Τρίτη 10 Μαΐου 2016

Defining Action Levels for In Vivo Dosimetry in Intraoperative Electron Radiotherapy

In vivo dosimetry is recommended in intraoperative electron radiotherapy (IOERT). To perform real-time treatment monitoring, action levels (ALs) have to be calculated. Empirical approaches based on observation of samples have been reported previously, however, our aim is to present a predictive model for calculating ALs and to verify their validity with our experimental data. We considered the range of absorbed doses delivered to our detector by means of the percentage depth dose for the electron beams used. Then, we calculated the absorbed dose histograms and convoluted them with detector responses to obtain probability density functions in order to find ALs as certain probability levels. Our in vivo dosimeters were reinforced TN-502RDM-H mobile metal-oxide-semiconductor field-effect transistors (MOSFETs). Our experimental data came from 30 measurements carried out in patients undergoing IOERT for rectal, breast, sarcoma, and pancreas cancers, among others. The prescribed dose to the tumor bed was 90%, and the maximum absorbed dose was 100%. The theoretical mean absorbed dose was 90.3% and the measured mean was 93.9%. Associated confidence intervals at P = .05 were 89.2% and 91.4% and 91.6% and 96.4%, respectively. With regard to individual comparisons between the model and the experiment, 37% of MOSFET measurements lay outside particular ranges defined by the derived ALs. Calculated confidence intervals at P = .05 ranged from 8.6% to 14.7%. The model can describe global results successfully but cannot match all the experimental data reported. In terms of accuracy, this suggests an eventual underestimation of tumor bed bleeding or detector alignment. In terms of precision, it will be necessary to reduce positioning uncertainties for a wide set of location and treatment postures, and more precise detectors will be required. Planning and imaging tools currently under development will play a fundamental role.



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Bifidobacteria Expressing Tumstatin Protein for Antitumor Therapy in Tumor-Bearing Mice

Tumstatin (Tum) is a powerful angiostatin that inhibits proliferation and induces apoptosis of tumorous vascular endothelial cells. A nonpathogenic and anaerobic bacterium, Bifidobacterium longum (BL), selectively localizes to and proliferates in the hypoxia location within solid tumor. The aims of this study were to develop a novel delivery system for Tum using engineered Bifidobacterium and to investigate the inhibitory effect of Tum on tumor in mice. A vector that enabled the expression of Tum under the control of the pBBADs promoter of BL was constructed and transformed into BL NCC2705 by electroporation. The mouse colon carcinoma cells CT26 (1 x 107/mL) were subcutaneously inserted in the left armpit of BALB/c mice. The tumor-bearing mice were treated with Tum-transformed BL, and green fluorescent protein (GFP)-transformed BL was used as a negative control. The microvessel density (MVD) in the transplanted tumor was determined, and terminal deoxynucleotidyl transferase-mediated 2'-deoxyuridine 5'-triphosphate nick end labeling was used to detect apoptosis of vascular endothelial cells in transplanted tumor. The in vitro expression of Tum was examined in BL after l-arabinose induction. Bifidobacterium longum with pBBAD-Tum (BL-Tum) showed significant antitumor effect in tumor-bearing mice. The weight, volume, growth, and MVD, as well as the percentage of apoptotic vascular endothelial cells of transplanted tumors in the tumor-bearing mice treated with Tum-transformed BL were all significantly lower than those in the GFP negative control group. Intragastric administration, injection in tumor and vena caudalis injection of Tum-transformed BL exerted marked antitumor effects in tumor-bearing mice. This is the first demonstration of the utilization of Tum-transformed BL as a specific gene delivery system for treating tumor.



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Adaptation, Commissioning, and Evaluation of a 3D Treatment Planning System for High-Resolution Small-Animal Irradiation

Although spatially precise systems are now available for small-animal irradiations, there are currently limited software tools available for treatment planning for such irradiations. We report on the adaptation, commissioning, and evaluation of a 3-dimensional treatment planning system for use with a small-animal irradiation system. The 225-kV X-ray beam of the X-RAD 225Cx microirradiator (Precision X-Ray) was commissioned using both ion-chamber and radiochromic film for 10 different collimators ranging in field size from 1 mm in diameter to 40 x 40 mm2. A clinical 3-dimensional treatment planning system (Metropolis) developed at our institution was adapted to small-animal irradiation by making it compatible with the dimensions of mice and rats, modeling the microirradiator beam orientations and collimators, and incorporating the measured beam data for dose calculation. Dose calculations in Metropolis were verified by comparison with measurements in phantoms. Treatment plans for irradiation of a tumor-bearing mouse were generated with both the Metropolis and the vendor-supplied software. The calculated beam-on times and the plan evaluation tools were compared. The dose rate at the central axis ranges from 74 to 365 cGy/min depending on the collimator size. Doses calculated with Metropolis agreed with phantom measurements within 3% for all collimators. The beam-on times calculated by Metropolis and the vendor-supplied software agreed within 1% at the isocenter. The modified 3-dimensional treatment planning system provides better visualization of the relationship between the X-ray beams and the small-animal anatomy as well as more complete dosimetric information on target tissues and organs at risk. It thereby enhances the potential of image-guided microirradiator systems for evaluation of dose–response relationships and for preclinical experimentation generally.



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Upregulation of Leucine Zipper Protein mRNA in Hepatocellular Carcinoma Associated With Poor Prognosis

Background:

Leucine zipper protein (LUZP) plays key roles in development. Overexpression of LUZP was documented in several types of solid tumors. In this study, expression of LUZP messenger RNA (LUZP mRNA) in human hepatocellular carcinoma (HCC) was examined, and the correlations of LUZP mRNA level with patients' characteristics and prognosis were also investigated.

Methods:

Total RNA was extracted from HCC and paired noncancerous liver tissues of 77 patients. Expression of LUZP mRNA in the tissues was determined by real-time quantitative reverse transcriptase polymerase chain reaction. Using average LUZP mRNA level in noncancerous liver tissues as the cutoff, patients with HCC were categorized into high-expression group and low-expression group. Correlations of LUZP mRNA with clinical parameters were analyzed. Overall survival of the patients in the 2 groups was analyzed by Kaplan-Meier method.

Results:

The LUZP mRNA level was significantly higher in HCC samples than in the noncancerous liver tissues (1.87 ± 0.11 vs 0.58 ± 0.05, P < .01). Significant differences were found between the 2 groups in terms of portal vein invasion, Tumor Lymph Node Metastasis (TNM) stage, and recurrence of HCC. The current study failed to find significant differences between the 2 groups in clinical characteristics such as age, gender, lymph node metastasis, hepatitis B virus infection, family HCC history, and alcohol intake. Overall survival in high-expression group was 12 months while that in the low-expression group was 34 months (P = .03).

Conclusion:

The LUZP mRNA is a prognostic indicator in HCC, and overexpression is associated with poor prognosis in patients with HCC.



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Tobacco-specific N-nitrosamines and polycyclic aromatic hydrocarbons in cigarettes smoked by the participants of the Shanghai Cohort Study

Abstract

Our recent studies on tobacco smoke carcinogen and toxicant biomarkers and cancer risk among male smokers in the Shanghai Cohort Study showed that exposure to tobacco-specific nitrosamines (TSNA) and polycyclic aromatic hydrocarbons (PAH) is prospectively associated with the risk of cancer. These findings support the hypothesis that the smokers' cancer risk is a function of the dose of select tobacco carcinogens and highlight the importance of understanding the factors that affect the intake of these carcinogens by smokers. Given that tobacco constituent exposures are driven, at least in part, by the levels of these constituents in cigarette smoke, we measured mainstream smoke TSNA and PAH levels in 43 Chinese cigarette brands that participants of the Shanghai Cohort Study reported to smoke. In all brands analyzed here, mainstream smoke levels of NNN and NNK, the two carcinogenic TSNA, were generally relatively low, averaging (±SD) 16.8(±25.1) and 14.2(±9.5) ng/cigarette, respectively. The levels of PAH were comparable to those found in U.S. cigarettes, averaging 15(±9) ng/cigarette for benzo[a]pyrene, 119(±66) ng/cigarette for phenanthrene, and 37(±19) ng/cigarette for pyrene. Our findings indicate that the generally low levels of NNN and NNK are most likely responsible for the relatively low levels of the corresponding biomarkers in the urine of the Shanghai Cohort Study participants as compared to those found in the U.S. smokers, supporting the role of the levels of these constituents in cigarette smoke in smokers' exposures. Our findings also suggest that, in addition to smoking, other sources contribute to Chinese smokers' exposure to PAH. This article is protected by copyright. All rights reserved.



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Deletion of macrophage migration inhibitory factor inhibits murine oral carcinogenesis: Potential role for chronic pro-inflammatory immune mediators

Abstract

Oral cancer kills about 1 person every hour, each day in the United States and is the 6th most prevalent cancer worldwide. The pro-inflammatory cytokine 'macrophage migration inhibitory factor' (MIF) has been shown to be expressed in oral cancer patients, yet its precise role in oral carcinogenesis is not clear. In this study, we examined the impact of global Mif deletion on the cellular and molecular process occurring during oral carcinogenesis using a well-established mouse model of oral cancer with the carcinogen 4-nitroquinoline-1-oxide (4NQO). C57BL/6 Wild-type (WT) and Mif knock-out mice were administered with 4NQO in drinking water for 16 weeks, then regular drinking water for 8 weeks. Mif knock-out mice displayed fewer oral tumor incidence and multiplicity, accompanied by a significant reduction in the expression of pro-inflammatory cytokines Il-1β, Tnf-α, chemokines Cxcl1, Cxcl6 and Ccl3 and other molecular biomarkers of oral carcinogenesis Mmp1 and Ptgs2. Further, systemic accumulation of myeloid-derived tumor promoting immune cells was inhibited in Mif knock-out mice. Our results demonstrate that genetic Mif deletion reduces the incidence and severity of oral carcinogenesis, by inhibiting the expression of chronic pro-inflammatory immune mediators. Thus, targeting MIF is a promising strategy for the prevention or therapy of oral cancer. This article is protected by copyright. All rights reserved.



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Tyrosine kinase inhibitor sunitinib therapy is effective in treatment of bone metastasis from cancer of unknown primary: Identification of clinical and immunohistochemical biomarkers predicting survival

Abstract

Bone metastasis from cancer of unknown primary (BMCUP) brings poor survival prognosis and its management remains controversial. Sunitinib (SUTENT) proved effective in many sorts of solid tumors but has never been applied for patients with occult primary cancers, and there is no study to identify sensitive or resistant biomarkers for sunitinib therapy in CUP patients. An analysis was carried out to investigate the efficacy of sunitinib by multivariate survival analysis of 286 patients with BMCUP. We further carried out multivariate analysis to identify histological and clinical biomarkers that could predict sensitivity or resistance for sunitinib therapy. Of the 286 patients included from January 2011 to March 2016, sunitinib therapy proved effective to prolong survival in patients with BMCUP. Sensitive and resistant biomarkers were identified in histological specimen of patients receiving sunitinib therapy. Clinical factors were also identified that predict poor survival prognosis for sunitinib therapy. Sunitinib therapy proved effective to prolong survival in patients with BMCUP. Sensitive markers for sunitinib therapy include KDR positivity and early-developed treatment-induced hypertension. Resistance factors for sunitinib include VEGF positivity, CAIX positivity and squamous cell carcinoma pathology type. Prolonged symptom time and severe weight loss before therapy seemed to be associated with poor survival prognosis for sunitinib therapy. This article is protected by copyright. All rights reserved.



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Compartmentalization of hepatitis C virus variants in patients with hepatocellular carcinoma

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ABSTRACT

Chronic Hepatitis C Virus (HCV) infection is a major risk for hepatocellular carcinoma (HCC) development. HCV Core protein has been associated with the modulation of potentially oncogenic cellular processes and E2 protein has been useful in evolutive studies to analyze the diversity of HCV. Thus, the aim of this study was to evaluate HCV compartmentalization in tumoral, non-tumoral liver tissue and serum and to identify viral mutations potentially involved in carcinogenesis. Samples were obtained from four patients with HCC who underwent liver transplantation. Core and E2 were amplified, cloned and sequenced. Phylogenies and BaTS Test were performed to analyze viral compartmentalization and a signature sequence analysis was conducted by VESPA. The likelihood and Bayesian phylogenies showed a wide degree of compartmentalization in the different patients, ranging from total clustering to a more scattered pattern with small groups. Nevertheless, the association test showed compartmentalization for the three compartments and both viral regions tested in all the patients. Signature amino acid pattern supported the compartmentalization in three of the cases for E2 protein and in two of them for Core. Changes observed in Core included polymorphism R70Q/H previously associated with HCC. In conclusion, evidence of HCV compartmentalization in the liver of HCC patients was provided and further biological characterization of these variants may contribute to the understanding of carcinogenesis mediated by HCV infection. This article is protected by copyright. All rights reserved



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How much do tumor stage and treatment explain socioeconomic inequalities in breast cancer survival? Applying causal mediation analysis to population-based data

Abstract

Substantial socioeconomic inequalities in breast cancer survival persist in England, possibly due to more advanced cancer at diagnosis and differential access to treatment. We aim to disentangle the contributions of differential stage at diagnosis and differential treatment to the socioeconomic inequalities in cancer survival. Information on 36,793 women diagnosed with breast cancer during 2000–2007 was routinely collected by an English population-based cancer registry. Deprivation was determined for each patient according to her area of residence at the time of diagnosis. A parametric implementation of the mediation formula using Monte Carlo simulation was used to estimate the proportion of the effect of deprivation on survival mediated by stage and by treatment. One-third (35 % [23–48 %]) of the higher mortality experienced by most deprived patients at 6 months after diagnosis, and one tenth (14 % [−3 to 31 %]) at 5 years, was mediated by adverse stage distribution. We initially found no evidence of mediation via differential surgical treatment. However, sensitivity analyses testing some of our study limitations showed in particular that up to thirty per cent of the higher mortality in most deprived patients could be mediated by differential surgical treatment. This study illustrates the importance of using causal inference methods with routine medical data and the need for testing key assumptions through sensitivity analyses. Our results suggest that, although effort for earlier diagnosis is important, this would reduce the cancer survival inequalities only by a third. Because of data limitations, role of differential surgical treatment may have been under-estimated.



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Postoperative infectious complications-driven recurrence after radical resection for esophageal cancer

Abstract

Background

Few reports have reported the long-term outcome of esophageal cancer patients suffering from postoperative infectious complications. Here, we investigated the impact of postoperative infectious complications in patients who had undergone curative resection for esophageal cancer.

Methods

The study population comprised 97 patients who underwent radical resection for esophageal cancer with curative intent between 2001 and 2008. Postoperative infectious complications were defined as surgical site infections and pneumonia. We compared clinical features, tumor histology, recurrence, and overall survival between patients with postoperative infections and those who did not.

Results

Of the 97 patients studied, 37 had postoperative infectious complications. The disease-free and overall survival rates of the entire cohort did not significantly differ between patients with and without postoperative infectious complications. Univariate analysis revealed that among patients with stage III esophageal cancer, those with postoperative infectious complications demonstrated significantly shorter disease-free survival than those without. Multivariate analysis demonstrated that postoperative infectious complications were independent prognostic indicators for disease-free survival of stage III esophageal cancer patients.

Conclusions

Our findings suggest that postoperative infectious complications in stage III esophageal cancer patients have a negative impact on disease-free survival.



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Genetic analysis of radiation-specific biomarkers in sinonasal squamous cell carcinomas

Abstract

The aim of this study was to investigate the differences in the gene expression profiles of radiation-sensitive (RS) and radiation-resistant (RR) sinonasal squamous cell carcinoma (SNSCC) and to identify prognostic markers for the radiation reaction of SNSCC. We first examined the differentially expressed genes (DEGs) in RS and RR SNSCC tissues by analyzing clinical samples with GeneChip Human Transcriptome Array 2.0 (HTA 2.0).To understand the functional significance of the molecular changes, we examined the DEGs with Gene Ontology (GO) and pathway analyses to identify the core genes. The expression of several core genes (CCND2, COL5A2, GADD45B, and THBS2) was confirmed with reverse transcription quantitative PCR (RT-qPCR) in a larger series of tissues. We identified 208 DEGs, of which 76 were upregulated and 132 downregulated in the RS tissues relative to the RR tissues. The DEGs were mainly involved in the regulation of cell proliferation, the NF-kappaB signaling pathway, the cell adhesion molecule signaling pathway, and the extracellular matrix–receptor interaction signaling pathway. RT-qPCR confirmed that the CCND2, COL5A2, GADD45B, and THBS2 genes were significantly differentially expressed in the RS and RR tissues, consistent with the GeneChip data. These results extend our understanding of the molecular mechanisms underlying the sensitivity of SNSCC to radiation. The DEGs are involved in the differential response to radiation therapy and the dysregulated core genes identified in this study can be used to predict radiation sensitivity in SNSCC.



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Serial cerebrospinal fluid examinations to diagnose hematological malignancy causing neurological disease

Abstract

To determine the diagnostic utility of serial cerebrospinal fluid (CSF) examinations for hematological malignancy causing neurological disease. All CSF cytology reports at Mayo Clinic Rochester from 2005 to 2014 (n = 20,018) were reviewed. Study inclusion criteria were: repeated CSF examinations within 1 year in patients without known hematological malignancy performed to determine if hematological malignancy was the cause of neurological disease. Exclusion criteria were: preexisting hematological malignancy; >1 year between CSF examinations, serial CSF examinations for infection, tumor surveillance or intrathecal therapies, and for assessment or treatment of CSF dynamics (e.g. idiopathic intracranial hypertension, CSF shunt or persistent CSF leak). The initial study population included patients undergoing three or more serial CSF examinations; subsequently those undergoing two serial CSF examinations were investigated. A total of 613 patients met the study criteria with 477 having two CSF examinations and 136 having three or greater CSF examinations. Of those with three or greater serial CSF examinations none were found to have hematological malignancy exclusively on the third or subsequent CSF examinations. Of those with two CSF examinations 0.4 % (2/477) were found to have hematological malignancy (large B cell lymphomas) exclusively on the second CSF. Ten patients (1.6 %) had suspicious hematological abnormalities on initial CSF examinations confirmed on subsequent CSF examinations. Serial CSF examinations are of low yield to diagnose hematological malignancy as a cause of neurological disease but may confirm atypical features observed in an initial CSF examination.



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Phase II trial of weekly Docetaxel, Zoledronic acid, and Celecoxib for castration-resistant prostate cancer

Summary

Background Treatment options for patients with metastatic castration-resistance prostate cancer are unsatisfactory. Docetaxel monotherapy offers promising results with a tolerable toxicity profile. However, enhancing the clinical index of Docetaxel-based therapy remains the ultimate goal. Methods We conducted a phase II, open label, multinational prospective trial to evaluate the efficacy of weekly Docetaxel combined with Zoledronic acid and Celecoxib. Eligible patients received 25 mg/m2 Docetaxel weekly for 3 consecutive weeks every 4 weeks, 4 mg Zoledronic acid every 4 weeks, and 200 mg oral Celecoxib twice daily. Enrollment was terminated prematurely upon the publication of reports of cardiac toxicity associated with cyclooxygenase (COX) 2 inhibitors. Results Our study enrolled 22 patients with a median of 4.7 cycles per patient. The median overall survival (OS) was 9.8 months (range 0.7 to 24.1 months) with 36 % and 4.5 % survival rates at 1 and 2 years, respectively. Our patients had a biologic response in 40.1 % of cases and a palliative response in 72.7 %. Among the eight patients with measurable disease, three had partial responses, two had stable disease, and three had progressive disease, leading to a response rate (RR) of 62.5 %. The observed toxicities were mild and limited to grade 3 events. Nine patients had anemia (40.1 %), 5 had sensory neuropathy (22.7 %) and 2 had stomatitis (9.1 %). Conclusion The combination of Docetaxel, Celecoxib, and Zoledronic acid failed to improve OS or to offer an acceptable biologic response. We do not believe that there is compelling evidence to include either Celecoxib or Zoledronic acid in further phase II/III trials.



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Tumescent TAPP: laparoscopic inguinal hernia repair after the preperitoneal tumescent injection of diluted lidocaine and epinephrine saline solution and carbon dioxide gas

Abstract

Purpose

Laparoscopic transabdominal preperitoneal inguinal hernia repair (TAPP) is technically difficult and not infrequently followed by postoperative complications and pain, especially when performed by inexperienced surgeons. To simplify TAPP and reduce postoperative pain, we devised a novel procedure whereby TAPP is carried out after the inguinal preperitoneal infiltration of diluted lidocaine and epinephrine saline solution and carbon dioxide gas (tumescent TAPP). This report introduces the concept of tumescent TAPP and summarizes its operative results.

Methods

About 120 ml of diluted lidocaine and epinephrine solution and 60 ml of CO2 gas were infiltrated into the inguinal preperitoneal space through a transabdominal needle before TAPP. Tumescent TAPP was performed for 400 patients (355 men, 45 women; mean age, 63.2 years).

Results

Using tumescent TAPP, we found it easier to confirm the inguinal anatomy and dissect the preperitoneal layer and inguinal floor, with less bleeding. The mean operation time was 101.9 min and there were few perioperative complications and minimal pain.

Conclusions

Tumescent TAPP makes conventional TAPP easier and safer; however, this procedure should be verified by a comparative study with conventional TAPP.



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Reference intervals for hematological and blood biochemistry reference values in healthy mules and hinnies

Abstract

Little scientific information is known regarding mules and even less is known about hinnies. Due to increased popularity of both as recreational animals which are still commonly found as working equids, there is a need for such basic information for practitioners and owners. The purpose of this study was to begin to establish reference ranges for hematological and biochemical parameters of clinically healthy mules and hinnies compared to those of their sires and dams (horses and donkeys of similar genotype, phenotype within species) used for hybrid offspring production. Such information will contribute to our understanding and attempts to improve management and disease diagnosis of hinnies and mules. Eighty-one healthy equids (n = 30 hinnies, 20 mules, 20 donkeys, and 11 horses) were sampled. Clinical data recorded age, gender, BCS, and temperature. Two 10-mL blood samples were collected by venipuncture of the jugular vein, using "vacutainer" plain and EDTA tubes. These samples were analyzed for RBC, PCV, Hb, WBC, platelets, proteins, fatty acids, electrolytes, enzymes, and glucose. Average and standard deviations were calculated. Kruskal-Wallis test was used to test the significant value. Findings were considered to be significant if P ≤ 0.05. When comparing all parameters among four groups of equids, differences were found for temperature, red blood cell lines, white blood cell lines, electrolytes, and enzymes. Differences in mules and hinnies were seen in RBC, WBC, magnesium, bilirubin, creatinine, and AST. The results are constricted to very few known populations of equid hybrids with similar genetics. In this study, hinnies and mules showed results that were closer to those of horses than those of donkeys. Some differences recorded in hinnies may be related to age: RBC, WBC, MCH, MCV, eosinophils, magnesium, total bilirubin, creatinine, and AST. Findings may help establish new, relevant hematological and biochemical parameters which may prevent medical misdiagnosis. Additional research is needed with larger populations of healthy mules and hinnies.



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Relationships between follicular fluid steroid concentrations and uterine infections in ovarian cystic cows

Abstract

The present study aimed to determine the relationships among uterine bacterial infection, ovarian cysts, and endometritis. A total of 21 genital tracts with ovarian cysts were collected from the abattoir. Cystic fluids were aspirated from ovarian cysts (follicular cysts, n = 10; luteal cysts, n = 11) and eight large follicles (<15 mm) with clear appearance as control for hormone assay. Samples from the internal surface of the uterine body, right and left uterine horns were collected and cultured for bacteriological examinations. In addition, samples from the cystic walls, uterine horns, and bodies were subjected to histopathological examinations. E2/P4 ratio was higher in follicular fluid in cows without ovarian cysts but with endometritis than that of cows with both ovarian cysts and endometritis (3.47 ± 1.37; 0.25 ± 0.11, p = 0.004). Further, cows that had endometritis and no ovarian cyst had a higher E2/P4 ratio than those of endometritic cows with either follicular cyst (3.47 ± 1.37; 0.51 ± 0.17, p = 0.03) or luteal cyst (3.47 ± 1.37; 0.003 ± 0.002, p = 0.01). As the E2/P4 ratio increased, the numbers of isolated bacterial species decreased from nine to one species of bacterial isolates. In conclusion, as the E2/P4 ratio increased in the follicular fluid, the numbers and diversity of bacterial species significantly decreased irrespective of pathogenicity of the uterine bacteria.



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Circulating tumor cells and circulating tumor DNA in colon cancer

Abstract

It is known that tumor cells have the ability to penetrate into the bloodstream. The identification of such circulating tumor cells (CTC) determines the prognosis in several tumors, including colon cancer. Tumor DNA (ctDNA), which is only a part of the total circulating DNA obtained from the blood of cancer patients, is also further separated from plasma. This separation of the neoplastic derivatives of the primary tumor and metastases (CTC, ctDNA, RNA, proteome) in plasma is called "liquid biopsy." CTC increasingly represents the pool of tumor cells that can initiate the growth of metastatic lesions, while the ctDNA provides the information about the whole tumor mass. Traditional tissue biopsy gives information based only on one small section of the primary tumor or metastasis, often retrieved before the start of treatment; however, liquid biopsy provides real-time information about the molecular disorders for the whole tumor mass and allows us to estimate the dynamics of the evolutionary tumor changes, the heterogeneity of the disease, and the effect of chemotherapy. With the possibility of obtaining multiple blood samples for analysis during the therapy, in contrast to traditional biopsy, it also allows us to evaluate the mechanisms of resistance to treatment, which in the future will perhaps lead to modification of the treatment in accordance with the detected molecular defects in tumors. Thus, this would facilitate implementing the principles of personalized therapy. In this literature review, we concentrate on liquid biopsy in patients with colon cancer.



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Design of a multicentre randomized controlled trial to evaluate the effectiveness of a tailored clinical support intervention to enhance return to work for gastrointestinal cancer patients

Abstract

Background

Gastrointestinal (GI) cancer is frequently diagnosed in people of working age, and many GI cancer patients experience work-related problems. Although these patients often experience difficulties returning to work, supportive work-related interventions are lacking. We have therefore developed a tailored work-related support intervention for GI cancer patients, and we aim to evaluate its cost-effectiveness compared with the usual care provided. If this intervention proves effective, it can be implemented in practice to support GI cancer patients after diagnosis and to help them return to work.

Methods/Design

We designed a multicentre randomized controlled trial with a follow-up of twelve months. The study population (N = 310) will include individuals aged 18–63 years diagnosed with a primary GI cancer and employed at the time of diagnosis. The participants will be randomized to the intervention or to usual care. 'Usual care' is defined as psychosocial care in which work-related issues are not discussed. The intervention group will receive tailored work-related support consisting of three face-to-face meetings of approximately 30 min each. Based on the severity of their work-related problems, the intervention group will be divided into groups receiving three types of support (A, B or C). A different supportive healthcare professional will be available for each group: an oncological nurse (A), an oncological occupational physician (B) and a multidisciplinary team (C) that includes an oncological nurse, oncological occupational physician and treating oncologist/physician. The primary outcome measure is return to work (RTW), defined as the time to a partial or full RTW. The secondary outcomes are work ability, work limitations, quality of life, and direct and indirect costs.

Discussion

The hypothesis is that tailored work-related support for GI cancer patients is more effective than usual care in terms of the RTW. The intervention is innovative in that it combines oncological and occupational care in a clinical setting, early in the cancer treatment process.

Trial registration

METC protocol number NL51444.018.14/Netherlands Trial Register number NTR5022. Registered 6 March 2015.



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Metformin in pancreatic cancer treatment: from clinical trials through basic research to biomarker quantification

Abstract

Purpose

Three major chemotherapy strategies have emerged in the treatment of PDAC in the recent past: multiple drug combination, stroma depletion, and use of nanodrug therapy. Anti-diabetic metformin was shown to improve the outcome of a number of cancer types the first seminal report on an observational study published in 2005 and the first hospital-based case–control study on pancreatic cancer in 2009.

Methods

In this review paper, we confront the findings of a selected number of epidemiological studies and clinical trials on the use of metformin in pancreatic cancer treatment with basic knowledge and research. We particularly emphasize on the point that contradictory clinical results likely originate from heterogeneous study design due to a trial and error approach rather than an evidence-based and scientific approach. A non-rigorous selection of patients suffering from PDAC and often a poor understanding of the biological mechanism of metformin coupled with lack of scientific data has led to general statements on metformin positive or negative action, another aspect which we highlight in the review.

Results

We here present a few pathways which in our opinion are predominant for pancreatic cancer specifically: mitochondrial activity, AMPK activation, mTOR inhibition, and decreased IGF-1R and HIF-1α expression.

Conclusion

We stress on the need for a better stratification of patients and a more rigorous planning of clinical trials not only focusing on classical parameters but also on potential predictive biomarkers (AMPK, mTOR, HIF-1α, IGF-1R) and metformin dosage for positive outcome.



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A Comparison of Clinical and Radiologic Outcomes Between Frame-based and Frameless Stereotactic Radiosurgery for Brain Metastases

Publication date: Available online 9 May 2016
Source:Practical Radiation Oncology
Author(s): Nathan R. Bennion, Timothy Malouff, Vivek Verma, Kyle Denniston, Abhijeet Bhirud, Weining Zhen, Andrew Wahl, Chi Lin
Purpose/Objective(s)Modern experiences in stereotactic radiosurgery (SRS) report non-invasive frameless techniques as an effective alternative to frame-based SRS. Frameless techniques potentially increase positional uncertainty and planning target volume (PTV) margins are frequently employed. Here we compare rates of local control and radiation necrosis in frameless versus frame-based SRS.Materials/MethodsNinety-eight patients (170 lesions) with radiologic and clinical follow-up were analyzed. Group 1 contained 34 patients (61 lesions) immobilized with an invasive stereotactic frame. Group 2 had 64 patients (109 lesions) immobilized with a frameless SRS mask. Patient, tumor, and treatment characteristics were recorded, as were intervals to local recurrence and radiation necrosis (asymptomatic and symptomatic).ResultsMedian patient age was 59 years (range 25–89), and KPS was 80 (range 50–100). Median radiologic and clinical follow-up was 6.5 months (range 0.7-44.3) and 7 months (range 0.7-45.7). A median of 2 tumors were treated per course (range 1–5) with a median dose of 18 Gy (range 13–24 Gy). The median time to local failure was not reached, and Kaplan-Meier estimates of local failure were not statistically significant between groups (p=0.303). Actuarial 6-month local failure rates were 7.2% in Group 1 and 12.6% in Group 2 (p=0.295), with 12-month local failure rates of 14.5% and 26.8% (p=0.185), respectively. There was no statistically significant difference in symptomatic (p=0.391) or asymptomatic (p=0.149) radiation necrosis. Six-month radiation necrosis was 0% in Group 1 and 1.6% in Group 2 (p=0.311) with 12-month rates of 20.2% and 3.8%, respectively (p=0.059). Median time to necrosis was not reached in Group 1, but was 44 months in Group 2.ConclusionFrameless SRS demonstrates clinical outcomes comparable to frame-based techniques with respect to local failure and radiation necrosis.



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Individual patient information to select patients for different radiation techniques

Publication date: July 2016
Source:European Journal of Cancer, Volume 62
Author(s): E.H. Quik, T.L. Feenstra, D. Postmus, B.J. Slotman, C.R. Leemans, P.F.M. Krabbe, J.A. Langendijk
Background and purposeProton therapy is an emerging technique in radiotherapy which results in less dose to the normal tissues with similar target dose than photon therapy, the current standard. Patient-level simulation models support better decision making on which patients would benefit most.Materials and methodsA simulation model was developed tracking individual patients' status regarding the primary tumour and multiple complications. As a proof of principle, the model was populated based on information from a cohort of 1013 head and neck cancer patients. Dose–volume parameters for photon and proton radiation treatment plans were then fed into the model to compare outcomes in terms of length and quality of life and select patients that would benefit most.ResultsThe illustrative model could adequately replicate the outcomes of photon therapy in the cohort. Improvements from proton therapy varied considerably between patients. The model projects medium-term outcomes for specific individuals and determines the benefits of applying proton rather than photon therapy.ConclusionsWhile the model needs to be fed with more and especially recent data before being fully ready for use in clinical practice, it could already distinguish between patients with high and low potential benefits from proton therapy. Benefits are highest for patients with both good prognosis and high expected damage to adjacent organs. The model allows for selecting such patients a priori based on patient relevant outcomes.



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Survival of elderly patients with multiple myeloma—Effect of upfront autologous stem cell transplantation

Publication date: July 2016
Source:European Journal of Cancer, Volume 62
Author(s): Maximilian Merz, Lina Jansen, Felipe A. Castro, Jens Hillengass, Hans Salwender, Katja Weisel, Christof Scheid, Sabine Luttmann, Katharina Emrich, Bernd Holleczek, Alexander Katalinic, Alice Nennecke, Christian Straka, Christian Langer, Monika Engelhardt, Hermann Einsele, Nicolaus Kröger, Dietrich Beelen, Peter Dreger, Hermann Brenner, Hartmut Goldschmidt
BackgroundThe aim of this study was to determine the value of upfront autologous transplantation (ASCT) in elderly patients (60–79 years) with myeloma.MethodsWe analysed relative survival (RS) of patients diagnosed in 1998–2011 and treated with ASCT within 12 months after diagnosis in Germany (n = 3591; German Registry of Stem Cell Transplantation) and compare RS with survival of myeloma patients diagnosed in the same years in Germany (n = 13,903; population-based German Cancer Registries).ResultsUtilisation of ASCT has increased rapidly between 2000–2002 and 2009–2011 (60–64years: 7.0–43.0%; 65–69 years: 6.6–23.7%; 70–79 years: 0.4–4.0%). Comparison of 5-year RS of patients from the general German myeloma population who have survived the first year after diagnosis with 5-year RS of patients treated with ASCT revealed higher survival for transplanted patients among all age groups (60–64: 59.2% versus 66.1%; 65–69: 57.4% versus 61.7%; 70–79: 51.0% versus 56.6%). RS increased strongly between 2003–2005 and 2009–2011 for the general German myeloma population (+8.5%) and for patients treated with ASCT (+11.8%). Differences in RS between these groups increased over time from +1.9% higher age-standardised survival in transplanted patients in 2003–2005 to 5.2% higher survival in 2009–2011.ConclusionWe conclude that upfront ASCT might be a major contributor to improved survival for elderly myeloma patients in Germany.



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Phase 1 study of dalotuzumab monotherapy and ridaforolimus–dalotuzumab combination therapy in paediatric patients with advanced solid tumours

Publication date: July 2016
Source:European Journal of Cancer, Volume 62
Author(s): Didier Frappaz, Sara M. Federico, Andrew DJ. Pearson, Lia Gore, Margaret E. Macy, Steven G. DuBois, Isabelle Aerts, Robert Iannone, Ryan Geschwindt, Arne Van Schanke, Rui Wang, Birgit Geoerger
AimDalotuzumab is a highly specific, humanised immunoglobulin G1 monoclonal antibody against insulin-like growth factor receptor 1. This multicenter phase 1 study (NCT01431547) explored the safety and pharmacokinetics of dalotuzumab monotherapy (part 1) and the combination of dalotuzumab with the mammalian target of rapamycin inhibitor ridaforolimus (part 2) in paediatric patients with advanced solid tumours.MethodsDalotuzumab was administered intravenously every 3 weeks starting at 900 mg/m2 and escalating to 1200 and 1500 mg/m2. Combination therapy included intravenous dalotuzumab at the defined single-agent recommended phase 2 dose (RP2D) and oral ridaforolimus 28 mg/m2 daily (days 1–5), repeated weekly. Pharmacokinetic studies were performed to evaluate the mean serum trough dalotuzumab concentration, which guided the RP2D.ResultsTwenty-four patients were enrolled (part 1, n = 20; part 2, n = 4). No dose-limiting toxicities were observed in patients receiving dalotuzumab alone. One patient experienced dose-limiting stomatitis in the combination arm. Pharmacokinetic data showed dose-dependent increases in exposure (area under the curve from zero to infinity [AUC0–∞]) (87,900, 164,000, and 186,000 h*mg/ml for the 900, 1200, and 1500 mg/m2 dose levels, respectively), maximum serum concentration (Cmax) (392, 643, and 870 mg/ml), and serum trough concentration (Ctrough) (67.1, 71.6, and 101 mg/ml). The mean half-life was 265, 394, and 310 h, respectively. Dalotuzumab pharmacokinetics were not affected by coadministration with ridaforolimus. One of six patients with Ewing sarcoma had confirmed partial response to dalotuzumab monotherapy at 900 mg/m2. Time to response was 41 d, and progression occurred at 126 d.ConclusionDalotuzumab was well tolerated in paediatric patients with advanced solid malignancies. The RP2D of dalotuzumab is 900 mg/m2 (ClinicalTrials.gov identifier: NCT01431547, Protocol PN062).



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Can postoperative radiotherapy be omitted in localised standard-risk Ewing sarcoma? An observational study of the Euro-E.W.I.N.G group

Publication date: July 2016
Source:European Journal of Cancer, Volume 61
Author(s): Stéphanie Foulon, Bernadette Brennan, Nathalie Gaspar, Uta Dirksen, Lee Jeys, Anna Cassoni, Line Claude, Beatrice Seddon, Perrine Marec-Berard, Jeremy Whelan, Michael Paulussen, Arne Streitbuerger, Odile Oberlin, Heribert Juergens, Robert Grimer, Marie-Cécile Le Deley
BackgroundThe role of postoperative radiotherapy (PORT) in Ewing sarcoma (ES) is unclear. We assessed the impact of PORT on local control in patients with localised ES and good histological response to chemotherapy (<10% cells).Patients and methodsAll randomised patients in the EE99-R1 trial (comparing two consolidation chemotherapy regimens) undergoing surgery after induction chemotherapy were included. Local relapse (LR) cumulative incidence was estimated using a competing risk approach. Impact of PORT was assessed in multivariable models, adjusted for country, age, tumour site and volume, quality of resection and histological response. We also evaluated the heterogeneity of PORT effect by patient and tumour characteristics.ResultsOne hundred forty-two (24%) of the 599 patients included from 1999 to 2009 received PORT (median dose: 45 Grays). With median follow-up of 6.2 years, 67 patients had an LR (with concomitant metastases in 28), leading to an 8-year LR-incidence = 11.9% (standard error [se] = 1.4%). Overall survival (OS) = 21% (se = 5%) 3 years after LR (31% in isolated LR). Controlling for possible confounders, we observed a statistically significant reduction of LR in patients treated by surgery + PORT compared to surgery alone (subdistribution-hazard ratio = 0.43, 95% confidence interval, 0.21–0.88, p = 0.02). The benefit of PORT was particularly marked for tumours larger than 200 ml at diagnosis and 100% necrosis. We observed a non-significant trend for benefit associated with PORT for disease-free, event-free and OS.ConclusionRadiotherapy appears to improve local control. We now recommend PORT in case of incomplete removal of the tissues involved by the pre-chemotherapy tumour volume. Further studies are required to assess the balance between benefit and risks.



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Sexual Dysfunction in Young Adult Survivors of Childhood Cancer

Background

Disruption of psychosexual development and sexual dysfunction are well recognized as profoundly distressing long-term side effects of pediatric cancer treatment. However, little is known about the specific sexual problems facing young adult survivors of childhood cancer (YASCC) and their unmet clinical needs. In this study, we aimed to utilize qualitative methods to characterize sexual dysfunction in YASCC and identify survivor-reported unmet clinical need regarding sexual health information and care.

Procedure

Semistructured interviews were conducted with 22 YASCC (ages 18–31; 10 men, 12 women) reporting sexual dysfunction. Interviews were conducted in English by phone or in person. All interviews were audiorecorded, transcribed verbatim, and analyzed using a thematic analysis approach. Inductive open-coding procedures identified participants' experiences with sexual dysfunction and clinical care needs. Themes were identified by grouping pattern-forming codes in the data.

Results

Interviews with YASCC reporting sexual dysfunction revealed five overarching themes including interruption of adolescent psychosocial development, physical and psychological problems with sexual function, altered perceptions of body image, concern about fertility, and inadequate clinical support.

Conclusions

The experiences described by YASCC provide valuable insight into the nature of sexual dysfunction in this population and their clinical care needs. These data provide the framework for future research on sexual dysfunction screening measures, patient–physician communication, and effective interventions to address sexual dysfunction in YASCC.



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Successful Curative Therapy With Rituximab and Allogeneic Haematopoietic Stem Cell Transplantation for MALT Lymphoma Associated With STK4-Mutated CD4+ Lymphocytopenia

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Idiopathic CD4+ lymphocytopenia and extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) are rare diseases in children. We report the first case of a child with STK4-mutated CD4+ lymphocytopenia who developed Epstein–Barr virus associated MALT lymphoma arising in the salivary gland. The child achieved complete remission with rituximab, and her immunodeficiency was cured by haematopoietic stem cell transplantation. The child remained well 24 months post transplantation.



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Immunological Reconstitution in Children After Completing Conventional Chemotherapy of Acute Lymphoblastic Leukemia is Marked by Impaired B-cell Compartment

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Humoral and cellular immunity were studied in 28 children completing conventional treatment of standard-risk (SR) or intermediate-risk (IR) acute lymphoblastic leukemia (ALL). Both naïve and memory B cells were most severely affected and showed slow recovery during the 2-year follow-up, while the T-cell compartment showed only minor changes. Immunoglobulins and IgG subclasses, components, and antibodies against vaccine-preventable diseases were not significantly affected. In conclusion, immune recovery after conventional chemotherapy for SR and IR ALL is marked by B-cell depletion, but otherwise did not show any severe deficiencies in lymphocyte function.



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Association Between Combined Presence of Hepatitis C Virus and Polymorphisms in Different Genes With Toxicities of Methotrexate and 6-Mercaptopurine in Children With Acute Lymphoblastic Leukemia

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Background

The aim of the present study is to determine the correlation of hepatitis C virus (HCV) infection and polymorphisms in different genes with toxicity of either methotrexate (MTX) or 6-mercaptopurine (6-MP) administered to children with acute lymphoblastic leukemia (ALL).

Procedure

One hundred children with low-risk ALL, who were treated according to the St. Jude Total therapy XV, were recruited. The recruited children were receiving MTX and 6-MP during maintenance phase. Patients were excluded from the study if they had other types of leukemia. Genotyping analyses for the thiopurine methyltransferase (TPMT), methylenetetrahydrofolate reductase (MTHFR), and glutathione S-transferase (GST) genes were performed using a combination of polymerase chain reaction (PCR) and PCR-RFLP (where RFLP is restriction fragment length polymorphism) protocols. Relevant clinical data on adverse drug reactions were collected objectively (blinded to genotypes) from the patient medical records.

Results

There was a significant correlation between the combined presence of HCV and TPMT*3B G460A gene polymorphisms and grades 2–4 hepatotoxicity as aspartate aminotransferase (AST) elevation (P < 0.04). The same observation was seen when comparing either the presence of HCV alone or the presence of the gene polymorphism alone. A significant association between the combined presence of HCV and MTHFR C677T polymorphism and grades 2–4 hepatotoxicity as alanine aminotransferase (ALT), AST, and alkaline phosphatase (ALP) elevation was observed (P values <0.001, 0.02, and 0.001, respectively). The presence of HCV infection had a significant negative effect on hepatic transaminases.

Conclusions

The present data support a role for combining analysis of genetic variation in drug-metabolizing enzymes and the presence of HCV in the assessment of specific drugs toxicities in multiagent chemotherapeutic treatment regimens.



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Concomitant targeting of programmed death-1 (PD-1) and CD137 improves the efficacy of radiotherapy in a mouse model of human BRAFV600-mutant melanoma

Abstract

T cell checkpoint blockade with antibodies targeting programmed cell death (ligand)-1 (PD-1/PD-L1) and/or cytotoxic T lymphocyte-antigen 4 (CTLA-4) has improved therapy outcome in melanoma patients. However, a considerable proportion of patients does not benefit even from combined α-CTLA-4 and α-PD-1 therapy. We therefore examined to which extent T cell (co)stimulation and/or stereotactic body radiation therapy (SBRT) could further enhance the therapeutic efficacy of T cell checkpoint blockade in a genetically engineered mouse melanoma model that is driven by PTEN-deficiency, and BRAFV600 mutation, as in human, but lacks the sporadic UV-induced mutations. Tumor-bearing mice were treated with different combinations of immunomodulatory antibodies (α-CTLA-4, α-PD-1, α-CD137) or interleukin-2 (IL-2) alone or in combination with SBRT. None of our immunotherapeutic approaches (alone or in combination) had any anti-tumor efficacy, while SBRT alone delayed melanoma outgrowth. However, α-CD137 combined with α-PD-1 antibodies significantly enhanced the anti-tumor effect of SBRT, while the anti-tumor effect of SBRT was not enhanced by interleukin-2, or the combination of α-CTLA-4 and α-PD-1. We conclude that α-CD137 and α-PD-1 antibodies were most effective in enhancing SBRT-induced tumor growth delay in this mouse melanoma model, outperforming the ability of IL-2, or the combination of α-CTLA-4 and α-PD-1 to synergize with SBRT. Given the high mutational load and increased immunogenicity of human melanoma with the same genotype, our findings encourage testing α-CD137 and α-PD-1 alone or in combination with SBRT clinically, particularly in patients refractory to α-CTLA-4 and/or α-PD-1 therapy.



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Effects of implementing an “enhanced recovery after surgery” program on patients undergoing resection of hepatocellular carcinoma

Abstract

Purpose

To evaluate the effects of implementing an "enhanced recovery after surgery" (ERAS) program on the feasibility, safety, and effectiveness of extensive and potentially curative liver resection for hepatocellular carcinoma (HCC).

Methods

We compared clinicopathologic factors, surgical factors, and outcomes of patients who underwent extended hepatectomy (defined as resection of more than two sections) for HCC, before and after the introduction of an ERAS program.

Results

Operating times and postoperative hospital stay were significantly shorter, and total volume infused during surgery was significantly lower, for the ERAS group than for the control group. Although the ERAS group had a significantly lower percentage of patients with retention of abdominal drainage, this group had a higher frequency of abdominal paracentesis in patients without intraoperative abdominal drainage. Oral dietary intake and the ability to walk steadily resumed significantly earlier in the ERAS group. Postoperative serum concentrations of albumin and cholinesterase were significantly higher in the ERAS group than in the control group.

Conclusions

The ERAS program was feasible and effective for patients with chronic liver disease undergoing extended liver resection for HCC, because it allowed earlier oral dietary intake and promoted faster postoperative recovery.



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Changes in the survival of older patients with hematologic malignancies in the early 21st century

BACKGROUND

Survival for patients with hematologic malignancies has improved during the early 21st century. However, it is unclear whether older patients have benefited to the same extent as younger patients. This study examines changes in survival for older patients with the 7 most common hematologic malignancies.

METHODS

Period analysis was used to examine survival for patients who were 65 years old or older and were diagnosed with a common hematologic malignancy between 1992 and 2012 with data from the Surveillance, Epidemiology, and End Results database.

RESULTS

Five-year relative survival increased for older patients with hematologic malignancies with the partial exception of acute myelogenous leukemia, for which no change in survival was seen for patients who were 75 years old or older. Patients with chronic lymphocytic leukemia and non-Hodgkin lymphoma, including the oldest patients, had especially strong improvements, with increases in 5-year relative survival for patients who were 85 years old or older of 31.5% and 39.6%, respectively, between 1997-2000 and 2009-2012.

CONCLUSIONS

Despite these increases, survival rates did not reach those observed for patients aged 50 to 59 years for any hematologic malignancy. Newer therapies and a better understanding of how to treat older patients have led to increased survival expectations for older patients with most hematologic malignancies, but an age-related survival disparity persists. Cancer 2016. © 2016 American Cancer Society.



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Vismodegib or cixutumumab in combination with standard chemotherapy for patients with extensive-stage small cell lung cancer: A trial of the ECOG-ACRIN Cancer Research Group (E1508)

BACKGROUND

Preclinical targeting of the hedgehog pathway by vismodegib and of insulin-like growth factor 1 receptor by cixutumumab enhances the efficacy of chemotherapy and also demonstrates activity against the tumor cell fraction responsible for disease recurrence in small cell lung cancer.

METHODS

Patients with newly diagnosed extensive-stage small cell lung cancer (SCLC-ED) were randomized to receive four 21-day cycles of cisplatin and etoposide alone (cisplatin at 75 mg/m2 on day 1 and etoposide at 100 mg/m2 on days 1-3; arm A) or in combination with either vismodegib (150 mg/d by mouth; arm B) or cixutumumab (6 mg/kg/wk intravenously on day 1; arm C). The primary endpoint was progression-free survival (PFS). Circulating tumor cells (CTCs) were isolated/enumerated with the Veridex CellSearch platform at the baseline.

RESULTS

One hundred fifty-two eligible patients were treated. Patient demographics and disease characteristics were well balanced between the 3 arms except for the higher rate with a performance status of 0 in arm B (P = .03). The median PFS times in arms A, B, and C were 4.4, 4.4, and 4.6 months, respectively; the median overall survival (OS) times were 8.8, 9.8, and 10.1 months, respectively; and the response rates were 48%, 56%, and 50%, respectively. None of the comparisons of these outcomes were statistically significant. The median OS was 10.5 months for those with low CTC counts (≤100/7.5 mL) at baseline and 7.2 months for those with high CTC counts (hazard ratio, 1.74; P = .006).

CONCLUSIONS

There was no significant improvement in PFS or OS with the addition of either vismodegib or cixutumumab to chemotherapy in patients with SCLC-ED. A low baseline CTC count was associated with a favorable prognosis. Cancer 2016. © 2016 American Cancer Society.



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Association of androgen metabolism gene polymorphisms with prostate cancer risk and androgen concentrations: Results from the Prostate Cancer Prevention Trial

BACKGROUND

Prostate cancer is highly influenced by androgens and genes. The authors investigated whether genetic polymorphisms along the androgen biosynthesis and metabolism pathways are associated with androgen concentrations or with the risk of prostate cancer or high-grade disease from finasteride treatment.

METHODS

A nested case-control study from the Prostate Cancer Prevention Trial using data from men who had biopsy-proven prostate cancer (cases) and a group of biopsy-negative, frequency-matched controls was conducted to investigate the association of 51 single nucleotide polymorphisms (SNPs) in 12 genes of the androgen pathway with overall (total), low-grade, and high-grade prostate cancer incidence and serum hormone concentrations.

RESULTS

There were significant associations of genetic polymorphisms in steroid 5α-reductase 1 (SRD5A1) (reference SNPs: rs3736316, rs3822430, rs1560149, rs248797, and rs472402) and SRD5A2 (rs2300700) with the risk of high-grade prostate cancer in the placebo arm of the Prostate Cancer Prevention Trial; 2 SNPs were significantly associated with an increased risk (SRD5A1 rs472402 [odds ratio, 1.70; 95% confidence interval, 1.05-2.75; Ptrend = .03] and SRD5A2 rs2300700 [odds ratio, 1.94; 95% confidence interval, 1.19-3.18; Ptrend = .01]). Eleven SNPs in SRD5A1, SRD5A2, cytochrome P450 family 1, subfamily B, polypeptide 1 (CYP1B1), and CYP3A4 were associated with modifying the mean concentrations of serum androgen and sex hormone-binding globulin; and 2 SNPs (SRD5A1 rs824811 and CYP1B1 rs10012; Ptrend < .05) consistently and significantly altered all androgen concentrations. Several SNPs (SRD5A1 rs3822430, SRD5A2 rs2300700, CYP3A43 rs800672, and CYP19 rs700519; Ptrend < .05) were significantly associated with both circulating hormone levels and prostate cancer risk.

CONCLUSIONS

Germline genetic variations of androgen-related pathway genes are associated with serum androgen concentrations and the risk of prostate cancer. Further studies to examine the functional consequence of novel causal variants are warranted. Cancer 2016. © 2016 American Cancer Society.



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Understanding the value of cancer drugs–the devil is in the detail

New tools to assess the value of cancer drugs are not sufficiently detailed. Economic modeling provides the ideal method with which to assess their value.



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Genomic alterations and molecular subtypes of gastric cancers in Asians

Gastric cancer (GC) is a highly heterogenic disease, and it is the second leading cause of cancer death in the world. Common chemotherapies are not very effective for GC, which often presents as an advanced or...

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Pediatric spinal glioblastoma of the conus medullaris: a case report of long survival

High-grade gliomas of the spinal cord represent a rare entity in children. Their biology, behavior, and controversial treatment options have been discussed in a few pediatric cases. These tumors are associated...

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Radiotherapy for gynecologic cancer in nonagenarian patients: a framework for new paradigms

No consensus exists regarding the role of radiotherapy in the management of gynecologic cancer in nonagenarian patients. We retrospectively reviewed the outcomes of 19 consecutive nonagenarian patients with gy...

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Does adding intraperitoneal paclitaxel to standard intraperitoneal regimen yield incremental survival? A propensity score-matched cohort study

We recruited consecutive patients with stage III epithelial ovarian, tubal, and peritoneal cancers who had optimal residual tumor after primary cytoreductive surgery and who received intraperitoneal chemothera...

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Issue Information — Information for Authors



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Issue Information — Table of Contents



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Issue Information — UICC



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Does adding intraperitoneal paclitaxel to standard intraperitoneal regimen yield incremental survival? A propensity score-matched cohort study

Abstract

We recruited consecutive patients with stage III epithelial ovarian, tubal, and peritoneal cancers who had optimal residual tumor after primary cytoreductive surgery and who received intraperitoneal chemotherapy between 2002 and 2012. Two propensity score-matched sample cohorts were created. We found that the addition of paclitaxel as a second intraperitoneal agent on a 3-week dosing schedule did not yield significant incremental survival benefits over the intraperitoneal delivery of a single cisplatin-based regimen. If our findings could be confirmed by a prospective randomized study, then it would be interesting to explore the efficacy of shifting back to a dose-dense intraperitoneal delivery of paclitaxel or a dose-dense delivery of a new formulation of paclitaxel for the patients with stage III epithelial ovarian, tubal, and peritoneal cancers.



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Radiotherapy for gynecologic cancer in nonagenarian patients: a framework for new paradigms

Abstract

No consensus exists regarding the role of radiotherapy in the management of gynecologic cancer in nonagenarian patients. We retrospectively reviewed the outcomes of 19 consecutive nonagenarian patients with gynecologic cancer (6 endometrial cancers, 6 cervical cancers, 4 vulvar cancers, and 3 vaginal cancers) who were treated with radiotherapy. Radiotherapy was performed mainly in a palliative setting (n = 12; 63.2%), with a median dose of 45 Gy (range, 6–76 Gy). Infrequent major acute or late toxicities were reported. Among 19 patients, 9 (47.4%) experienced tumor progression, 5 (26.3%) experienced complete response, 2 (10.5%) experienced stable disease and/or partial response. At last follow-up, 12 patients (63.2%) had died; most deaths (n = 9) occurred because of the cancer. These results suggest that radiotherapy is feasible in the treatment of nonagenarian patients with gynecologic cancer.



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Pediatric spinal glioblastoma of the conus medullaris: a case report of long survival

Abstract

High-grade gliomas of the spinal cord represent a rare entity in children. Their biology, behavior, and controversial treatment options have been discussed in a few pediatric cases. These tumors are associated with severe disability and poor prognosis. We report a case of a 4-year-old child diagnosed with an isolated glioblastoma multiforme of the conus medullaris. The patient underwent subtotal surgical excision, followed by adjuvant radiotherapy and oral chemotherapy. He is alive with mild neurologic deficits at 52 months after diagnosis. We describe the peculiar characteristics of this rare condition in pediatric oncology. We also provide an overview of current multidisciplinary therapeutic approaches and prognostic factors for this disease.



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Genomic alterations and molecular subtypes of gastric cancers in Asians

Abstract

Gastric cancer (GC) is a highly heterogenic disease, and it is the second leading cause of cancer death in the world. Common chemotherapies are not very effective for GC, which often presents as an advanced or metastatic disease at diagnosis. Treatment options are limited, and the prognosis for advanced GCs is poor. The landscape of genomic alterations in GCs has recently been characterized by several international cancer genome programs, including studies that focused exclusively on GCs in Asians. These studies identified major recurrent driver mutations and provided new insights into the mutational heterogeneity and genetic profiles of GCs. An analysis of gene expression data by the Asian Cancer Research Group (ACRG) further uncovered four distinct molecular subtypes with well-defined clinical features and their intersections with actionable genetic alterations to which targeted therapeutic agents are either already available or under clinical development. In this article, we review the ACRG GC project. We also discuss the implications of the genetic and molecular findings from various GC genomic studies with respect to developing more precise diagnoses and treatment approaches for GCs.



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A novel genetic score model of UGT1A1 and TGFB pathway as predictor of severe irinotecan-related diarrhea in metastatic colorectal cancer patients

Abstract

Purpose

UGT1A1*28/*6 as predictors of severe irinotecan-related diarrhea (SIRD) were duplicated by many studies. However, some patients of lower risk genotype (UGT1A1*1/*1) still suffered SIRD and the extremely low frequency of UGT1A1*6/*6 limited its clinical usage. Previous studies proved that the transforming growth factor (TGFB) family may have some effect on MTX-induced mucositis. However, the associations between TGFB gene variants and SIRD have never been reported so far. Our aim was to improve the predictive value of UGT1A1 gene variants on SIRD.

Methods

Six SNPs (TGFB1 rs1800469; TGFBR1 rs10733710, rs334354 and rs6478974; TGFBR2 rs3087465; UGT1A1*6) and UGT1A1*28 were selected for genotyping in 160 metastatic colorectal cancer patients treated with irinotecan in a prospective multicenter trial (NCT01282658).

Results

UGT1A1*6, UGT1A1*28, rs1800469 and rs3087465 were all associated with SIRD (p = 0.026, 0.014, 0.047 and 0.045 respectively). A novel genetic score model (with a cut off value of 1.5) based on them was created to predict SIRD (OR = 11.718; 95 % CI 2.489–55.157, p = 0.002). In patients of gene score > 1.5, the risk of SIRD was much higher (23.5 vs. 2.8 %, p = 2.24E−04) and continued in the first 6 cycles of chemotherapy, while in patients with gene score ≤1.5, the risk was much lower and none of them suffered SIRD after the first cycle of chemotherapy (p = 0.0003).

Conclusions

The novel genetic score model improved the predictive value of UGT1A1 on SIRD. If validated, it will provide valuable information for clinical use of irinotecan.



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Concomitant targeting of programmed death-1 (PD-1) and CD137 improves the efficacy of radiotherapy in a mouse model of human BRAFV600-mutant melanoma

Abstract

T cell checkpoint blockade with antibodies targeting programmed cell death (ligand)-1 (PD-1/PD-L1) and/or cytotoxic T lymphocyte-antigen 4 (CTLA-4) has improved therapy outcome in melanoma patients. However, a considerable proportion of patients does not benefit even from combined α-CTLA-4 and α-PD-1 therapy. We therefore examined to which extent T cell (co)stimulation and/or stereotactic body radiation therapy (SBRT) could further enhance the therapeutic efficacy of T cell checkpoint blockade in a genetically engineered mouse melanoma model that is driven by PTEN-deficiency, and BRAFV600 mutation, as in human, but lacks the sporadic UV-induced mutations. Tumor-bearing mice were treated with different combinations of immunomodulatory antibodies (α-CTLA-4, α-PD-1, α-CD137) or interleukin-2 (IL-2) alone or in combination with SBRT. None of our immunotherapeutic approaches (alone or in combination) had any anti-tumor efficacy, while SBRT alone delayed melanoma outgrowth. However, α-CD137 combined with α-PD-1 antibodies significantly enhanced the anti-tumor effect of SBRT, while the anti-tumor effect of SBRT was not enhanced by interleukin-2, or the combination of α-CTLA-4 and α-PD-1. We conclude that α-CD137 and α-PD-1 antibodies were most effective in enhancing SBRT-induced tumor growth delay in this mouse melanoma model, outperforming the ability of IL-2, or the combination of α-CTLA-4 and α-PD-1 to synergize with SBRT. Given the high mutational load and increased immunogenicity of human melanoma with the same genotype, our findings encourage testing α-CD137 and α-PD-1 alone or in combination with SBRT clinically, particularly in patients refractory to α-CTLA-4 and/or α-PD-1 therapy.



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MEK5 overexpression is associated with the occurrence and development of colorectal cancer

Abstract

Background

Mitogen/extracellular signal-regulated kinase kinase-5 (MEK5) has been confirmed to play a pivotal role in tumor carcinogenesis and progression. However, few studies have investigated the role of MEK5 in colorectal cancer (CRC).

Methods

MEK5 expression was determined by immunohistochemistry (IHC) in tissue microarrays (TMAs) containing 2 groups of tissues, and western blotting was used to confirm MEK5 expression in 8 cases of primary CRC tissues and paired normal mucosa. RNA interference was used to verify the biological function of MEK5 gene in the development of CRC.

Results

IHC revealed the expression of MEK5 was higher in tumor tissues (38.1 %), compared with adjacent normal tissue (8.3 %). Western blot showed that, MEK5 expression was upregulated in CRC tumor tissues compared with normal tissue. Analysis of clinical pathology parameters indicated MEK5 overexpression was significantly correlated with the depth of invasion, lymph node metastasis, distant metastasis and histological grade. Survival analysis revealed that MEK5 overexpression negatively correlated with cancer-free survival (hazard ratio 1.64, P = 0.017). RNA interference-mediated knockdown of MEK5 in SW480 colon cancer cells decreased their proliferation, division, migration and invasiveness in vitro and slowed down tumors growth in mice engrafted with the cells.

Conclusion

MEK5 plays an important role in CRC progression and may be a potential molecular target for the treatment of CRC.



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Concomitant targeting of programmed death-1 (PD-1) and CD137 improves the efficacy of radiotherapy in a mouse model of human BRAFV600-mutant melanoma

Abstract

T cell checkpoint blockade with antibodies targeting programmed cell death (ligand)-1 (PD-1/PD-L1) and/or cytotoxic T lymphocyte-antigen 4 (CTLA-4) has improved therapy outcome in melanoma patients. However, a considerable proportion of patients does not benefit even from combined α-CTLA-4 and α-PD-1 therapy. We therefore examined to which extent T cell (co)stimulation and/or stereotactic body radiation therapy (SBRT) could further enhance the therapeutic efficacy of T cell checkpoint blockade in a genetically engineered mouse melanoma model that is driven by PTEN-deficiency, and BRAFV600 mutation, as in human, but lacks the sporadic UV-induced mutations. Tumor-bearing mice were treated with different combinations of immunomodulatory antibodies (α-CTLA-4, α-PD-1, α-CD137) or interleukin-2 (IL-2) alone or in combination with SBRT. None of our immunotherapeutic approaches (alone or in combination) had any anti-tumor efficacy, while SBRT alone delayed melanoma outgrowth. However, α-CD137 combined with α-PD-1 antibodies significantly enhanced the anti-tumor effect of SBRT, while the anti-tumor effect of SBRT was not enhanced by interleukin-2, or the combination of α-CTLA-4 and α-PD-1. We conclude that α-CD137 and α-PD-1 antibodies were most effective in enhancing SBRT-induced tumor growth delay in this mouse melanoma model, outperforming the ability of IL-2, or the combination of α-CTLA-4 and α-PD-1 to synergize with SBRT. Given the high mutational load and increased immunogenicity of human melanoma with the same genotype, our findings encourage testing α-CD137 and α-PD-1 alone or in combination with SBRT clinically, particularly in patients refractory to α-CTLA-4 and/or α-PD-1 therapy.



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Concomitant targeting of programmed death-1 (PD-1) and CD137 improves the efficacy of radiotherapy in a mouse model of human BRAFV600-mutant melanoma

Abstract

T cell checkpoint blockade with antibodies targeting programmed cell death (ligand)-1 (PD-1/PD-L1) and/or cytotoxic T lymphocyte-antigen 4 (CTLA-4) has improved therapy outcome in melanoma patients. However, a considerable proportion of patients does not benefit even from combined α-CTLA-4 and α-PD-1 therapy. We therefore examined to which extent T cell (co)stimulation and/or stereotactic body radiation therapy (SBRT) could further enhance the therapeutic efficacy of T cell checkpoint blockade in a genetically engineered mouse melanoma model that is driven by PTEN-deficiency, and BRAFV600 mutation, as in human, but lacks the sporadic UV-induced mutations. Tumor-bearing mice were treated with different combinations of immunomodulatory antibodies (α-CTLA-4, α-PD-1, α-CD137) or interleukin-2 (IL-2) alone or in combination with SBRT. None of our immunotherapeutic approaches (alone or in combination) had any anti-tumor efficacy, while SBRT alone delayed melanoma outgrowth. However, α-CD137 combined with α-PD-1 antibodies significantly enhanced the anti-tumor effect of SBRT, while the anti-tumor effect of SBRT was not enhanced by interleukin-2, or the combination of α-CTLA-4 and α-PD-1. We conclude that α-CD137 and α-PD-1 antibodies were most effective in enhancing SBRT-induced tumor growth delay in this mouse melanoma model, outperforming the ability of IL-2, or the combination of α-CTLA-4 and α-PD-1 to synergize with SBRT. Given the high mutational load and increased immunogenicity of human melanoma with the same genotype, our findings encourage testing α-CD137 and α-PD-1 alone or in combination with SBRT clinically, particularly in patients refractory to α-CTLA-4 and/or α-PD-1 therapy.



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via IFTTT