Technology in Cancer Research & Treatment

Radiation enteritis is one of the most feared complications of abdominal and pelvic regions. Thus, radiation to abdominal or pelvic malignancies unavoidably injures the intestine. Because of rapid cell turnover, the intestine is highly sensitive to radiation injury, which is the limiting factor in the permissible dosage of irradiation. Bowel injuries such as fistulas, strictures, and chronic malabsorption are potentially life-threatening complications and have an impact on patient quality of life. The incidence of radiation enteritis is increasing because of the current trend of combined chemotherapy and radiation. The consequences of radiation damage to the intestine may result in considerable morbidity and even mortality. The observed effects of ionizing radiation are mediated mainly by oxygen-free radicals that are generated by its action on water and are involved in several steps of signal transduction cascade, leading to apoptosis. The oxyradicals also induce DNA strand breaks and protein oxidation. An important line of defense against free radical damage is the presence of antioxidants. Therefore, administration of antioxidants may ameliorate the radiation-induced damage to the intestine.

Prostate cancer is the most common solid cancer and genetic factors play important roles in its pathogenesis. XPD is one of the 8 core genes involved in the nucleotide excision repair pathway. The relationship between Asp312Asn, Lys751Gln, and Arg156Arg polymorphisms in XPD and prostate cancer risk is a controversial topic. Therefore, we conducted a meta-analysis to explore the relationship between these 3 polymorphisms and the risk of developing prostate cancer. We searched the electronic literature in PubMed and Google Scholar for all relevant studies (last updated January 1, 2017). The pooled odds ratios and 95% confidence intervals for the associations between the Asp312Asn, Lys751Gln, or Arg156Arg polymorphisms in XPD and prostate cancer risk were calculated. To evaluate the effects of specific study characteristics on the association of these 3 polymorphisms and prostate cancer risk, we performed subgroup analysis if 2 or more studies were available. After an extensive literature review, 7 publications regarding Asp312Asn genotype distribution with 8 case–controls, 9 publications regarding Lys751Gln genotype distribution with 10 case–controls, and 3 publications regarding Arg156Arg genotype distribution with 4 case–controls were selected. The results showed that Asp312Asn (odds ratio = 1.34, 95% confidence interval: 0.96-1.87, P = .000), Lys751Gln (odds ratio = 0.98, 95% confidence interval: 0.89-1.08, P = .986), and Arg156Arg (odds ratio = 1.05, 95% confidence interval: 0.91-1.22, P = .57) polymorphisms do not increase the risk of prostate cancer in the dominant model. Further, in the subgroup analysis by ethnicity, no relationships were observed between Lys751Gln and Arg156Arg polymorphisms and prostate cancer risk. However, stratified analysis by ethnicity revealed that Asp312Asn affects African (odds ratio = 1.57, 95% confidence interval: 1.06-2.33, P = .382) and Asian populations (odds ratio = 2.09, 95% confidence interval: 1.39-3.14, P = .396) in homozygote comparison. In conclusion, this meta-analysis suggests that there is no general association between the Asp312Asn, Lys751Gln, and Arg156Arg polymorphisms in XPD and prostate cancer susceptibility.

Multiple myeloma is a monoclonal B-cell malignancy characterized by an accumulation of malignant plasma cells in the bone marrow, the presence of a monoclonal protein in the serum and/or urine, decreased normal immunoglobulin levels, and lytic bone disease. Patients with multiple myeloma benefit from combination therapy including novel therapeutic agents followed by autologous stem cell transplantation prolonged maintenance therapy. However, multiple myeloma remains incurable; most patients with multiple myeloma will eventually become resistant to chemotherapy, and progression or relapse of the disease is inevitable. Immunotherapy represents a novel therapeutic approach with few adverse effects and good targeting capability that might be a powerful pool to allow long-term control of minimal residual disease. This article reviews the literature evaluating 4 major immunotherapeutic approaches for multiple myeloma including cellular immunotherapy, humoral immunotherapy, radio immunotherapy, and immunomodulation.

Accumulating studies have reported that long noncoding RNA BRAF-activated nonprotein coding RNA plays vital role in various cancers. However, the prognostic values of BRAF-activated nonprotein coding RNA in solid tumors remain controversial. Thus, we assessed the prognostic values of BRAF-activated nonprotein coding RNA by this meta-analysis. We comprehensively searched PubMed, Web of Science, Medline, China National Knowledge Infrastructure (CNKI), and the Cochrane Library at November 2016. After carefully screening, we ultimately included 14 studies in this meta-analysis. This meta-analysis brought all relevant articles into determining the association of BRAF-activated nonprotein coding RNA expression with overall survival and clinicopathologic features. The results showed that high BRAF-activated nonprotein coding RNA expression significantly shorten the overall survival of solid tumors (pooled hazard ratios 1.66, 95% confidence interval: 1.19-2.32). Moreover, high BRAF-activated nonprotein coding RNA expression was also strongly associated with advanced tumor stage (odds ratios = 2.57, 95% confidence interval: 1.14-5.79), differentiation grade (odds ratio = 1.71, 95% confidence interval: 1.26-2.31), lymph node metastasis (odds ratio = 2.67, 95% confidence interval: 1.93-3.70, P < .001), and distant metastasis (odds ratio = 2.98, 95% confidence interval: 1.76-5.07, P = .02). In conclusion, this meta-analysis demonstrated that high BRAF-activated nonprotein coding RNA expression may be a potential novel biomarker for indicating a poor prognosis and progression in human solid tumors.

While new cancer treatments continue to improve patient outcomes, for some cancers there have been limited or no improvements for a long time. It is for these cases radically new approaches are required. Recent publications proposing ribosome biogenesis, in particular RNA polymerase I transcription, as a suitable target for cancer treatment has been gaining momentum. For example, we demonstrated that CX-5461, a specific RNA polymerase I transcription inhibitor, is effective in treating an aggressive subtype of acute myeloid leukemia, regardless of p53 status. Notably, CX-5461 reduces the leukemia initiating/stem cells, the cell population believed to be responsible for chemotherapy resistance and disease relapse in numerous cancers. Targeting ribosome biogenesis, once considered merely a “housekeeping process,” is showing promise in a continuously growing list of cancers including lymphoma, prostate, and now acute myeloid leukemia. Evidence suggests the therapeutic efficacy of RNA polymerase I therapy in preclinical models is mediated through a variety of mechanisms including nucleolar stress activation of p53, DNA damage-like activation of ataxia-telangiectasia mutated/ataxia-telangiectasia and Rad3 related, and cellular differentiation. Overall, the available data suggests the potential for targeting ribosome biogenesis to be effective in a broad spectrum of cancers. The outcomes of 2 phase 1/2 trials of CX-5461 in hematological malignancies and breast cancer are eagerly awaited.

In this work, we studied the possibility of merging proton therapy with grid therapy. We hypothesized that patients with larger targets containing solid tumor growth could benefit from being treated with this method, proton grid therapy. We performed treatment planning for 2 patients with abdominal cancer with the suggested proton grid therapy technique. The proton beam arrays were cross-fired over the target volume. Circular or rectangular beam element shapes (building up the beam grids) were evaluated in the planning. An optimization was performed to calculate the fluence from each beam grid element. The optimization objectives were set to create a homogeneous dose inside the target volume with the constraint of maintaining the grid structure of the dose distribution in the surrounding tissue. The proton beam elements constituting the grid remained narrow and parallel down to large depths in the tissue. The calculation results showed that it is possible to produce target doses ranging between 100% and 130% of the prescribed dose by cross-firing beam grids, incident from 4 directions. A sensitivity test showed that a small rotation or translation of one of the used grids, due to setup errors, had only a limited influence on the dose distribution produced in the target, if 4 beam arrays were used for the irradiation. Proton grid therapy is technically feasible at proton therapy centers equipped with spot scanning systems using existing tools. By cross-firing the proton beam grids, a low tissue dose in between the paths of the elemental beams can be maintained down to the vicinity of a deep-seated target. With proton grid therapy, it is possible to produce a dose distribution inside the target volume of similar uniformity as can be created with current clinical methods.

The worldwide high mortality rate of lung cancer could be reduced significantly by its noninvasive early detection. The quantitative analysis of cell-free circulating DNA in plasma presents a potential noninvasive approach for liquid biopsy of tumor. In this study, real-time polymerase chain reaction–based approach was used to quantify free circulating DNA in plasma. The concentration of free circulating DNA was checked using human telomerase reverse transcriptase gene as marker, and amplification status of oncogene RAC-β serine/threonine protein kinase along with the DNA methylation status of tumor suppressor gene (deleted in colorectal cancer) was assessed. The concentration of free circulating DNA in patients with lung cancer (22.8 ng/mL) was found approximately 6 times above than the value detected in controls (2.8 ng/mL). Considerable variation in the AKT2 copy number was observed in patients with lung cancer and controls (P < .000). Aberrant methylation of the deleted in colorectal cancer promoter was found to be highly specific (100%), as none of the control plasma samples showed aberrant methylation. The quantification of free circulating DNA along with determination of AKT2 amplification and deleted in colorectal cancer promoter methylation status appeared promising to differentiate patients with lung cancer from healthy individuals.

Epithelial–mesenchymal transition (EMT) is associated with cancer metastasis and poor prognosis, but the exact mechanism has not been clarified. Centrosomal Aurora-A kinase gene is frequently overexpressed in a variety of cancers and plays a pivotal role in the growth and survival of cancer cells. However, its role in colorectal cancer metastasis has not been confirmed. Here we demonstrate that Aurora-A plays a crucial role in the progression and metastasis of colorectal cancer by regulating epithelial–mesenchymal transition. In our study, increased Aurora-A expression was detected in colorectal cancer clinical specimens compared to normal colorectal tissues. Moreover, overexpressed Aurora-A significantly promoted the proliferation, migration, and invasion capacity of colorectal cancer cells and then enhanced metastatic capacity of colorectal cancer in vitro and in vivo and eventually led to poor prognosis. Conversely, silencing Aurora-A expression in colorectal cancer cells decreased the capacity of proliferation, migration, and invasion and further reduced colorectal cancer metastasis. Mechanistically, we found that Slug was involved in Aurora-A–induced migration and invasion of colorectal cancer cells. Silencing Slug expression could block Aurora-A–induced migration, invasion, and metastasis of colorectal cancer cells. Furthermore, the expression of Aurora-A and Slug were positively correlated in colorectal cancer tissues and paired normal colorectal tissue. Taken together, our findings revealed a critical role of Aurora-A in colorectal cancer progression and metastasis by regulating epithelial–mesenchymal transition.

Stereotactic body radiation therapy is a well-tolerated modality for the treatment of primary and metastatic liver lesions, and fiducials are often used as surrogates for tumor tracking during treatment. We evaluated respiratory-induced liver deformation by measuring the rigidity of the fiducial configuration during the breathing cycle. Seventeen patients, with 18 distinct treatment courses, were treated with stereotactic body radiosurgery using multiple fiducials. Liver deformation was empirically quantified by measuring the intrafiducial distances at different phases of respiration. Data points were collected at the 0%, 50%, and 100% inspiration points, and the distance between each pair of fiducials was measured at the 3 phases. The rigid body error was calculated as the maximum difference in the intrafiducial distances. Liver disease was calculated with Child-Pugh score using laboratory values within 3 months of initiation of treatment. A peripheral fiducial was defined as within 1.5 cm of the liver edge, and all other fiducials were classified as central. For 5 patients with only peripheral fiducials, the fiducial configuration had more deformation (average maximum rigid body error 7.11 mm, range: 1.89-11.35 mm) when compared to patients with both central and peripheral and central fiducials only (average maximum rigid body error 3.36 mm, range: 0.5-9.09 mm, P = .037). The largest rigid body errors (11.3 and 10.6 mm) were in 2 patients with Child-Pugh class A liver disease and multiple peripheral fiducials. The liver experiences internal deformation, and the fiducial configuration should not be assumed to act as a static structure. We observed greater deformation at the periphery than at the center of the liver. In our small data set, we were not able to identify cirrhosis, which is associated with greater rigidity of the liver, as predictive for deformation. Treatment planning based only on fiducial localization must take potential intraorgan deformation into account.

Irreversible electroporation is a novel tissue ablation technique which entails delivering intense electrical pulses to target tissue, hence producing fatal defects in the cell membrane. The present study numerically analyzes the potential impact of liver blood vessels on ablation by irreversible electroporation because of their influence on the electric field distribution. An anatomically realistic computer model of the liver and its vasculature within an abdominal section was employed, and blood vessels down to 0.4 mm in diameter were considered. In this model, the electric field distribution was simulated in a large series of scenarios (N = 576) corresponding to plausible percutaneous irreversible electroporation treatments by needle electrode pairs. These modeled treatments were relatively superficial (maximum penetration depth of the electrode within the liver = 26 mm) and it was ensured that the electrodes did not penetrate the vessels nor were in contact with them. In terms of total ablation volume, the maximum deviation caused by the presence of the vessels was 6%, which could be considered negligible compared to the impact by other sources of uncertainty. Sublethal field magnitudes were noticed around vessels covering volumes of up to 228 mm³. If in this model the blood was substituted by a liquid with a low electrical conductivity (0.1 S/m), the maximum volume covered by sublethal field magnitudes was 3.7 mm³ and almost no sublethal regions were observable. We conclude that undertreatment around blood vessels may occur in current liver ablation procedures by irreversible electroporation. Infusion of isotonic low conductivity liquids into the liver vasculature could prevent this risk.

The Polycomb group genes are a general class of regulators that are responsible for maintaining homeotic gene expression throughout cell division. Polycomb group expression plays an important role in oncogenesis of several types of human cancer. Melanoma nuclear protein 18 and B-cell-specific Moloney leukemia virus insert site 1 are key Polycomb group proteins. Studies have shown that melanoma nuclear protein 18 is a potential tumor suppression, and B-cell-specific Moloney leukemia virus insert site 1 is overexpressed in several human malignancies. However, the roles of melanoma nuclear protein 18 and B-cell-specific Moloney leukemia virus insert site 1 in esophageal squamous cell carcinoma are still unclear. In this study, we analyzed the expression levels of melanoma nuclear protein 18 and B-cell-specific Moloney leukemia virus insert site 1 in 89 esophageal cancer tissues and paired normal mucosal tissues using immunohistochemistry, Western blotting, and quantitative real-time polymerase chain reaction analyses. We found that the expression of melanoma nuclear protein 18 in the carcinoma tissues was significantly lower than that in the noncancerous mucosal tissues (P < .05), and B-cell-specific Moloney leukemia virus insert site 1 expression in the carcinoma tissues was significantly higher than that in the noncancerous mucosal tissues (P < .05). In addition, the expression of melanoma nuclear protein 18 was correlated with clinical stage, depth of invasion, and lymph node metastasis (P < .05) but was not correlated with gender, age, degree of differentiation, or disease-free survival (P > .05). B-cell-specific Moloney leukemia virus insert site 1 expression was strongly correlated with the degree of differentiation, clinical stage, and lymph node metastasis (P <.05) but was not correlated with the gender, age, depth of invasion or disease-free survival (P > .05). Moreover, there was a negative correlation between melanoma nuclear protein 18 and B-cell-specific Moloney leukemia virus insert site 1 expressions in esophageal squamous cell carcinoma (P < .05). Our study suggests that melanoma nuclear protein 18 and B-cell-specific Moloney leukemia virus insert site 1 may play a crucial role in esophageal squamous cell carcinoma. Melanoma nuclear protein 18 or B-cell-specific Moloney leukemia virus insert site 1 may be a potential biomarker for diagnosis and prognosis of esophageal squamous cell carcinoma.

Deformable image registration is a powerful tool for mapping information, such as radiation therapy dose calculations, from one computed tomography image to another. However, deformable image registration is susceptible to mapping errors. Recently, an automated deformable image registration evaluation of confidence tool was proposed to predict voxel-specific deformable image registration dose mapping errors on a patient-by-patient basis. The purpose of this work is to conduct an extensive analysis of automated deformable image registration evaluation of confidence tool to show its effectiveness in estimating dose mapping errors. The proposed format of automated deformable image registration evaluation of confidence tool utilizes 4 simulated patient deformations (3 B-spline-based deformations and 1 rigid transformation) to predict the uncertainty in a deformable image registration algorithm’s performance. This workflow is validated for 2 DIR algorithms (B-spline multipass from Velocity and Plastimatch) with 1 physical and 11 virtual phantoms, which have known ground-truth deformations, and with 3 pairs of real patient lung images, which have several hundred identified landmarks. The true dose mapping error distributions closely followed the Student t distributions predicted by automated deformable image registration evaluation of confidence tool for the validation tests: on average, the automated deformable image registration evaluation of confidence tool–produced confidence levels of 50%, 68%, and 95% contained 48.8%, 66.3%, and 93.8% and 50.1%, 67.6%, and 93.8% of the actual errors from Velocity and Plastimatch, respectively. Despite the sparsity of landmark points, the observed error distribution from the 3 lung patient data sets also followed the expected error distribution. The dose error distributions from automated deformable image registration evaluation of confidence tool also demonstrate good resemblance to the true dose error distributions. Automated deformable image registration evaluation of confidence tool was also found to produce accurate confidence intervals for the dose–volume histograms of the deformed dose.

Multisession stereotactic radiation therapy is increasingly being seen as a preferred option for intracranial diseases in close proximity to critical structures and for larger target volumes. The objective of this study is to investigate the reproducibility of the Extend system from Elekta. A retrospective review was conducted for all patients treated with multisession Gamma Knife between July 2010 and June 2015, including both malignant and benign lesions. Eighty-four patients were treated in this 5-year span. The average residual daily setup uncertainty was 0.48 (0.19) mm. We compare measurements of setup uncertainty from the Extend system to measurements performed with a linac-based approach previously used in our center. The Extend system has significantly reduced setup uncertainty for fractionated intracranial treatments at our institution. Positive results were observed in a small population of edentulous patients. The Extend system compares favorably with other approaches to delivering intracranial stereotactic radiotherapy and is a robust, simple-to-use, and precise method for treating multisession intracranial lesions.

As the clinical use of cryoablation for the treatment of cancer has increased, so too has the need for knowledge on the dynamic environment within the frozen mass created by a cryoprobe. While a number of factors exist, an understanding of the iceball size, critical isotherm distribution/penetration, and the resultant lethal zone created by a cryoprobe are critical for clinical application. To this end, cryoprobe performance is typically characterized based on the iceball size and temperature penetration in phantom gel models. Although informative, these models do not provide information as to the impact of heat input from surrounding tissue nor give any information on the ablative zone created. As such, we evaluated the use of a tissue-engineered tumor model (TEM) to assess cryoprobe performance including iceball size, real-time thermal profile distribution, and resultant ablative zone. Studies were conducted using an Endocare V-probe cryoprobe, with a 10/5/10 double freeze–thaw protocol using prostate and renal cancer TEMs. The data demonstrate the generation of a 33- to 38-cm3 frozen mass with the V-Probe cryoprobe following the double freeze of which ∼12.7 and 6.5 cm3 was at or below −20°C and −40°C, respectively. Analysis of ablation zone using fluorescence microscopy 24 hours postthaw demonstrated that the internal ∼40% of the frozen mass was completely ablated, whereas in the periphery of the iceball (outer 1 cm region), a gradient of partial to minimal destruction was observed. These findings correlated well with clinical reports on renal and prostate cancer cryoablation. Overall, this study demonstrates that TEMs provide an effective model for a more complete characterization of cryoablation device performance. The data demonstrate that while the overall iceball size generated in the TEM was consistent with published reports from phantom models, the integration of an external heat load, circulation, and cellular components more closely reflect an in vivo setting and the impact of penetration of the critical (−20°C and −40°C) isotherms into the tissue. This is important as it is well appreciated in clinical practice that the heat load of a tissue, cryoprobe proximity to vasculature, and so on, can impact outcome. The TEM model provides a means of characterizing the impact on ablative dose delivery allowing for a better understanding of probe performance and potential impact on ablative outcome.

Patients with nasopharyngeal carcinoma undergoing intensity-modulated radiation therapy may experience significant anatomic changes throughout the entire treatment course, and adaptive radiation therapy may be necessary to maintain optimal dose delivered both to the targets and to the critical structures. The timing of adaptive radiation therapy, however, is largely unknown. This study was to evaluate the dosimetric benefits of a 3-phase adaptive radiation therapy technique for nasopharyngeal carcinoma. Twenty patients with nasopharyngeal carcinoma treated with intensity-modulated radiation therapy were recruited prospectively. After fractions 5 and 15, each patient had repeat computed tomography scans, and adaptive replans with recontouring the targets and organs at risk on the new computed tomography images were generated and used for subsequent treatment (replan 1 and replan 2). Two hybrid intensity-modulated radiation therapy plans (plan 1 and plan 2) were generated by superimposing the initial plan (plan 0) to each repeated new computed tomography image, reflecting the actual dose delivered to the targets and organs at risk if no changes were made to the original plan. Dosimetric comparisons were made between the adaptive replans (adaptive radiation therapy plans: plan 0 + replan 1 + replan 2) and their corresponding nonadaptive radiation therapy plans (plan 0 + plan 1 + plan 2). Comparing with the nonadaptive radiation therapy plans, the adaptive radiation therapy plans resulted in a significant improvement in conformity index for planning target volumes for primary disease, involved lymph node, high-risk clinical target volume, and low-risk clinical target volume (PTVnx, PTVnd, PTV1, and PTV2, respectively). Median V95 for PTVnx; D95, D99, V100, V95, and V93 for PTVnd; D99 and V100 for PTV1; and D95, D99, V100, V95, and V93 for PTV2 were increased significantly. There were significant dose–volume reductions, including maximum doses to the brainstem and temporal lobes, mean doses to the glottis, V50 for the supraglottis, D_mean and V30 for the left parotid, median dose to the right optic nerve, and V55 for the skin. The 3-phase adaptive intensity-modulated radiation therapy for patients with nasopharyngeal carcinoma results in improvements in target coverage and conformity index and decreased doses to some organs at risk.

Our purpose was to investigate polymeric gels for use as a highly transparent radiotherapy bolus and determine the relevant physical and dosimetric properties. We first quantified tensile properties (maximum stress, strain, and Young modulus) for various polymeric gels, along with a commercial bolus product in order to illustrate the wide variety of potential materials. For a select polymeric gel with tensile properties similar to currently used radiotherapy bolus, we also evaluated mass and electron density, effective atomic number, optical transparency, and percent depth dose in clinical megavoltage photon and electron beams. For this polymeric gel, mass density was 872 ± 12 and 896 ± 13 g/cm³ when measured via weight/volume and computed tomography Hounsfield units, respectively. Electron density was 2.95 ± 0.04 ×10²³ electrons/cm³. Adding fused silica (9% by weight) increases density to that of water. The ratio of the effective atomic number to that of water without and with added silica was 0.780 and 0.835 at 1 MeV, 0.767 and 0.826 at 6 MeV, and 0.746 and 0.809 at 20 MeV. Percent depth dose for 6 MV photons was within 2% of water within the first 2.5 cm and after scaling by the density coincided within 1% out to >7 cm. For 6 and 20 MeV electrons, after scaling for density D_80% was within 1.3 and 1.5 mm of water, respectively. The high transparency and mechanical flexibility of polymeric gels indicate potential for use as a radiotherapy bolus; differences in density from water may be managed via either using “water equivalent thickness” or by incorporating fused silica into the material.

The treatment methods available for large primary hepatocellular carcinomas (diameter >5 cm) are inadequate. Here, we report the successful management of 80 cases of large hepatocellular carcinoma, using a combination of custom-designed permanent interstitial iodine-125 seed brachytherapy and palliative surgery. Patients were enrolled in the study between 2011 and 2014. All patients underwent surgical treatment along with permanent interstitial iodine-125 seed brachytherapy; for the latter, patients received minimum doses covering 90% of the target (D90 s) of iodine-125 seeds ranging from 100 to 160 Gy (median: 110 Gy). All patients received 6 cycles of chemotherapy and were followed up at 6, 12, 24, and 36 months postoperatively. The clinical symptom remission rate was 95.3% (61 of 64). Alanine aminotransferase and aspartate aminotransferase levels decreased to normal in 80% (50 of 60) and 75% of the patients (45 of 60), respectively. The posttreatment alpha-fetoprotein levels decreased by 50% in 80% of the patients (40 of 50). The effective therapy rates were 80% (76 of 95) for 95 tumor nodules (diameters 5-10 cm) and 78.6% (33 of 42) for 42 tumor nodules (diameters >10 cm). The 3-year disease-free survival rate was 66.6%. Palliative surgery plus permanent interstitial iodine-125 seed brachytherapy appears to be a reasonable therapeutic alternative for large hepatocellular carcinoma.

The conclusion of the relationship between vascular endothelial growth factor gene polymorphism and renal cell carcinoma risk was inconsistent. This study was performed to assess the relationship between vascular endothelial growth factor gene polymorphism and renal cell carcinoma risk using meta-analysis. The association studies were identified from PubMed, Embase, and Web of Science, and eligible studies were included and calculated. Ten studies were included for this meta-analysis. vascular endothelial growth factor (VEGF) +405G > CC allele and GG genotype were associated with renal cell carcinoma risk for overall populations in this meta-analysis (C allele: odds ratio = 1.18, 95% confidence interval: 1.05-1.33, P = .004; CC genotype: odds ratio = 1.20, 95% confidence interval: 0.96-1.50, P = .12; GG genotype: odds ratio = 0.79, 95% confidence interval: 0.67-0.93, P = .004). Furthermore, VEGF +936C>T gene polymorphism and VEGF −2578 C>A gene polymorphism were associated with renal cell carcinoma risk for overall populations (+936C>T: T allele: odds ratio = 1.16, 95% confidence interval: 1.05-1.29, P = .004; TT genotype: odds ratio = 1.25, 95% confidence interval: 1.02-1.52, P = .03; CC genotype: odds ratio = 0.86, 95% confidence interval: 0.75-0.98, P = .03; −2578 C>A: A allele: odds ratio = 1.26, 95% confidence interval: 1.15-1.38, P < .00001; AA genotype: odds ratio = 1.39, 95% confidence interval: 1.16-1.67, P = .0004; CC genotype: odds ratio = 0.75, 95% confidence interval: 0.61-0.92, P = .006). However, VEGF −634G>C, VEGF −460T>C, VEGF −1154 G>A, and VEGF +1612 G>A gene polymorphisms were not associated with renal cell carcinoma risk. In conclusion, VEGF +405G>CC allele and GG genotype, VEGF +936C>T gene polymorphism, and VEGF −2578 C>A gene polymorphism were associated with renal cell carcinoma risk for overall populations. However, more studies should be performed to assess this relationship in the future.

Nanosecond pulsed electric fields are emerging as a new modality for tissue and tumor ablation. We previously reported that cells exposed to pulsed electric fields develop hypersensitivity to subsequent pulsed electric field applications. This phenomenon, named electrosensitization, is evoked by splitting the pulsed electric field treatment in fractions (split-dose treatments) and causes in vitro a 2- to 3-fold increase in cytotoxicity. The aim of this study was to show the benefit of split-dose treatments for in vivo tumor ablation by nanosecond pulsed electric field. KLN 205 squamous carcinoma cells were embedded in an agarose gel or grown subcutaneously as tumors in mice. Nanosecond pulsed electric field ablations were produced using a 2-needle probe with a 6.5-mm interelectrode distance. In agarose gel, splitting a pulsed electric field dose of 300, 300-ns pulses (20 Hz, 4.4-6.4 kV) in 2 equal fractions increased cell death up to 3-fold compared to single-train treatments. We then compared the antitumor effectiveness of these treatments in vivo. At 24 hours after treatment, sensitizing tumors by a split-dose pulsed electric field exposure (150 + 150, 300-ns pulses, 20 Hz, 6.4 kV) caused a 4- and 2-fold tumor volume reduction as compared to sham and single-train treatments, respectively. Tumor volume reduction that exceeds 75% was 43% for split-dose–treated animals compared to only 12% for single-dose treatments. The difference between the 2 experimental groups remained statistically significant for at least 1 week after the treatment. The results show that electrosensitization occurs in vivo and can be exploited to assist in vivo cancer ablation.

Protein instability is a major obstacle in the production and delivery of monoclonal antibody–based therapies for cancer. This study presents real-time isothermal differential scanning fluorimetry as an emerging method to evaluate the stability of human immunoglobulin G protein with high sensitivity. The stability of polyclonal human immunoglobulin G against urea-induced denaturation was assessed following: (1) oxidation by the free-radical generator 2,2-Azobis[2-amidinopropane]dihydrochloride and (2) in selected storage buffers. Significant differences in immunoglobulin G stability were detected by real-time isothermal differential scanning fluorimetry when the immunoglobulin G was stored in 1,4-Piperazinediethanesulfonic acid buffer compared to phosphate-buffered saline, with half-maximal rate of denaturation occurring at a higher urea concentration in 1,4-Piperazinediethanesulfonic acid than phosphate-buffered saline (K _nd;PIPES = 3.56 ± 0.09 M, K _nd;PBS = 2.94 ± 0.08 M; P < .01), but differential scanning fluorimetry did not detect differences in unfolding temperature (T _m;PIPES = 70.5 ± 0.3°C, T _m;PBS = 69.7 ± 0.2°C). The effects of 2,2-Azobis[2-amidinopropane]dihydrochloride-induced oxidation on immunoglobulin G stability were analyzed by real-time isothermal differential scanning fluorimetry; the oxidized protein showed greater sensitivity to urea (K _nd;CNTRL = 3.96 ± 0.19 M, K _nd;AAPH = 3.49 ± 0.07 M; P < .05). Similarly, differential scanning fluorimetry indicated greater thermal sensitivity of oxidized immunoglobulin G (T _m;CNTRL = 70.5 ± 0.3°C, T _m;AAPH = 62.9 ± 0.1°C; P < .001). However, a third method for assessing protein stability, pulse proteolysis, proved to be substantially less sensitive and did not detect significant effects of 2,2-Azobis[2-amidinopropane]dihydrochloride on the half-maximal concentration of urea needed to denature immunoglobulin G (C _m;CNTRL= 6.8 ± 0.1 M; C _m;AAPH = 6.4 ± 0.7 M). Overall these results demonstrate the merit of using real-time isothermal differential scanning fluorimetry as a rapid and sensitive technique for the evaluation of protein stability in solution using a quantitative real-time thermocycler.

Lupus anticoagulants is related to both recurrent thrombosis and cancer. Thrombotic complications occur more frequently in patients with lung cancer. The aim of this study is to investigate the association of lupus anticoagulants with hypercoagulability and thrombotic complications, as well as prognostic significance of lupus anticoagulants for patients with lung cancer. The study comprised 205 patients with non–small cell lung cancer. Plasma normalized LAC ratio, D-dimer, fibrinogen, activities of antithrombin, and FVIII before treatment were analyzed by coagulation analyzer, and routine hematologic and biochemical parameters were also evaluated. In patients, normalized LAC ratio, D-dimer, fibrinogen, and procoagulant activity of coagulating factor VIII levels significantly increased, whereas antithrombin activity significantly decreased compared with healthy controls (P < .001). Normalized LAC ratio was positively correlated with D-dimer, fibrinogen, and procoagulant activity of coagulating factor VIII, and negatively correlated with antithrombin activity, respectively (P < .01). D-dimer, procoagulant activity of coagulating factor VIII, and antithrombin levels revealed statistical difference in non–deep venous thrombosis patients with elevated or normal normalized LA ratio (P < .05). The incidence of deep venous thrombosis and tumor metastasis was higher, and 1-year survival rate was lower in elevated normalized LAC ratio patients than in normal ones, respectively (P < .01). There was higher normalized LAC ratio level in patients with deep venous thrombosis and/or metastasis (P < .05). In 1-year deceased patients, normalized LAC ratio level and the incidence of deep venous thrombosis and metastasis were higher than those in survivors, respectively (P < .05). Hazard regression analysis demonstrated normalized LAC ratio was independently associated with short survival time in patients with non–small cell lung cancer (hazard regression: 2.871, 95%confidence interval: 1.704-4.835; χ² : 19.130; P < .01). Our study suggests that lupus anticoagulants is a useful marker to predict thrombotic complications and prognosis in patient with lung cancer.

MicroRNAs have been reported to play an important role in diverse biological processes and cancer progression. MicroRNA-7 has been observed to be downregulated in human gastric cancer tissues, but the function of microRNA-7 in gastric cancer has not been well investigated. In this study, we demonstrate that the expression of microRNA-7 was significantly downregulated in 30 pairs of human gastric cancer tissues compared to adjacent normal tissues. Enforced expression of microRNA-7 inhibited cell proliferation and migration abilities of gastric cancer cells, BGC823 and SGC7901. Furthermore, microRNA-7 targeted mTOR in gastric cancer cells. In human clinical specimens, mTOR was higher expressed in gastric cancer tissues compared with adjacent normal tissues. More interestingly, microRNA-7 also sensitizes gastric cancer cells to cisplatin (CDDP) by targeting mTOR. Collectively, our results demonstrate that microRNA-7 is a tumor suppressor microRNA and indicate its potential application for the treatment of human gastric cancer in future.

Accelerated partial breast irradiation has caused higher than expected rates of poor cosmesis. At our institution, a novel breast stereotactic radiotherapy device has demonstrated dosimetric distributions similar to those in brachytherapy. This study analyzed comparative dose distributions achieved with the device and intensity-modulated radiation therapy accelerated partial breast irradiation. Nine patients underwent computed tomography simulation in the prone position using device-specific immobilization on an institutional review board–approved protocol. Accelerated partial breast irradiation target volumes (planning target volume_10mm) were created per the National Surgical Adjuvant Breast and Bowel Project B-39 protocol. Additional breast stereotactic radiotherapy volumes using smaller margins (planning target volume_3mm) were created based on improved immobilization. Intensity-modulated radiation therapy and breast stereotactic radiotherapy accelerated partial breast irradiation plans were separately generated for appropriate volumes. Plans were evaluated based on established dosimetric surrogates of poor cosmetic outcomes. Wilcoxon rank sum tests were utilized to contrast volumes of critical structures receiving a percentage of total dose (Vx). The breast stereotactic radiotherapy device consistently reduced dose to all normal structures with equivalent target coverage. The ipsilateral breast V20-100 was significantly reduced (P < .05) using planning target volume_10mm, with substantial further reductions when targeting planning target volume_3mm. Doses to the chest wall, ipsilateral lung, and breast skin were also significantly lessened. The breast stereotactic radiotherapy device’s uniform dosimetric improvements over intensity-modulated accelerated partial breast irradiation in this series indicate a potential to improve outcomes. Clinical trials investigating this benefit have begun accrual.

Long noncoding RNA (LncRNA) homeotic genes (HOX) transcript antisense RNA (HOTAIR) has been reported to play a vital role in various cancers. It has been found that HOTAIR was upregulated in non–small cell lung cancer (NSCLC) and involved in cell invasion and metastasis. The aberrant expression of HOTAIR is expected to serve as a potential biomarker for patients with NSCLC. Our aim in this study was to detect the plasma levels of HOTAIR and further evaluate its diagnostic value for NSCLC. The levels of HOTAIR were measured in 105 patients with NSCLC and 80 healthy controls by quantitative real-time polymerase chain reaction. The results indicated that plasma HOTAIR levels were higher in NSCLC than in healthy controls. Besides, plasma HOTAIR levels were associated with histology subtype (P = .039) and tumor-node-metastasis stage (P = .022). The ROC curves showed that plasma HOTAIR has high diagnostic accuracy for NSCLC, and the area under curve (AUC) for NSCLC versus healthy was 0.791 (95% CI: 0.727-0.855) which was higher than carcinoembryonic antigen (CEA) (AUC = 0.737, 95% CI: 0.666-0.808). Moreover, the combination of HOTAIR and CEA could provide a more accurate diagnosis than HOTAIR or CEA alone (AUC = 0.841, 95% CI: 0.783-0.898). Plasma HOTAIR levels were significantly lower in postoperative samples than in preoperative samples. Plasma HOTAIR could serve as a promising biomarker for diagnosing and monitoring NSCLC.

The combination of radiotherapy and immunotherapy has shown great promise in eradicating tumors. For example, ¹²⁵I radioactive particle implantation and cytokine-induced killer cell therapies have demonstrated efficacy in treating hepatocellular carcinoma. However, the mechanism of this combination therapy remains unknown. In this study, we utilized cytokine-induced killer cells obtained from human peripheral blood mononuclear cells along with ¹²⁵I radioactive particle implantation to treat subcutaneous hepatocellular carcinoma xenograft tumors in BALB/c nude mice. The effects of combination therapy on tumor growth, tumor cell apoptosis and proliferation, animal survival, and immune indexes were then assessed. The results indicated that ¹²⁵I radioactive particle implantation combined with cytokine-induced killer cells shows a much greater antitumor therapeutic effect than either of the therapies alone when compared to control treatments. Mice treated with a combination of radiotherapy and immunotherapy displayed significantly reduced tumor growth. ¹²⁵I radioactive particle implantation upregulated the expression of major histocompatibility complex (MHC) class I chain-related gene A in hepatocellular carcinoma cells and enhanced cytokine-induced killer cell–mediated apoptosis through activation of caspase-3. Furthermore, cytokine-induced killer cells supplied immune substrates to induce a strong immune response after ¹²⁵I radioactive particle implantation therapy. In conclusion, ¹²⁵I radioactive particle implantation combined with cytokine-induced killer cell therapy significantly inhibits the growth of human hepatocellular carcinoma cells in vivo and improves animal survival times through mutual promotion of antitumor immunity, presenting a promising therapy for hepatocellular carcinoma.

Histological differentiation is a major pathological criterion indicating the risk of tumor invasion and metastasis in patients with hepatocellular carcinoma. The degree of tumor differentiation is controlled by a complex interacting network of associated proteins. The principal aim of the present study is to identify the possible differentiation-related proteins which may be used for early diagnosis and more effective therapies. We compared poorly differentiated and well-differentiated hepatocellular carcinoma tissues by using 2-dimensional gel electrophoresis and matrix-assisted laser desorption ionization time-of-flight mass spectrometry. Among the 11 identified protein spots, 6 were found to be upregulated in poorly differentiated hepatocellular carcinoma tissues and 5 were correspondingly downregulated. Immunohistochemistry was performed on 106 hepatocellular carcinoma tissues to confirm the results of the proteomic analysis. By using bioinformatic tools GO and STRING, these proteins were found to be related to catalytic activity, binding, and antioxidant activity. In particular, our data suggest that overexpression of peroxiredoxin-2, annexin A2, and heat shock protein β-1 was correlated with tumor invasion, metastasis, and poor prognosis, and therefore, these proteins may serve as potential diagnostic and therapeutic biomarkers.

Thyroid cancer is a common endocrine gland malignancy which exhibited rapid increased incidence worldwide in recent decades. This study was aimed to investigate the role of long noncoding RNA H19 in thyroid cancer. Long noncoding RNA H19 was overexpressed or knockdown in thyroid cancer cells SW579 and TPC-1, and the expression of long noncoding RNA H19 was detected by real-time polymerase chain reaction. The cell viability, migration, and invasion were determined by 3-(4, 5-dimethyl-2-thiazolyl)-2, 5-diphenyl-2-H-tetrazolium bromide assay, Transwell assay, and wound healing assay, respectively. Furthermore, cell apoptosis was analyzed by flow cytometry, and expressions of some factors that were related to phosphatidyl inositide 3-kinases/protein kinase B and nuclear factor κB signal pathway were measured by Western blotting. This study revealed that cell viability and migration/invasion of SW579 and TPC-1 were significantly decreased by long noncoding RNA H19 overexpression compared with the control group (P < .05), whereas cell apoptosis was statistically increased (P < .001). Meanwhile, cell viability and migration/invasion were significantly increased after long noncoding RNA H19 knockdown (P < .05). Furthermore, long noncoding RNA H19 negatively regulated the expression of insulin receptor substrate 1 and thus effect on cell proliferation and apoptosis. Insulin receptor substrate 1 regulated the activation of phosphatidyl inositide 3-kinases/AKT and nuclear factor κB signal pathways. In conclusion, long noncoding RNA H19 could suppress cell viability, migration, and invasion via downregulation of insulin receptor substrate 1 in SW579 and TPC-1 cells. These results suggested the important role of long noncoding RNA H19 in thyroid cancer, and long noncoding RNA H19 might be a potential target of thyroid cancer treatment.

In view of their superior soft tissue contrast compared to computed tomography, magnetic resonance images are commonly involved in stereotactic radiosurgery/radiotherapy applications for target delineation purposes. It is known, however, that magnetic resonance images are geometrically distorted, thus deteriorating dose delivery accuracy. The present work focuses on the assessment of geometric distortion inherent in magnetic resonance images used in stereotactic radiosurgery/radiotherapy treatment planning and attempts to quantitively evaluate the consequent impact on dose delivery. The geometric distortions for 3 clinical magnetic resonance protocols (at both 1.5 and 3.0 T) used for stereotactic radiosurgery/radiotherapy treatment planning were evaluated using a recently proposed phantom and methodology. Areas of increased distortion were identified at the edges of the imaged volume which was comparable to a brain scan. Although mean absolute distortion did not exceed 0.5 mm on any spatial axis, maximum detected control point disposition reached 2 mm. In an effort to establish what could be considered as acceptable geometric uncertainty, highly conformal plans were utilized to irradiate targets of different diameters (5-50 mm). The targets were mispositioned by 0.5 up to 3 mm, and dose–volume histograms and plan quality indices clinically used for plan evaluation and acceptance were derived and used to investigate the effect of geometrical uncertainty (distortion) on dose delivery accuracy and plan quality. The latter was found to be strongly dependent on target size. For targets less than 20 mm in diameter, a spatial disposition of the order of 1 mm could significantly affect (>5%) plan acceptance/quality indices. For targets with diameter greater than 2 cm, the corresponding disposition was found greater than 1.5 mm. Overall results of this work suggest that efficacy of stereotactic radiosurgery/radiotherapy applications could be compromised in case of very small targets lying distant from the scanner’s isocenter (eg, the periphery of the brain).

X-ray repair cross complementary group gene is one of the most studied candidate gene involved in different types of cancers. Studies have shown that X-ray repair cross complementary genes are significantly associated with increased risk of breast cancer in females. Moreover, studies have revealed that X-ray repair cross complementary gene polymorphism significantly varies between and within different ethnic groups globally. The present case–control study was aimed to investigate the association of X-ray repair cross complementary 1A (Arg194Trp) and X-ray repair cross complementary 3 (Thr241Met) polymorphism with the risk of breast cancer in females from northeastern region of India. The present case–control study includes histopathologically confirmed and newly diagnosed 464 cases with breast cancer and 534 apparently healthy neighborhood community controls. Information on sociodemographic factors and putative risk factors were collected from each study participant by conducting face-to-face interviews. Genotyping of X-ray repair cross complementary 1A (Arg194Trp) and X-ray repair cross complementary 3 (Thr241Met) was carried out by polymerase chain reaction-restriction fragment length polymorphism. For statistical analysis, both univariate and multivariate logistic regression analyses were performed. We also performed stratified analysis to find out the association of X-ray repair cross complementary genes with the risk of breast cancer stratified based on menstrual status. This study revealed that tryptophan allele (R/W-W/W genotype) in X-ray repair cross complementary 1A (Arg194Trp) gene significantly increased the risk of breast cancer (adjusted odds ratio = 1.44, 95% confidence interval = 1.06-1.97, P < .05 for R/W-W/W genotype). Moreover, it was found that tryptophan allele (W/W genotype) at codon 194 of X-ray repair cross complementary 1A (Arg194Trp) gene significantly increased the risk of breast cancer in premenopausal females (crude odds ratio = 1.66, 95% confidence interval = 1.11-2.46, P < .05 for R/W-W/W genotype). The present study did not reveal any significant association of X-ray repair cross complementary 3 (Thr241Met) polymorphism with the risk of breast cancer. The present study has explored that X-ray repair cross complementary 1A (Arg194Trp) gene polymorphism is significantly associated with the increased risk of breast cancer in premenopausal females from northeastern region of India which may be beneficial for prognostic purposes.

MicroRNAs refer to small RNA molecules that destroy the messenger RNA by binding on them inhibiting the production of protein. However, the role of miR-155 in uveal melanoma metastasis remains largely unknown. In this study, we found that miR-155 was upregulated in both uveal melanoma cells and tissues. Transfection of miR-155 mimic into uveal melanoma cells led to an increase in cell growth and invasion; in contrast, inhibition of miR-155 resulted in opposite effects. Also, we identified Nedd4-family interacting protein 1 as a direct target of miR-155, and the expression of Nedd4-family interacting protein 1 was inhibited by miR-155. Furthermore, ectopic expression of Nedd4-family interacting protein 1 restored the effects of miR-155 on cell proliferation and invasion of uveal melanoma cells. In conclusion, miR-155 acts as a tumor promotor in uveal melanoma through increasing cell proliferation and invasion. Thus, miR-155 might serve as a potential therapeutic target in patients with uveal melanoma.

Vasculogenic mimicry refers to the process by which highly invasive cancer cells mimic endothelial cells by forming blood channels. Vasculogenic mimicry is important for the invasion and metastasis of tumor cells in colorectal cancer. STAT3 was initially identified as a mediator of the inflammation-associated acute phase response. The phosphorylation of Signal Transducers and Activators of Transcription 3 (p-STAT3) is closely related to tumor invasion and migration. We analyzed the relationship between p-STAT3 and vasculogenic mimicry formation in 65 human colorectal cancer samples, and the results showed that the expression of p-STAT3 is significantly correlated with vasculogenic mimicry, tumor metastasis, Tumor, Lymph Node and Metastasis Stage (TNM Stage), and poor prognosis. It is known that interleukin 6 can induce the phosphorylation of STAT3. We found that using interleukin 6 to induce p-STAT3 activation in colorectal cancer cell lines can result in vasculogenic mimicry and using AG490 to suppress p-STAT3 activation restrained vasculogenic mimicry. Furthermore, the state of p-STAT3 activation can affect epithelial-to-mesenchymal transition. By immunofluorescence double staining, we discovered that p-STAT3 expression is more directly correlated with the epithelial-to-mesenchymal transition marker vimentin than with the vasculogenic mimicry-related protein VE-cadherin. These data show that activated p-STAT3 upregulates epithelial-to-mesenchymal transition–related proteins and promotes vasculogenic mimicry.

Log file–based methods are attracting increasing interest owing to their ability to validate volumetric-modulated arc therapy outputs with high resolution in the leaf and gantry positions and in delivered dose. Cross-validation of these methods for comparison with measurement-based methods using the ionization chamber/ArcCHECK-3DVH software (version 3.2.0) under the same conditions of treatment anatomy and plan enables an efficient evaluation of this method. In this study, with the purpose of cross-validation, we evaluate the accuracy of a log file–based method using Elekta log files and an X-ray voxel Monte Carlo dose calculation technique in the case of leaf misalignment during prostate volumetric-modulated arc therapy. In this study, 10 prostate volumetric-modulated arc therapy plans were used. Systematic multileaf collimator leaf positional errors (±0.4 and ±0.8 mm for each single bank) were deliberately introduced into the optimized plans. Then, the delivered 3-dimensional doses to a phantom with a certain patient anatomy were estimated by our system. These doses were compared with the ionization chamber dose and the ArcCHECK-3DVH dose. For the given phantom and patient anatomy, the estimated dose strongly coincided with the ionization chamber/ArcCHECK-3DVH dose (P < .01). In addition, good agreement between the estimated dose and the ionization chamber/ArcCHECK-3DVH dose was observed. The dose estimation accuracy of our system, which combines Elekta log files and X-ray voxel Monte Carlo dose calculation, was evaluated.

The inhibitor of kappa B kinase epsilon is overexpressed in glioma and plays antiapoptotic role via activating nuclear factor-kappa B. microRNA-98 can suppress glioma, modulate the activities of nuclear factor-kappa B, and bind to the 3′-untranslated region of inhibitor of kappa B kinase epsilon messenger RNA. This study was aimed to investigate the modulation of inhibitor of kappa B kinase epsilon/nuclear factor-kappa B by microRNA-98 in glioma. The results indicated that microRNA-98 was downregulated in glioma cell lines and human glioma tissues. Overexpression of microRNA-98 in U87MG and T98G glioma cells significantly increased the apoptosis induced by ultraviolet irradiation and suppressed nuclear factor-kappa B luciferase activity, nuclear factor-kappa B p50 subunit expression, and B-cell lymphoma-2 (Bcl-2) expression in glioma cells. Silencing inhibitor of kappa B kinase epsilon decreased the expression of nuclear factor-kappa B p50 subunit and the luciferase activity of nuclear factor-kappa B, while the nuclear factor-kappa B activity could be significantly retrieved when inhibitor of kappa B kinase epsilon was expressed in microRNA-98-transfected cells. These findings indicated that microRNA-98 could promote apoptosis of glioma cells via inhibiting inhibitor of kappa B kinase epsilon/nuclear factor-kappa B signaling and presented a novel regulatory pathway of microRNA-98 by direct suppression of inhibitor of kappa B kinase epsilon/nuclear factor-kappa B expression in glioma cells.

This study aimed to explore the mechanisms of bridging integrator-3 dysregulation, its prognostic value, and related signaling pathways in colorectal cancer . Bioinformatic analysis was performed based on the data from The Cancer Genome Atlas–colorectal cancer and Human Protein Atlas. Colorectal cancer cell lines, LoVo and HT29 cells, were used as in vitro cell model to assess the effect of demethylation on bridging integrator-3 expression. Results showed that bridging integrator-3 was downregulated in colorectal cancer tissues compared to normal colon and rectum tissues. Heatmap of bridging integrator-3 messenger RNA expression, exon expression, and DNA methylation indicated a negative correlation between bridging integrator-3 expression and methylation of some CpG sites within the coding sequence. Demethylation treatment significantly increased bridging integrator-3 expression in LoVo and HT29 cells. Low bridging integrator-3 messenger RNA and exon expression were associated with significantly worse overall survival (P = .015 and .013, respectively). Multivariate analysis confirmed that low bridging integrator-3 messenger RNA expression was an independent prognostic factor of unfavorable overall survival (Hazard Ratio (HR) = 1.596, 95% confidence interval: 1.024-2.486; P = .039). High bridging integrator-3 DNA methylation was also associated with significantly worse overall survival (P = .013). Kyoto Encyclopedia of Genes and Genomes analysis indicated that the genes correlated with bridging integrator-3 (absolute Pearson r ≥ 0.3, n = 121) were enriched in sphingolipid signaling pathway, natural killer cell-mediated cytotoxicity, p53 signaling pathway, and apoptosis. Based on these findings, we infer that DNA hypermethylation might be an important mechanism of suppressed bridging integrator-3 expression in colorectal cancer . Its low expression is an independent predictor of unfavorable survival in patients with primary colorectal cancer . Bridging integrator-3 might act as a tumor suppressor via modulating natural killer cell-mediated cytotoxicity, p53 signaling pathway, and apoptosis.

Endoscopic retrograde cholangiopancreatography with brushed cytology is still the standard method for the diagnosis of extrahepatic cholangiocarcinoma in obstructive jaundice; however, the diagnostic yield is limited. To improve the diagnostic sensitivity, DNA methylation analysis is an attractive candidate, since this may constitute a stable marker in brushed specimens. Therefore, this study aims to evaluate the importance of such epigenetic markers in brushed biliary cells from patients with obstructive jaundice for the diagnosis of extrahepatic cholangiocarcinoma. The cells examined were those that were left over from brushed cytology done during routine endoscopic retrograde cholangiopancreatography of patients with extrahepatic cholangiocarcinoma. The methylation states of HOXA1, RASSF1A, P16, and NEUROG1 genes in extrahepatic cholangiocarcinoma were measured by quantitative methylation-specific polymerase chain reaction and compared between brushed biliary cells and normal gall bladder epithelial cells. The results showed that the sensitivity of the methylation index measurements of HOXA1 and NEUROG1 genes from brushed samples was markedly superior to that of standard cytology. In conclusion, measurement of the DNA methylation status of HOXA1 and NEUROG1 genes in leftover brushed biliary cells might serve as a useful supplement in the detection of malignant biliary obstruction by increasing the sensitivity of diagnosis by routine cytology.

The -149C>T and -579G>T, 2 single nucleotide polymorphisms in de novo methyltransferase 3B gene promoter, have been previously reported to potentially alter the promoter activity and to influence cancer risk. However, the results from previous studies remain conflicting rather than conclusive. In view of this, we conducted a case–control study and then a meta-analysis to examine the association between these 2 single-nucleotide polymorphisms with risk of lung and gastric cancer in Chinese population. The genotyping was performed by polymerase chain reaction-restriction fragment length polymorphism and confirmed by sequencing. In this case–control study, no significant association with lung or gastric cancer risk was observed for -149C>T, while -579G>T was significantly correlated with the risk of gastric cancer but not lung cancer. Moreover, haplotype analysis showed that haplotype -149T/-579 T, which carried the risk -579 T allele, significantly increased the susceptibility to gastric cancer. However, none of the haplotypes was associated with the risk of lung cancer. The following meta-analysis involved only Chinese population and further confirmed the significant association of -579G>T with gastric cancer but not lung cancer and suggested no significant association between -149C>T and risk of lung or gastric cancer. Collectively, DNMT3B -579G>T polymorphism is associated with gastric cancer risk in Chinese population, and the -579G>T may be used as a genetic biomarker to predict the risk of gastric cancer in Chinese population.

The current study aims to explore possible relationships between various prostate shapes and the difficulty in creating a computer-based plan for cryosurgery. This research effort is a part of an ongoing study to develop computational means in order to improve cryosurgery training and education. This study uses a computerized planner—a key building block of a recently developed prototype for cryosurgery training. The quality of planning is measured by the overall defect volume, a proprietary concept which refers to undercooled areas internal to the target region and overcooled areas external to it. Results of this study numerically confirm that the overall defect volume decreases with an increasing number of cryoprobes, regardless of the geometry of the prostate. However, the number of cryoprobes required to achieve the smallest possible defect may be unrealistically high (<30). Results of this study also demonstrate that the optimal cryoprobe layout is associated with a smaller defect for symmetric prostate geometries and, independently, for prostate models that better resemble a sphere. Furthermore, a smaller defect is typically achieved when the urethra passes through the center of the prostate model. This study proposes to create a cryoprobe convex hull for the purpose of initial planning, which is a subdomain similar in shape to the prostate but at a reduced size. Parametric studies indicate that a cryoprobe convex hull contracted by 7 to 9 mm in all directions from the prostate capsule serves as a quasi-optimal initial condition for planning, that is, a preselected number of cryoprobes placed in the cryoprobe convex hull yields favorable results for optimization. The cryoprobe convex hull could accelerate computer-based planning, while also being adopted as a concept for traditional cryosurgery training, when computerized means are absent.