MEK1/2 and BRAFV600E inhibitors are used to treat BRAFV600E-positive melanoma, with other cancers under evaluation. Genetic perturbation of copper import or pharmacological reduction of copper with the clinical copper chelator TTM inhibits MEK1/2 kinase activity and reduces BRAFV600E-driven tumorigenesis. In this study, we report that TTM inhibited transformed growth of melanoma cell lines resistant to BRAF or MEK1/2 inhibitors and enhanced the antineoplastic activity of these inhibitors. TTM also provided a survival advantage in a genetically engineered mouse model of melanoma, and when accounting for putative overdosing, trended towards an increase in the survival benefit afforded by BRAF inhibition. This effect was phenocopied by genetically inhibiting copper import in tumors, which was linked to a reduction in MAPK signaling. Thus, TTM reduces copper levels and MAPK signaling, thereby inhibiting BRAFV600E-driven melanoma tumor growth. These observations inform and support clinical evaluation of TTM in melanoma.
from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2y674nf
via IFTTT
Εμφάνιση αναρτήσεων με ετικέτα ORL-AlexandrosSfakianakis. Εμφάνιση όλων των αναρτήσεων
Εμφάνιση αναρτήσεων με ετικέτα ORL-AlexandrosSfakianakis. Εμφάνιση όλων των αναρτήσεων
Παρασκευή 6 Οκτωβρίου 2017
Loss of FOXO1 cooperates with TMPRSS2-ERG overexpression to promote prostate tumorigenesis and cell invasion
E26 transformation-specific (ETS) transcription factor ERG is aberrantly overexpressed in approximately 50% of all human PCa due to TMPRSS2-ERG gene rearrangements. However, mice with prostate-specific transgenic expression of PCa-associated ERG alone fail to develop PCa, highlighting that ERG requires other lesions to drive prostate tumorigenesis. Forkhead box (FOXO) transcription factor FOXO1 is a tumor suppressor that is frequently inactivated in human PCa. Here we demonstrate that FOXO1, but not other FOXO proteins (FOXO3 and FOXO4), binds and inhibits the transcriptional activity of PCa-associated ERG independently of FOXO1 transcriptional activity. Knockdown of endogenous FOXO1 increased invasion of TMPRSS2-ERG fusion positive VCaP cells, an effect completely abolished by ERG knockdown. Patient specimen analysis demonstrated that FOXO1 and ERG protein expression inversely correlated in a subset of human PCa. Although human ERG transgene expression or homozygous deletion of Foxo1 alone in the mouse prostate failed to promote tumorigenesis, concomitant ERG transgene expression and Foxo1 deletion resulted in upregulation of ERG target genes, increased cell proliferation and formation of high-grade prostatic intraepithelial neoplasia (HGPIN). Overall, we provide biochemical and genetic evidence that aberrantly activated ERG cooperates with FOXO1 deficiency to promote prostate tumorigenesis and cell invasion. Our findings enhance understanding of PCa etiology and suggest that the FOXO1-ERG signaling axis can be a potential target for treatment of PCa.
from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2z4X6Rh
via IFTTT
from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2z4X6Rh
via IFTTT
Chemotherapeutic dose scheduling based on tumor growth rates provide a case for low-dose metronomic high entropy therapies
We extended the classical tumor regression models such as Skipper's laws and the Norton-Simon hypothesis from instantaneous regression rates to the cumulative effect over repeated cycles of chemotherapy. To achieve this end, we used a stochastic Moran process model of tumor cell kinetics coupled with a prisoner's dilemma game-theoretic cell-cell interaction model to design chemotherapeutic strategies tailored to different tumor growth characteristics. Using the Shannon entropy as a novel tool to quantify the success of dosing strategies, we contrasted maximum tolerated dose (MTD) strategies as compared with low-dose, high-density metronomic strategies (LDM) for tumors with different growth rates. Our results show that LDM strategies outperformed MTD strategies in total tumor cell reduction (TCR). This advantage was magnified for fast growing tumors that thrive on long periods of unhindered growth without chemotherapy drugs present and was not evident after a single cycle of chemotherapy but grew after each subsequent cycle of repeated chemotherapy. The evolutionary growth/regression model introduced in this paper agrees well with murine models. Overall, this model supports the concept of designing different chemotherapeutic schedules for tumors with different growth rates and develops quantitative tools to optimize these schedules for maintaining low volume tumors.
from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2y5ZMjk
via IFTTT
from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2y5ZMjk
via IFTTT
Astrocytes promote medulloblastoma progression through hedgehog secretion
Astrocytes, the most abundant type of glial cells in the brain, play critical roles in supporting neuronal development and brain function. While astrocytes have been frequently detected in brain tumors, including medulloblastoma (MB), their functions in tumorigenesis are not clear. Here we demonstrate that astrocytes are essential components of the MB tumor microenvironment. Tumor-associated astrocytes (TAA) secreted the ligand sonic hedgehog (Shh), which is required for maintaining MB cell proliferation despite the absence of its primary receptor Patched-1 (Ptch1). Shh drove expression of Nestin in MB cells through a Smoothened-dependent, Gli1-independent mechanism. Ablation of TAA dramatically suppressed Nestin expression and blocked tumor growth. These findings demonstrate an indispensable role for astrocytes in MB tumorigenesis and reveal a novel Ptch1-independent Shh pathway involved in MB progression.
from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2z3H7CV
via IFTTT
from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2z3H7CV
via IFTTT
A phase IB dose-escalation study of the safety and pharmacokinetics of pictilisib in combination with either paclitaxel and carboplatin (with or without bevacizumab) or pemetrexed and cisplatin (with or without bevacizumab) in patients with advanced non–small cell lung cancer
Source:European Journal of Cancer, Volume 86
Author(s): Jean-Charles Soria, Alex A. Adjei, Rastilav Bahleda, Benjamin Besse, Charles Ferte, David Planchard, Jing Zhou, Joseph Ware, Kari Morrissey, Geetha Shankar, Wei Lin, Jennifer L. Schutzman, Grace K. Dy, Harry J.M. Groen
AimThe phosphatidylinositol 3-kinase (PI3K) pathway is a potential therapeutic target in non–small cell lung cancer (NSCLC). This study aimed to evaluate the pan-PI3K inhibitor pictilisib in combination with first-line treatment regimens that were the standard of care at the time of study, in patients with NSCLC.Patients and methodsA 3 + 3 dose-escalation study was performed using a starting daily dose of 60 mg pictilisib on days 1–14 of a 21-day cycle. Depending on bevacizumab eligibility and NSCLC histology, patients also received either paclitaxel + carboplatin or pemetrexed + cisplatin, ± bevacizumab every 3 weeks. The primary objectives of the study were to assess safety and tolerability and to identify dose-limiting toxicities (DLTs), the maximum tolerated dose (MTD) and a recommended phase II dose (RP2D), for each combination.ResultsAll 66 treated patients experienced at least one adverse event (AE). Grade ≥III AEs, serious AEs and deaths occurred in 57 (86.4%), 56 (84.8%) and 9 (13.6%) patients, respectively. Three patients reported DLTs across the four arms of the study. The MTD was not reached in any arm and the RP2D of pictilisib was determined to be 330 mg (capsules) or 340 mg (tablets) on a ‘14 days on, 7 days off’ schedule. The best confirmed response was partial response in 29 (43.9%) patients and stable disease in 20 (30.9%) patients.ConclusionCombining pictilisib with various standard-of-care first-line treatment regimens is feasible from a safety perspective in patients with NSCLC, and encouraging preliminary anti-tumour activity was observed.
from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2yvpH5l
via IFTTT
Diarrhoea during checkpoint blockade, not always colitis
Source:European Journal of Cancer
Author(s): Josephine J. Koldenhof, Karijn P.M. Suijkerbuijk
from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2xo8NRd
via IFTTT
Potential role of polymorphisms in the transporter genes ENT1 and MATE1/OCT2 in predicting TAS-102 efficacy and toxicity in patients with refractory metastatic colorectal cancer
Source:European Journal of Cancer, Volume 86
Author(s): Mitsukuni Suenaga, Marta Schirripa, Shu Cao, Wu Zhang, Dongyun Yang, Vincenzo Dadduzio, Lisa Salvatore, Beatrice Borelli, Filippo Pietrantonio, Yan Ning, Satoshi Okazaki, Martin D. Berger, Yuji Miyamoto, Roel Gopez, Afsaneh Barzi, Toshiharu Yamaguchi, Fotios Loupakis, Heinz-Josef Lenz
BackgroundTrifluridine (FTD) is an active cytotoxic component of the metastatic colorectal cancer (mCRC) drug TAS-102, and thymidine phosphorylase inhibitor (TPI) inhibits the rapid degradation of FTD. We tested whether single nucleotide polymorphisms (SNPs) in genes involved in FTD metabolism and TPI excretion could predict outcome in patients with mCRC treated with TAS-102.Patients and methodsWe investigated three different cohorts: a training cohort (n = 52) and a testing cohort (n = 129) both receiving TAS-102 and a control cohort (n = 52) receiving regorafenib. SNPs of TK1, ENT1, CNT1, MATE1, MATE2 and OCT2 were analysed by polymerase chain reaction-based direct DNA sequencing.ResultsIn the training cohort, patients with any ENT1 rs760370 G allele had a significantly longer progression-free survival (PFS; 3.5 versus 2.1 months, respectively, hazard ratio [HR] 0.44, P = 0.004) and overall survival (OS; 8.7 versus 5.3 months, respectively, HR 0.27, P = 0.003) than the A/A genotype. These findings were validated in the testing cohort (P = 0.021 and 0.009 for PFS and OS, respectively). In addition, the combination of ENT1 rs760370, MATE1 rs2289669 and OCT2 rs316019 SNPs significantly stratified patients with the risk of PFS and OS in both cohorts (P < 0.001 for PFS and OS in the training cohort; P = 0.053 and 0.025 for PFS and OS, respectively, in the testing cohort). No significant differences were observed in the control group.ConclusionsThe combination of ENT1, MATE1 and OCT2 SNPs may serve as a predictive and prognostic marker in mCRC patients treated with TAS-102.
from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2yvpv67
via IFTTT
Bridging the gap between the randomised clinical trial world and the real world by combination of population-based registry and electronic health record data: A case study in haemato-oncology
Source:European Journal of Cancer, Volume 86
Author(s): R.E. Kibbelaar, B.E. Oortgiesen, A.M. van der Wal-Oost, K. Boslooper, J.W. Coebergh, N.J.G.M. Veeger, P. Joosten, H. Storm, E.N. van Roon, M. Hoogendoorn
Randomised clinical trials (RCTs) are considered the basis of evidence-based medicine. It is recognised more and more that application of RCT results in daily practice of clinical decision-making is limited because the RCT world does not correspond with the clinical real world. Recent strategies aiming at substitution of RCT databases by improved population-based registries (PBRs) or by improved electronic health record (EHR) systems to provide significant data for clinical science are discussed. A novel approach exemplified by the HemoBase haemato-oncology project is presented. In this approach, a PBR is combined with an advanced EHR, providing high-quality data for observational studies and support of best practice development. This PBR + EHR approach opens a perspective on randomised registry trials.
from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2xojrqZ
via IFTTT
A 3D-printed modular device for imaging the brain of small birds
Source:Journal of Neuroscience Methods
Author(s): Christine R. Lattin, Maxwell A. Emerson, Jean-Dominique Gallezot, Tim Mulnix, J. Elliott Brown, Richard E. Carson
BackgroundOne potential barrier to using in vivo imaging in any new animal species is solving the basic problem of how to hold animals safely and securely during scans.New MethodIn this paper, we describe the design, fabrication, use, and positional reproducibility of a 3D-printed plastic device (the Avian Imaging Device, or AID) for imaging the brain of 1 or 2 small songbirds. We designed two different types of head cones to use with this device: one that was not contoured and designed for anesthesia induction, and one contoured to the shape of a house sparrow head, designed to be used with a pre-anesthetized animal.ResultsCompared to no holder, using the AID with both contoured and non-contoured head cones significantly reduced the amount of translation necessary to align the head in pairs of CT scans (by 78% and 90%, respectively); using the contoured head cone also significantly reduced the amount of rotation necessary for head alignment in registering pairs of scans (by 90%).Comparison with Existing Method(s)Using an animal holder that can not only securely hold animals but which has high positional reproducibility is essential to take advantage of the maximum resolution possible with small animal imaging. 3D-printed materials are also compatible with PET and CT, environmentally stable, and fast and inexpensive to make.ConclusionsResearchers can learn from the design of the AID and use our CAD models as a starting point for fabricating devices for multiple small-animal imaging needs.
from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2y6sAYV
via IFTTT
A Novel Technology to Model Pressure-Induced Cellular Injuries in the Brain
Publication date: Available online 6 October 2017
Source:Journal of Neuroscience Methods
Author(s): Michael E. Smith, Ramin Eskandari
BackgroundElevated intracranial pressure (ICP) accompanying a number of neurological emergencies is poorly understood, and lacks a model to determine cellular pathophysiology. This limits our ability to identify cellular and molecular biomarkers associated with the pathological progression from physiologic to pathologic ICP.New MethodWe developed an ex vivo model of pressure-induced brain injury, which combines 3D neural cell cultures and a newly developed Pressure Controlled Cell Culture Incubator (PC3I). Human astrocytes and neurons maintained in 3D peptide-conjugated alginate hydrogels were subjected to pressures that mimic both physiologic and pathologic levels of ICP for up to 48hours to evaluate the earliest impacts of isolated pressure on cellular viability and quantify early indicators of pressure-induced cellular injury.ResultsCompared to control cell cultures grown under physiologic pressure, sustained pathologic pressure exposure increased the release of intracellular ATP in a cell-specific manner. Eighteen hours of sustained pressure resulted in increased ATP release from neurons but not astrocytes.Comparison with Existing MethodsCell culture incubators maintain cultures at normal atmospheric pressure. Based on multiple literature searches, we are not aware of any other cell culture incubator systems that modify the pressure at which primary CNS cells are maintained.ConclusionThis model simulates the clinical features of elevated ICP encountered in patients with hydrocephalus, and provides a first estimate of the pathological signaling encountered during the earliest perid of progression in neonatal hydrocephalus. This model should provide a means to better understand the pathological biomarkers associated with the earliest stages of elevated ICP.
from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2y1QG5w
via IFTTT
Source:Journal of Neuroscience Methods
Author(s): Michael E. Smith, Ramin Eskandari
BackgroundElevated intracranial pressure (ICP) accompanying a number of neurological emergencies is poorly understood, and lacks a model to determine cellular pathophysiology. This limits our ability to identify cellular and molecular biomarkers associated with the pathological progression from physiologic to pathologic ICP.New MethodWe developed an ex vivo model of pressure-induced brain injury, which combines 3D neural cell cultures and a newly developed Pressure Controlled Cell Culture Incubator (PC3I). Human astrocytes and neurons maintained in 3D peptide-conjugated alginate hydrogels were subjected to pressures that mimic both physiologic and pathologic levels of ICP for up to 48hours to evaluate the earliest impacts of isolated pressure on cellular viability and quantify early indicators of pressure-induced cellular injury.ResultsCompared to control cell cultures grown under physiologic pressure, sustained pathologic pressure exposure increased the release of intracellular ATP in a cell-specific manner. Eighteen hours of sustained pressure resulted in increased ATP release from neurons but not astrocytes.Comparison with Existing MethodsCell culture incubators maintain cultures at normal atmospheric pressure. Based on multiple literature searches, we are not aware of any other cell culture incubator systems that modify the pressure at which primary CNS cells are maintained.ConclusionThis model simulates the clinical features of elevated ICP encountered in patients with hydrocephalus, and provides a first estimate of the pathological signaling encountered during the earliest perid of progression in neonatal hydrocephalus. This model should provide a means to better understand the pathological biomarkers associated with the earliest stages of elevated ICP.
Graphical abstract
from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2y1QG5w
via IFTTT
Preparation of polysomal fractions from mouse brain synaptoneurosomes and analysis of polysomal-bound mRNAs
Source:Journal of Neuroscience Methods
Author(s): Bozena Kuzniewska, Magdalena Chojnacka, Jacek Milek, Magdalena Dziembowska
BackgroundHere we describe a detailed, reliable protocol for isolation of polysomal fractions from mouse brain synaptoneurosomes. This method is an important tool to study local protein synthesis in neurons.New MethodWe combined rapid preparation of synaptoneurosomes by filtration with polysome profiling. We provide a detailed protocol highlighting difficulties and critical steps of: i) preparation of synaptoneurosomes; ii) polyribosome fractionation from synaptoneurosomes; iii) extraction of proteins and RNA from sucrose gradient fractions.Resultsand Comparison with Existing Methods We fractionated polyribosomes from synaptoneurosomes and detected the association of Mmp9, Camk2a and Stx1B mRNA with polysomes in the unstimulated conditions. Synaptic stimulation led to increased levels of Mmp9 and Camk2a mRNA in the heavy polysomal fractions. We compared our protocol with existing methodsConclusionsWe have developed a reliable, effective method to prepare polyribosomal fractions from synaptoneurosomes to study polyribosomal binding of mRNAs as an aspect of synaptic translation in vitro.
from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2y1dXVd
via IFTTT
Mucous Membrane Pemphigoid Causing Central Airway Obstruction
Mucous membrane pemphigoid (MMP) is a rare variant of the skin disease pemphigoid, which predominantly involves the mucous membranes. This rare autoimmune disease that infrequently affects the respiratory tract is characterized by subepithelial blister formation that may result in scarring. Immunopathologic examination of mucous membranes reveals the deposition of immunoglobulins and complement within the subepithelial basement membrane. We describe a patient with undiagnosed MMP, with a near-fatal presentation of central airway obstruction causing acute respiratory distress. The patient was successfully treated with emergent rigid bronchoscopic resection of a ball valve-like endotracheal mass, and diagnosed with a rare variant of pemphigoid disease, MMP. The patient was treated with mycophenolate and was clinically in remission, with bronchoscopically stable lesions at 1 year of follow-up.from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2y5XJvD
via IFTTT
Cynthia Diane Ray, MD, August 28, 1970—April 5, 2017: Erratum
No abstract available
from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2y1Qao6
via IFTTT
from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2y1Qao6
via IFTTT
Usefulness of Medical Thoracoscopy in the Management of Pleural Effusion Caused by Chronic Renal Failure
Introduction: Although pleural effusion (PE) can be caused by several pathologies like congestive heart failure, infections, malignancies, and pulmonary embolism, it is also a common finding in chronic kidney disease (CKD). Diagnostic thoracentesis is of limited value in the differential diagnosis, and the role of more invasive investigations like medical thoracoscopy (MT) is still unclear. Aim: To evaluate the usefulness of MT in unexplained PE in CKD. Materials and Methods: In the electronic database of our Institution, we retrospectively searched for patients with CKD who underwent MT for unexplained PE between January 2008 and August 2016. Results: Ten patients were included in the present study. The average age was 72.4 years, the male:female ratio 9:1 and the average blood creatinine value 5.96 mg/dL. The average follow-up was 18 months. A thoracentesis showed an exudate was found in 9 patients and in 1 case pleural fluid characteristics were not recorded for technical reasons; in none of them the cytologic or microbiological analyses were considered diagnostic. The clinical suspicion was a neoplastic (5) or an infectious disease (5). In 4 patients with recurrent PE, MT was performed to obtain talc pleurodesis. No immediate procedure-related complications were recorded; 1 patient developed empyema after 2 months. In 6 cases final diagnosis was chronic uremic pleuritis, hydrothorax in 2, and chronic lymphocytic pleurisy in 2. Conclusions: MT represents a safe and effective diagnostic and therapeutic procedure in patients with CKD, that itself is a common cause of exudative effusion, and those patients may not require MT.from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2y1NhmW
via IFTTT
Airway Stenting Revisited: 30 Years, the Age of Reason?
No abstract available
from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2y5ZpVZ
via IFTTT
from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2y5ZpVZ
via IFTTT
In situ hybridization detection methods for HPV16 E6/E7 mRNA in identifying transcriptionally active HPV infection of oropharyngeal carcinoma: an updating
Publication date: Available online 6 October 2017
Source:Human Pathology
Author(s): Chiara C. Volpi, Chiara M. Ciniselli, Ambra V. Gualeni, Maddalena Plebani, Salvatore Alfieri, Paolo Verderio, Laura Locati, Federica Perrone, Pasquale Quattrone, Antonino Carbone, Silvana Pilotti, Annunziata Gloghini
The aim of this study is comparing two in situ hybridization (ISH) detection methods for human papilloma virus (HPV) 16 E6/E7 mRNA, i.e. the RNAscope® 2.0 High Definition (HD) and the upgraded RNAscope® 2.5 HD version. The RNAscope® 2.5 HD has recently replaced the RNAscope® 2.0 HD detection kit. Therefore, this investigation starts from the need to analytically validate the new mRNA ISH assay and, possibly, to refine the current algorithm for HPV detection in oropharyngeal squamous cell carcinoma (OSCC) with the final goal to apply it to daily laboratory practice. The study was based on HPV status and on generated data, interpreted by a scoring algorithm. The results highlighted that the compared RNAscope HPV tests had a good level of interchangeability and enabled to identify OSCC that are truly driven by high risk-HPV infection. This was also supported by the comparison of the RNAscope HPV test with HPV E6/E7 mRNA real time reverse transcriptase-polymerase chain reaction (RT-PCR), in a fraction of cases where material for HPV E6/E7 mRNA real time RT-PCR was available. Furthermore, the algorithm that associates p16 immunohistochemistry (IHC) with the identification of HPV mRNA by RNAscope was more effective than the one that associated p16 IHC with the identification of HPV DNA by ISH.
from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2yvEU6u
via IFTTT
Source:Human Pathology
Author(s): Chiara C. Volpi, Chiara M. Ciniselli, Ambra V. Gualeni, Maddalena Plebani, Salvatore Alfieri, Paolo Verderio, Laura Locati, Federica Perrone, Pasquale Quattrone, Antonino Carbone, Silvana Pilotti, Annunziata Gloghini
The aim of this study is comparing two in situ hybridization (ISH) detection methods for human papilloma virus (HPV) 16 E6/E7 mRNA, i.e. the RNAscope® 2.0 High Definition (HD) and the upgraded RNAscope® 2.5 HD version. The RNAscope® 2.5 HD has recently replaced the RNAscope® 2.0 HD detection kit. Therefore, this investigation starts from the need to analytically validate the new mRNA ISH assay and, possibly, to refine the current algorithm for HPV detection in oropharyngeal squamous cell carcinoma (OSCC) with the final goal to apply it to daily laboratory practice. The study was based on HPV status and on generated data, interpreted by a scoring algorithm. The results highlighted that the compared RNAscope HPV tests had a good level of interchangeability and enabled to identify OSCC that are truly driven by high risk-HPV infection. This was also supported by the comparison of the RNAscope HPV test with HPV E6/E7 mRNA real time reverse transcriptase-polymerase chain reaction (RT-PCR), in a fraction of cases where material for HPV E6/E7 mRNA real time RT-PCR was available. Furthermore, the algorithm that associates p16 immunohistochemistry (IHC) with the identification of HPV mRNA by RNAscope was more effective than the one that associated p16 IHC with the identification of HPV DNA by ISH.
from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2yvEU6u
via IFTTT
A distinctive subgroup of oral EBV+ B-cell neoplasm with polymorphous features is potentially identical to EBV+ mucocutaneous ulcer
Publication date: Available online 6 October 2017
Source:Human Pathology
Author(s): Yae Ohata, Anna Tatsuzawa, Yoshio Ohyama, Ayako Ichikawa, Yumi Mochizuki, Sachiko Ishibashi, Yuri Itakura, Kei Sakamoto, Tohru Ikeda, Masanobu Kitagawa, Kouhei Yamamoto
EBV-positive mucocutaneous ulcer (EBVMCU) is a newly recognized provisional entity, included in mature B-cell neoplasm in the latest 2016 World Health Organization Classification. It has a self-limited growth potential with a high predilection for oral cavities, and occurs in age-related or iatrogenic immunodeficiency with indolent clinical courses. However, it shares histological features with EBV-positive diffuse large B-cell lymphoma (DLBCL), and this often leads to diagnostic challenges and controversies in patients with an oral EBV-positive B-cell neoplasm. The aim of this study was to better characterize and comprehend the pathophysiology of DLBCL and EBVMCU in the oral cavity. We conducted clinicopathologic and recurrent gene mutation analysis of 49 cases (14 EBV-positive, 35 EBV-negative) including cases diagnosed as DLBCL or B-cell lymphoproliferative disorders with high-grade morphology in the oral cavity. All EBV-positive cases matched the criteria of EBVMCU, with significantly earlier clinical stages than the EBV-negative group (P=.0006). Besides, histological analysis showed that all EBV-positive cases presented polymorphous features, while 91.4% (32/35) of the EBV-negative cases showed diffuse and monotonous proliferation (P<.0001). Further, EBV-positive cases presented favorable clinical outcomes without disease-related death or recurrence. Gene mutation analysis (MYD88, CD79A, CD79B, CARD11, and EZH2) revealed that 33.3% (9/27) of EBV-negative cases harbored at least one gene mutation, while no gene mutation was observed in the EBV-positive group (0/11). These results suggest that oral EBV-positive B-cell lymphoid proliferation with polymorphous features often fulfill the criteria for EBVMCU, with clinicopathologically and genetically distinctive properties.
from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2gh44Lh
via IFTTT
Source:Human Pathology
Author(s): Yae Ohata, Anna Tatsuzawa, Yoshio Ohyama, Ayako Ichikawa, Yumi Mochizuki, Sachiko Ishibashi, Yuri Itakura, Kei Sakamoto, Tohru Ikeda, Masanobu Kitagawa, Kouhei Yamamoto
EBV-positive mucocutaneous ulcer (EBVMCU) is a newly recognized provisional entity, included in mature B-cell neoplasm in the latest 2016 World Health Organization Classification. It has a self-limited growth potential with a high predilection for oral cavities, and occurs in age-related or iatrogenic immunodeficiency with indolent clinical courses. However, it shares histological features with EBV-positive diffuse large B-cell lymphoma (DLBCL), and this often leads to diagnostic challenges and controversies in patients with an oral EBV-positive B-cell neoplasm. The aim of this study was to better characterize and comprehend the pathophysiology of DLBCL and EBVMCU in the oral cavity. We conducted clinicopathologic and recurrent gene mutation analysis of 49 cases (14 EBV-positive, 35 EBV-negative) including cases diagnosed as DLBCL or B-cell lymphoproliferative disorders with high-grade morphology in the oral cavity. All EBV-positive cases matched the criteria of EBVMCU, with significantly earlier clinical stages than the EBV-negative group (P=.0006). Besides, histological analysis showed that all EBV-positive cases presented polymorphous features, while 91.4% (32/35) of the EBV-negative cases showed diffuse and monotonous proliferation (P<.0001). Further, EBV-positive cases presented favorable clinical outcomes without disease-related death or recurrence. Gene mutation analysis (MYD88, CD79A, CD79B, CARD11, and EZH2) revealed that 33.3% (9/27) of EBV-negative cases harbored at least one gene mutation, while no gene mutation was observed in the EBV-positive group (0/11). These results suggest that oral EBV-positive B-cell lymphoid proliferation with polymorphous features often fulfill the criteria for EBVMCU, with clinicopathologically and genetically distinctive properties.
from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2gh44Lh
via IFTTT
The CD4/CD8 Ratio of Tumor-infiltrating Lymphocytes at the Tumor-host Interface Has Prognostic Value in Triple Negative Breast Cancer
Publication date: Available online 6 October 2017
Source:Human Pathology
Author(s): Kai Wang, Tiansheng Shen, Gene P Siegal, Shi Wei
Compelling evidence has demonstrated the prognostic value of tumor-infiltrating lymphocytes (TILs), especially in triple-negative breast cancer (TNBC). However, only a limited number of studies to investigate the importance of the subsets of T cells in TILs has been carried out, less so the significance of the location of these TILs. In this study, we explored in a cohort of 42 consecutive TNBC cases the prognostic significance of TIL subsets at the tumor-host interface (within one high power field [0.5 μm] of the invasive front) and compared them to TILs within the intratumoral stroma. Given the reported importance of TILs in HER2-overexpressing breast cancer, a subset of such tumors were also included for comparison. The range was wide in both locations, never-the-less the mean CD4+ and CD8+ T cell count was significantly higher at the tumor-host interface than that found within the intratumoral stroma (both P<.0001). The number of CD4+ or CD8+ T cells at either location was not significantly associated with distant relapse-free or overall survival. However, the CD4/CD8 ratio at the tumor-host interface was significantly associated with both relapse-free survival (hazard ratio [HR] 0.2, P=.002) and overall survival (HR 0.13, P=.002), while this association was not seen for the CD4/CD8 ratio within the intratumoral stroma. As expected, both tumor size and nodal status were significantly associated with survival outcomes. The findings further support the contention that TILs, as a marker of regional immune escape, is of prognostic importance in TNBC progression, and that the CD4/CD8 ratio of TILs at the tumor-host interface plays a distinctive role, thus appearing to be of clinical relevance.
from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2yunXcl
via IFTTT
Source:Human Pathology
Author(s): Kai Wang, Tiansheng Shen, Gene P Siegal, Shi Wei
Compelling evidence has demonstrated the prognostic value of tumor-infiltrating lymphocytes (TILs), especially in triple-negative breast cancer (TNBC). However, only a limited number of studies to investigate the importance of the subsets of T cells in TILs has been carried out, less so the significance of the location of these TILs. In this study, we explored in a cohort of 42 consecutive TNBC cases the prognostic significance of TIL subsets at the tumor-host interface (within one high power field [0.5 μm] of the invasive front) and compared them to TILs within the intratumoral stroma. Given the reported importance of TILs in HER2-overexpressing breast cancer, a subset of such tumors were also included for comparison. The range was wide in both locations, never-the-less the mean CD4+ and CD8+ T cell count was significantly higher at the tumor-host interface than that found within the intratumoral stroma (both P<.0001). The number of CD4+ or CD8+ T cells at either location was not significantly associated with distant relapse-free or overall survival. However, the CD4/CD8 ratio at the tumor-host interface was significantly associated with both relapse-free survival (hazard ratio [HR] 0.2, P=.002) and overall survival (HR 0.13, P=.002), while this association was not seen for the CD4/CD8 ratio within the intratumoral stroma. As expected, both tumor size and nodal status were significantly associated with survival outcomes. The findings further support the contention that TILs, as a marker of regional immune escape, is of prognostic importance in TNBC progression, and that the CD4/CD8 ratio of TILs at the tumor-host interface plays a distinctive role, thus appearing to be of clinical relevance.
from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2yunXcl
via IFTTT
Therapies for Inner Ear Disorders Are One Step Closer to Reality
Spiral Therapeutics (http://ift.tt/2xooDek), a pre-clinical stage company developing first-in-class therapies targeting inner ear disorders, has received positive feedback from the U.S. Drug and Food Administration (FDA) regarding its first Pre-Investigational New Drug (Pre-IND) package submission. The FDA answered Spiral's product development questions related to manufacturing and non-clinical testing, and concurred with the company's clinical development plans for its LPT99 program for preventing chemotherapy-induced hearing loss in pediatric patients. Pre-IND is a program through which the FDA's Office of Antimicrobial Products could provide advice on drug development before it begins. Spiral plans to raise additional funds for an initial Phase 1 trial, the development of new preclinical data, and the company's operations for the next 18 months.
Published: 10/6/2017 1:51:00 PM
from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2yvLGcg
via IFTTT
Εγγραφή σε:
Αναρτήσεις (Atom)