver disease with high morbidity and mortality.
AIM: The aim was to assess the role of serum talin-1 and non-invasive brosis in patients with HCC.
MATERIALS AND METHODS: A total of eighty seven subjects were enrolled, with 22 two healthy individuals as a control group (n=22), 22 patients in the cirrhosis group and finally 43 in the group with HCC diagnosed with positive triphasic CT abdomen criteria. Serum talin-1 and noninvasive fibrosis parameters were assessed in all subjects.
RESULTS: Compared to the cirrhosis group, patients with HCC had higher serum talin-1 (32.9±12.6 vs. 11.1±2.79 ng/ml), FIB4 (9.96±15.3 vs. 2.90±1.87) and bro-α (10.9±18.1 vs. 1.55±0.28) but not fibrosis index scores (4.47±0.95 vs. 4.98±0.96; p=0.046). Patients with large focal lesions (≥5cm) had different ALBI scores (-1.02±0.63 vs. -1.72±0.59; p=0.001) serum talin-1 (9.72±13.81 vs. 28.6±38.89 ng/ml; p=0.007) and brosis index scores (0.85 ± 0.99 vs. 4.20±4.85; p=0.026). No statistical differences were noted between patients with and without portal vein thrombosis. For detection of HCC, serum talin-1 had 97.7% sensitivity and 100% specificity with a 17.2 ng/ml cutoff. AFP at a 13.7 ng/ml cutoff had 72.1% sensitivity and 6.3.6% specificity. The cutoff for the bro-α score was 1.61 with 81.4% sensitivity and 77.3% specificity. Serum talin-1 (odds=1.08; C.I=1.016-1.150; p=0.014), brosis index score (odds=2.35; C.I=1.055-5.217; p=0.037) and the ALBI score (odds=6.9; C.I=1.924-24.708; p=0.003) were predictors of large focal lesions.
CONCLUSIONS: Serum talin-1, AST/ALT ratio, bro-α score are useful for the assessment of HCC patients.

HER2/neu is a well-established prognostic and predictive factor for invasive breast cancer. However, the role of HER2/neu in ductal breast carcinoma in situ (DCIS) is debated and recent data have suggested that it is mainly linked to in situ local recurrence. Although molecular data suggest that atypical ductal hyperplasia (ADH) and duct carcinoma in situ (DCIS) are related lesions, albeit with vastly different clinical implications, the role of HER2/neu expression in atypical ductal hyperplasia is not well defined either. The aim of this study was to evaluate over expression of HER2/neu in DCIS and cases of ADH in comparison with invasive breast carcinoma. Archival primary breast carcinoma paraffin blocks (n=15), DCIS only (n=10) and ductal epithelial hyperplasia and other breast benign lesions (n=25) were analyzed for HER2/neu immunoexpression. Follow up was available for 40% of the patients. HER2/neu was positive in 80%of both DCIS and invasive carcinoma, and 67% of atypical ductal hyperplasia (ADH) cases. Thus at least a subset of patients with preinvasive breast lesions were positive, which strongly suggests a role for Her2/neu in identifying high-risk patients for malignant transformation. Although these are preliminary data, which need further studies of gene amplification within these patients as well as a larger patient cohort with longer periods of follow up, they support the implementation of routine Her2/neu testing in patients diagnosed as pure DCIS and in florid ADH.

PURPOSE: To characterize parotid tumors with dynamic susceptibility contrast perfusion-weighted magnetic resonance (MR) imaging and diffusion-weighted MR imaging.
MATERIAL AND METHODS: Prospective study was conducted upon 48 consecutive patients (27 men, 21 women; aged 15-75 years; mean, 45 years) with parotid tumors that underwent dynamic susceptibility contrast perfusion-weighted MR imaging was performed after bolus injection of gadopentate dimeglumine and diffusion-weighted MR imaging. The dynamic susceptibility contrast percentage (DSC%) and apparent diffusion coefficient (ADC) values of parotid tumors were calculated and correlated with histopathological findings.
RESULTS: The DSC% of malignant parotid tumors (33.53% ± 3.99%) was significantly different (P = 0.001) from that of benign parotid tumors (22.29% ± 4.13%). The threshold values of DSC% and ADC used in differentiating malignant from benign parotid tumors were 26.5% and 1.07 × 10 mm/s, respectively, with area under the curve (AUC) of 0.96 and 0.81, respectively. The DSC% of malignant parotid tumors was significantly different from that of Warthin tumors (P = 0.001). The cutoff DSC% used to differentiate malignancy from Warthin tumors was 26.9% with an AUC of 0.99. There was a significant difference in DSC% and ADC values between pleomorphic adenomas and Warthin tumors (P = 0.001). The threshold values of DSC% and ADC used in differentiating pleomorphic adenomas from Warthin tumors was 22.5% and 0.99 × 10 mm/s, respectively, with AUC of 0.88 and 0.98, respectively.
CONCLUSIONS: Dynamic susceptibility contrast-enhanced perfusion-weighted MR imaging and diffusion-weighted MR imaging are noninvasive promising methods that are used for differentiation of malignant from benign parotid tumors and for characterization of some benign parotid tumors.

BACKGROUND: Diagnosis of pancreatic cancer (PC) by using sensitive and specific biomarkers is considered necessary. MiRNAs are master regulators of gene expression and several biological processes, and they are dysregulated in various cancers, where they play a vital role in either cancer progression or suppression. So, this study was designed to investigate the role of plasma miR-22-3p, miR-642b-3p and miR-885-5p expression as possible diagnostic markers in PC patients as compared to serum CA19-9. In addition, the correlation of those miRNAs and CA19-9 with clinical characteristics of PC patients was analyzed.
METHODS: The expression levels of selected miRNAs and serum CA19-9 concentration were determined for 35 patients with PDAC and 15 healthy controls by quantitative real-time RT-PCR and electro-chemiluminescence immune assay, respectively. The sensitivities of miRNAs as biomarkers of PC were evaluated and compared with CA19-9 using a receiver operating characteristic analysis.
RESULTS: The levels of three miRNAs (miR-22-3p, miR-642b-3p and miR-885-5p) and CA19-9 were significantly higher in PC patients, even those with early-stage disease (IB and IIB), than in healthy control. Both miRNAs and CA19-9 were associated with tumor stage. The high sensitivities of the three selected miRNAs and CA19-9 were observed.
CONCLUSION: The measurement of miR-22-3p, miR-642b-3p and miR-885-5p may prove to have clinical utility in diagnosis of PC. Those miRNAs are ideal early biomarkers for PC diagnosis. So, they can effectively be used with serum CA19-9 for PC screening in early tumor stage.

INTRODUCTION: The aim of this study was to evaluate the treatment outcomes of differentiated thyroid cancer in Saudi patients aged above 60 years.
MATERIALS AND METHODS: Comparative analysis was performed in 252 patients aged 46-60 years (Group A) and 118 patients aged above 60 years (Group B), who had thyroidectomy, radioactive iodine-131, and thyroid-stimulating hormone suppression therapy between July 2000 and December 2012. Different clinicopathological features, treatment, complications, disease-free survival, and overall survival rates were compared.
RESULTS: Mean age of patients in Group A was 51.9 years (range: 46-60), and mean age of those in Group B was 68.6 years (range: 62-97). Group B patients had higher positive lymph nodes (43.2%), P=0.011. The frequency of extrathyroidal extension, multifocality, and lymphovascular space invasion was seen more in Group B than in Group A. Postsurgical complications (permanent hypoparathyroidism, bleeding, and wound infections) were also seen more in Group B (P=0.043, P=0.011, and P=0.021, respectively). Group B patients experienced more locoregional recurrences (11.0%, P=0.025); similarly, more distant metastases were observed in Group B (15.3%, P=0.003). The 10-year disease-free survival rates were 87.6% in Group A and 70.8% in Group B (P<0.0001).
CONCLUSION: Differentiated thyroid cancer in patients aged above 60 years are more aggressive biologically and associated with a worse prognosis, and the morbidity is significantly high as compared to patients aged below 60 years.

BACKGROUND: Achieving a high rate of complete pathological response with pre-operative chemoradiotherapy in rectal cancer is an unmet need. We evaluated the efficacy and toxicity of the combination of cetuximab, capecitabine and radiation therapy in the pre-operative setting of localized rectal cancer.
PATIENTS AND METHODS: Patients with clinically staged T3, T4 or nodepositive rectal cancer were treated with concurrent capecitabine and radiotherapy with weekly cetuximab starting one week before the start of radiation. This was followed by total mesorectal excision within 6-8 weeks. All patients achieving R0 resection received adjuvant capecitabine for 6 cycles.
RESULTS: Fifteen patients were treated and all underwent surgery. Sphincter preservation was achieved in 11 patients (73.3%) and pathological complete response in two. With a median follow up of 48 months (range 8.4-57.5), 12 patients were relapse-free and 14 were alive with 4-year relapse free survival of 80%. Overall survival was 93%. Significant grade 3 and 4 toxicity was mainly cetuximab-induced skin reactions (33%), radiation-induced skin toxicity (13%) and diarrhea (20%).
CONCLUSIONS: Adding cetuximab to pre-operative concurrent capecitabine and radiotherapy provides modest efficacy with manageable toxicity.

Hepatocellular carcinoma (HCC) is one of the most common cancer types with a high prevalence and itis the leading cause of cancer deaths worldwide. This study aimed to investigate the antiproliferative effect of aqueous and ethanol extracts of Origanum majorana leaf on human hepatocellular carcinoma (HepG2) cell line through incubation of various concentrations of origanum majorana extracts with HepG2 and at different time intervals. The effects of aqueous and ethanol extracts of O. majorana L. on HepG2 cell viability, nuclear factor kappa B (NF-kB) gene expression were examined. The results of the cell viability assays showed that aqueous and ethanol extracts exhibited a highly significant inhibitory effect on HepG2 cell proliferation which was evidenced by a reduction in viable cell count. The results were confirmed by microscopical examination of cell morphology. Furthermore, the O. majorana L. extracts suppressed the activity of NF-kB gene expression of HepG2 cells compared to the control.The conclusions from this study suggest that marjoram extracts exhibit anti-proliferative effect against HCC through suppressing the activity of NF-kB gene expression and high antioxidant activity.

AIM: The aim of this article is to assess diffusion tensor imaging (DTI) metrics in differentiating low-grade from high-grade gliomas.
PATIENTS AND METHODS: A prospective study was conducted on 35 patients with gliomas who underwent DTI. Gliomas were classified into low-grade and high-grade gliomas. The fractional anisotropy (FA), mean diffusivity (MD), linear coefficient (CL), planar coefficient (CP) and spherical coefficient (CS) of the solid tumoral part and peri-tumoral regions were calculated.
RESULTS: There was significant difference (p = 0.001) in MD of the solid tumoral part of low-grade (1.78 ± 0.33 × 10(-3 )mm(2)/s) and high-grade (1.16 ± 0.22 × 10(-3 )mm(2)/s) gliomas. The selection of 1.42 × 10(-3 )mm(2)/s as a cutoff value of MD of the tumoral part was used to differentiate low-grade and high-grade gliomas; the best results were obtained with area under the curve (AUC) of 0.957 and accuracy of 91.4%. There was a significant difference in FA, MD, CP and CS of peri-tumoral regions of both groups with p values of 0.006, 0.042, 0.030 and 0.037, respectively. The cutoff values of MD, FA, CS and CP of the peri-tumoral region used to differentiate low-grade from high-grade gliomas were 1.24, 0.315, 0.726 and 0.321 with AUC of 0.694, 0.773, 0.734 and 0.724 and accuracy of 68.6%, 80.0%, 74.3% and 74.3%, respectively. The combined MD of the solid tumoral part and FA of the peri-tumoral region used to differentiate low-grade from high-grade gliomas revealed AUC of 0.974 and accuracy of 88.6%.
CONCLUSION: We conclude that the combination of MD of the solid tumoral part and FA of the peri-tumoral region is a noninvasive method to differentiate low-grade from high-grade gliomas.

BACKGROUND: Identification of patients with advanced HCC-deriving preferential benefit from sorafenib is desirable, and treatment-related adverse events are potential clinical biomarkers.
METHODS: Survival and toxicity data for patients with HCC treated with sorafenib at the Christie NHS Foundation Trust from 11/09 to 02/15 were collected retrospectively.
RESULTS: Eighty-five eligible patients were identified. The most common grade 3 or 4 treatment-related toxicities were hypertension (HTN, 45 %), fatigue (8 %), and hand-foot syndrome (HFS, 8 %). Any-grade HFS and/or worsening HTN (HFS/HTN) were experienced by 58 % of patients. Estimated median progression-free and overall survival (OS) were 4.6 (95 % CI 2.8-5.2) and 6.5 (95 % CI 4.9-8.01) months, respectively. Child-Pugh score (p value <0.001) and the development of HFS/HTN were independent prognostic factors impacting on OS on multivariable analysis. Patients who developed HFS/HTN had median OS of 8.2 months (95 % CI 6.5-12.4) compared with 4.1 (95 % CI 2.7-5.4) for those without this toxicity (Hazard Ratio (HR) 0.4, 95 % CI 0.2-0.7, p value 0.003). The prognostic impact of HFS/HTN was confirmed by landmark analyses limited to patients who lived a minimum of 2 months (p value 0.019) or who developed HFS/HTN in the first 3 months of treatment (p value 0.006).
CONCLUSION(S): The development of toxicities specific to sorafenib is associated with prolonged survival in a UK-based HCC patient series; prospective assessment of their significance is required.

AIMS: The study aimed to investigate the quantitative expression of NANOG, p38 α , NCF2, ELF and TGF-β genes in patients with colorectal adenocarcinoma, adenoma and normal colonic tissue and their correlation with SIRT-1 protein level expression.
METHOD: This study enrolled one hundred sixty seven patients; group A: 87 patients with colonoscopic findings of no adenoma or adenocarcinoma and group B: 80 patients with colorectal mass. Consecutive colonoscopic examinations were conducted, and tissue samples were taken from the colonic lesions/masses. Total RNA was isolated and mRNA expression level of NANOG, mitogen activated p38α , Neutrophil Cytosol Factor 2 (NCF2), Embryonic Liver Fodrin (ELF) and Transforming Growth Factor Beta (TGF-β) genes were quantified by qRT-PCR. Sirt-1 protein expression level was assessed by quantitative western blot.
RESULTS: There were significantly high level of mRNA transcripts expression of the genes studied in patients with adenocarcinoma and adenoma compared with normal tissue (P value < 0.01), NANOG, NCF2, ELF and TGF-β at a cut of > 0.314, > 0.392, 0.349 and 0.333 respectively showed sensitivity (96.5%, 98.8%, 95.3%, 98.8%) and specificity of (95.3%, 92.6%, 89.5%, 93.8%) respectively in diagnosing colonic adenocarcinoma. Sirt-1 protein level was significantly highly expressed in colorectal adenocarcinoma compared to normal and adenoma colonic tissue and positively correlated with NANOG.
CONCLUSION: Over expression of NANOG, p38α , NCF2, ELF and TGF-β genes in both cases of adenocarcinoma and adenoma could have a diagnostic value. SIRT-1 and NANOG are high correlated biological markers for diagnosis and prognosis follow up in patients with adenocarcinoma.