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Mouse models of breast cancer with specific molecular subtypes (e.g., ER or HER2 positive) in an immunocompetent or an immunocompromised environment significantly contribute to our understanding of cancer biology, despite some limitations, and they give insight into targeted therapies. However, an ideal triple-negative breast cancer (TNBC) mouse model is lacking. What has been missing in the TNBC mouse model is a sequential progression of the disease in an essential native microenvironment. This notion inspired us to develop a TNBC-model in syngeneic mice using a mammary intraductal (MIND) method. To achieve this goal, Mvt-1and 4T1 TNBC mouse cell lines were injected into the mammary ducts via nipples of FVB/N mice and BALB/c wild-type immunocompetent mice, respectively. We established that the TNBC-MIND model in syngeneic mice could epitomize all breast cancer progression stages and metastasis into the lungs via lymphatic or hematogenous dissemination within four weeks. Collectively, the syngeneic mouse-TNBC-MIND model may serve as a unique platform for further investigation of the underlying mechanisms of TNBC growth and therapies.

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid progenitor cells that are expanded in cancer and act as potent suppressors of the anti-tumor immune response. MDSCs consist of two major subsets, namely monocytic (M-) MDSCs and granulocytic (G-) MDSCs that differ with respect to their phenotype, morphology and mechanisms of suppression. Here, we cultured bone marrow cells with IL-6 and GM-CSF in vitro to generate a population of bone marrow MDSCs (BM-MDSCs) similar to G-MDSCs from tumor-bearing mice in regards to phenotype, morphology and suppressive-function. Through fluorescent labeling of these BM-MDSCs and optical imaging, we could visualize the recruitment and localization of BM-MDSCs in breast tumor-bearing mice in vivo. Furthermore, we were able to demonstrate that BM-MDSCs home to primary and metastatic breast tumors, but have no significant effect on tumor growth or progression. Ex vivo flow cytometry characterization of BM-MDSCs after adoptive transfer demonstrated both organ-and tumor-specific effects on their phenotype and differentiation, demonstrating the importance of the local microenvironment on MDSC fate and function. In this study, we have developed a method to generate, visualize and detect BM-MDSCs in vivo and ex vivo through optical imaging and flow cytometry, in order to understand the organ-specific changes rendered to MDSCs in breast cancer.

Angiogenesis plays an essential role in tumors development. In case of central nervous system tumors, the most important role in this process plays VEGF-A. The purpose of this study was to determine the plasma concentration of this agent in patients treated surgically because of intracranial tumors. The study involved 48 adult patients, both sexes, treated surgically because of a brain tumor. The control group consisted of 50 adult volunteers of both sexes, without cancer diagnosis. Based on the studies, it was found that serum VEGF-A levels before surgery are higher in patients with central nervous system tumors (10.39-150.57 pg/ml, median 41.70 pg/ml) than in non-cancer patients (0.00-130.77 pg/ml, median 22.56 pg/ml). The association between serum VEGF-A level and malignancy and histological type of intracranial tumor has not beed confirmed. The highest average preoperative serum VEGF-A level was found in patients with low grade gliomas, slightly lower (close to each other) in those with high grade gliomas and meningiomas, while the lowest level was characteristic for metastatic tumors. High variation in results was observed in patients with low grade gliomas (52.56 pg/ml)-higher than those reported in patients with high grade gliomas (32.38 pg/ml). In the rest types of tumors the differentiation was similar and oscillated within 23.08-27.50 pg/ml.

Background and Purpose There are no generally accepted criteria for the etiologic classification of intracerebral hemorrhage (ICH). For this reason, we have developed a set of etiologic criteria and have applied them to a large number of patients to determine their utility. Methods The H-ATOMIC classification includes 7 etiologic categories: Hypertension, cerebral Amyloid angiopathy, Tumour, Oral anticoagulants, vascular Malformation, Infrequent causes and Cryptogenic. For each category, the etiology is scored with three degrees of certainty: Possible(3), Probable(2) and Definite(1). Our aim was to perform a basic study consisting of neuroimaging, blood tests, and CT-angio when a numerical score (SICH) suggested an underlying structural abnormality. Combinations of >1 etiologic category for an individual patient were acceptable. The criteria were evaluated in a multicenter and prospective study of consecutive patients with spontaneous ICH. Results Our study included 439 patients (age 70.8 ± 14.5 years; 61.3% were men). A definite etiology was achieved in 176 (40.1% of the patients: Hypertension 28.2%, cerebral Amyloid angiopathy 0.2%, Tumour 0.2%, Oral anticoagulants 2.2%, vascular Malformation 4.5%, Infrequent causes 4.5%). A total of 7 patients (1.6%) were cryptogenic. In the remaining 58.3% of the patients, ICH was attributable to a single (n = 56, 12.7%) or the combination of 2 (n = 200, 45.5%) possible/probable etiologies. The most frequent combinations of etiologies involved possible hypertension with possible CAA (H3A3, n = 38) or with probable CAA (H3A2, n = 29), and probable hypertension with probable OA (H2O2, n = 27). The most frequent category with any degree of certainty was hypertension (H1+2+3 = 80.6%) followed by cerebral amyloid angiopathy (A1+2+3 = 30.9%). Conclusions According to our etiologic criteria, only about 40% patients received a definite diagnosis, while in the remaining patients ICH was attributable to a single possible/probable etiology or to more than one possible/probable etiology. The use of these criteria would likely help in the management of patients with ICH. This work was supported by Ministery of Health-Instituto de Salud Carlos III: RETICS (Redes temáticas de Investigación Cooperativa) INVICTUS RD012/0014 (JM-F, PC-R, AM-D, LP-S, RD-M), FEDER (Fondo Europeo de Desarrollo Regional).

Purpose The purpose of this study was to investigate the clinical feasibility of spectral analyses using dual-layer detector spectral computed tomography (CT) in acute intracerebral haemorrhage (ICH). Material and methods We retrospectively reviewed patients with acute ICH who underwent CT angiography on a dual-layer detector spectral CT scanner. A spectral data analysis was performed to detect contrast enhancement in or adjacent to acute ICH by using spectral image reconstructions including monoenergetic (MonoE), virtual noncontrast (VNC), and iodine overlay fusion images. We also acquired a spectral plot to assess material differentiation within lesions. Results Among the 30 patients, the most common cause of acute ICH was chronic hypertension (18/30, 60%) followed by trauma (5/30, 16.7%), brain tumour (3/30, 10%), Moyamoya disease (2/30, 6.7%), and haemorrhagic diathesis from anticoagulation therapy (2/30, 6.7%). Of 30 patients, 13 showed suboptimal iodine suppression in the subcalvarial spaces on VNC images compared with true noncontrast images. The CT angiographic spot sign within the acute ICH was detected in four patients (4/30, 13.3%). All three tumours were metastatic and included lung cancer (n = 2) and hepatocellular carcinoma (n = 1) which showed conspicuous delineation of an enhancing tumour portion in the spectral analysis. Spectral analyses allowed the discrimination of acute haemorrhage and iodine with enhanced lesion visualization on the MonoE images obtained at lower keVs (less than 70 keV) and spectral plot. Conclusions Even though the image quality of VNC is perceived to be inferior, it is feasible to evaluate acute ICH in clinical settings using dual-layer detector spectral CT. The MonoE images taken at lower keVs were useful for depicting contrast enhancing lesion, and spectral plot might be helpful for material differentiation in patients with acute ICH.

Background The dysregulation of microRNAs (miRNAs) alters expression level of pro-oncogenic or tumor suppressive mRNAs in breast cancer, and in the long run, causes multiple biological abnormalities. Identification of such interactions of miRNA-mRNA requires integrative analysis of miRNA-mRNA expression profile data. However, current approaches have limitations to consider the regulatory relationship between miRNAs and mRNAs and to implicate the relationship with phenotypic abnormality and cancer pathogenesis. Methodology/Findings We modeled causal relationships between genomic expression and clinical data using a Bayesian Network (BN), with the goal of discovering miRNA-mRNA interactions that are associated with cancer pathogenesis. The Multiple Beam Search (MBS) algorithm learned interactions from data and discovered that hsa-miR-21, hsa-miR-10b, hsa-miR-448, and hsa-miR-96 interact with oncogenes, such as, CCND2, ESR1, MET, NOTCH1, TGFBR2 and TGFB1 that promote tumor metastasis, invasion, and cell proliferation. We also calculated Bayesian network posterior probability (BNPP) for the models discovered by the MBS algorithm to validate true models with high likelihood. Conclusion/Significance The MBS algorithm successfully learned miRNA and mRNA expression profile data using a BN, and identified miRNA-mRNA interactions that probabilistically affect breast cancer pathogenesis. The MBS algorithm is a potentially useful tool for identifying interacting gene pairs implicated by the deregulation of expression.

A new ovarian near-diploid cell line, OVDM1, was derived from a highly aneuploid serous ovarian metastatic adenocarcinoma. A metastatic tumor was obtained from a 47-year-old Ashkenazi Jewish patient three years after the first surgery removed the primary tumor, both ovaries, and the remaining reproductive organs. OVDM1 was characterized by cell morphology, genotyping, tumorigenic assay, mycoplasma testing, spectral karyotyping (SKY), and molecular profiling of the whole genome by aCGH and gene expression microarray. Targeted sequencing of a panel of cancer-related genes was also performed. Hierarchical clustering of gene expression data clearly confirmed the ovarian origin of the cell line. OVDM1 has a near-diploid karyotype with a low-level aneuploidy, but samples of the original metastatic tumor were grossly aneuploid. A number of single nucleotide variations (SNVs)/mutations were detected in OVDM1 and the metastatic tumor samples. Some of them were cancer-related according to COSMIC and HGMD databases (no founder mutations in BRCA1 and BRCA2 have been found). A large number of focal copy number alterations (FCNAs) were detected, including homozygous deletions (HDs) targeting WWOX and GATA4. Progression of OVDM1 from early to late passages was accompanied by preservation of the near-diploid status, acquisition of only few additional large chromosomal rearrangements and more than 100 new small FCNAs. Most of newly acquired FCNAs seem to be related to localized but massive DNA fragmentation (chromothripsis-like rearrangements). Newly developed near-diploid OVDM1 cell line offers an opportunity to evaluate tumorigenesis pathways/events in a minor clone of metastatic ovarian adenocarcinoma as well as mechanisms of chromothripsis.

Background The aim of this study was to determine the prevalence of MCPyV in Merkel cell carcinoma (MCC) primaries versus lymph node metastasis and to evaluate possible prognostic factors. Methods Samples of MCC primaries and lymph node metastases were stained immunohistochemically for the MCPyV large T-antigen and expression was compared to patients´ clinical outcome. Results 41 MCC patients were included. 33 (61%) out of 54 specimens were MCPyV-positive in the immunohistochemistry. 15 (47%) out of 32 primary tumors were positive compared to 18 (82%) out of 22 lymph node metastases. Eleven patients with positive polyomavirus expression died from the carcinoma compared to 4 patients without virus expression. Cox regression analysis showed worse disease-free survival in patients with MCPyV compared to virus-negative lymph nodes (p = 0.002). Conclusions To our knowledge this is the first study to describe a negative prognostic effect of the MCPyV expression in lymph node metastasis in MCC patients.

Autophagy is a vital process controlling the lysosomal degradation of cellular organelles and thereby regulating tissue homeostasis in an environment-dependent fashion. Recent studies have unveiled the critical role of tumor cell-derived autophagy in regulating pro-tumor and anti-tumor processes depending on different stages and tumor microenvironments. However, the precise mechanism whereby autophagy regulates tumor progression remains largely unclear. Since myeloid cells contribute to tumor progression and metastasis, we evaluated the role of myeloid cell-specific autophagy in the regulation of tumor progression. We found that the number and size of metastatic lesions were smaller in myeloid cell-specific autophagy-deficient mice. Furthermore, autophagy-mediated regulation of TGF-β in myeloid cells was associated with the induction of epithelial-mesenchymal transition (EMT), which increases the invasive and metastatic potentials of tumor cells. Myeloid-derived autophagy also plays a critical role in impairing antitumor immune responses and promoting the survival and accumulation of M2 macrophages in tumor tissues in a CSF-1 and TGF-β-dependent manner. Taken together, our findings elucidate previously unrecognized mechanisms by which myeloid cells promote tumor progression through autophagy-mediated regulation of malignancy and immune tolerance.

Approximately 9% of cancer-related deaths are caused by colorectal cancer. Liver metastasis is a major factor for the high colorectal cancer mortality rate. However, the molecular mechanism underlying colorectal cancer liver metastasis remains unclear. Using a global and multidimensional integration approach, we studied sequencing data, protein-protein interactions, and regulation of transcription factor and non-coding RNAs in primary tumor samples and liver metastasis samples to unveil the potential bridging molecules and the regulators that functionally link different stages of colorectal cancer liver metastasis. Primary tumor samples and liver metastasis samples had modules with significant overlap and crosstalk from which we identified several bridging genes (e.g. KNG1 and COX5B), transcription factors (e.g. E2F4 and CDX2), microRNAs (e.g. miR-590-3p and miR-203) and lncRNAs (e.g. lincIRX5 and lincFOXF1) that may play an important role in the process of colorectal cancer liver metastasis. This study enhances our understanding of the genetic alterations and transcriptional regulation that drive the metastatic process, but also provides the methodology to guide the studies on other metastatic cancers.

Pancreatic cancer (PC) accumulates multiple genetic mutations, including activating KRAS mutations and inactivating TP53, SMAD4 and CDKN2A mutations, during progression. The combination of mutant KRAS with a single inactivating TP53, SMAD4 or CDKN2A mutation in genetically engineered mouse models (GEMMs) showed that these mutations exert different synergistic effects in PC. However, the effect of the combination of TP53, CDKN2A and KRAS mutations on the trajectory of PC progression is unknown. Here, we report a GEMM that harbors KRAS (KrasG12D), TP53 (Trp53R172H/+), CDKN2A (Ink4flox/+) and Ptf1/p48-Cre (KPIC) mutations. Histopathology showed that KPIC mice developed adenocarcinoma that strongly resembled the pathology of human PC, characterized by rich desmoplastic stroma and low microvascularity. The median survival of KPIC mice was longer than that of LSL-KrasG12D; Ink4flox/flox; Ptf1/p48-Cre mice (KIC) (89 vs 62 days) and shorter than that of KRAS (KrasG12D), TP53 (Trp53R172H/+) and Ptf1/p48-Cre (KPC) mice. Moreover, the neoplastic cells of KPIC mice were epithelial, highly proliferative tumor cells that exhibited ERK and MAPK pathway activation and high glucose uptake. Isolated neoplastic cells from spontaneous KPIC tumors showed all molecular profiles and cellular behaviors of spontaneous KPIC tumors, including epithelial-mesenchymal transition (EMT) under drug stress as well as tumorigenic, metastatic and invasive abilities in immunocompetent mice. Furthermore, orthotopic and metastatic tumors of KPIC cells almost recapitulated the pathology of spontaneous KPIC tumors. These data show that in addition to spontaneous KPIC tumors, KPIC cells are a valuable tool for preclinical studies of locally invasive and metastatic PC.

Tumours of the Central Nervous System (CNS) are an important cause of mortality from cancer. Epidemiological data on neoplams affecting the CNS are scarce in Brazil, especially in the Amazon region. The study aims at describing the histopathological profile of CNS tumours cases at a high-complexity referral cancer center. This study has described a 17-year-series profile of CNS tumours, registered at a high-complexity referral cancer center in Pará state, from January 1997 until July 2014 in the Brazilian Amazon Region. Data was gathered from histopathology reports kept in the hospital's cancer registry and 949 cases of CNS tumours were analyzed. The most common histopathology were neuroepithelial tumours (approx. 40%) and meningioma was the most frequent especific tumor histologic subtype (22.2%). Neuroepithelial tumours were more frequent in patients with ages ranging from less than a year to 19 years, whereas metastatic tumours were prevalent in patients over 40 years of age. It was not found temporal trends during the studied period. The knowledge of these tumours profile is valuable for the understanding of cancer epidemiology in the region, since its prevalence is currently underreported and more awareness on the disease is needed.

Context The molecular subtype of breast tumours plays a major role in cancer prognosis and treatment options. Triple negative tumours (TN) carry the worst prognosis and affects most frequently women of low socioeconomic status (SES). Studies have shown that non-biologic factors, such as the socioeconomic status could have an influence on tumour biology. To this date no study has been done investigating this association in French women. The objective is to study the association between the SES and the molecular tumour subtype of breast cancer patients in the French county of Cote d’Or. This study benefits from the population data from the Cote d’Or breast cancer registry known for its strict quality control policy. Methods Invasive breast cancer cases between 2003 and 2013 were extracted from the Breast cancer registry database in Cote d’Or. A multivariate analysis was conducted using a hierarchical polytomous regression for the multinomial outcomes for the cancer subtype with HR+/HER2 as reference category. Results A total of 4553 cases were included in our study. There was no significant association found between SES and tumour subtype in French women at diagnosis. Women older than 75 years were less likely to have a TN and HR+/HER2+ breast cancer (OR = 0.66; CI95% = [0.46–0.94] and OR = 0.51; CI95% = [0.37–0.70] respectively). Women with TN tumour subtype had significantly less lymph node invasion when compared to HR+/HER2- subtype (OR = 0.71; CI95% = [0.54–0.92]). Conclusion No significant association was found between socioeconomic status and molecular subtype. Further studies are needed to clarify the mechanisms associated with developing each tumour subtype.

Background Metastatic disease is the principal cause of mortality in cancer, yet the underlying mechanisms are not fully understood. Macrophage-cancer cell fusion as a cause of metastasis was proposed more than a century ago by German pathologist Prof. Otto Aichel. Since then this theory has been confirmed in numerous animal studies and recently in a patient with metastatic melanoma. Methods Here we analyzed tumor DNA from a 51-year-old man who, 8 years following an allogeneic BMT from his brother for treatment of chronic myelogenous leukemia (CML), developed a nodular malignant melanoma on the upper back with spread to an axillary sentinal lymph node. We used laser microdissection to isolate FFPE tumor cells free of leucocytes. They were genotyped using forensic short tandem repeat (STR) length-polymorphisms to distinguish donor and patient genomes. Tumor and pre-transplant blood lymphocyte DNAs were analyzed for donor and patient alleles at 15 autosomal STR loci and the sex chromosomes. Results DNA analysis of the primary melanoma and the nodal metastasis exhibit alleles at each STR locus that are consistent with both the patient and donor. The doses vary between these samples indicative of the relative amounts of genomic DNA derived from the patient and donor. Conclusion The evidence supports fusion and hybridization between donor and patient cells as the initiator of metastasis in this patient. That this phenomenon has now been seen in a second case suggests that fusion is likely to play a significant role for melanoma and other solid tumor metastasis, perhaps leading to new avenues of treatment for this most problematic disease.

Ovarian carcinosarcoma (OCS) accounts for high mortality and lacks effective therapeutic methods. So far, we lack reliable biomarkers capable of predicting the risk of aggressive course of the disease. Programmed death ligand-1 (PD-L1) is expressed in various tumors, and antibodies targeting its receptor programmed cell death 1 (PD-1) are emerging cancer therapeutics. This study was designed to evaluate the expression of PD-L1 and intratumoral CD8+ T lymphocytes by immunohistochemistry from 19 OCS patients who underwent primary surgery at Fudan University Shanghai Cancer Center. The correlations between PD-L1 expression and CD8+ T lymphocytes as well as the patients' clinicopathologic characteristics were integrated and statistically analyzed. PD-L1-positive expression was observed in 52.6% of intraepithelial tissues and 47.4% of mesenchymal tissues (p = 0.370). Meanwhile, intraepithelial and mesenchymal CD8+ T lymphocytes were positive in 36.8% and 84.2% of OCS, respectively (p = 0.628). A significantly negative correlation was found between mesenchymal CD8+ T lymphocytes and PD-L1 expression (r = -0.630, p = 0.011). Intraepithelial PD-L1-positive expression was associated only with positive ascitic fluid (p = 0.008). Mesenchymal PD-L1-positive patients had a poorer survival than those with negative expression (p = 0.036). Meanwhile, intraepithelial PD-L1-positive patients had a better survival trend than PD-L1-negative patients, though no statistical significance was found (p = 0.061). There was a better postoperative survival noted in mesenchymal CD8-positive patients (p = 0.024), and allthough a better trend of OS was observed in intraepithelial CD8-positive patients, no statistical significance was found (p = 0.382). Positive tumoral CD8+ T lymphocytes and mesenchymal PD-L1-negative expression seem to be associated with better survival in OCS. It is possible that immunotherapy targeting PD-L1 pathway could be used in OCS.

Objective To evaluate the potency of Gd-EOB-DTPA to support hepatic catheter placement in laser ablation procedures by quantifying time-dependent delineation effects for instrumentation and target tumor within liver parenchyma. Monitoring potential influence on online MR thermometry during the ablation procedure is a secondary aim. Materials and Methods 30 cases of MR-guided laser ablation were performed after i.v. bolus injection of gadoxetic acid (0.025 mmol/Kg Gd-EOB-DTPA; Bayer Healthcare, Berlin, Germany). T1-weighted GRE sequences were used for applicator guidance (FLASH 3D) in the catheter placement phase and for therapy monitoring (FLASH 2D) in the therapy phase. SNR and consecutive CNR values were measured for elements of interest plotted over time both for catheter placement and therapy phase and compared with a non-contrast control group of 19 earlier cases. Statistical analysis was realized using the paired Wilcoxon test. Results Sustainable signal elevation of liver parenchyma in the contrast-enhanced group was sufficient to silhouette both target tumor and applicator against the liver. Differences in time dependent CNR alteration were highly significant between contrast-enhanced and non-contrast interventions for parenchyma and target on the one hand (p = 0.020) and parenchyma and instrument on the other hand (p = 0.002). Effects lasted for the whole procedure (monitoring up to 60 min) and were specific for the contrast-enhanced group. Contrasting maxima were seen after median 30 (applicator) and 38 (tumor) minutes, in the potential core time of a multineedle procedure. Contrast influence on T1 thermometry for real-time monitoring of thermal impact was not significant (p = 0.068–0.715). Conclusion Results strongly support anticipated promotive effects of Gd-EOB-DTPA for MR-guided percutaneous liver interventions by proving and quantifying the delineating effects for therapy-relevant elements in the procedure. Time benefit, cost effectiveness and oncologic outcome of the described beneficiary effects will have to be part of further investigations.

Background Metastasis accounts for the most deaths in patients with hepatocellular carcinoma (HCC). Receptor activator of nuclear factor kappa B ligand (RANKL) is associated with cancer metastasis, while its role in HCC remains largely unknown. Methods Immunohistochemistry was performed to determine the expression of RANK in HCC tissue (n = 398). Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot were used to examine the expression of RANK, E-cadherin, N-cadherin, vimentin, Snail, Slug, Twist and MMPs in HCC cells. Wound healing and Transwell assays were used to evaluate cell migration and invasion ability. Results We found that expression of RANK, the receptor of RANKL, was significantly higher in HCC tumor tissues than in peritumor liver tissues (p

BACKGROUND: For advanced pancreatic cancer, many regimens have been compared with gemcitabine (G) as the standard arm in randomized controlled trials. Few regimens have been directly compared with each other in randomized controlled trials and the relative efficacy and safety among them remains unclear. METHODS: A systematic review was performed through MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and ASCO meeting abstracts up to May 2013 to identify randomized controlled trials that included advanced pancreatic cancer comparing the following regimens: G, G+5-fluorouracil, G+ capecitabine, G+S1, G+ cisplatin, G+ oxaliplatin, G+ erlotinib, G+ nab-paclitaxel, and FOLFIRINOX. Overall survival and progression-free survival with 95% credible regions were extracted using the Parmar method. A Bayesian multiple treatment comparisons was performed to compare all regimens simultaneously. RESULTS: Twenty-two studies were identified and 16 were included in the meta-analysis. Median overall survival, progression free survival, and response rates for G arms from all trials were similar, suggesting no significant clinical heterogeneity. For overall survival, the mixed treatment comparisons found that the probability that FOLFIRINOX was the best regimen was 83%, while it was 11% for G+ nab-paclitaxel and 3% for G+ S1 and G+ erlotinib, respectively. The overall survival hazard ratio for FOLFIRINOX versus G+ nab-paclitaxel was 0.79 [0.50-1.24], with no obvious difference in toxicities. The hazard ratios from direct pairwise comparisons were consistent with the mixed treatment comparisons results. CONCLUSIONS: FOLFIRINOX appeared to be the best regimen for advanced pancreatic cancer probabilistically, with a trend towards improvement in survival when compared with other regimens by indirect comparisons.

Thirty-one patients with spinal tumors underwent reconstructive surgery with our spinal instrumentation system (MPDS and MADS), with or without our new vertebral tumor prosthesis. The characteristics of the spinal tumors were analysed statistically and the treatment outcome was evaluated. There were 4 benign tumors, 6 malignant tumors, and 21 metastatic tumors. The malignant tumors involved the sacrum more frequently than the benign tumors (p=0.0098). Metastatic tumors involved the thoracic spine more frequently than benign or malignant tumors (p=0.0161). The average number of affected vertebrae was 1.2 in the benign tumors, 1.8 in the malignant tumors, and 2.4 in the metastatic tumors. The metastatic tumors had a tendency to involve the anterior or middle part of the spine more frequently than the benign or malignant tumors (statistically not significant). After surgery, neurological improvement was noted in 8 patients, nochange in 19 patients, and impairment due to resection of the nerve roots in sacral tumors in 4 patients.

Introduction: The increasing use of endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) cytology to examine pancreatic neoplasms has led to an increase in the diagnosis of metastases to the pancreas. Renal cell carcinoma (RCC) is the most common metastasis to the pancreas. Our study examines 33 cases of metastatic RCC to the pancreas sampled by EUS-FNA from four large tertiary care hospitals. Materials and Methods: We searched the cytopathology database for RCC metastatic to the pancreas diagnosed by EUS-FNA from January 2005 to January 2015. Patient age, history of RCC, nephrectomy history, follow-up postnephrectomy, radiological impression, and EUS-FNA cytologic diagnosis were reviewed. Results: Thirty-three patients were identified. The average age was 67.5 years (range, 49–84 years). Thirty-two patients had a previous documented history of RCC. One patient had the diagnosis of pancreatic metastasis at the same time of the kidney biopsy. Thirty-one patients had been treated with nephrectomy. Twenty-seven patients were being monitored annually by computed tomography or magnetic resonance imaging. Twenty-five patients had multiple masses by imaging, but 8 patients had a single mass in the pancreas at the time of EUS-FNA. EUS-FNA of 20 cases showed classic morphology of RCC. Thirteen cases had either “atypical” clinical-radiologic features or morphologic overlaps with primary pancreatic neoplasms or other neoplasms. Cell blocks were made on all 13 cases and immunochemical stains confirmed the diagnosis. Conclusions: EUS-FNA cytology is useful for the diagnosis of metastatic RCC to the pancreas. Cytomorphology can be aided with patient history, imaging analyses, cell blocks, and immunochemical stains.

In cancer diseases, the appearance of metastases is a very pejorative forecast. Chemotherapies are systemic treatments which aim at the elimination of the micrometastases produced by a primitive tumour. The efficiency of chemotherapies closely depends on the protocols of administration. Mathematical modeling is an invaluable tool to help in evaluating the best treatment strategy. Iwata et al. [K. Iwata, K. Kawasaki, N. Shigesad, A dynamical model for the growth and size distribution of multiple metastatic tumors, J. Theor. Biol. 203 (2000) 177.] proposed a partial differential equation (PDE) that describes the metastatic evolution of an untreated tumour. In this article, we conducted a thorough mathematical analysis of this model. Particularly, we provide an explicit formula for the growth rate parameter, as well as a numerical resolution of this PDE. By increasing our understanding of the existing model, this work is crucial for further extension and refinement of the model. It settles down the framework necessary for the consideration of drugs administration effects on tumour development.

Cancer is one of the greatest killers in the world, particularly in western countries. A lot of the effort of the medical research is devoted to cancer and mathematical modeling must be considered as an additional tool for the physicians and biologists to understand cancer mechanisms and to determine the adapted treatments. Metastases make all the seriousness of cancer. In 2000, Iwata et al. [9] proposed a model which describes the evolution of an untreated metastatic tumors population. We provide here a mathematical analysis of this model which brings us to the determination of a Malthusian rate characterizing the exponential growth of the population. We provide as well a numerical analysis of the PDE given by the model.

Background. To detect epigenetic changes in head and neck squamous cell carcinoma (HNSCC) and between metastatic and nonmetastatic tumors, we performed a system- atic phosphorylation screening on different protein kinases. Methods. The phosphorylation levels of the serine-threonine kinase Akt, of mitogen-activated protein kinase (MAPK), and of protein kinase C (PKC) beta and epsilon were measured in a series of 94 biopsy specimens, corresponding to 47 HNSCCs and paired controls taken from clinically uninvolved tissue of the same patients. Results. Akt and MAPK were significantly underphosphoryl- ated (two-sided p < .004) in tumors, whereas PKCs showed no differences from control samples. Second, although in control tissue there was a significant correlation between phosphoryla- tion levels of Akt, MAPK, and PKC (all two-sided p < .05), many correlated activations were lost in tumors and even more in lymph node-positive tumors.Finally, p44 MAPK and Akt pThr308 were phosphorylated in a coordinated fashion only in lymph node-positive tumors (two-sided p < .01). Conclusions. This novel evidence documents important changes in the phosphorylation program during cancer pro- gression of HNSCC. A 2005 Wiley Periodicals, Inc. Head Neck 27: 130-137, 2005

Background EGFR mutation detection has been widely applied in the prediction of TKIs therapy in Non-Small Cell Lung Cancer (NSCLC). Metastatic tumors rather than primary tumors were usually assayed for those patients in advanced stages. Although the difference of EGFR mutation status in primary and metastatic tumors has been reported, the quantitative difference (ratio of mutated EGFR among total EGFR) in primary and metastatic tumors as well as in different sites of primary tumors was not clear. Methods Genomic DNA in Formalin Fixed-Paraffin Embedded samples of primary and metastatic tumors of 50 NSCLC patients was extracted. Real-time fluorescent PCR was performed to quantify the EGFR mutation ratios. Results The EGFR mutation ratios detected in different sites of primary tumors were highly concordant, whereas the EGFR mutation ratios in metastatic tumors were lower than those in primary tumors. Conclusions Randomly chosen sample may reliably represent the type and ratio of mutations of EGFR in primary tumors. EGFR mutation ratios in primary tumors and metastatic tumors are different. If metastatic tumors are used for the detection of EGFR mutation, the sensitivity of the detection assay must be considered.

Cancer is a disease involving complex multiple sequential irreversible dysregulated processes showing metastasis that results in morbidity and mortality. Metastasis is a complex biological course that begins with detachment of tumor cells from the primary tumor, spreading into the distant tissues and/or organs, invading through the lymphovascular structures followed by their survival in the circulation. Metastatic tumors to the oro-facial region are uncommon and may occur in the oral soft tissues or jawbones. The clinical presentation of metastatic tumors can be variable, which may lead to erroneous diagnosis or may create diagnostic dilemma. Therefore, they should be considered in the differential diagnosis of inflammatory and reactive lesions that are common to the oral region. Most of the literature on oral metastases involves either single case reports or reviews of these reported cases from scattered geographical areas. Hence this present article is an attempt to provide a detailed review of pathogenesis, epidemiological details including clinical and radiographic presentations, microscopic features and treatment of metastatic tumors to the jaws and oral cavity.

Background Targeting CTLA-4 is a recent strategic approach in cancer control: blocking CTLA-4 enhances an antitumor immunity by promoting T-cell activation and cytotoxic T-lymphocyte proliferation. This induction of a tolerance break against the tumor may be responsible for immune-related adverse events (irAEs). Our objective was to assess the incidence and nature of irAEs in oncologic patients receiving anti-CTLA-4 antibodies (ipilimumab and tremelimumab). Methods A systematic search of literature up to February 2014 was performed in MEDLINE, EMBASE, and Cochrane databases to identify relevant articles. Paired reviewers independently selected articles for inclusion and extracted data. Pooled incidence was calculated using R©, package meta. Results Overall, 81 articles were included in the study, with a total of 1265 patients from 22 clinical trials included in the meta-analysis. Described irAEs consisted of skin lesions (rash, pruritus, and vitiligo), colitis, and less frequently hepatitis, hypophysitis, thyroiditis, and some rare events such as sarcoidosis, uveitis, Guillain-Barré syndrome, immune-mediated cytopenia and polymyalgia rheumatic/Horton. The overall incidence of all-grade irAEs was 72 % (95 % CI, 65–79 %). The overall incidence of high-grade irAEs was 24 % (95 % CI, 18–30 %). The risk of developing irAEs was dependent of dosage, with incidence of all-grade irAEs being evaluated to 61 % (95 % CI, 56–66 %) for ipilimumab 3 mg/kg and 79 % (95 % CI, 69–89 %) for ipilimumab 10 mg/kg. Death due to irAEs occurred in 0.86 % of patients. The median time of onset of irAEs was about 10 weeks (IQR, 6–12) after the onset of treatment, corresponding with the first three cycles but varied according to the organ system involved. Such immune activation could also be indicative for tumor-specific T-cell activation and irAE occurrence was associated with clinical response to CTLA-4 blocking in 60 % of patients. Conclusion The price of potential long-term survival to metastatic tumors is an atypical immune toxicity, reflecting the mechanism of action of anti-CTLA-4 antibodies. A better knowledge of these irAEs and its management in a multidisciplinary approach will help to reduce morbidity and therapy interruptions. Electronic supplementary material The online version of this article (doi:10.1186/s12916-015-0455-8) contains supplementary material, which is available to authorized users.