Publication date: Available online 5 April 2017
Source:Practical Radiation Oncology
Author(s): Shearwood McClelland, Charles R Thomas, Lynn D Wilson, Emma B Holliday, Jerry J Jaboin
IntroductionThe decision of radiation oncology residents to pursue academic versus private practice careers plays a central role in shaping the present and future of the field, yet factors potentially predictive of this decision are lacking. This study was performed to examine the role of several factors publicly available prior to residency on post-residency career choice, including pre-residency peer-reviewed publications (PRP) which have been associated with resident career choice in comparably competitive subspecialties such as neurosurgery.MethodsUsing a combination of internet searches, telephone interviews, and the 2015 Association of Residents in Radiation Oncology (ARRO) directory, a list of 2016 radiation oncology resident graduates was compiled along with their post-residency career choice. PRP was defined as the number of PubMed publications encompassing the end of the calendar year (2010) in which residency applications were due; this number was then correlated with career choice.Results163 residents from 76 Accreditation Council for Graduate Medical Education-certified programs were examined. 78% were male, 22% were MD/PhD, and 79 graduates (48%) chose academic careers. 52% of graduates had at least one PRP at the time of application to radiation oncology residency; 35% had more than one PRP. Regarding career choice, the difference between 0 and 1+ PRP was statistically significant (odds ratio=3.3; p<0.01), but not between 1 and >1 PRP. Gender, PhD or non-PhD dual degree status were not associated with career choice.ConclusionRadiation oncology residency graduates with one or more peer-reviewed publications at the time of residency application were roughly two times more likely to choose an academic career as their initial career choice than graduates with no pre-residency peer-reviewed publications. This information may prove useful to medical students, medical school advisors and residency program directors, and deserves further prospective investigation.
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Cancer Medicine by Alexandros G.Sfakianakis,Anapafseos 5 Agios Nikolaos,Crete 72100,Greece,tel :00302841026182 & 00306932607174
Τετάρτη 5 Απριλίου 2017
Association of Pre-residency Peer Reviewed Publications with Radiation Oncology Resident Choice of Academic Versus Private Practice Career
Predictors of chest wall toxicity after stereotactic ablative radiotherapy using real-time tumor tracking for lung tumors
To evaluate the incidence of chest wall toxicity after lung stereotactic ablative radiotherapy (SABR) and identify risk factors for the development of rib fracture.
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Post surgery circulating free tumor DNA is a predictive biomarker for relapse of lung cancer
Abstract
Cancer cells release DNA fragments into plasma as circulating free DNA (cfDNA). However, quantitative measurement of tumor-derived DNA in cfDNA remains challenge. The purpose of this study was to quantitatively assess tumor-derived DNA in lung cancer patients. By optimizing competitive allele-specific TaqMan PCR (CAST-PCR), we assessed the copy number of mutated Kirsten rat sarcoma viral oncogene homolog (KRAS) and epidermal growth factor receptor (EGFR) alleles in the pre/post surgery plasma of 168 lung cancer patients. An absolute quantitative PCR method was developed to assess the number of total cfDNA. All mutations detected in tumors were also found in the plasma after surgery. At the time of 30 days after surgery, EGFR mutation of circulating cell-free DNA was detected only in two patients who recurred in 4 months after surgery. Compared to that of normal control at 30 days after surgery, five patients who recurred in 4 months had significantly higher circulating cell-free DNA (P < 0.001), whereas six patients who recurred after 4 months (P = 0.207) and five patients without recurrence (P = 0.901) demonstrated significantly lower circulating cell-free DNA. Our findings suggest that cfDNA analysis in plasma is an alternative and supplement to tissue analysis and hold promise for clinical application. Stratification of patients according to cfDNA levels at 30 days after surgery might be helpful in selecting lung cancer patients for adjuvant therapy after surgery.
In this manuscript, we report the levels of tumor circulating cell-free DNA (cfDNA) initially increased immediate after surgery, followed by a rapid decrease. Importantly, the tumor cfDNA levels 30 days post surgery were predictive for subsequent relapse in patients.
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The impact of presence of Hashimoto's thyroiditis on diagnostic accuracy of ultrasound-guided fine-needle aspiration biopsy in subcentimeter thyroid nodules: A retrospective study from FUSCC
Abstract
The incidence of PTMC has been increasing in the recent years. This study aimed to investigate the diagnostic value of US-FNA in thyroid nodules ≤1 cm and whether the presence of Hashimoto's thyroiditis (HT) in thyroid could influence the accuracy. The patients who accepted US-FNA at FUSCC from December 2012 to November 2015 and followed our criteria were enrolled in this study. We extracted the cytological, pathological, and follow-up US/US-FNA data of patients with subcentimeter nodules. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), false-negative rate (FNR), false-positive rate (FPR), and AUC were calculated to define FNA diagnostic performance in patients. The association of HT with cytological results was analyzed in univariate and multivariate logistic regression analysis. In total, 754 patients with 817 subcentimeter nodules were collected to comprise the FUSCC cohort. Of the 817 nodules, the cytological results were ND/UNS in 80 nodules (9.8%), benign in 74 (9.1%), AUS/FLUS in 80 (9.8%), FN/SFN in 6 (0.7%), suspicious for malignancy (SM) in 222 (27.2%), and malignant in 355 (43.5%). The sensitivity, specificity, PPV, NPV, and AUC of US-FNA for the subcentimeter nodules were 98.8%, 90.5%, 98.8%, 90.5%, and 94.7%, respectively. In comparison with HT-positive subcentimeter nodules, the diagnostic value of US-FNA for HT-negative nodules was significantly higher (HT-positive: AUC = 91.6%, HT-negative: AUC = 95.9%, P = 0.028). The coexistent HT was found to increase the risk of the FNR and indeterminate cytological results. US-FNA demonstrated an effective method for diagnosis of subcentimeter thyroid nodules with a low nondiagnostic rate in our study. The presence of HT in thyroid could be a risk factor for the increased FNR and indeterminate cytological results during US-FNA.
The incidence of PTMC has been increasing in the recent years. This study aimed to investigate the diagnostic value of US-FNA in thyroid nodules ≤1 cm and whether the presence of Hashimoto's thyroiditis (HT) in thyroid could influence the accuracy.
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Protein kinase B: emerging mechanisms of isoform-specific regulation of cellular signaling in cancer.
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Targeted radionuclide therapy for lung cancer with iodine-131-labeled peptide in a nude-mouse model.
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Isatin inhibits SH-SY5Y neuroblastoma cell invasion and metastasis through MAO/HIF-1[alpha]/CXCR4 signaling.
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Baicalin inhibits human osteosarcoma cells invasion, metastasis, and anoikis resistance by suppressing the transforming growth factor-[beta]1-induced epithelial-to-mesenchymal transition.
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A case of pulsating sternal and clavicular metastases of thyrofollicular carcinoma
DESCRIPTION
Bony metastases are not infrequently encountered with follicular carcinoma of thyroid. Rarely, papillary thyroid carcinoma spreads to bones1; however, anterior chest wall (sternal and clavicular) involvement are rare. A 54-year-old man with long-standing (~25 years) multinodular goitre presented with recent-onset rapid enlargement of the sternoclavicular area beneath the goitre. On examination, the swelling was hard, warm and pulsatile and in addition showed engorged anterior chest wall veins (figure 1). He was clinically and biochemically euthyroid. Chest X-ray (figure 2) showed huge thyroid mass with sternal and clavicular erosion confirmed by CT (figure 3). Fine-needle aspiration cytology of the goitre and bony mass confirmed follicular carcinoma. He underwent total thyroidectomy with excision of the sternal and clavicular metastases and reconstruction of the chest wall defect with Marlex mesh. Following surgery, he underwent radioiodine therapy (200 mCi) and the post-therapy scan showed multiple pulmonary macronodular...
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Poncet’s disease: two case reports
One of the rare presentations of active pulmonary or even extrapulmonary tuberculosis is polyarthropathy which is the involvement of multiple large and small joints in the body; a reactive constellation known ...
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Relative effectiveness of adjuvant chemotherapy for invasive lobular compared with invasive ductal carcinoma of the breast
BACKGROUND
Invasive ductal carcinoma (IDC) and invasive lobular carcinoma (ILC) have distinct clinical, pathologic, and genomic characteristics. The objective of the current study was to compare the relative impact of adjuvant chemotherapy on the survival of patients with ILC versus those with IDC.
METHODS
Women with estrogen receptor (ER)-positive, human epidermal growth factor receptor 1 (HER2) -negative, stage I/II IDC and ILC who received endocrine therapy were identified from the 2000 to 2014 California Cancer Registry. Patient, tumor, and treatment characteristics were collected. Ten-year overall survival (OS) was estimated using the Kaplan-Meier method and Cox proportional-hazards modeling.
RESULTS
In total, 32,997 women with IDC and 4638 with ILC were identified. The receipt of chemotherapy significantly decreased during the study for both subtypes. For patients with IDC, the 10-year OS rate was 95% among those who received endocrine therapy alone versus 93% (P < .01) among those who received endocrine therapy plus chemotherapy. For patients with ILC, the 10-year OS rate was 94% among those who received endocrine therapy alone versus 92% (P < .01) among those who received endocrine therapy plus chemotherapy. After adjusting for patient and treatment factors, adjuvant chemotherapy was significantly associated with a decreased 10-year hazard of death for patients with IDC (hazard ratio, 0.83; 95% confidence interval, 0.74-0.92). In contrast, adjuvant chemotherapy was not independently associated with the adjusted 10-year hazard of death for patients with ILC (hazard ratio, 1.14; 95% confidence interval, 0.90-1.46).
CONCLUSIONS
Adjuvant chemotherapy was not associated with improved OS for patients with ER-positive, HER2-negative, stage I/II ILC. Avoidance of ineffective chemotherapy will markedly reduce the adverse effects and economic burden of breast cancer treatment for a large proportion of patients with breast cancer. Cancer 2017. © 2017 American Cancer Society.
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eIF5A-PEAK1 Signaling Regulates YAP1/TAZ Protein Expression and Pancreatic Cancer Cell Growth
In pancreatic ductal adenocarcinoma (PDAC), mutant KRAS stimulates the translation initiation factor eIF5A and upregulates the focal adhesion kinase PEAK1, which transmits integrin and growth factor signals mediated by the tumor microenvironment. Although eIF5A-PEAK1 signaling contributes to multiple aggressive cancer cell phenotypes, the downstream signaling processes that mediate these responses are uncharacterized. Through proteomics and informatic analyses of PEAK1-depleted PDAC cells, we defined protein translation, cytoskeleton organization, and cell-cycle regulatory pathways as major pathways controlled by PEAK1. Biochemical and functional studies revealed that the transcription factors YAP1 and TAZ are key targets of eIF5A-PEAK1 signaling. YAP1/TAZ coimmunoprecipitated with PEAK1. Interfering with eIF5A-PEAK1 signaling in PDAC cells inhibited YAP/TAZ protein expression, decreasing expression of stem cell–associated transcription factors (STF) including Oct4, Nanog, c-Myc, and TEAD, thereby decreasing three-dimensional (3D) tumor sphere growth. Conversely, amplified eIF5A-PEAK1 signaling increased YAP1/TAZ expression, increasing expression of STF and enhancing 3D tumor sphere growth. Informatic interrogation of mRNA sequence databases revealed upregulation of the eIF5A-PEAK1-YAP1-TEAD signaling module in PDAC patients. Taken together, our findings indicate that eIF5A-PEAK1-YAP signaling contributes to PDAC development by regulating an STF program associated with increased tumorigenicity. Cancer Res; 77(8); 1–11. ©2017 AACR.
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Expression of neuroendocrine factor VGF in lung cancer cells confers resistance to EGFR kinase inhibitors and triggers epithelial-to-mesenchymal transition
Mutations in EGFR drive tumor growth but render tumor cells sensitive to treatment with EGFR tyrosine kinase inhibitors (TKIs). Phenotypic alteration in epithelial-to-mesenchymal transition (EMT) has been linked to the TKI resistance in lung adenocarcinoma. However, the mechanism underlying this resistance remains unclear. Here we report that high expression of a neuroendocrine factor termed VGF induces the transcription factor TWIST1 to facilitate TKI resistance, EMT, and cancer dissemination in a subset of lung adenocarcinoma cells. VGF silencing resensitized EGFR-mutated lung adenocarcinoma cells to TKI. Conversely, overexpression of VGF in sensitive cells conferred resistance to TKIs and induced EMT, increasing migratory and invasive behaviors. Correlation analysis revealed a significant association of VGF expression with advanced tumor grade and poor survival in patients with lung adenocarcinoma. In a mouse xenograft model of lung adenocarcinoma, suppressing VGF expression was sufficient to attenuate tumor growth. Overall, our findings show how VGF can confer TKI resistance and trigger EMT, suggesting its potential utility as a biomarker and therapeutic target in lung adenocarcinoma.
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Drug resistance mechanisms in colorectal cancer dissected with cell type-specific dynamic logic models
Genomic features are used as biomarkers of sensitivity to kinase inhibitors used widely to treat human cancer, but effective patient stratification based on these principles remains limited in impact. Insofar as kinase inhibitors interfere with signaling dynamics, and, in turn, signaling dynamics affects inhibitor responses, we investigated associations in this study between cell-specific dynamic signaling pathways and drug sensitivity. Specifically, we measured 14 phosphoproteins under 43 different perturbed conditions (combinations of 5 stimuli and 7 inhibitors) in 14 colorectal cancer cell lines, building cell line-specific dynamic logic models of underlying signaling networks. Model parameters representing pathway dynamics were used as features to predict sensitivity to a panel of 27 drugs. Specific parameters of signaling dynamics correlated strongly with drug sensitivity for 14 of the drugs, 9 of which had no genomic biomarker. Following one of these associations, we validated a drug combination predicted to overcome resistance to MEK inhibitors by co-blockade of GSK3, which was not found based on associations with genomic data. These results suggest that, in order to better understand cancer resistance and move toward personalized medicine, it is essential to consider signaling network dynamics that can not be inferred from static genotypes.
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SETD1B activates iNOS expression in myeloid-derived suppressor cells
Inducible nitric oxide synthase (iNOS) generates nitric oxide (NO) in myeloid cells that acts as a defense mechanism to suppress invading microorganisms or neoplastic cells. In tumor-bearing mice, elevated iNOS expression is a hallmark of myeloid-derived suppressor cells (MDSC). MDSCs use NO to nitrate both the T cell receptor and STAT1, thus inhibiting T cell activation and the anti-tumor immune response. The molecular mechanisms underlying iNOS expression and regulation in tumor-induced MDSCs are unknown. We report here that deficiency in IRF8 results in diminished iNOS expression in both mature CD11b+Gr1- and immature CD11b+Gr1+ myeloid cells in vivo. Strikingly, although IRF8 was silenced in tumor-induced MDSC, iNOS expression was significantly elevated in tumor-induced MDSC, suggesting that the expression of iNOS is regulated by an IRF8-independent mechanism under pathological conditions. Furthermore, tumor-induced MDSC exhibited diminished STAT1 and NF-κB Rel protein levels, the essential inducers of iNOS in myeloid cells. Instead, tumor-induced MDSC showed increased SETD1B expression as compared to their cellular equivalents in tumor-free mice. Chromatin immunoprecipitation revealed that H3K4me3, the target of SETD1B, was enriched at the nos2 promoter in tumor-induced MDSC, and inhibition or silencing of SETD1B diminished iNOS expression in tumor-induced MDSC. Our results show how tumor cells use the SETD1B-H3K4me3 epigenetic axis to bypass a normal role for IRF8 expression in activating iNOS expression in MDSC, when they are generated under pathological conditions.
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Modulation of Bax and mTOR for cancer therapeutics
A rationale exists for pharmacologic manipulation of the serine (S)184 phosphorylation site of the proapoptotic Bcl2 family member Bax as an anticancer strategy. Here we report the refinement of the Bax agonist SMBA1 to generate CYD-2-11, which has characteristics of a suitable clinical lead compound. CYD-2-11 targeted the structural pocket proximal to S184 in the C-terminal region of Bax, directly activating its proapoptotic activity by inducing a conformational change enabling formation of Bax homooligomers in mitochondrial membranes. In murine models of small cell and non-small cell lung cancers, including patient-derived xenograft and the genetically engineered mutant KRAS-driven lung cancer models, CYD-2-11 suppressed malignant growth without evident significant toxicity to normal tissues. In lung cancer patients treated with mTOR inhibitor RAD001, we observed enhanced S184 Bax phosphorylation in lung cancer cells and tissues which inactivates the propaoptotic function of Bax, contributing to rapalog resistance. Combined treatment of CYD-2-11 and RAD001 in murine lung cancer models displayed strong synergistic activity and overcame rapalog resistance in vitro and in vivo. Taken together, our findings provide preclinical evidence for a pharmacologic combination of Bax activation and mTOR inhibition as a rational strategy to improve lung cancer treatment.
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Androgens are differentially associated with ovarian cancer subtypes in the Ovarian Cancer Cohort Consortium
Invasive epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy. The etiology of EOC remains elusive; however, experimental and epidemiologic data suggest a role for hormone-related exposures in ovarian carcinogenesis and risk factor differences by histologic phenotypes and developmental pathways. Research on pre-diagnosis androgen concentrations and EOC risk has yielded inconclusive results, and analyses incorporating EOC subtypes are sparse. We conducted a pooled analysis of 7 nested case-control studies in the Ovarian Cancer Cohort Consortium to investigate the association between pre-diagnosis circulating androgens (testosterone, free testosterone, androstenedione, dehydroepiandrosterone sulfate (DHEAS)), sex hormone binding globulin (SHBG), and EOC risk by tumor characteristics (i.e. histology, grade, and stage). The final study population included 1,331 EOC cases and 3,017 matched controls. Multivariable conditional logistic regression was used to assess risk associations in pooled individual data. Testosterone was positively associated with EOC risk (all subtypes combined, Odds Ratio (OR)log2=1.12 [95% Confidence Interval (CI) 1.02-1.24]); other endogenous androgens and SHBG were not associated with overall risk. Higher concentrations of testosterone and androstenedione associated with an increased risk in endometrioid and mucinous tumors (e.g., testosterone, endometrioid tumors, ORlog2=1.40 [1.03-1.91]), but not serous or clear cell. An inverse association was observed between androstenedione and high grade serous tumors (ORlog2=0.76 [0.60-0.96]). Our analyses provide further evidence for a role of hormone-related pathways in EOC risk, with differences in associations between androgens and histologic subtypes of EOC.
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Personalized Management of Pancreatic Ductal Adenocarcinoma Patients Through Computational Modeling
Phenotypic diversity in pancreatic ductal adenocarcinoma (PDAC) results in a variety of treatment responses. Rapid autopsy studies have revealed a subgroup of PDAC patients with a lower propensity to develop metastatic disease, challenging the common perception that all patients die of widely metastatic disease, but questions remain about root causes of this difference and the potential impact on treatment strategies. In this study, we addressed these questions through the development of a mathematical model of PDAC progression that incorporates the major alteration status of specific genes with predictive utility. The model successfully reproduced clinical outcomes regarding metastatic patterns and the genetic alteration status of patients from two independent cohorts from the United States and Japan. Using this model, we defined a candidate predictive signature in patients with low metastatic propensity: if a primary tumor contained a small fraction of cells with KRAS and additional alterations to CDKN2A, TP53, or SMAD4 genes, the patient was likely to exhibit low metastatic propensity. By using this predictive signature, we computationally simulated a set of clinical trials to model whether this subgroup would benefit from locally intensive therapies such as surgery or radiation therapy. The largest overall survival benefit resulted from complete resection followed by adjuvant chemoradiation therapy and salvage therapies for isolated recurrence. While requiring prospective validation in a clinical trial, our results suggest a new tool to help personalize care in PDAC patients in seeking the most effective therapeutic modality for each individual.
Major findings
The mathematical model was feasible in analyzing major clinical features in two independent cohorts. A patient is likely to exhibit low metastatic propensity if the primary tumor contains a small fraction of cells (from Cancer via ola Kala on Inoreader http://ift.tt/2oFw9RJ
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HER2-overexpressing breast cancers amplify FGFR signaling upon acquisition of resistance to dual therapeutic blockade of HER2
Purpose: Dual blockade of HER2 with trastuzumab and lapatinib or pertuzumab has been shown to be superior to single-agent trastuzumab. However, a significant fraction of HER2-overexpressing (HER2+) breast cancers escape from these drug combinations. In this study, we sought to discover the mechanisms of acquired resistance to the combination of lapatinib + trastuzumab.<br /><br />Experimental Design: HER2+ BT474 xenografts were treated with lapatinib + trastuzumab long-term until resistance developed. Potential mechanisms of acquired resistance were evaluated in lapatinib + trastuzumab-resistant (LTR) tumors by targeted capture next-generation sequencing. In vitro experiments were performed to corroborate these findings and a novel drug combination was tested against LTR xenografts. Gene expression and copy number analyses were performed to corroborate our findings in clinical samples. <br /><br />Results: LTR tumors exhibited an increase in FGF3/4/19 copy number, together with an increase in FGFR phosphorylation, marked stromal changes in the tumor microenvironment, and reduced tumor uptake of lapatinib. Stimulation of BT474 cells with FGF4 promoted resistance to lapatinib + trastuzumab in vitro. Treatment with FGFR tyrosine kinase inhibitors reversed these changes and overcame resistance to lapatinib + trastuzumab. High expression of FGFR1 correlated with a statistically shorter progression-free survival in patients with HER2+ early breast cancer treated with adjuvant trastuzumab. Finally, FGFR1 and/or FGF3 gene amplification correlated with a lower pathological complete response in patients with HER2+ early breast cancer treated with neoadjuvant anti-HER2 therapy.<br /><br />Conclusions: Amplification of FGFR signaling promotes resistance to HER2 inhibition, which can be diminished by the combination of HER2 and FGFR inhibitors.
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A Phase 2/3 Multicenter, Randomized, Open-Label Study of Lenalidomide vs Investigator's Choice in Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma
Purpose: Randomized, multicenter, open-label, phase 2/3 trial investigating lenalidomide versus investigator's choice (IC) in relapsed/refractory diffuse large B-cell lymphoma (DLBCL). Experimental Design: Patients with DLBCL who received ≥2 prior therapies were stratified by DLBCL subtype (germinal center B-cell [GCB] vs non-GCB; determined by immunohistochemistry [IHC]), then randomized 1:1 to lenalidomide (25 mg/day, 21 days of 28-day cycle) or IC (gemcitabine, rituximab, etoposide, or oxaliplatin). Crossover to lenalidomide was permitted for IC-treated patients with radiologically confirmed progressive disease. The primary endpoint was overall response rate (ORR). Progression-free survival (PFS), overall survival, and subtype analysis (GCB vs activated B-cell [ABC]) using gene expression profiling (GEP) were exploratory endpoints. Results: Stage 1: 102 DLBCL patients (by IHC: non-GCB, n=54; GCB, n=48) received ≥1 dose of lenalidomide or IC. Hematologic treatment-emergent adverse events with lenalidomide versus IC included neutropenia (42.6%; 36.4%), anemia (33.3%; 47.3%), thrombocytopenia (24.1%; 43.6%), and leukopenia (5.6%; 12.7%), respectively. Overall, lenalidomide-treated patients had an ORR of 27.5% versus 11.8% in IC (ORRs were similar regardless of IHC-defined DLBCL subtype). Median PFS was increased in patients receiving lenalidomide (13.6 weeks) versus IC (7.9 weeks; P=0.041), with greater improvements in non-GCB patients (15.1 weeks versus 7.1 weeks, respectively; P=0.021) compared with GCB (10.1 weeks versus 9.0 weeks, respectively; P=0.550). Conclusions: The clinical benefit of lenalidomide monotherapy in DLBCL patients was more evident in the non-GCB subtype. Exploratory analyses suggest this preferential benefit was more pronounced in the GEP-defined ABC population, demonstrating a need for additional studies of lenalidomide in DLBCL using GEP subtyping.
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Discrepancy Between Tumor Antigen Distribution and Radiolabeled Antibody Binding in a Nude Mouse Xenograft Model of Human Melanoma
Cancer Biotherapy & Radiopharmaceuticals , Vol. 0, No. 0.
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Evaluation of augmented pulse pressure variation using the Valsalva manoeuvre as a predictor of fluid responsiveness under open-chest conditions: A prospective observational study
BACKGROUND: Pulse pressure variation (PPV) is a well known dynamic preload indicator of fluid responsiveness. However, its usefulness in open-chest conditions remains controversial. OBJECTIVE: We evaluated whether augmented PPV during a Valsalva manoeuvre can predict fluid responsiveness after sternotomy. DESIGN: A prospective, observational study. SETTING: Single-centre trial, study period from October 2014 to June 2015. PATIENTS: Forty-nine adult patients who underwent off-pump coronary arterial bypass grafting. INTERVENTION: After midline sternotomy, haemodynamic parameters were measured before and after volume expansion (6 ml kg−1 of crystalloids). PPV was calculated both automatically (PPVauto) and manually (PPVmanual). For PPV augmentation, we performed Valsalva manoeuvres with manual holding of the rebreathing bag and constant airway pressure of 30 cmH2O for 10 s before fluid loading and calculated PPV during the Valsalva manoeuvre (PPVVM). MAIN OUTCOME MEASURES: The predictive ability of PPVVM for fluid responsiveness using receiver-operating characteristic curve analysis. Responders were identified when an increase in cardiac index of at least 12% occurred after fluid loading. RESULTS: Twenty-one patients were responders and 28 were nonresponders. PPVVM successfully predicted fluid responsiveness with an area under the curve (AUC) of 0.88 [95% confidence interval (95% CI) 0.75 to 0.95; sensitivity 91%, specificity 79%, P http://ift.tt/2nMptgW
Evaluation of the diagnostic accuracy of nonverbal signs used by medical staff to assess postoperative pain: A prospective study
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Dobutamine aggravates haemodynamic deterioration induced by pleural effusion: A randomised controlled porcine study
BACKGROUND: Pleural effusion is a common finding in critically ill patients and may contribute to circulatory instability and the need for inotropic support. OBJECTIVE: We hypothesised that dobutamine would affect the physiological determinants preload, afterload, contractility and changes of inferior vena cava characteristics during experimental pleural effusion. DESIGN: A randomised, controlled laboratory study. SETTING: Animal laboratory, conducted from March 2013 to May 2013. ANIMALS: Twenty-four Landrace and Yorkshire female piglets (21.3 ± 1.7 kg). INTERVENTION: Twenty piglets were included in the analyses. After inducing bilateral pleural effusion (30 ml kg−1), the piglets were block randomised to either incremental dobutamine infusion (n = 10) or control (n = 10). MAIN OUTCOME MEASURES: Ultrasonographic measures of left ventricular end-diastolic area, left ventricular afterload, left ventricular fractional area change and inferior vena cava diameter and distensibility were used to assess the basic physiological effect of incremental dobutamine administration during experimental pleural effusion. RESULTS: In the dobutamine group, preload, measured as left ventricular end-diastolic area, decreased from 11.3 ± 2.0 cm2 after creation of the pleural effusion to 8.1 ± 1.5 cm2 at a dobutamine infusion rate of 20 μg kg−1 min−1 (P http://ift.tt/2oF4JeS
Significance of new Q waves and their location in postoperative ECGs after elective on-pump cardiac surgery: An observational cohort study
BACKGROUND: The clinical significance of new pathological Q waves after on-pump cardiac surgery is uncertain. OBJECTIVES: To determine whether or not either the occurrence per se or the location of new pathological Q waves after on-pump cardiac surgery is associated with 12-month, all-cause mortality and/or major adverse cardiac events (MACEs). DESIGN: Observational cohort study. SETTING: Single university hospital from January 2007 to October 2010. PATIENTS: Consecutive adult patients undergoing elective on-pump cardiac surgery with MACE-free survival until at least the 7th postoperative day and available ECGs both preoperatively and on the 7th postoperative day (n = 1464). We conducted a subgroup analysis in patients undergoing isolated coronary artery bypass grafting (n = 740). MAIN OUTCOME MEASURE: Our primary endpoint was 12-month, all-cause mortality and/or MACE, defined as acute coronary syndrome, cardiac arrest, congestive heart failure or re-vascularisation at 12 months. Using logistic regression, we examined the prognostic value of new pathological Q waves according to the Minnesota ECG Code, adjusting for the EuroSCORE II, cardiopulmonary bypass time and peak postoperative troponin T concentrations. RESULTS: We included 1464 patients (74% men; mean ± SD age 66 ± 10 years) and observed 103 (7.0%) all-cause deaths and/or MACEs at 12 months. A total of 236 patients (16.1%) had definite or probable new pathological Q waves according to the Minnesota ECG Code. The occurrence of new pathological Q waves per se was not associated with our primary endpoint [adjusted odds ratio, 0.970 (95% confidence interval, 0.540 to 1.648)]. However, the occurrence of a new pathological Q wave in V1 to V5 (anterior) was a strong independent predictor for poor outcome [adjusted odds ratio, 3.461 (95% confidence interval, 1.501 to 7.242)]. CONCLUSION: The current analysis suggests that for patients undergoing elective on-pump cardiac surgery, only new pathological Q waves in V1 to V5 (anterior) in the 7th postoperative day ECG are associated with 12-month, all-cause mortality and/or MACE. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT00468598.http://ift.tt/2nZrveH
Aprotinin vs. tranexamic acid in isolated coronary artery bypass surgery: A multicentre observational study
BACKGROUND: Aprotinin appears to be more efficacious than lysine analogues to reduce bleeding and transfusion of blood products in high-transfusion-risk cardiac surgical patients. However, in isolated coronary artery bypass graft (CABG) surgery, the results from head-to-head trials remain less conclusive. OBJECTIVE: Our objective was to compare the efficacies and safety of aprotinin and tranexamic acid (TXA) in patients undergoing isolated on-pump CABG. DESIGN: A multicentre before-and-after study pooling individual data from published trials and unpublished data from three other databases. SETTING: Four tertiary care teaching hospitals (Haut-Lévêque Hospital in Bordeaux, Pitié-Salpêtrière Hospital and Bichat-Claude Bernard Hospital in Paris, and Laennec Hospital in Nantes). PATIENTS: We included data of 2496 isolated on-pump CABG surgery patients who received either aprotinin between November 2003 and May 2008 (n = 1267) or TXA between November 2007 and November 2013 (n = 1229). MAIN OUTCOME MEASURES: The primary outcome was total blood loss within 24 h after operation. Secondary outcomes were transfusion of blood products, reoperation for bleeding, renal replacement therapy, ICU length of stay and in-hospital mortality. RESULTS: Adjusted mean (SEM) 24-h blood loss after surgery [483 (11) vs. 634 (11) ml, P http://ift.tt/2oF2W9T
Dipyrone (metamizole) markedly interferes with platelet inhibition by aspirin in patients with acute and chronic pain: A case-control study
BACKGROUND: Nonopioid analgesic drugs may interfere with platelet inhibition by aspirin. Recent in vitro and clinical studies in patients with cardiovascular disease have suggested that this pharmacodynamic interaction may also occur with dipyrone, a nonopioid analgesic popular in Europe, Asia and South America. OBJECTIVE: Dipyrone is used extensively in acute and chronic pain. This study was undertaken to provide clinical data, so far missing, on its interactions in this group of patients. DESIGN: A case-control study. SETTING: Primary care in one European university hospital centre. PATIENTS: In total, 27 patients with stable cardiovascular, cerebrovascular or peripheral arterial disease and acute or chronic pain were identified and given dipyrone for at least 5 days in combination with low-dose aspirin. In total, 10 comparable patients on low-dose aspirin alone served as controls. MAIN OUTCOME MEASURES: Platelet-rich plasma was prepared to determine arachidonic acid-induced aggregation (aggregometry) and thromboxane formation (immunoassay). Platelet sensitivity to aspirin was examined in vitro. The presence of dipyrone (metabolites) in plasma was confirmed by HPLC. Additional in vitro measurements examined the aspirin/dipyrone interaction in healthy donors. RESULTS: Inhibition of aggregation was observed in only six of 27 patients receiving aspirin with dipyrone, with absence of complete inhibition by antiplatelet therapy showing in 78% of patients. In contrast, aggregation was completely inhibited in nine of 10 control patients (P http://ift.tt/2nZvqIi
Quantitative pupillometry to assess nociception in a sedated patient with hemispheric cerebral infarction
No abstract availablehttp://ift.tt/2nZu2pj
Intraoperative monitoring of analgesia using nociceptive reflexes correlates with delayed extubation and immediate postoperative pain: A prospective observational study
BACKGROUND: Immediate postoperative pain could be prevented by the administration of long-lasting analgesics before the end of the anaesthesia. However, to prevent over or underdosing of analgesics under anaesthesia, tools are required to estimate the analgesia–nociception balance. OBJECTIVE: We investigated whether the pupillary dilation reflex (PDR) and the nociceptive flexion reflex (NFR) at the end of general anaesthesia correlate with immediate postoperative pain, as a sign of analgesic underdosing, and with delayed tracheal extubation as a sign of analgesic overdosing. DESIGN: Prospective observational study. SETTING: Klinikum im Friedrichshain, Berlin, Germany, from May 2013 to April 2015. PATIENTS: A total of 110 patients scheduled for primary hip arthroplasty under general anaesthesia. OBSERVATIONS: Psychometric and clinical data were obtained preoperatively. The PDR and the NFR were assessed preoperatively and at the end of anaesthesia. Shortly after extubation of the trachea, patients rated their pain intensity. ENDPOINTS: The primary endpoint was the immediate postoperative numeric rating scale pain intensity (0 to 10) and the secondary endpoint was the length of the time interval between reflex measurements and tracheal extubation. RESULTS: PDR correlated significantly with the immediate postoperative pain intensity (Spearman's ρ = −0.28, P http://ift.tt/2nZrMOB
Postoperative administration of metamizole for one single day: A retrospective cohort study
No abstract availablehttp://ift.tt/2nZkLgL
Time course of copeptin during a model of experimental pain and hyperalgesia: A randomised volunteer crossover trial
BACKGROUND: A reliable biomarker for quantifying pain or hyperalgesia has yet to be found. A surrogate marker of arginine vasopressin, copeptin, is elevated in a number of states of physiological and psychological stress and may have a role in quantifying pain and/or hyperalgesia. OBJECTIVES: To evaluate copeptin as a biomarker for pain or hyperalgesia developing after 120 min of sustained electrical stimulation. DESIGN: Secondary analysis of a randomised, double-blinded, crossover trial. SETTING: Single, tertiary university hospital from September 2014 to January 2015. PARTICIPANTS: A total of 16 healthy, opioid-naïve white men with no confounding medication or history of pain. INTERVENTIONS: Copeptin and cortisol were measured five times during an established model of transdermal electrical stimulation designed to assess pain and hyperalgesia. MAIN OUTCOME MEASURES: The primary outcome was the change in copeptin concentration after 120 min of sustained electrical stimulation. Secondary outcomes were copeptin and cortisol concentrations after a subsequent period of rest and analyses of copeptin and cortisol concentrations were made in high-dose and low-dose fentanyl groups separately. RESULTS: Total copeptin concentrations were not significantly elevated after 120 min [9.15 pmol l−1 (interquartile ranges (IQR), 3.45 to 35.45 pmol l−1); P = 0.150] compared with baseline [6.15 pmol l−1 (IQR, 3.60 to 10.62 pmol l−1)]. In the high-dose fentanyl group, there was a significant increase in copeptin within individuals [P = 0.001; median, 37.9 pmol l−1 (IQR, 8.1 to 62 pmol l−1)] after 120 min, and in the low-dose fentanyl group a significant decrease in copeptin concentrations within individuals [P = 0.006; median, 4.7 pmol l−1 (IQR, 3.13 to 9.35 pmol l−1)]. No correlation between copeptin concentration and either the area under the pain curve or area under the hyperalgesia curve could be found, indicating that the observed differences may be due to other fentanyl-mediated effects. CONCLUSION: Copeptin concentrations do not appear to be associated directly with pain and hyperalgesia. Instead, some fentanyl-mediated effect or effects appear to have greatly increased copeptin concentrations from baseline to 120 min. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT02252458.http://ift.tt/2nZkKcH
Using Appearance-Based Messages to Increase Sun Protection in Adolescent Young Adult Cancer Survivors: A Pilot Study of Ultraviolet Light Photography
Journal of Adolescent and Young Adult Oncology , Vol. 0, No. 0.
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Adherence to nutrition-based cancer prevention guidelines and breast, prostate and colorectal cancer risk in the MCC-Spain case-control study
Abstract
Prostate, breast and colorectal cancer are the most common tumours in Spain. The aim of the present study was to evaluate the association between adherence to nutrition-based guidelines for cancer prevention and prostate, breast and colorectal cancer, in the MCC-Spain case-control study. A total of 1718 colorectal, 1343 breast and 864 prostate cancer cases and 3431 population-based controls recruited between 2007 and 2012, were included in the present study. The World Cancer Research Fund/American Institute for Cancer Research (WCRC/AICR) score based on six recommendations for cancer prevention (on body fatness, physical activity, foods and drinks that promote weight gain, plant foods, animal foods and alcoholic drinks; score range 0-6) was constructed. We used unconditional logistic regression analysis adjusting for potential confounders. One-point increment in the WCRF/AICR score was associated with 25% (95% CI 19%; 30%) lower risk of colorectal, and 15% (7%; 22%) lower risk of breast cancer; no association with prostate cancer was detected, except for cases with a Gleason Score ≥ 7 (poorly differentiated/undifferentiated tumours) (OR 0.87, 95% CI 0.76; 0.99). These results add to the wealth of evidence indicating that a great proportion of common cancer cases could be avoided by adopting healthy lifestyle habits. This article is protected by copyright. All rights reserved.
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Spontaneous lung metastasis formation of human Merkel cell carcinoma cell lines transplanted into scid mice
Abstract
Merkel cell carcinoma (MCC) is an aggressive skin cancer entity that frequently leads to rapid death due to its high propensity to metastasize. The etiology of most MCC cases is linked to Merkel cell polyomavirus (MCPyV), a virus which is monoclonally integrated in up to 95% of tumors. While there are presently no animal models to study the role of authentic MCPyV infection on transformation, tumorigenesis or metastasis formation, xenograft mouse models employing engrafted MCC derived cell lines (MCCL) represent a promising approach to study certain aspects of MCC pathogenesis. Here, the two MCPyV positive MCC cell lines WaGa and MKL-1 were subcutaneously engrafted in scid mice. Engraftment of both MCC cell lines resulted in the appearance of circulating tumor cells and metastasis formation, with WaGa-engrafted mice showing a significantly shorter survival time as well as increased numbers of spontaneous lung metastases compared to MKL-1 mice. Interestingly, explanted tumors compared to parental cell lines exhibit an upregulation of MCPyV sT-Antigen expression in all tumors, with WaGa tumors showing significantly higher sT-Antigen expression than MKL-1 tumors. RNA-Seq analysis of explanted tumors and parental cell lines furthermore revealed that in the more aggressive WaGa tumors, genes involved in inflammatory response, growth factor activity and Wnt signaling pathway are significantly upregulated, suggesting that sT-Antigen is the driver of the observed differences in metastasis formation. This article is protected by copyright. All rights reserved.
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Metformin Use and Survival after Non-Small Cell Lung Cancer: A Cohort Study in the U.S. Military Health System
Abstract
Research suggests that metformin may be associated with improved survival in cancer patients with type II diabetes. This study assessed whether metformin use after non-small cell lung cancer (NSCLC) diagnosis is associated with overall survival among type II diabetic patients with NSCLC in the U.S. military health system (MHS). The study included 636 diabetic patients with histologically confirmed NSCLC diagnosed between 2002 and 2007, identified from the linked database from the Department of Defense's Central Cancer Registry (CCR) and the Military Health System Data Repository (MDR). Time-dependent multivariate Cox proportional hazards models were used to assess the association between metformin use and overall survival during follow up. Among the 636 patients, 411 died during the follow up. The median follow up time was 14.6 months. Increased post-diagnosis cumulative use (per one-year of use) conferred a significant reduction in mortality (adjusted hazard ratio (HR)=0.76; 95% CI=0.65 to 0.88). Further analysis by duration of use revealed that compared to non-users, the lowest risk reduction occurred among patients with the longest duration of use (i.e. use for more than 2 years) (HR=0.19; 95% CI=0.09 to 0.40). Finally, the reduced mortality was particularly observed only among patients who also used metformin before lung cancer diagnosis and among patients at early stage of diagnosis. Prolonged duration of metformin use in the study population was associated with improved survival, especially among early stage patients. Future research with a larger number of patients is warranted. This article is protected by copyright. All rights reserved.
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Clinicopathological analysis of methotrexate-associated lymphoproliferative disorders: comparison of diffuse large B-cell lymphoma and classical Hodgkin lymphoma types
Abstract
Patients with rheumatoid arthritis often develop methotrexate-associated lymphoproliferative disorders (MTX-LPD) during MTX treatment. MTX-LPD occasionally regresses spontaneously after simply discontinuing MTX treatment. In patients without spontaneous regression, additional chemotherapy is required to avoid disease progression. However, the differences between spontaneous and non-spontaneous regression have yet to be elucidated.
To clarify the factors important for spontaneous regression, we analyzed the clinicopathological features of 51 patients with rheumatoid arthritis who developed MTX-LPD (diffuse large B-cell lymphoma [DLBCL]-type [n = 34] and classical Hodgkin lymphoma [CHL]-type [n = 17]). We examined the interval from MTX discontinuation to the administration of additional chemotherapy. The majority of DLBCL-type MTX-LPD patients (81%) exhibited remission with MTX discontinuation alone. In contrast, the majority of CHL-type MTX-LPD patients (76%) required additional chemotherapy. This difference was statistically significant (p = 0.001). However, overall survival was not significantly different between DLBCL-type and CHL-type (91% vs. 94%, respectively; p > 0.05). Thus, the morphological differences in the pathological findings of MTX-LPD may be a factor for spontaneous or non-spontaneous regression after discontinuation of MTX.
This article is protected by copyright. All rights reserved.
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Optimal timing for telescoping endotracheal tube into an introducer during nasotracheal intubation
Epistaxis or postpharyngeal injury is the most common complication during nasotracheal intubation. Prior thermosoftening of the endotracheal tube [1] and using a red rubber catheter as an introducer [2] were suggested to prevent these complications. When both maneuvers were simultaneously implemented [3], the timing of attaching the red rubber catheter to the endotracheal tube is also crucial to the effectiveness of the injury prevention. If the red rubber catheter telescoped to the endotracheal tube in the beginning of anesthesia induction, even though after warmed water immersion, the tube thermosoftening effect would rapidly disappear after the process of the red rubber catheter manipulation in the cold operating room.
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Intake of meat and fish and risk of head–neck cancer subtypes in the Netherlands Cohort Study
Abstract
Purpose
To date, the role of meat and fish intake in head–neck cancer (HNC) etiology is not well understood and prospective evidence is limited. This prompted us to study the association between meat, fish, and HNC subtypes, i.e., oral cavity cancer (OCC), oro- and hypopharyngeal cancer (OHPC), and laryngeal cancer (LC), within the Netherlands Cohort Study (NLCS).
Methods
In 1986, 120,852 participants (aged 55–69 years) completed a baseline 150-item food frequency questionnaire (FFQ), from which daily meat and fish intake were calculated. After 20.3 years of follow-up, 430 HNC overall (134 OCC, 90 OHPC and 203 LC) cases and 4,111 subcohort members were found to be eligible for case–cohort analysis. Multivariate hazard ratios were calculated using Cox's proportional hazards model within quartiles of energy-adjusted meat and fish intake.
Results
Processed meat intake, but not red meat intake, was positively associated with HNC overall [HR(Q4 vs. Q1) = 1.46, 95% CI 1.06–2.00; ptrend = 0.03]. Among HNC subtypes, processed meat was positively associated with OCC, while no associations were found with OHPC and LC. Fish intake was not associated with HNC risk. Tests for interaction did not reveal statistically significant interaction between meat, fish, and alcohol or smoking on HNC overall risk.
Conclusions
In this large cohort study, processed meat intake was positively associated with HNC overall and HNC subtype OCC, but not with OHPC and LC.
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The 150 most important questions in cancer research and clinical oncology series: questions 15–24
Abstract
To accelerate our endeavors to overcome cancer, Chinese Journal of Cancer has launched a program of publishing 150 most important questions in cancer research and clinical oncology. In this article, 10 more questions are presented as follows. Question 15: Can tumor-induced erythrogenesis provide qualified red blood cells for carrying oxygen to distant organs? Question 16: Can we overcome tumor resistance to platinum-containing antineoplastic drugs by activating the sensitivity factors in the tumor? Question 17: How can a cancer cell stay dormant for years? Question 18: Why do cancer cells use distinct transcriptomic and proteomic programs to reach the same metastatic phenotype? Question 19: Why do some cancers regress spontaneously? Question 20: What are the regulatory mechanisms occurring in donor cells that determine selective sorting of biological content into vesicles and their biological consequences in recipient cells? Are the genetic transfer and exchange of biological messages between cells transient? Is the phenotypic manipulation of recipient cells temporary or prolonged and persistent? If extracellular vesicles possess immune-modulatory potential, how could they be exploited for immune interventions and cancer immunotherapy? Presumably the cargo of extracellular vesicles reflects the cells of their origin and can be used for cancer diagnosis, how could the uniform/stringent capture criteria be met universally for applying EVs in point-of-care diagnostics for cancer patients? Question 21: Can we use self-sampling technologies to monitor the tumor genetic alterations for more precise targeted therapy? Can we cure a heterogeneous tumor by sequentially targeting the driver molecules? Question 22: Can we postpone the onset of non-infection-related cancers? Question 23: How many types of cells can jointly form the tumor vasculature to provide blood supply for tumor progression? Question 24: How tumor cells transmit their epigenetic features to daughter cells and maintain the malignant phenotype?
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Biomarkers to predict prognosis and response to checkpoint inhibitors
Abstract
Nivolumab is a fully human immunoglobulin (Ig) G4 antibody that selectively inhibits the programmed death 1 (PD-1) immune checkpoint molecule, and has recently been launched for the treatment of renal cell cancer (RCC) in Japan. Based on its promising anti-tumor efficacy and manageable safety profile demonstrated in the phase III Checkmate 025 trial, nivolumab therapy is rapidly being introduced in metastatic RCC clinical practice. The phase Ia study of atezolizumab, which is a humanized anti-PD-ligand 1 (PD-L1) monoclonal IgG1 antibody, also demonstrated excellent treatment results. The identification of biomarkers to predict the response and side-effects of checkpoint inhibitor therapy is thus urgently needed. In this review, we introduce the current candidate biomarkers of immune checkpoint inhibitor therapy. Based on the mechanism of efficacy, the number of neoantigens and expression of major histocompatibility complex molecules are strong candidate biomarkers. Despite the various interference factors, PD-L1 expression can be considered a potential biomarker. In terms of clinical factors, serum clinical factors and severity of adverse events are examined. Although further implementation in prospective studies is necessary, if validated, these biomarkers can be utilized to measure therapeutic response and design treatment strategies for metastatic RCC.
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Response to the treatment immediately before nivolumab monotherapy may predict clinical response to nivolumab in patients with non-small cell lung cancer
Abstract
Background
Currently, no markers predictive of response to nivolumab monotherapy in patients with advanced non-small cell lung cancer (NSCLC) are currently recognized in Japan. The present study was undertaken to identify such markers.
Materials and methods
Medical records of 50 patients with advanced NSCLC and treated with nivolumab monotherapy at Shizuoka Cancer Center between December 2015 and April 2016 were retrospectively reviewed. The parameters studied were age, sex, Eastern Cooperative Oncology Group performance status, smoking history, histological diagnosis, epidermal growth factor receptor or anaplastic lymphoma kinase status, therapeutic line of nivolumab, efficacy of treatment immediately before nivolumab monotherapy, and time since previous therapy.
Results
The objective response rate to nivolumab monotherapy was 18% [95% confidence interval (CI) 10–31]. Multivariate logistic regression identified "squamous histology" [odds ratio (OR) 0.00054; 95% CI 0–0.27] and "response to the treatment immediately before nivolumab monotherapy" (OR 0.0011; 95% CI 0–0.092) as independently associated with response to nivolumab monotherapy.
Conclusion
"Response to the treatment immediately before nivolumab monotherapy" might be a predictive marker of response to nivolumab in patients with advanced NSCLC.
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Predictors of chest wall toxicity after stereotactic ablative radiotherapy using real-time tumor tracking for lung tumors
Abstract
Background
To evaluate the incidence of chest wall toxicity after lung stereotactic ablative radiotherapy (SABR) and identify risk factors for the development of rib fracture.
Methods
Thirty-nine patients with 49 lesions underwent SABR for primary or metastatic lung tumors using Cyberknife® with tumor tracking systems. Patient characteristics, treatment factors and variables obtained from dose-volume histograms (DVHs) were analyzed to find the association with chest wall toxicity. Four-dimensional (4D) dose calculations were done to investigate the effect of respiratory motion on dose to the ribs.
Results
After follow-up of median 26.7 months (range: 8.4 – 80.0), 8 patients (20.5%) experienced rib fractures and among these patients, three (37.5%) had chest wall pain at 2–3 months after SABR. Median time to rib fracture was 13.4 months (range: 8.0 – 38.5) and the 2-year actuarial risk of rib fracture was 12.2%. Dose to the 4.6 cc of the ribs (D4.6cc) and rib volume received 160 Gy or more (V160) were significant predictor for rib fracture. No significant differences between three-dimensional (3D) and 4D dose calculations were found.
Conclusions
Parameters from DVH are useful in predicting the risk of chest wall toxicity after SABR for lung tumors. Efforts should be made to reduce the risk of the rib fracture after lung SABR.
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Ramelteon, a selective MT1/MT2 receptor agonist, suppresses the proliferation and invasiveness of endometrial cancer cells
Abstract
The incidence of endometrial cancer is increasing, making it the fifth most common cancer worldwide. To date, however, there is no standard therapy for patients with recurrent endometrial cancer. Melatonin, a hormone secreted by the pineal gland, has been shown to have anti-tumor effects in various tumor types. Although melatonin is available as a supplement, it has not been approved for cancer treatment. Ramelteon, a selective melatonin receptor type 1 and 2 (MT1/MT2) receptor agonist, has been approved to treat sleep disorders, suggesting that ramelteon may be effective in the treatment of endometrial cancer. To determine whether this agent may be effective in the treatment of endometrial cancer, this study investigated the ability of ramelteon to suppress the proliferation and invasiveness of HHUA cells, an estrogen receptor-positive endometrial cancer cell line. Ramelteon at 10−8 M maximally suppressed the proliferation of HHUA cells, reducing the percentage of Ki-67 positive proliferating cells. This effect was completely blocked by luzindole, a MT1/MT2 receptor antagonist. Furthermore, ramelteon inhibited HHUA cell invasion and reduced the expression of the MMP-2 and MMP-9 genes. These results suggested that ramelteon may be a candidate for the treatment of recurrent endometrial cancer, with activity similar to that of melatonin.
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Serum global metabolomics profiling reveals profound metabolic impairments in patients with MPS IIIA and MPS IIIB
Abstract
The monogenic defects in specific lysosomal enzymes in mucopolysaccharidosis (MPS) III lead to lysosomal storage of glycosaminoglycans and complex CNS and somatic pathology, for which the detailed mechanisms remain unclear. In this study, serum samples from patients with MPS IIIA (age 2-9 yr) and MPS IIIB (2-13 yr) and healthy controls (age 2-9 yr) were assayed by global metabolomics profiling of 658 metabolites using mass spectrometry. Significant alterations were detected in 423 metabolites in all MPS III patients, of which 366 (86.5%) decreased and 57 (13.5%) increased. Similar profiles were observed when analyzing data from MPS IIIA and MPS IIIB samples separately, with only limited age variations in 36 metabolites. The observed metabolic disturbances in MPS III patients involve virtually all major pathways of amino acid (101/150), peptide (17/21), carbohydrate (19/23), lipid (221/325), nucleotide (15/25), energy (8/9), vitamins and co-factors (8/21), and xenobiotics (34/84) metabolism. Notably, detected serum metabolite decreases involved all key amino acids, all major neurotransmitter pathways, and broad neuroprotective compounds. The elevated metabolites are predominantly lipid derivatives, and also include cysteine metabolites and a fibrinogen peptide fragment, consistent with the status of oxidative stress and inflammation in MPS III. This study demonstrates that the lysosomal glycosaminoglycans storage triggers profound metabolic disturbances in patients with MPS III disorders, leading to severe functional depression of virtually all metabolic pathways, which emerge early during the disease progression. Serum global metabolomics profiling may provide an important and minimally invasive tool for better understanding the disease mechanisms and identification of potential biomarkers for MPS III.
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Long-Acting Injectable Antipsychotics in Schizophrenia: Literature Review and Practical Perspective, with a Focus on Aripiprazole Once-Monthly
Abstract
Introduction
Prevention of relapse is a major challenge in schizophrenia, a disease characterized by poor adherence to antipsychotic medication leading to multiple rehospitalizations and a substantial burden-of-care.
Methods
We narratively review published clinical data from the development of long-acting injectable (LAI) formulations of antipsychotic drugs and examine the comparative effectiveness of oral versus LAIs in schizophrenia, with a focus on the second-generation LAI antipsychotic aripiprazole. Evidence is presented from studies with naturalistic/pragmatic as well as explanatory trial designs, supported by the clinical experience of the authors.
Results
LAI formulations of antipsychotic drugs offer advantages over oral medications and there is good evidence for their use as a first-choice treatment and in younger patients. Key phase III studies have shown aripiprazole once-monthly 400 mg (AOM 400) to be effective and well tolerated, with high rates of adherence and low rates of impending relapse. In a recent randomized trial with a "naturalistic" study design more representative of routine clinical practice, AOM 400 was well tolerated and had significantly greater effectiveness than paliperidone LAI overall and in younger patients aged ≤35 years.
Conclusion
Results across the "full spectrum" of efficacy in traditional clinical trials as well as those encompassing the concept of effectiveness in a more naturalistic setting of real-life clinical practice support the use of AOM 400 as a valid long-term treatment option in schizophrenia overall, as well as earlier in the treatment course, and not solely in situations of poor adherence or when oral antipsychotics have failed.
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CCR5 in recruitment and activation of myeloid-derived suppressor cells in melanoma
Abstract
Malignant melanoma is characterized by the development of chronic inflammation in the tumor microenvironment, leading to the accumulation of myeloid-derived suppressor cells (MDSCs). Using ret transgenic mouse melanoma model, we found a significant migration of MDSCs expressing C-C chemokine receptor (CCR)5 into primary tumors and metastatic lymph nodes, which was correlated with tumor progression. An increased CCR5 expression on MDSCs was associated with elevated concentrations of CCR5 ligands in melanoma microenvironment. In vitro experiments showed that the upregulation of CCR5 expression on CD11b+Gr1+ immature myeloid cells was induced by CCR5 ligands, IL-6, GM-CSF, and other inflammatory factors. Furthermore, CCR5+ MDSCs infiltrating melanoma lesions displayed a stronger immunosuppressive pattern than their CCR5− counterparts. Targeting CCR5/CCR5 ligand signaling via a fusion protein mCCR5-Ig, which selectively binds and neutralizes all three CCR5 ligands, increased the survival of tumor-bearing mice. This was associated with a reduced migration and immunosuppressive potential of tumor MDSCs. In melanoma patients, circulating CCR5+ MDSCs were increased as compared to healthy donors. Like in melanoma-bearing mice, we observed an enrichment of these cells and CCR5 ligands in tumors as compared to the peripheral blood. Our findings define a critical role for CCR5 not only in the recruitment but also in the activation of MDSCs in tumor lesions, suggesting that novel strategies of melanoma treatment could be based on blocking CCR5/CCR5 ligand interactions.
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Determinants of Cancer Screening Disparities Among Asian Americans: A Systematic Review of Public Health Surveys
Abstract
We conducted a systematic analysis of 24 peer-reviewed literary works that examined Asian Americans' breast, cervical, and colon cancer screening, focusing on empirical findings from large-scale public health surveys (i.e., NHIS, CHIS, HINTS, BRFSS). We provide an overview of relevant research in terms of study characteristics, samples, predictor/covariate of cancer screenings, and key findings. Our analysis indicates that Asian Americans' cancer screening rates are lower than for non-Hispanic Whites for all cancer types in four large-scale public health surveys throughout 17 study years. Acculturation and healthcare access were two significant factors in explaining Asian Americans' cancer screening rates. Cancer fatalism and family cancer history emerged as potential factors that may account for more variances. However, the screening disparities between Asian Americans and whites persist even after adjusting all covariates, including SES, acculturation, healthcare access, health status, and health perception/literacy. More individual and cultural factors should be identified to address these disparities.
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Treatment of Philadelphia Chromosome-Positive Acute Lymphocytic Leukemia
Opinion statement
Over the past 15 years, the landscape of Ph+ ALL has changed dramatically. No longer the most dreaded form of acute leukemia, the advent of tyrosine kinase inhibitors (TKIs) has ushered in a new era, as TKIs have become the backbone of any treatment regimen for Ph+ ALL. A greater number achieve a complete remission allowing for more patients to get the transplant, although probably less patients need a transplant. For the first time in decades, there is hope for older patients with Ph+ ALL. Defining residual disease at an increasingly lower level of disease burdens termed minimal residual disease (MRD) has allowed treatment algorithms to be designed based on deep molecular responses. The aggregate of recent data suggest that this is the most important endpoint to predict for long-term outcome and to decide on the optimal post-remission approach, including transplant. Novel agents, such as blinatumumab, are likely to be incorporated into therapy for relapse and as initial therapy in an attempt to increase the number of patients who may have deep molecular responses. Many more patients with Ph+ ALL are long-term survivors, and the future is looking brighter for this group of patients.
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Treatment of Philadelphia Chromosome-Positive Acute Lymphocytic Leukemia
Opinion statement
Over the past 15 years, the landscape of Ph+ ALL has changed dramatically. No longer the most dreaded form of acute leukemia, the advent of tyrosine kinase inhibitors (TKIs) has ushered in a new era, as TKIs have become the backbone of any treatment regimen for Ph+ ALL. A greater number achieve a complete remission allowing for more patients to get the transplant, although probably less patients need a transplant. For the first time in decades, there is hope for older patients with Ph+ ALL. Defining residual disease at an increasingly lower level of disease burdens termed minimal residual disease (MRD) has allowed treatment algorithms to be designed based on deep molecular responses. The aggregate of recent data suggest that this is the most important endpoint to predict for long-term outcome and to decide on the optimal post-remission approach, including transplant. Novel agents, such as blinatumumab, are likely to be incorporated into therapy for relapse and as initial therapy in an attempt to increase the number of patients who may have deep molecular responses. Many more patients with Ph+ ALL are long-term survivors, and the future is looking brighter for this group of patients.
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Impact of esophageal flexion level on the surgical outcome in patients with sigmoid esophageal achalasia
Abstract
Purpose
Esophageal achalasia can be roughly divided into non-sigmoid and sigmoid types. Laparoscopic surgery has been reported to be less than optimally effective for sigmoid type. The aim of this study was to examine the impact of the esophageal flexion level on the clinical condition and surgical outcomes of patients with sigmoid esophageal achalasia.
Methods
The subjects were 36 patients with sigmoid esophageal achalasia who had been observed for >1 year after surgery. The subjects were divided into sigmoid type (Sg) and advanced sigmoid type (aSg) groups based on the flexion level of the lower esophagus to compare their clinical parameters and surgical outcomes.
Results
The Sg and aSg groups included 26 (72%) and 10 subjects, respectively. There were no marked differences in the clinical parameters or surgical outcomes between the two groups. However, the clearance rate calculated using the timed barium esophagogram was lower in the aSg group than in the Sg group. No differences were found in the postoperative symptom scores between the two groups, and both reported a high level of satisfaction.
Conclusions
Although laparoscopic surgery for symptoms of sigmoid esophageal achalasia was highly successful regardless of the flexion level, the improvement in esophageal clearance was lower when the flexion level was higher.
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The impact of the omission or inadequate dosing of radiotherapy in extranodal natural killer T-cell lymphoma, nasal type, in the United States
BACKGROUND
Extranodal natural killer T-cell lymphoma, nasal-type (NKTCL), is a rare malignancy in Western populations and is thus challenging for standardization of care and a prospective study. This study was aimed at defining patterns of care for NKTCL in the context of radiotherapy (RT) use and dose selection in the United States.
METHODS
Six hundred forty-two stage I-II NKTCL patients from 1998 to 2012 were identified from the National Cancer Data Base. Binary logistic regression analyses were performed to identify sociodemographic, treatment, and tumor characteristics predictive of the treatment selection and RT dose. Overall survival (OS) analyses were completed with the Kaplan-Meier and Cox multivariate methods, including a propensity score adjustment for a potential indication bias.
RESULTS
Of the 642 included NKTCL patients, 70% were at stage I, 79% were white, and 66% were ≤ 60 years old. Fifty-five percent received chemotherapy plus RT, 19% received RT alone, and 27% received chemotherapy alone. The median RT dose was 50 Gy (interquartile range, 43.2-54 Gy), 37% received < 45 Gy, and 43% received < 50 Gy. A multivariate survival analysis showed improved OS in comparison with chemotherapy alone for RT alone at ≥50 Gy (hazard ratio [HR], 0.41; 95% confidence interval [CI], 0.23-0.70; P < .01), for chemotherapy plus RT at <50 Gy (HR, 0.55, 95% CI, 0.36-0.86; P < .01), and for chemotherapy plus RT at ≥50 Gy (HR, 0.41; 95% CI, 0.27-0.63; P < .01).
CONCLUSIONS
Stage I-II NKTCL patients in the United States commonly receive chemotherapy alone or suboptimal-dose RT. The omission of RT or the use of suboptimal RT is negatively associated with OS. Efforts to continue improving evidenced-based management are warranted. Cancer 2017. © 2017 American Cancer Society.
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The addition of whole-body magnetic resonance imaging to body computerised tomography alters treatment decisions in patients with metastatic breast cancer
Source:European Journal of Cancer, Volume 77
Author(s): Michael Kosmin, Andreas Makris, Priya V. Joshi, Mei-Lin Ah-See, David Woolf, Anwar R. Padhani
AimAccurate evaluation of distribution of disease and response to systemic anti-cancer therapy (SACT) is important in the optimal management of metastatic breast cancer. Whole-body magnetic resonance imaging (WB-MRI) has increased accuracy over computerised tomography of the chest, abdomen and pelvis (CT-CAP) for detecting liver and bone disease, but its effect on patient management is largely unexplored. This study investigates the effects of using WB-MRI alongside CT-CAP on SACT decisions in standard clinical practice for patients with metastatic breast cancer.MethodsMetastatic breast cancer patients who had undergone WB-MRI within 14 d of CT-CAP were studied. Data on distribution and extent of disease and SACT response assessment from original WB-MRI and CT-CAP reports were compared. Contemporaneous medical records provided data on therapy decisions at each time point.ResultsAnalyses were performed on 210 pairs of WB-MRI and CT-CAP in 101 patients. In 53.3% of episodes, WB-MRI reported additional sites of disease not reported on CT-CAP. Differences in SACT assessment were found in 28.0% of episodes, most commonly due to progressive disease (PD) on WB-MRI being reported as stable disease on CT-CAP (18.9%). Discordant SACT assessments were less common in first-line SACT than in subsequent lines of SACT (15.0% versus 41.6%; p = 0.0102). In 34.7% of episodes when SACT was changed, PD had been reported on WB-MRI only.ConclusionsSACT decisions in routine practice were altered by the use of WB-MRI. Further research is required to investigate whether earlier identification of PD by WB-MRI leads to improved patient outcomes.
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Androgen deprivation therapy and cardiovascular risk: No meaningful difference between GnRH antagonist and agonists—a nationwide population-based cohort study based on 2010–2013 French Health Insurance data
Source:European Journal of Cancer, Volume 77
Author(s): Lucie-Marie Scailteux, Sébastien Vincendeau, Frédéric Balusson, Christophe Leclercq, André Happe, Béranger Le Nautout, Elisabeth Polard, Emmanuel Nowak, Emmanuel Oger
BackgroundObservational studies suggested that androgen deprivation therapy (ADT) is associated with an increased cardiovascular (CV) risk. They all compared ADT-treated cancer patients to non-treated patients or non-cancer subjects. Our aim was to evaluate whether CV risk differs by type of ADT.MethodsThrough nationwide population-based claims reimbursement database linked to hospital discharge database, we identified adult men with prostate cancer who initiated ADT (gonadotrophin releasing hormone [GnRH] agonist or antagonist, antiandrogen [AA], combined androgen blockade [CAB]) or had orchiectomy (OT) between 1st July, 2010, and the 31st December, 2011, and followed them up to 31st December, 2013. The main analysis followed an 'on-treatment' approach that censored all patients at the time of first therapeutic modification; it used Cox regression analysis to estimate hazard ratios (HRs) for hospitalisations for ischaemic events (myocardial infarction or ischaemic stroke, whichever came first), adjusted on age, baseline co-morbidities and taking into account death as a competing risk.ResultsAmong the 35,118 new ADT users, 71% received GnRH agonist (reference group), 12% CAB, 13% AA, 3.6% GnRH antagonist and 0.6% had OT. CAB was associated with an increased risk (adjusted HR [95% confidence interval {CI}], 1.6 [1.3–2.0]) and AA with a decreased risk (adjusted HR [95% CI], 0.6 [0.4–0.9]) of ischaemic events when compared to GnRH agonist. No significant association was found with GnRH antagonist (adjusted HR [95% CI], 1.2 (0.7–2.1)).ConclusionCV risk appeared different across ADT modalities. The probability of a clinically meaningful difference when comparing GnRH antagonists to agonists appears rather low. In a context where better overall and cancer specific survival without worsening quality of life is a challenge for clinicians, a potential heterogeneity in CV morbidity becomes crucial when choosing an ADT.
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Pseudoprogression, radionecrosis, inflammation or true tumor progression? challenges associated with glioblastoma response assessment in an evolving therapeutic landscape
Abstract
The wide variety of treatment options that exist for glioblastoma, including surgery, ionizing radiation, anti-neoplastic chemotherapies, anti-angiogenic therapies, and active or passive immunotherapies, all may alter aspects of vascular permeability within the tumor and/or normal parenchyma. These alterations manifest as changes in the degree of contrast enhancement or T2-weighted signal hyperintensity on standard anatomic MRI scans, posing a potential challenge for accurate radiographic response assessment for identifying anti-tumor effects. The current review highlights the challenges that remain in differentiating true disease progression from changes due to radiation therapy, including pseudoprogression and radionecrosis, as well as immune or inflammatory changes that may occur as either an undesired result of cytotoxic therapy or as a desired consequence of immunotherapies.
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Management of GBM: a problem of local recurrence
Abstract
Forty years ago, adjuvant treatment of patients with GBM using fractionated radiotherapy following surgery was shown to substantially improve survival compared to surgery alone. However, even with the addition of temozolomide to radiotherapy, overall survival is quite limited and local failure remains a fundamental problem, despite multiple attempts to increase dose to the tumor target. This review presents the historical background and clinical rationale leading to the current standard of care consisting of 60 Gy total dose in 2 Gy fractions to the MRI-defined targets in younger, high performance status patients and more hypofractionated regimens in elderly and/or debilitated patients. Particle therapies offer the potential to increase local control while reducing dose and, potentially, long-term neurocognitive toxicity. However, improvements in systemic therapies for GBM will need to be implemented before the full benefits of improved local control can be realized.
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CCR5 in recruitment and activation of myeloid-derived suppressor cells in melanoma
Abstract
Malignant melanoma is characterized by the development of chronic inflammation in the tumor microenvironment, leading to the accumulation of myeloid-derived suppressor cells (MDSCs). Using ret transgenic mouse melanoma model, we found a significant migration of MDSCs expressing C-C chemokine receptor (CCR)5 into primary tumors and metastatic lymph nodes, which was correlated with tumor progression. An increased CCR5 expression on MDSCs was associated with elevated concentrations of CCR5 ligands in melanoma microenvironment. In vitro experiments showed that the upregulation of CCR5 expression on CD11b+Gr1+ immature myeloid cells was induced by CCR5 ligands, IL-6, GM-CSF, and other inflammatory factors. Furthermore, CCR5+ MDSCs infiltrating melanoma lesions displayed a stronger immunosuppressive pattern than their CCR5− counterparts. Targeting CCR5/CCR5 ligand signaling via a fusion protein mCCR5-Ig, which selectively binds and neutralizes all three CCR5 ligands, increased the survival of tumor-bearing mice. This was associated with a reduced migration and immunosuppressive potential of tumor MDSCs. In melanoma patients, circulating CCR5+ MDSCs were increased as compared to healthy donors. Like in melanoma-bearing mice, we observed an enrichment of these cells and CCR5 ligands in tumors as compared to the peripheral blood. Our findings define a critical role for CCR5 not only in the recruitment but also in the activation of MDSCs in tumor lesions, suggesting that novel strategies of melanoma treatment could be based on blocking CCR5/CCR5 ligand interactions.
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Reproducibility and repeatability of same-day two sequential FDG PET/MR and PET/CT
Abstract
Background
To determine PET/CT and PET/MR reproducibility and PET/MR repeatability of fluorine 18 fluorodeoxyglucose (FDG) uptake measurements in tumors in cancer patients.
Methods
This IRB approved prospective study was performed between October 2015 and February 2016 in consecutive patients who performed same day PET/CT and two sequential PET/MR. Thirty three patients with visible tumors (N = 63) were included. SUV for body weight (SUV) and lean body mass (SUL) were obtained. Volume of interest (VOI) with a threshold of 40% was used and SUV/L's, metabolic tumor volume (MTV) and tumor to liver ratio (T/L) were calculated. Measurements were plotted in a scattered diagram to visually identify correlation, a regression line was drawn and the equation of the line was calculated. Bland-Altman plots expressed as percentages were constructed to assess the agreement between measurements. The maximal clinically acceptable limits range was defined as ±30%.
Results
Lesional SUV's, SUL's and MTV corrected to body weight (BW) and lean body mass (LBM) demonstrated strong positive linear correlation between PET/CT and PET/MR and between two sequential PET/MR. The 95% limits of agreement ranged from -27.7 to 17.5 with a mean of -5.1 and -27.6 to 17.9 with a mean of -4.9 for SUVpeak and SULpeak, respectively for sequential PET/MR. Other PET metrics demonstrated limits range that is above ±30% between PET/CT and PET/MR and between two sequential PET/MR.
Conclusion
PET/MR SUV/L peak has a clinically acceptable repeatability performance and can be used to evaluate the response to treatment.
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CCR5 in recruitment and activation of myeloid-derived suppressor cells in melanoma
Abstract
Malignant melanoma is characterized by the development of chronic inflammation in the tumor microenvironment, leading to the accumulation of myeloid-derived suppressor cells (MDSCs). Using ret transgenic mouse melanoma model, we found a significant migration of MDSCs expressing C-C chemokine receptor (CCR)5 into primary tumors and metastatic lymph nodes, which was correlated with tumor progression. An increased CCR5 expression on MDSCs was associated with elevated concentrations of CCR5 ligands in melanoma microenvironment. In vitro experiments showed that the upregulation of CCR5 expression on CD11b+Gr1+ immature myeloid cells was induced by CCR5 ligands, IL-6, GM-CSF, and other inflammatory factors. Furthermore, CCR5+ MDSCs infiltrating melanoma lesions displayed a stronger immunosuppressive pattern than their CCR5− counterparts. Targeting CCR5/CCR5 ligand signaling via a fusion protein mCCR5-Ig, which selectively binds and neutralizes all three CCR5 ligands, increased the survival of tumor-bearing mice. This was associated with a reduced migration and immunosuppressive potential of tumor MDSCs. In melanoma patients, circulating CCR5+ MDSCs were increased as compared to healthy donors. Like in melanoma-bearing mice, we observed an enrichment of these cells and CCR5 ligands in tumors as compared to the peripheral blood. Our findings define a critical role for CCR5 not only in the recruitment but also in the activation of MDSCs in tumor lesions, suggesting that novel strategies of melanoma treatment could be based on blocking CCR5/CCR5 ligand interactions.
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The 150 most important questions in cancer research and clinical oncology series: questions 15–24
To accelerate our endeavors to overcome cancer, Chinese Journal of Cancer has launched a program of publishing 150 most important questions in cancer research and clinical oncology. In this article, 10 more quest...
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Doublecortin and CaM kinase-like-1 expression in pathological stage I non-small cell lung cancer
Abstract
Purpose
Doublecortin and CaM kinase-like-1 (DCLK1) regulates microtubule polymerization in migrating neurons. Recently, DCLK1 has been reported to act as an intestinal tumor stem cell marker and has been shown to be expressed in cancer cells and in the stroma of breast, colon, pancreatic, and prostate cancers. Here, we studied DCLK1 expression in non-small cell lung cancer (NSCLC) by immunohistochemistry in association with clinicopathological factors and patient prognosis.
Methods
DCLK1 expression was analyzed by immunohistochemical staining of surgical specimens from 232 patients with pathological stage I NSCLC, including 187 adenocarcinomas. Relationships between the expression status of DCLK1 and clinicopathological factors were examined. The impact of DCLK1 expression status and other clinicopathological factors on survival was evaluated by univariate and multivariate analyses.
Results
Thirty-three (14.2%) of 232 patients had DCLK1-positive cancer cells. DCLK1 was also expressed in the tumor stroma in most of the specimens and was significantly associated with DCLK1 expression in cancer cells. DCLK1-positive cancer cells were more common in non-adenocarcinoma tissues (44.4%) than in adenocarcinoma tissues (7.0%). Moreover, positive DCLK1 expression in cancer cells and stromal cells was correlated with a worse prognosis. Histological analyses revealed that the presence of DCLK1-positive cancer cells was an independent risk factor for poor prognosis in adenocarcinoma, but was not significantly associated with prognosis in non-adenocarcinoma.
Conclusions
DCLK1 expression was observed in tumor cells in patients with pathological stage I NSCLC and was correlated with adverse prognosis, especially in patients with adenocarcinoma. DCLK1 may be a potential new therapeutic target.
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Treatment Planning System Calculation Errors Are Present in the Majority of IROC-Houston Phantom Failures
Publication date: Available online 4 April 2017
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): James R. Kerns, Francesco Stingo, David Followill, Rebecca Howell, Adam Melancon, Stephen F. Kry
PurposeThe anthropomorphic phantom program at the Houston branch of the Imaging and Radiation Oncology Core (IROC-Houston) is an end-to-end test that can be used to determine whether an institution can accurately model, calculate, and deliver an intensity-modulated radiation therapy (IMRT) dose distribution. Currently, institutions that do not meet IROC-Houston's criteria have no specific information with which to identify and correct problems. In this work an independent recalculation system is developed that can identify treatment planning system (TPS) calculation errors.MethodsA recalculation system was commissioned and customized using IROC-Houston measurement reference dosimetry data for common linear accelerator classes. Using this system, 259 head and neck phantom irradiations were recalculated. Both the recalculation and the institution's TPS calculation were compared with the delivered dose that was measured. In cases where the recalculation was statistically more accurate by 2% on average or 3% at a single measurement location than was the institution's TPS, the irradiation was flagged as having a "considerable" institutional calculation error. Error rates were also examined according to the linac vendor and delivery technique.ResultsSurprisingly, on average, the reference recalculation system had better accuracy than the institution's TPS. Considerable TPS errors were found in 17% (45) of head and neck irradiations. 68% (13) of irradiations that failed to meet IROC-Houston criteria were found to have calculation errors.ConclusionNearly 1 in 5 institutions were found to have TPS errors in their IMRT calculations, highlighting the need for careful beam modeling and calculation in the TPS. An independent recalculation system can help identify the presence of TPS errors and pass on knowledge to the institution.
Teaser
IROC-Houston recalculated over 250 head and neck phantom irradiations performed between 2012 and 2016 using a customized independent calculation system that was modeled after IROC-Houston linear accelerator measurement reference data. Dose recalculations that were substantially more accurate than the institution's calculations suggested that the institution had treatment planning system calculation errors. Among all recalculations, 17% revealed such errors; among irradiations that failed IROC-Houston criteria, 68% had such errors.from Cancer via ola Kala on Inoreader http://ift.tt/2oDmXxq
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Radiotherapy after high-dose chemotherapy with autologous hematopoietic cell rescue: Quality assessment of Head Start III
Abstract
Background
The use of high-dose chemotherapy with autologous hematopoietic cell rescue (AuHCR) in Head Start III is a potentially curative approach for the management of young children with central nervous system neoplasms. We report the potential influence of quality and timing of radiation therapy on the survival of patients treated on the study.
Procedure
Between 2003 and 2009, 220 children with newly diagnosed central nervous system neoplasms were enrolled on the study. Radiation therapy was indicated following AuHCR for children between 6 and 10 years old or those younger than 6 years with residual tumor preconsolidation. Records were received for 42 patients and reviewed to determine adherence to protocol treatment volume and dose guidelines. Of these patients, seven were irradiated prior to consolidation, and additional four patients who initially avoided radiation therapy after AuHCR were subsequently treated at relapse.
Results
Of the 31 patients who were fully evaluable, 2 refused radiation therapy until recurrence and 4 progressed between recovery from AuHCR and radiation therapy. Of the remaining 25 patients, 8 had violations in their indication, dose, or treatment volume. All violations occurred in patients under 6 years of age. Two patients could have avoided radiation therapy. There were 6 violations in the 23 patients who received radiation therapy for guideline indications.
Conclusion
All protocol violations occurred in patients under 6 years of age and were associated with decreased overall survival as was the time to start radiotherapy of greater than 11 weeks. When indicated, starting radiation therapy soon after neutrophil and platelet recovery may improve the outcome for these high-risk children.
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CCR5 in recruitment and activation of myeloid-derived suppressor cells in melanoma
Abstract
Malignant melanoma is characterized by the development of chronic inflammation in the tumor microenvironment, leading to the accumulation of myeloid-derived suppressor cells (MDSCs). Using ret transgenic mouse melanoma model, we found a significant migration of MDSCs expressing C-C chemokine receptor (CCR)5 into primary tumors and metastatic lymph nodes, which was correlated with tumor progression. An increased CCR5 expression on MDSCs was associated with elevated concentrations of CCR5 ligands in melanoma microenvironment. In vitro experiments showed that the upregulation of CCR5 expression on CD11b+Gr1+ immature myeloid cells was induced by CCR5 ligands, IL-6, GM-CSF, and other inflammatory factors. Furthermore, CCR5+ MDSCs infiltrating melanoma lesions displayed a stronger immunosuppressive pattern than their CCR5− counterparts. Targeting CCR5/CCR5 ligand signaling via a fusion protein mCCR5-Ig, which selectively binds and neutralizes all three CCR5 ligands, increased the survival of tumor-bearing mice. This was associated with a reduced migration and immunosuppressive potential of tumor MDSCs. In melanoma patients, circulating CCR5+ MDSCs were increased as compared to healthy donors. Like in melanoma-bearing mice, we observed an enrichment of these cells and CCR5 ligands in tumors as compared to the peripheral blood. Our findings define a critical role for CCR5 not only in the recruitment but also in the activation of MDSCs in tumor lesions, suggesting that novel strategies of melanoma treatment could be based on blocking CCR5/CCR5 ligand interactions.
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Genome-wide copy number variation pattern analysis and a classification signature for non-small cell lung cancer
Abstract
The accurate classification of non-small cell lung carcinoma (NSCLC) into lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) is essential for both clinical practice and lung cancer research. Although the standard WHO diagnosis of NSCLC on biopsy material is rapid and economic, more than 13% of NSCLC tumors in the USA are not further classified. The purpose of this study was to analyze the genome-wide pattern differences in copy number variations (CNVs) and to develop a CNV signature as an adjunct test for the routine histopathologic classification of NSCLCs. We investigated the genome-wide CNV differences between these two tumor types using three independent patient datasets. Approximately half of the genes examined exhibited significant differences between LUAD and LUSC tumors and the corresponding non-malignant tissues. A new classifier was developed to identify signature genes out of 20,000 genes. Thirty-three genes were identified as a CNV signature of NSCLC. Using only their CNV values, the classification model separated the LUADs from the LUSCs with an accuracy of 0.88 and 0.84, respectively, in the training and validation datasets. The same signature also classified NSCLC tumors from their corresponding non-malignant samples with an accuracy of 0.96 and 0.98, respectively. We also compared the CNV patterns of NSCLC tumors with those of histologically similar tumors arising at other sites, such as the breast, head and neck, and four additional tumors. Of greater importance, the significant differences between these tumors may offer the possibility of identifying the origin of tumors whose origin is unknown. This article is protected by copyright. All rights reserved.
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