LETTER TO EDITOR JPRAS Re: Hernandez Rosa et al 2017

Publication date: Available online 27 December 2017
Source:Journal of Plastic, Reconstructive & Aesthetic Surgery
Author(s): J.L. See, J. Przybylska, L. MacLennan, C.M. Malata




from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2zG8PEX

Letter in response to: skin tattooing following correction of prominent ears

Publication date: Available online 27 December 2017
Source:Journal of Plastic, Reconstructive & Aesthetic Surgery
Author(s): J.T. Hardwicke




from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2C3QTKw

Dutch breast reconstruction guideline

Publication date: Available online 27 December 2017
Source:Journal of Plastic, Reconstructive & Aesthetic Surgery
Author(s): Marc A.M. Mureau
Treatment of breast cancer is complex and multidisciplinary by nature, with protocols that are updated continuously. During preoperative multidisciplinary team meetings, regularly there is discussion between team members regarding optimal timing and type of breast reconstruction, due to conflicting interests of oncological and reconstructive treatments.Therefore, a multidisciplinary, evidence-based guideline for breast reconstruction in women undergoing breast conserving therapy or mastectomy for breast cancer, or following prophylactic mastectomy was developed by a multidisciplinary working group. The guideline was drafted in accordance with the AGREE II instrument, designed to assess the quality of guidelines with broad international support. For the recommendations, scientific evidence was considered together with other key aspects, such as working group member expertise, patient preferences, costs, availability of facilities and/or organizational aspects. Recommendations provide an answer to the primary questions, and are based on the best scientific evidence available together with the most important considerations by the working group. In accordance with the GRADE method, the level of scientific evidence and the importance given to considerations by the working group jointly determined the strength of the recommendation.The guideline aims to provide practical guidance for plastic surgeons and other members of the multidisciplinary breast cancer team. The implementation of the present breast reconstruction guideline may contribute to optimizing the delivery of care and support for breast reconstruction patients, it may stimulate evidence-based plastic surgery, it may reduce undesirable variation in clinical practice between health care providers, and improve the overall quality of life of breast reconstruction patients.



from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2zEWhOh

Identification of a novel gene pairs signature in the prognosis of gastric cancer

Abstract

Current prognostic signatures need to be improved in identifying high-risk patients of gastric cancer (GC). Thus, we aimed to develop a reliable prognostic signature that could assess the prognosis risk in GC patients. Two microarray datasets of GSE662254 (n = 300, training set) and GSE15459 (n = 192, test set) were included into analysis. Prognostic genes were screened to construct prognosis-related gene pairs (PRGPs). Then, a penalized Cox proportional hazards regression model identified seven PRGPs, which constructed a prognostic signature and divided patients into high- and low-risk groups according to the signature score. High-risk patients showed a poorer prognosis than low-risk patients in both the training set (hazard ratios [HR]: 6.086, 95% confidence interval [CI]: 4.341–8.533) and test set (1.773 [1.107–2.840]). The PRGPs signature also achieved a higher predictive accuracy (concordance index [C-index]: 0.872, 95% CI: 0.846–0.897) than two existing molecular signatures (0.706 [0.667–0.744] for a 11-gene signature and 0.684 [0.642–0.726] for a 24-lncRNA signature) and TNM stage (0.764 [0.715–0.814]). In conclusion, our study identified a novel gene pairs signature in the prognosis of GC.

We used a novel method to identify a prognostic signature in gastric cancer, which removed the batch effects. The signature also showed a better predictive accuracy than other prognostic signatures.

from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2zFrMrB

AKT3 drives adenoid cystic carcinoma development in salivary glands

Abstract

Salivary gland cancer is an aggressive and painful cancer, but a rare tumor type accounting for only ~0.5% of cancer cases. Tumors of the salivary gland exhibit heterogeneous histologic and genetic features and they are subdivided into different subtypes, with adenoid cystic carcinomas (ACC) being one of the most abundant. Treatment of ACC patients is afflicted by high recurrence rates, the high potential of the tumors to metastasize, as well as the poor response of ACC to chemotherapy. A prerequisite for the development of targeted therapies is insightful genetic information for driver core cancer pathways. Here, we developed a transgenic mouse model toward establishment of a preclinical model. There is currently no available mouse model for adenoid cystic carcinomas as a rare disease entity to serve as a test system to block salivary gland tumors with targeted therapy. Based on tumor genomic data of ACC patients, a key role for the activation of the PI3K-AKT-mTOR pathway was suggested in tumors of secretory glands. Therefore, we investigated the role of Akt3 expression in tumorigenesis and report that Akt3 overexpression results in ACC of salivary glands with 100% penetrance, while abrogation of transgenic Akt3 expression could revert the phenotype. In summary, our findings validate a novel mouse model to study ACC and highlight the druggable potential of AKT3 in the treatment of salivary gland patients.

AKT3 expression is associated with bad prognosis in head and neck cancer. Taking advantage of a novel mouse model, we report that conditional Akt3 overexpression triggers adenoid cystic carcinomas in the salivary glands of mice with 100% penetrance. We further show that these adenoid cystic carcinomas are completely dependent on expression of the oncogene.

from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2C3gZxq

Autophagy: novel applications of nonsteroidal anti-inflammatory drugs for primary cancer

Abstract

In eukaryotic cells, autophagy is a process associated with programmed cell death. During this process, cytoplasmic proteins and organelles are engulfed by double-membrane autophagosomes, which then fuse with lysosomes to form autolysosomes. These autolysosomes then degrade their contents to recycle the cellular components. Autophagy has been implicated in a wide variety of physiological and pathological processes that are closely related to tumorigenesis. In recent years, an increasing number of studies have indicated that nonsteroidal anti-inflammatory drugs, such as celecoxib, meloxicam, sulindac, aspirin, sildenafil, rofecoxib, and sodium salicylate, have diverse effects in cancer that are mediated by the autophagy pathway. These nonsteroidal anti-inflammatory drugs can modulate tumor autophagy through the PI3K/Akt/mTOR, MAPK/ERK1/2, P53/DRAM, AMPK/mTOR, Bip/GRP78, CHOP/ GADD153, and HGF/MET signaling pathways and inhibit lysosome function, leading to p53-dependent G1 cell-cycle arrest. In this review, we summarize the research progress in autophagy induced by nonsteroidal anti-inflammatory drugs and the molecular mechanisms of autophagy in cancer cells to provide a reference for the potential benefits of nonsteroidal anti-inflammatory drugs in cancer chemotherapy.

Autophagy: Novel applications of nonsteroidal anti-inflammatory drugs for primary cancer.

from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2C3Dnqg

Analysis of long-term survival in multiple myeloma after first-line autologous stem cell transplantation: impact of clinical risk factors and sustained response

Abstract

The widespread use of high-dose therapy and autologous stem cell transplantation (ASCT) as well as the introduction of novel agents have significantly improved outcomes in multiple myeloma (MM) enabling long-term survival. We here analyze factors influencing survival in 865 newly diagnosed MM patients who underwent first-line ASCT at our center between 1993 and 2014. Relative survival and conditional survival were assessed to further characterize long-term survivors. Achievement of complete response (CR) post-ASCT was associated with prolonged progression-free survival (PFS) in the whole cohort and with significantly superior overall survival (OS) in the subgroup of patients receiving novel agent-based induction therapy. Landmark analyses performed at 1, 3, and 5 years post-ASCT revealed that sustainment of any response had a highly significant influence on survival with no significant differences between sustained CR and sustained inferior responses. Furthermore, outcome was independently improved by administration of maintenance therapy. A subset of patients did experience long-term survival >15 years. However, conditional survival demonstrated a persistent risk of myeloma-associated death and cumulative relative survival curves did not show development of a clear plateau, even in prognostically advantageous groups. In conclusion, in this large retrospective study, sustained response after first-line ASCT was found to be a major prognostic factor for OS independent of depth of sustained response. Administration of maintenance therapy further improved outcome, supporting the hypothesis that interventions to prolong responses achieved post-ASCT may be essential to reach long-term survival, especially in the setting of persisting residual disease.

Long-term analysis of 865 patients with newly diagnosed multiple myeloma treated with first-line autologous stem cell transplantation reveals sustained response after transplantation as a major prognostic factor for survival. Administration of maintenance therapy independently improves outcome, supporting the hypothesis that interventions to prolong responses achieved may be essential to reach long-term survival.

from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2zFuNbm

Inhibited, trapped or adducted: The optimal selective synthetic lethal mix for BRCAness

from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2ljHy6i

Immune related adverse events of immune checkpoint inhibitors and the impact of sex - what we know and what we need to learne

from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2lbiwXP

Body mass index and 20-specific cancers: re-analyses of dose-response meta-analyses of observational studies.

Abstract

Background

Objectives were to provide an overview and understand the strength of evidence and extent of potential biases and validity of claimed associations between Body Mass Index (BMI) and risk of developing cancer.

Methods

We performed an umbrella review and comprehensively re-analysed the data of dose-response meta-analyses on associations between BMI and risk of 20-specific cancers (bladder, brain, breast, colonic, rectal, endometrial, gallbladder, gastric, leukemia, liver, lung, melanoma, multiple myeloma, non-Hodgkins lymphoma, oesophagus, ovarian, pancreatic, prostate, renal, thyroid) by adding big data or missed individual studies. Convincing evidence for an association was defined as a strong statistical significance in fixed-effects and random-effects meta-analyses at p < 0.001, 95% prediction interval (PI) excluded null, there was no large between-study heterogeneity and no small study effects. Suggestive evidence was defined as meeting the significance threshold for the random summary effects of p < 0.05, but 95% PI included the null. Weak evidence was defined as meeting the significance threshold for the random summary effects at a P < 0.05, but 95% PI included the null and there was large between-study heterogeneity or there were small study effects.

Results

Convincing evidence for an association with BMI was detectable for 5 cancers (leukemia, multiple myeloma, pancreatic, endometrial, rectal, and renal cell carcinoma). Suggestive evidence was detectable for malignant melanoma, non-Hodgkins lymphoma and oesophageal adenocarcinoma. Weak evidence was detectable for brain and central nervous system tumors, breast, colon, gall bladder, lung, liver, ovarian, and thyroid cancer. No evidence was detectable for bladder, gastric, and prostate cancer.

Conclusions

The association of increased BMI and cancer is heterogeneous across cancer types. Leukemia, multiple myeloma, pancreatic, endometrial, rectal, and renal cell carcinoma are convincingly associated with an increased BMI by dose-responsive meta-analyses.

from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2ljKwYs

Influenza B virus infection and Stevens–Johnson syndrome

Abstract

A 2-year-old boy with influenza B infection and rapidly worsening targetoid skin lesions with mucosal involvement was diagnosed with Stevens–Johnson syndrome (SJS) and treated with oseltamivir and intravenous immunoglobulin, with resolution of illness. Subsequent quadrivalent inactivated influenza vaccine was well tolerated. This case highlights the rarity of SJS in the setting of influenza B infection and addresses the safety of administering subsequent influenza vaccines to such individuals.

from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2ljBXg5

Respiratory and Laryngeal Function in Teachers: Pre- and Postvocal Loading Challenge

Publication date: Available online 27 December 2017
Source:Journal of Voice
Author(s): Nicole E. Herndon, Anusha Sundarrajan, M. Preeti Sivasankar, Jessica E. Huber
PurposeThe purpose of this study was to examine laryngeal and respiratory physiological changes in teachers before and after a 1-hour vocal loading challenge.MethodsTwelve teachers completed ratings of vocal tiredness, vocal effort, and produced a reading passage and monologue before and after a 1-hour vocal loading challenge (reading aloud in noise). Sound pressure level, lung volume parameters, cepstral peak prominence, and low/high spectral ratio were measured.ResultsAfter loading, participants significantly increased vocal effort, vocal tiredness, utterance length, and sound pressure level, and significantly decreased % vital capacity/syllable.ConclusionsFollowing the 1-hour reading-aloud challenge, tiredness and effort increased. However, lung volume did not change and cepstral peak prominence and low/high spectral ratio remained in the normal range. Future studies are needed to understand the effect of vocal use and vocal loading in teachers.



from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2Do0isw

Respiratory and Laryngeal Function in Teachers: Pre- and Postvocal Loading Challenge

Publication date: Available online 27 December 2017
Source:Journal of Voice
Author(s): Nicole E. Herndon, Anusha Sundarrajan, M. Preeti Sivasankar, Jessica E. Huber
PurposeThe purpose of this study was to examine laryngeal and respiratory physiological changes in teachers before and after a 1-hour vocal loading challenge.MethodsTwelve teachers completed ratings of vocal tiredness, vocal effort, and produced a reading passage and monologue before and after a 1-hour vocal loading challenge (reading aloud in noise). Sound pressure level, lung volume parameters, cepstral peak prominence, and low/high spectral ratio were measured.ResultsAfter loading, participants significantly increased vocal effort, vocal tiredness, utterance length, and sound pressure level, and significantly decreased % vital capacity/syllable.ConclusionsFollowing the 1-hour reading-aloud challenge, tiredness and effort increased. However, lung volume did not change and cepstral peak prominence and low/high spectral ratio remained in the normal range. Future studies are needed to understand the effect of vocal use and vocal loading in teachers.



from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2Do0isw

From Bad to Worse: When Lung Cancer Complicates Idiopathic Pulmonary Fibrosis

Abstract

Patients with idiopathic pulmonary fibrosis have a significantly increased risk for the development of lung cancer. The morbidity and mortality of this disease combination is substantial, and unfortunately, there is currently little data to help guide clinicians in its diagnosis and treatment. In a recent issue of this Journal, Hwang et al. present one of the first studies to evaluate lung cancer in idiopathic pulmonary fibrosis at the molecular level. They demonstrate variants in regulators of the cell cycle, which are known to be important in malignant transformation and may also be important in the pathogenesis of idiopathic pulmonary fibrosis. Further understanding of the pathogenic overlap between lung cancer and idiopathic pulmonary fibrosis could help point the direction to specific diagnostic modalities and targeted treatment of both conditions in the future.

from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2liS0e1

Multispectral imaging for quantitative and compartment-specific immune infiltrates reveals distinct immune profiles that classify lung cancer patients

Abstract

Semiquantitative assessment of immune markers by immunohistochemistry (IHC) has significant limitations for describing the diversity of the immune response in cancer. Therefore we evaluated a fluorescence-based multiplexed IHC method in combination with a multispectral imaging system to quantify immune infiltrates in situ in the environment of non-small cell lung cancer (NSCLC). A tissue microarray including 57 non-small cell lung cancer (NSCLC) cases was stained with antibodies to CD8, CD20, CD4, FOXP3, CD45RO and for pan-cytokeratin and immune cells were quantified in epithelial and stroma compartments. The results were compared to conventional IHC and related to corresponding RNAseq expression values. We found a strong correlation between the visual and digital quantification of lymphocytes for CD45RO (correlation coefficient: r=0.52), FOXP3 (0.87), CD4 (0.79), CD20 (0.81) and CD8 cells (0.90). The correlation with RNAseq data was comparable or better for digital (0.35-0.65) rather than visual (0.38-0.58) quantification. By combining the signals of the five immune markers, further subpopulations of lymphocytes were identified and localized. Specific pattern of immune cell infiltration based either on the spatial distribution (distance between regulatory CD8+ T and cancer cells) or the relation of lymphocyte subclasses to each other (e.g. cytotoxic/regulatory cell ratio) were associated with patient prognosis.

In conclusion, the fluorescence multiplexed IHC method, based on only one tissue section, provided a reliable quantification and localization of immune cells in cancer tissue. The application of this technique on clinical biopsies can provide a basic characterization of immune infiltrates to guide clinical decisions in the era of immunotherapy.

from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2CggDjT

Targeting DNA repair: the genome as a potential biomarker

Abstract

Genomic instability and mutations are fundamental aspects of human malignancies, leading to progressive accumulation of the hallmarks of cancer. For some time, it has been clear that key mutations may be used both as prognostic and predictive biomarkers, the best-known examples being the presence of germline BRCA1 or BRCA2 mutations, which are not only associated with improved prognosis in ovarian cancer, but are also predictive of response to poly(ADP-ribose) polymerase (PARP) inhibitors. Although biomarkers as specific and powerful as these are rare in human malignancies, next generation sequencing and improved bioinformatic analyses are revealing mutational signatures, broader patterns of alterations in the cancer genome that have the power to reveal information about underlying driver mutational processes. Thus, the cancer genome can act as a stratification factor in clinical trials and, ultimately, will be used to drive personalised treatment decisions.

In this review, we will use ovarian high grade serous carcinoma (HGSC) as an example of a disease of extreme genomic complexity that is marked by widespread copy number alterations, but which lacks powerful driver oncogene mutations. Understanding of the genomics of HGSC has led to the routine introduction of germline and somatic BRCA1/2 testing, as well as testing of mutations in other homologous recombination genes, widening the range of patients who may benefit from PARP inhibitors. We will discuss how whole genome-wide analyses, including loss of heterozygosity quantification and whole genome sequencing, may extend this paradigm to allow all patients to benefit from effective targeted therapies.

from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2DoVC5M

Inhibition of MDM2 by a rhein-derived compound AQ-101 suppresses cancer development in SCID mice

A novel small-molecule anthraquinone (AQ) analog, AQ-101, which was synthesized through chemical modification of the core structures of rhein, exhibited potent anticancer activity. In the present study, we evaluated the cancer-inhibiting mechanism of AQ-101 and tested the therapeutic potential of this compound for treating cancer in mice. We found that AQ-101 was able to induce MDM2 protein degradation through a self-ubiquitination and proteasome-mediated mechanism. This AQ-101-induced MDM2 downregulation led to activation of p53, which contributed to apoptosis of acute lymphoblastic leukemia (ALL), especially those with a wild-type p53 phenotype and MDM2 expression in vitro and in vivo. When given for a period of 2 weeks (20mg/kg/day, 3x/week), AQ-101 inhibited development of ALL in nude or SCID mice with a human ALL xenograft and achieved cure by the end of the 5-month experiment. Importantly, AQ-101 showed minimal or no inhibitory effect on normal human hematopoiesis in vitro and was well tolerated in vivo in animal models. Given that MDM2-overexpressing cancers are commonly refractory to current treatment options, our study results suggest that further development of AQ-101 is warranted, as it represents a potentially new, safe anticancer drug with a novel strategy for targeting MDM2.

from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2DpBLU4

An anti-GDNF Family Receptor Alpha 1(GFRA1) Antibody-Drug Conjugate for the Treatment of Hormone Receptor-Positive Breast Cancer

Luminal A (hormone receptor-positive) breast cancer constitutes 70% of total breast cancer patients. In an attempt to develop a targeted therapeutic for this cancer indication, we have identified and characterized Glial cell line-Derived Neurotrophic Factor (GDNF) Family Receptor Alpha 1 (GFRA1) antibody-drug conjugates (ADC) using a cleavable valine-citrulline-MMAE (vcMMAE) linker-payload. RNAseq and immunohistochemistry analysis confirmed the abundant expression of GFRA1 in luminal A breast cancer tissues, while minimal or no expression was observed in most normal tissues. Anti-GFRA-vcMMAE ADC internalized to the lysosomes and exhibited target-dependent killing of GFRA1 expressing cells both in vitro and in vivo. The ADCs employing humanized anti-GFRA1 antibodies displayed robust therapeutic activity in clinically relevant cell line derived (MCF7 and KPL-1) tumor xenograft models. The lead anti-GFRA1 ADC cross-reacts with rodent and cynomolgus monkey GFRA1 antigen and showed optimal pharmacokinetic properties in both species. These properties subsequently enabled a target-dependent toxicity study in rats. Anti-GFRA1 ADC is well tolerated in rats, as seen with other vcMMAE linker-payload based ADCs. Overall, these data suggest that anti-GFRA1-vcMMAE ADC may provide a targeted therapeutic opportunity for luminal A breast cancer patients.

from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2CdTFKb

Scavenger Receptor Type B1 and Lipoprotein Nanoparticle Inhibit Myeloid Derived Suppressor Cells

Myeloid derived suppressor cells (MDSCs) are innate immune cells that potently inhibit T cells. In cancer, novel therapies aimed to activate T cells can be rendered ineffective due to the activity of MDSCs. Thus, targeted inhibition of MDSCs may greatly enhance T cell-mediated anti-tumor immunity, but targeted mechanisms remain obscure. Here we show, for the first time, that scavenger receptor type B-1 (SCARB1), a high-affinity receptor for spherical high-density lipoprotein (HDL), is expressed by MDSCs. Furthermore, we demonstrate that SCARB1 is specifically targeted by synthetic high-density lipoprotein-like nanoparticles (HDL NP), which reduces MDSC activity. Using in vitro T cell proliferation assays, data show that HDL NPs specifically bind SCARB1 to inhibit MDSC activity. In murine cancer models, HDL NP treatment significantly reduces tumor growth, metastatic tumor burden, and increases survival due to enhanced adaptive immunity. Flow cytometry and immunohistochemistry demonstrate that HDL NP-mediated suppression of MDSCs increased CD8+ T cells and reduced Treg cells in the metastatic tumor microenvironment. Using transgenic mice lacking SCARB1, in vivo data clearly show that the HDL NPs specifically target this receptor for suppressing MDSCs. Ultimately, our data provide a new mechanism and targeted therapy, HDL NPs, to modulate a critical innate immune cell checkpoint to enhance the immune response to cancer.

from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2Dne8eP

{beta}-catenin mRNA silencing and MEK inhibition display synergistic efficacy in preclinical tumor models

Colorectal carcinomas (CRC) harbor well-defined genetic abnormalities including aberrant activation of Wnt/β-catenin and MAPK pathways, often simultaneously. While the MAPK pathway can be targeted using potent small molecule drugs, including BRAF and MEK inhibitors, β-catenin inhibition has been historically challenging. RNA interference (RNAi) approaches have advanced to the stage of clinical viability, and are especially well-suited for transcriptional modulators such as β-catenin. In this study, we report therapeutic effects of combined targeting of these pathways with pharmacological agents. Using a recently-described tumor-selective nanoparticle containing a β-catenin-targeting RNAi trigger, in combination with the FDA-approved MEK inhibitor (MEKi) trametinib, we demonstrate synergistic tumor growth inhibition in in vivo models of CRC, melanoma and hepatocellular carcinoma. At dose levels which were insufficient to significantly impact tumor growth as monotherapies, combination regimens resulted in synergistic efficacy and complete tumor growth inhibition. Importantly, dual MEKi/RNAi therapy dramatically improved survival of mice bearing CRC liver metastases. In addition, pharmacological silencing of β-catenin mRNA was effective against tumors which are inherently resistant or which acquire drug-induced resistance to trametinib. These results provide a strong rationale for clinical evaluation of this dual-targeting approach for cancers harboring Wnt/β-catenin and MAPK pathway mutations.

from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2CeWNp5

Arterial thrombosis and anti-PD-1 blockade

Publication date: Available online 27 December 2017
Source:European Journal of Cancer
Author(s): Céline Boutros, Jean-Yves Scoazec, Christine Mateus, Emilie Routier, Séverine Roy, Caroline Robert




from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2BLc7sw

The prognostic value of TP53 mutations in hypopharyngeal squamous cell carcinoma

Abstract

Background

TP53 is the most frequently mutated gene in human cancers. Previous studies reported that TP53 mutations correlated with poor prognoses in patients with head and neck squamous cell carcinoma (HNSCC). However, the relationship between TP53 mutations and hypopharyngeal squamous cell carcinoma (HPSCC) is not known. The current study aimed to evaluate TP53 mutation status as a predictive biomarker in patients with HPSCC.

Methods

We retrospectively reviewed the clinical charts of 57 HPSCC patients treated with initial surgery between 2008 and 2014. TP53 mutation status was determined by Sanger sequencing, and patients were classified into wild-type, missense mutation, and truncating mutation groups. Additionally, p53 expression was determined using immunohistochemistry in surgical specimens.

Results

TP53 mutations were identified in 39 (68%) patients. The 3-year disease-specific survival (DSS) rate of wild-type, missense mutation, and truncating mutation group were 94%, 61%, and 43%, respectively. The TP53 mutation group displayed significantly worse DSS and overall survival rates than the wild-type group (P = 0.01 and P = 0.007, respectively). Multivariate analyses revealed that the presence of TP53 mutations and ≥4 metastatic lymph nodes were independent adverse prognostic factors for HPSCC. p53 immunopositivity was detected in 22 patients, including 5 (28%) and 17 (71%) patients in the wild-type and missense mutation groups, whereas none of the patients with truncating mutation exhibited p53 immunopositivity (P = 0.0001).

Conclusion

The TP53 mutation status correlated with poor prognosis in surgically treated HPSCC patients. Specifically, truncating mutations which were not detected by p53 immunohistochemistry were predictive of worst survival.

from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2BNc9zY

Pathologic analysis of non-neoplastic parenchyma in renal cell carcinoma: a comprehensive observation in radical nephrectomy specimens

Abstract

Background

This study provides a comprehensive examination of the histological features of non-neoplastic parenchyma in renal cell carcinoma (RCC). We prospectively collected radical nephrectomy (RN) specimens, to analyze the histological changes within peritumoral and distant parenchyma.

Methods

Data of patients who underwent RN and had no known history of diabetes, hypertension, hyperlipidemia, or chronic kidney disease etc., were prospectively collected. Tumor pseudo-capsule (PC), and parenchyma within 2 cm from tumor margin, were pathologically assessed. The parenchyma beyond PC or tumor margin was divided into 20 subsections of 1 mm in width. Histological changes, including chronic inflammation, glomerulosclerosis, arteriosclerosis and nephrosclerosis, were given scores of 0, 1, 2 or 3 for each subsection of each specimen, according to their severity. The 20 subsections of each specimen were further divided into four groups according to the distance from the tumor edge (group 1: 0–2 mm; group 2: 2–5 mm; group 3: 5–10 mm; group 4: 10–20 mm), to better compare the peritumoral parenchyma with the distant parenchyma.

Results

In total, 53 patients were involved in this study. All tumors were confirmed RCCs (clear cell vs. papillary vs. chromophobe were 83% vs. 5.7% vs. 11.3%, respectively), with a mean size of 5.6 cm. Histological changes were more severe in peritumoral parenchyma close to PC or tumor edge (0–5 mm), and less common within parenchyma more distant from the tumor (5–20 mm) (p < 0.001). chronic inflammation and nephrosclerosis were the most common changes especially in peritumoral parenchyma (0-2 mm). PC was present in 49 tumors (92.5%), and PC invasion occurred in 5 cases (10.2%). Mean PC thickness was 0.7 mm. PCs were more likely to be present in clear cell RCC or papillary RCC than in chromophobe RCC (100% vs. 100% vs. 33.3%, respectively; p < 0.001).

Conclusions

Most RCCs have a well-developed PC, especially clear cell RCC. Histological changes mainly occur in peritumoral parenchyma, being rather uncommon in distant parenchyma. A compression band filled with severe histological changes was typically observed in renal parenchyma close to the tumor. Its preservation while performing an enucleation margin may not be entirely necessary.

from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2CeeyHr

Pricing appraisal of anti-cancer drugs in the South East Asian, Western Pacific and East Mediterranean Region

Abstract

Background

Globally, cancer is one of the leading causes of mortality. High treatment cost, partly owing to higher prices of anti-cancer drugs, presents a significant burden on patients and healthcare systems. The aim of the present study was to survey and compare retail prices of anti-cancer drugs between high, middle and low income countries in the South-East Asia, Western Pacific and Eastern Mediterranean regions.

Methods

Cross-sectional survey design was used for the present study. Pricing data from ten counties including one from South-East Asia, two from Western Pacific and seven from Eastern Mediterranean regions were used in this study. Purchasing power parity (PPP)-adjusted mean unit prices for 26 anti-cancer drug presentations (similar pharmaceutical form, strength, and pack size) were used to compare prices of anti-cancer drugs across three regions. A structured form was used to extract relevant data. Data were entered and analysed using Microsoft Excel®.

Results

Overall, Taiwan had the lowest mean unit prices while Oman had the highest prices. Six (23.1%) and nine (34.6%) drug presentations had a mean unit price below US$100 and between US$100 and US$500 respectively. Eight drug presentations (30.7%) had a mean unit price of more than US$1000 including cabazitaxel with a mean unit price of $17,304.9/vial. There was a direct relationship between income category of the countries and their mean unit price; low-income countries had lower mean unit prices. The average PPP-adjusted unit prices for countries based on their income level were as follows: low middle-income countries (LMICs): US$814.07; high middle income countries (HMICs): US$1150.63; and high income countries (HICs): US$1148.19.

Conclusions

There is a great variation in pricing of anticancer drugs in selected countires and within their respective regions. These findings will allow policy makers to compare prices of anti-cancer agents with neighbouring countries and develop policies to ensure accessibility and affordability of anti-cancer drugs.

from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2BLXTYs

Outcome of breast cancer screening in Denmark

Abstract

Background

In Denmark, national roll-out of a population-based, screening mammography program took place in 2007–2010. We report on outcome of the first four biennial invitation rounds.

Methods

Data on screening outcome were retrieved from the 2015 and 2016 national screening quality reports. We calculated coverage by examination; participation after invitation; detection-, interval cancer- and false-positive rates; cancer characteristics; sensitivity and specificity, for Denmark and for the five regions.

Results

At the national level coverage by examination remained at 75–77%; lower in the Capital Region than in the rest of Denmrk. Detection rate was slightly below 1% at first screen, 0.6% at subsequent screens, and one region had some fluctuation over time. Ductal carcinoma in situ (DCIS) constituted 13–14% of screen-detected cancers. In subsequent rounds, 80% of screen-detected invasive cancers were node negative and 40% ≤10 mm. False-positive rate was around 2%; higher for North Denmark Region than for the rest of Denmark. Three out of 10 breast cancers in screened women were diagnosed as interval cancers.

Conclusions

High coverage by examination and low interval cancer rate are required for screening to decrease breast cancer mortality. Two pioneer local screening programs starting in the 1990s were followed by a decrease in breast cancer mortality of 22–25%. Coverage by examination and interval cancer rate of the national program were on the favorable side of values from the pioneer programs. It appears that the implementation of a national screening program in Denmark has been successful, though regional variations need further evaluation to assure optimization of the program.

from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2CezKNu

Somatostatin and CXCR4 chemokine receptor expression in hepatocellular and cholangiocellular carcinomas: tumor capillaries as promising targets

Abstract

Background

Hepatocellular (HCC) and cholangiocellular carcinomas (CCC) display an exceptionally poor prognosis. Especially for advanced disease no efficient standard therapy is currently available. Recently, somatostatin analogs have been evaluated for the treatment of HCC, however, with contradictory results. Besides, for both malignancies the chemokine receptor CXCR4 has been discussed as a possible new target structure.

Methods

Expression of somatostatin receptor (SSTR) subtypes 1, 2A, 3, 4, and 5, and of CXCR4 was evaluated in a total of 71 HCCs and 27 CCCs by immunohistochemistry using well-characterized novel monoclonal antibodies.

Results

In HCC tumor cells, frequency and intensity of expression of SSTRs and CXCR4 were only low. CXCR4 was present in about 40% of the HCCs, although at a low intensity. SSTR5, SSTR2, and SSTR3 were detected in about 15%, 8%, and 5% of the HCC tumors, respectively. SSTR and CXCR4 expression was much higher in CCC than in HCC. CXCR4 and SSTR1 were present in 60% and 67% of the CCC samples, respectively, followed by SSTR2 and SSTR5, which were detected in 30% and 11% of the tumors, respectively. Most notably, CXCR4 was intensely expressed on the tumor capillaries in about 50% of the HCCs and CCCs. CXCR4 expression on tumor vessels was associated with poor patient outcomes.

Conclusions

CCC, but not HCC, may be suitable for SSTR-based treatments. Because of the predominant expression of SSTR1, pan-somatostatin analogs should be preferred. In both HCC and CCC, indirect targeting of tumors via the CXCR4-positive tumor capillaries may represent a promising additional therapeutic strategy.

from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2BMCqOQ

Recombinant human endostatin combined with radiotherapy inhibits colorectal cancer growth

Abstract

Background

To examine the effects of recombinant human endostatin combined with radiotherapy on colorectal cancer HCT-116 cell xenografts in nude mice.

Methods

Forty male BALB/c nude mice were injected with human colorectal cancer HCT-116 cells to form xenografts and then randomized into the following 4 groups (each group comprised ten mice): a control group, an endostatin group (20 mg/kg endostatin once a day for 10 days), a radiotherapy group (a 6-Gy dose was administered via a 6-MV X-ray on day 5 post-inoculation), and a combination therapy group (radiotherapy with endostatin treatment). The tumor growth inhibition rate were detected. CD31, vascular endothelial growth factor (VEGF), and hypoxia inducible factor-1α (HIF-1α) expression and microvascular density (MVD) were evaluated by immunohistochemistry. The expression of VEGF protein was also detected by western blotting.

Results

The tumor growth inhibition rate in the radiotherapy with endostatin treatment group was significantly higher than those in endostatin group or radiotherapy group (77.67% vs 12.31% and 38.59%; n = 8 per group, P < 0.05). The results of immunohistochemistry showed that treatment with radiotherapy induced significant increases in CD31, VEGF, and HIF-1α expression and MVD compared with treatment with saline, while treatment with endostatin or radiotherapy with endostatin induced reductions in CD31, VEGF, and HIF-1α expression and MVD compared with treatment with saline (n = 8 per group, P < 0.05). The results of western blotting showed that VEGF protein expression in radiotherapy group was significantly increased compared with that in the control group. However, VEGF protein expression in the endostatin or radiotherapy with endostatin groups was significantly decreased compared with that in the control group (n = 8 per group, P < 0.05).

Conclusions

Endostatin combined with radiotherapy can significantly inhibit HCT-116 cell xenograft growth, possibly by inhibiting angiogenesis and attenuating tumor cell hypoxia.

from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2CdeIPf

Common variants in glucuronidation enzymes and membrane transporters as potential risk factors for colorectal cancer: a case control study

Abstract

Background

Associations between polymorphisms of UDP-glucuronosyltransferases (UGTs) or efflux transporters (e.g., P-glycoprotein and MRP2) and different types of cancer have been described, whereas the role of influx transporters (e.g. OATP1B1 and OATP2B1) has been seldom explored. The GenColon study investigated potential associations between variant alleles of UGTs, efflux and influx transporters and CRC.

Methods

Three hundred CRC cases were matched with 300 controls for age, sex and enrolment site. Fifteen SNPs in UGT1A6–9, UGT2B7, ABCB1, ABCC2, SLCO1B1 and SLCO2B1 genes were characterized using Taqman® PCR. Using multivariate conditional logistic regression, we investigated the relationships between CRC and "environmental" risk factors (physical activity, housing and working areas, consumption of red meat, tobacco, alcohol); genetic polymorphisms, in the study population and in the subgroups with "environmental" risk factors.

Results

No significant association was observed for the analyzed SNPs (or haplotypes). However, an increased CRC risk was found in carriers of the UGT1A8 rs1042597-G variant allele (additive risk OR = 3.39[1.29–8.89], p = 0.02951) in the subgroup of meat-consumers (n = 84), and in carriers of the ABCB1 rs1045642-T (exon26) variant allele (additive risk; OR = 1.89[1.10–3.39], p = 0.0257) in the "never alcohol consumption subgroup" (n = 125). In addition, as previously reported, the following CRC risk factors were identified: absence of physical activity (OR = 6.35[3.70–10.9], p < 0.0001), living or working in rural or mix area (OR = 2.50[1.48–4.23], p = 0.0006 and OR = 2.99[1.63–5.48], p = 0.004, respectively) and tobacco exposure >30 years (3.37[1.63–6.96], p = 0.0010).

Conclusions

Variant genotypes of influx transporters (OATP1B1 and 2B1) were not associated with CRC. This study confirmed the influence of lifestyle factors, but not the previously reported detrimental effect of SNPs in intestinal UGTs or efflux transporters, except for a UGT1A8 variant in subjects consuming meat and the exon 26 SNP of ABCB1 in the never alcohol consumption subgroup.

Trial registration

Registered in Direction Générale de la Santé the 1st July 2008 under the number DGS2008–0144.

from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2BLSa4X

Survival benefit of hepatic resection versus transarterial chemoembolization for hepatocellular carcinoma with portal vein tumor thrombus: a systematic review and meta-analysis

Abstract

Background

No consensus treatment has been reached for hepatocellular carcinoma (HCC) with portal vein tumor thrombus (PVTT). Hepatic resection (HR) and transarterial chemoembolization (TACE) have been recommended as effective options, but which is better remains unclear. This meta-analysis is to compare the effectiveness of HR and TACE for HCC with PVTT patients.

Methods

The PubMed, EMBASE, Cochrane Library, VIP, Wan Fang, and Sino Med databases were systematically searched for comparing HR and TACE treating PVTT.

Results

Twelve retrospective studies with 3129 patients were included. A meta-analysis of 11 studies suggested that the 1-, 2-, 3-, and 5-year overall survival (OS) rates (OR = 0.48, 95% CI = 0.41–0.57, I² = 37%, P < 0.00001; OR = 0.21, 95% CI = 0.12–0.38, I² = 43%, P < 0.00001; OR = 0.35, 95% CI = 0.28–0.44, I² = 53%, P < 0.00001; OR = 0.28, 95% CI = 0.14–0.54, I² = 72%, P = 0.0001, respectively) favored HR over TACE. In a subgroup analysis, HR had better 1-, 2-,3, 5-year OS for type I PVTT (OR = 0.33, 95% CI = 0.17–0.64, I² = 20%, P = 0.001; OR = 0.32, 95% CI = 0.16–0.63, I2 = 0%, P = 0.001; OR = 0.18, 95% CI = 0.09–0.36, I2 = 0%, P < 0.00001; OR = 0.07, 95% CI = 0.01–0.32, I2 = 0%, P = 0.0006, respectively) and better 1-, 3-, and 5-year OS for type II PVTT (OR = 0.37, 95% CI = 0.20–0.70, I² = 59%, P = 0.002; OR = 0.22, 95% CI = 0.13–0.39, I² = 0%, P < 0.00001; OR = 0.16; 95% CI = 0.03–0.91; I² = 51%, P = 0.04, respectively). There was no difference in 1-, 3-, or 5-year OS between HR and TACE for type III PVTT (OR = 0.86, 95% CI = 0.61–1.21, I² = 0%, P = 0.39; OR = 0.83, 95% CI = 0.42–1.64, I² = 0%, P = 0.59; OR = 0.59, 95% CI = 0.06–-6.04, I² = 65%, P = 0.66, respectively).

Conclusions

HR may lead to longer OS for some selected HCC patients with PVTT than TACE, especially for type I or II PVTT, with less difference being observed for type III or IV PVTT.

from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2CdaKX0

Correction to: Estrogen-based hormone therapy in women with primary ovarian insufficiency: a systematic review

In the original publication, the given and family name of the author Mohammad Hassan Murad was incorrect. This has been corrected with this erratum.

from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2ljaJGp

Response to isolated limb perfusion and chemotherapy with epirubicin plus ifosfamide in a metastatic malignant ossifying fibromyxoid tumor

Abstract

Background

Ossifying fibromyxoid tumor (OFMT) is a rare soft tissue neoplasm of uncertain lineage and intermediate biological potential. It is more common in middle-aged men, usually arising from the deep tissues of the extremities. It is now established that it is a translocation related tumor, most often marked by translocation of PHF1 gene. Surgery is the mainstay of treatment and proves usually curative, although, in rarer cases the disease shows malignant features and tendency to recur both locally and at distant sites. In such cases, no standard treatment exists.

Case presentation

We report on a case of malignant advanced OFMT of the hand with lung metastases responding to isolated limb perfusion with human recombinant tumor necrosis factor and melphalan and chemotherapy with epirubicin and ifosfamide.

Conclusions

To our knowledge, this is the first report of activity of soft tissue sarcoma-oriented chemotherapy in advanced OFMT.

from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2BLSH6U

Implantable, wireless device platforms for neuroscience research

Publication date: June 2018
Source:Current Opinion in Neurobiology, Volume 50
Author(s): Philipp Gutruf, John A Rogers
Recently developed classes of ultraminiaturized wireless devices provide powerful capabilities in neuroscience research, as implantable light sources for simulation/inhibition via optogenetics, as integrated microfluidic systems for programmed pharmacological delivery and as multimodal sensors for physiological measurements. These platforms leverage basic advances in biocompatible materials, semiconductor device designs and systems engineering concepts to afford modes of operation that are qualitatively distinct from those of conventional approaches that tether animals to external hardware by means of optical fibers, electrical cables and/or fluidic tubing. Neuroscience studies that exploit the unique features of these technologies enable insights into neural function through targeted stimulation, inhibition and recording, with spatially and genetically precise manipulation of neural circuit activity. Experimental possibilities include studies in naturalistic, three dimensional environments, investigations of pair-wise or group related social interactions and many other scenarios of interest that cannot be addressed using traditional hardware.



from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2l82jTe

PDGFA/PDGFRα-regulated GOLM1 promotes human glioma progression through activation of AKT

Abstract

Background

Golgi Membrane Protein 1 (GOLM1), a protein involved in the trafficking of proteins through the Golgi apparatus, has been shown to be oncogenic in a variety of human cancers. Here, we examined the role of GOLM1 in the development of human glioma.

Methods

qRT-PCR, immunohistochemistry, and western blot analysis were performed to evaluate GOLM1 levels in cell lines and a cohort of primary human glioma and non-neoplastic brain tissue samples. Glioma cell lines were modified with lentiviral constructs expressing short hairpin RNAs targeting GOLM1 or overexpressing the protein to assess function in proliferation, viability, and migration and invasion in vitro using EdU, CCK8, clone-forming, Transwell assays, 3D tumor spheroid invasion assay and in vivo in orthotopic implantations. Protein lysates were used to screen a membrane-based antibody array to identify kinases mediated by GOLM1. Specific inhibitors of PDGFRα (AG1296) and AKT (MK-2206) were used to examine the regulation of PDGFA/PDGFRα on GOLM1 and the underlying pathway respectively.

Results

qRT-PCR, immunohistochemistry and western blot analysis revealed GOLM1 expression to be elevated in glioma tissues and cell lines. Silencing of GOLM1 attenuated proliferation, migration, and invasion of U251, A172 and P3#GBM (primary glioma) cells, while overexpression of GOLM1 enhanced malignant behavior of U87MG cells. We further demonstrated that activation of AKT is the driving force of GOLM1-promoted glioma progression. The last finding of this research belongs to the regulation of PDGFA/PDGFRα on GOLM1, while GOLM1 was also a key element of PDGFA/PDGFRα-mediated activation of AKT, as well as the progression of glioma cells.

Conclusions

PDGFA/PDGFRα-regulated GOLM1 promotes glioma progression possibly through activation of a key signaling kinase, AKT. GOLM1 interference may therefore provide a novel therapeutic target and improve the efficacy of glioma treatment, particularly in the case of the proneural molecular subtype of human glioma.

from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2CdRc4H

LncRNA AK023391 promotes tumorigenesis and invasion of gastric cancer through activation of the PI3K/Akt signaling pathway

Abstract

Background

Patients with gastric cancer commonly have a poor prognosis, owing to its invasiveness and distant metastasis. Recent studies have confirmed the pivotal role of long non-coding RNAs (lncRNAs) in tumorigenesis and the progression of malignant tumors, including gastric cancer. However, little is known about the molecular mechanism by which lncRNA AK023391 contributes to gastric cancer.

Methods

A lncRNA microarray was used to identify the differentially expressed lncRNA AK023391 in gastric cancer and adjacent normal tissues. In addition, RNA fluorescence in situ hybridization (FISH) was used to investigate the association between AK023391 expression and the clinicopathological characteristics and prognosis of patients with gastric cancer. Subsequently, a series of in vitro assays and a xenograft tumor model were used to observe the functions of lncRNA AK023391 in gastric cancer cells. A cancer pathway microarray, bioinformatic analysis, western blotting, and immunochemistry were carried out to verify the regulation of AK023391 and its downstream PI3K/Akt signaling pathway.

Results

Expression of lncRNA AK023391 was significantly upregulated in gastric cancer samples and cell lines in comparison to adjacent normal tissues, and was positively correlated with poor survival in patients with gastric cancer. The multivariate Cox regression model revealed that AK023391 expression acted as an independent prognostic factor for survival in patients with gastric cancer. Knockdown of AK023391 inhibited cell growth and invasion both in vitro and in vivo, and induced apoptosis and cell cycle arrest in gastric cancer cells, whereas its overexpression reversed these effects. Mechanistically, PI3K/Akt signaling mediated the NF-κB, FOXO3a, and p53 pathways. Moreover, downstream transcription factors, such as c-myb, cyclinB1/G2, and BCL-6 might be involved in AK023391-induced tumorigenesis in gastric cancer.

Conclusions

The novel oncogenic lncRNA AK023391 in gastric cancer exerts its effects through activation of the PI3K/Akt signaling pathway, and may act as a potential biomarker for survival in patients with gastric cancer.

from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2BPh17T

Correction to: Estrogen-based hormone therapy in women with primary ovarian insufficiency: a systematic review

In the original publication, the given and family name of the author Mohammad Hassan Murad was incorrect. This has been corrected with this erratum.

from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2ljaJGp

Laparoscopic intersphincteric resection versus an open approach for low rectal cancer: a meta-analysis

Abstract

Aim

The aim of this study was to compare the short-term and mid-term effects of laparoscopic intersphincteric resection with the conventional open approach for patients with low rectal cancer through a meta-analysis.

Methods

The PubMed, EMBASE, Cochrane, and Ovid databases were searched for eligible studies until March 2017. Operation time, blood loss, circumferential resection margin-positive rate, distal margin length, number of resected lymph nodes, diverting stoma rate, postoperative overall morbidity, anastomotic leakage, and hospital stay were the main short-term effect endpoints. We also examined disease-free survival, overall survival, local recurrence, and post-operational anal function as secondary outcomes to evaluate the mid-term effects of laparoscopic surgery.

Results

Five studies involving 620 patients were included in the analyses. Compared with the open approach, the laparoscopic ISR had less blood loss (weighted mean difference [WMD] = − 214.65 ml, 95% CI [− 370.44, − 196.13], p < 0.01), less postoperative overall morbidity (OR = 0.58, 95% CI [0.40, 0.86], p < 0.01), and shorter duration of hospital stay (WMD = − 5.87 days, 95% CI [− 11.35, − 0.40], p < 0.05); however, the operation time was significantly longer in the laparoscopic group (WMD = 47.34 min, 95% CI [4.10, 90.58], p < 0.05). No other significant differences were observed.

Conclusion

Laparoscopic ISR for low rectal cancer offers fewer complications and faster recovery, with similar operation quality and mid-term oncological results than the conventional approach. Although this technique is comparatively more complex than the conventional approach and requires practice, laparoscopic ISR shows great potential as a surgical option and deserves further clinical study.

from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2BLOeRG

Probe-based Confocal Laser Endomicroscopy in Metastatic Pulmonary Calcification

We report a case of metastatic pulmonary calcification in a patient with chronic renal failure on hemodialysis and secondary hyperparathyroidism. The diagnosis was made by using a probe-based confocal endomicroscopy which showed specific structures in the lung tissue and was proven by a transbronchial lung biopsy. To the best of our knowledge, this is the first reported case of the confocal endomicroscopy findings in a patient with metastatic pulmonary calcification.

from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2pM0joj

Pleural Metastasis From Cutaneous Malignant Melanoma

No abstract available

from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2pNSKgM

Venous-Airway Fistula With Aspergilloma: A Case of an Implanted Catheter Gone Bad

The implanted venous access catheter is commonly used in the treatment of oncology patients. Although common long-term complications of these devices, such as infection and thrombosis, have been widely reported, venous-airway fistula due to port placement is an extremely rare and poorly understood complication. We report a case of a 56-year-old woman with pancreatic adenocarcinoma whose implanted catheter was complicated by the development of an azygo-bronchial fistula with a concomitant aspergilloma. Herein is the first reported case of successful venous-airway fistula closure obtained through silicone stenting.

from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2pQ4Zd1

Metastatic Endobronchial Ameloblastoma

No abstract available

from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2pIfleJ

Use of Narrow Band Imaging in the Diagnosis of Hypovascular Endobronchial Sarcoidosis

Narrow band imaging (NBI) has been widely applied for the evaluation of numerous disease conditions that present with increased vascularity of the mucosa, most often malignancies. It is increasingly being used in benign conditions as well. We present the first case in which NBI was used, rather, to detect areas of bronchial hypovascularity due to its ability to increase the visual contrast between normal and hypovascular mucosa. Endobronchial biopsy of these nodules led to the diagnosis of sarcoidosis. Had conventional white light alone been utilized, the diagnosis would likely have been missed because not only were these lesions difficult to visualize under white light but transbronchial lung biopsy and transbronchial needle aspiration were unremarkable. We propose that NBI should be considered in the bronchoscopic evaluation of possible sarcoidosis or any other condition that could present with airway hypovascularity.

from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2pJcIJO

Incidence and Risk Factors of Hypoxemia During Interventional Rigid Bronchoscopy Under Spontaneous-assisted Ventilation

Background: Interventional rigid bronchoscopy for tracheobronchial stenosis can be performed under total intravenous anesthesia and spontaneous-assisted ventilation. Intraoperative hypoxemia can occur during this procedure, but the incidence and risk factors have not yet been determined. Methods: Medical records of patients who underwent rigid bronchoscopy for the treatment of tracheobronchial stenosis under total intravenous anesthesia and spontaneous-assisted ventilation during the study period from January 2011 to December 2012 were retrospectively reviewed. Results: There were 126 patients who underwent 263 procedures. The 2 main causes of tracheobronchial stenosis were tuberculosis (41.3%) and malignancy (35.7%). The 2 main locations of stenotic area were the trachea (58.6%) and the left main bronchus (46.4%). Tracheobronchial dilatation and stent insertion were performed in 78.7% and 21.3% of patients, respectively. The incidence of intraoperative hypoxemia was 25.5%. Independent risk factors for intraoperative hypoxemia were a degree of tracheal stenosis ≥75% (odds ratio: 2.48; 95% confidence interval, 1.19-5.17) and tumor removal procedure (odds ratio: 2.9; 95% confidence interval, 1.13-7.41). Conclusions: Incidence of intraoperative hypoxemia during interventional rigid bronchoscopy for tracheobronchial stenosis under spontaneous-assisted ventilation was 25.5%. Risk factors for hypoxemia were a degree of tracheal stenosis ≥75% and tumor removal procedure.

from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2pQ4Juz

Feasibility and Safety of Flexible Bronchoscopy Performed Via Tracheal Tubes in Patients With Tracheostomies: A Retrospective, Single-Center Experience

Background: Flexible bronchoscopy (FB) is commonly performed to assess, diagnose, and treat patients with respiratory disease, and is typically performed via transnasal or transoral approaches. FB can be performed via tracheal tubes in patients with tracheostomies; however, the safety and technical feasibility has not been established. The present study evaluates the safety and feasibility of performing FB via tracheal tubes. Materials and Methods: A total of 45 patients underwent 56 procedures involving FB via tracheal tubes at a single institution from November 2013 to November 2014 and were included in this retrospective case series. Results: Patients had a median age of 68 years (interquartile range, 56 to 82.5), and 51% were female. Most patients had 2 comorbidities (interquartile range, 1 to 3), with the most common being hypertension, diabetes mellitus, and chronic kidney disease. Upper airway obstruction was the primary indication for bronchoscopy in 40% of patients. Fifty-three percent of patients had a Shiley tube #6, [internal cannula diameter (ICD) of 6.5 mm]; tracheal tubes in the remaining patients ranged from Shiley #4 (ICD, 5.5 mm) to Shiley #8 (ICD, 8.5 mm). One patient did not complete the procedure due to severe hypertension (intraprocedural systolic blood pressure >180 mm Hg). During FB, no patients experienced cardiorespiratory arrest, arrhythmia, bleeding, or desaturation that required resuscitation. Eleven patients had a mucus plug leading to atelectasis during bronchoscopy, and 8 of these had a postprocedural chest x-ray finding of lung reexpansion. Conclusion: FB via tracheal tubes is a technically feasible and safe procedure that does not compromise patient oxygenation.

from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2pJcIcM

Endobronchial High-Grade Non-Hodgkin’s Lymphoma

No abstract available

from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2pJDcup

Orange-Pigmented Sputum as a Manifestation of Smoke Grenade Inhalation Injury

A 34-year-old man presented with scanty hemoptysis, orange-colored expectoration, and mild dyspnea. He was in an enclosed building taking part in a military training exercise inhaling an orange-colored smoke from a smoke grenade ignition. His symptoms developed immediately after the initial exposure but he sought medical assistance 20 hours later because of their persistence. Fiberoptic bronchoscopy was performed revealing diffuse inflammatory tracheobronchial tree with streaky orange-pigmented secretions in the trachea and both main-stem bronchi. Acute tracheobronchitis was diagnosed and the patient was treated with nebulized bronchodilators and intravenous corticosteroids showing complete recovery. To our knowledge, this is the first well-documented report of inhalation injury induced by a smoke bomb explosion including potassium chlorate oxidizer and Sudan I and presenting with orange-pigmented sputum production. Smoke inhalation injury is associated with significant morbidity and mortality. The heterogeneity of the smoke and the large variety of the resulting symptoms may be the reason why a definition, specific diagnostic criteria, and therapeutic guidelines are still lacking.

from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2pIQAiB

Small field dosimetry for the small animal radiotherapy research platform (SARRP)

Abstract

Background

Preclinical radiation biology has become increasingly sophisticated due to the implementation of advanced small animal image guided radiation platforms into laboratory investigation. These small animal radiotherapy devices enable state-of-the-art image guided therapy (IGRT) research to be performed by combining high-resolution cone beam computed tomography (CBCT) imaging with an isocentric irradiation system. Such platforms are capable of replicating modern clinical systems similar to those that integrate a linear accelerator with on-board CBCT image guidance.

Methods

In this study, we present a dosimetric evaluation of the small animal radiotherapy research platform (SARRP, Xstrahl Inc.) focusing on small field dosimetry. Physical dosimetry was assessed using ion chamber for calibration and radiochromic film, investigating the impact of beam focus size on the dose rate output as well as beam characteristics (beam shape and penumbra). Two film analysis tools) have been used to assess the dose output using the 0.5 mm diameter aperture.

Results

Good agreement (between 1.7–3%) was found between the measured physical doses and the data provided by Xstrahl for all apertures used. Furthermore, all small field dosimetry data are in good agreement for both film reading methods and with our Monte Carlo simulations for both focal spot sizes. Furthermore, the small focal spot has been shown to produce a more homogenous beam with more stable penumbra over time.

Conclusions

FilmQA Pro is a suitable tool for small field dosimetry, with a sufficiently small sampling area (0.1 mm) to ensure an accurate measurement. The electron beam focus should be chosen with care as this can potentially impact on beam stability and reproducibility.

from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2CfvkUo

Evaluation of a software module for adaptive treatment planning and re-irradiation

Abstract

Background

The aim of this work is to validate the Dynamic Planning Module in terms of usability and acceptance in the treatment planning workflow.

Methods

The Dynamic Planning Module was used for decision making whether a plan adaptation was necessary within one course of radiation therapy. The Module was also used for patients scheduled for re-irradiation to estimate the dose in the pretreated region and calculate the accumulated dose to critical organs at risk. During one year, 370 patients were scheduled for plan adaptation or re-irradiation. All patient cases were classified according to their treated body region. For a sub-group of 20 patients treated with RT for lung cancer, the dosimetric effect of plan adaptation during the main treatment course was evaluated in detail. Changes in tumor volume, frequency of re-planning and the time interval between treatment start and plan adaptation were assessed.

Results

The Dynamic Planning Tool was used in 20% of treated patients per year for both approaches nearly equally (42% plan adaptation and 58% re-irradiation). Most cases were assessed for the thoracic body region (51%) followed by pelvis (21%) and head and neck cases (10%). The sub-group evaluation showed that unintended plan adaptation was performed in 38% of the scheduled cases. A median time span between first day of treatment and necessity of adaptation of 17 days (range 4–35 days) was observed. PTV changed by 12 ± 12% on average (maximum change 42%). PTV decreased in 18 of 20 cases due to tumor shrinkage and increased in 2 of 20 cases. Re-planning resulted in a reduction of the mean lung dose of the ipsilateral side in 15 of 20 cases.

Conclusion

The experience of one year showed high acceptance of the Dynamic Planning Module in our department for both physicians and medical physicists. The re-planning can potentially reduce the accumulated dose to the organs at risk and ensure a better target volume coverage. In the re-irradiation situation, the Dynamic Planning Tool was used to consider the pretreatment dose, to adapt the actual treatment schema more specifically and to review the accumulated dose.

from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2Dpz6Ke

Revealing the Glioma Cancer Stem Cell Interactome, One Niche at a Time

Abstract

Glioblastoma cancer stem cells (CSCs) are insidious. They extensively infiltrate brain tissue, resist radio- and chemotherapy, and are thought to represent the ultimate drivers of disease progression. New research has identified CD109, a GPI-anchored protein, on a population of perivascular CSCs. Interrogation of primary human tumor tissue suggests a role for CD109-expressing CSCs in the progression from low- to high-grade glioma, and animal modeling reveals a critical role for CD109 in the maintenance of the GBM CSC phenotype. Further, CD109-expressing CSCs appear to drive the proliferation of adjacent non-stem tumor cells (NSTCs) in a rare example of CSC/NSTC cooperative interaction. With this Commentary, we highlight the newly revealed biology of CD109 and offer a synthesis of the published information on glioma CSCs in a variety of anatomical growth zones. We also discuss the landscape of interacting cells within GBM tumors and the few reported examples of pro-tumorigenic, interactive tumor cell partnerships, as well as a variety of tumor cell/non-transformed neural cell interactions.

from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2ll3VYL

The RENAISSANCE (AIO-FLOT5) trial: effect of chemotherapy alone vs. chemotherapy followed by surgical resection on survival and quality of life in patients with limited-metastatic adenocarcinoma of the stomach or esophagogastric junction – a phase III trial of the German AIO/CAO-V/CAOGI

Abstract

Background

Historical data indicate that surgical resection may benefit select patients with metastatic gastric and gastroesophageal junction cancer. However, randomized clinical trials are lacking. The current RENAISSANCE trial addresses the potential benefits of surgical intervention in gastric and gastroesophageal junction cancer with limited metastases.

Methods

This is a prospective, multicenter, randomized, investigator-initiated phase III trial. Previously untreated patients with limited metastatic stage (retroperitoneal lymph node metastases only or a maximum of one incurable organ site that is potentially resectable or locally controllable with or without retroperitoneal lymph nodes) receive 4 cycles of FLOT chemotherapy alone or with trastuzumab if Her2+. Patients without disease progression after 4 cycles are randomized 1:1 to receive additional chemotherapy cycles or surgical resection of primary and metastases followed by subsequent chemotherapy. 271 patients are to be allocated to the trial, of which at least 176 patients will proceed to randomization. The primary endpoint is overall survival; main secondary endpoints are quality of life assessed by EORTC-QLQ-C30 questionnaire, progression free survival and surgical morbidity and mortality. Recruitment has already started; currently (Feb 2017) 22 patients have been enrolled.

Discussion

If the RENAISSANCE concept proves to be effective, this could potentially lead to a new standard of therapy. On the contrary, if the outcome is negative, patients with gastric or GEJ cancer and metastases will no longer be considered candidates for surgical intervention.

Trial registration

The article reports of a health care intervention on human participants and is registered on October 12, 2015 under ClinicalTrials.gov Identifier: NCT02578368; EudraCT: 2014–002665-30.

from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2E4kAIM

Circulating microRNA’s as a diagnostic tool for hepatocellular carcinoma in a hyper endemic HIV setting, KwaZulu-Natal, South Africa: a case control study protocol focusing on viral etiology

Abstract

Background

A wide range of studies has investigated the diagnostic proficiency of extracellular microRNAs (miRNAs) in hepatocellular cancer (HCC). HCC is expected to increase in Sub-Saharan Africa (SSA), due to endemic levels of viral infection (HBV/HIV), ageing and changing lifestyles. This unique aetiological background provides an opportunity for investigating potentially novel circulating miRNAs as biomarkers for HCC in a prospective study in South Africa.

Methods

This study will recruit HCC patients from two South African cancer hospitals, situated in Durban and Pietermaritzburg in the province of KwaZulu-Natal. These cases will include both HBV mono-infected and HBV/HIV co-infected HCC cases. The control group will consist of two (2) age and sex-matched healthy population controls per HCC case randomly selected from a Durban based laboratory. The controls will exclude patients if they have any evidence of chronic liver disease. A standardised reporting approach will be adopted to detect, quantify and normalize the level of circulating miRNAs in the blood sera of HCC cases and their controls. Reverse transcription quantitative polymerase chain reaction (RT-qPCR) will be employed to quantity extracellular miRNAs. Differences in concentration of relevant miRNA by case/control status will be assessed using the Wilcoxon rank-sum (Mann-Whitney U) test. Adjustment for multiple testing (Bonferroni correction), receiver operating curves (ROC) and optimal breakpoint analyses will be employed to identify potential thresholds for the differentiation of miRNA levels of HCC cases and their controls.

Discussion

Although there is a growing base of literature regarding the role of circulating miRNAs as biomarkers, this promising field remains a 'work in progress'. The aetiology of HBV infection in HCC is well understood, as well as it's role in miRNA deregulation, however, the mediating role of HIV infection is unknown. HCC incidence in SSA, including South Africa, is expected to increase significantly in the next decade. A combination of factors, therefore, offers a unique opportunity to identify candidate circulating miRNAs as potential biomarkers for HBV/HIV infected HCC.

from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2E2rnmt

Dietary supplement use among cancer survivors and the general population: a nation-wide cross-sectional study

Abstract

Background

Use of dietary supplements among cancer survivors is common and controversial, but information on the amount of nutrients from supplements among cancer survivors is limited. We examined the amount of nutrients and their contribution to total nutrient intake from supplements and compared these data between cancer survivors and cancer-free individuals. We also identified factors associated with supplement use among cancer survivors.

Methods

We identified 400 cancer survivors and 10,387 cancer-free individuals, aged ≥ 19 years, from the fifth Korea National Health and Nutrition Examination Survey (KNHANES) V-1, 2 (2010, 2011). We calculated the amount of nutrients consumed from foods and supplements, the percent contributions of supplement nutrients to total nutrient intakes and cancer survivors' nutrient intakes relative to the Estimated Average Requirements (EARs) and the Tolerable Upper Intake Levels (ULs). We examined factors associated with supplement use among cancer survivors.

Results

We found that 33.3% of cancer survivors and 22.1% of cancer-free individuals reported the use of dietary supplements. Compared to cancer-free individuals, cancer survivors had higher intakes of riboflavin, folate, and iron from foods (p < 0.05 for each), and higher intakes of calcium (p = 0.05) and vitamin C (p = 0.01) from foods and supplements. The similar pattern was observed for the percent contributions to total nutrient intake. Cancer survivors had higher proportion of participants below EARs than cancer-free individuals for thiamin and niacin (p < 0.05 for each). The proportions of cancer survivors below the EARs were 61.2% for calcium, 49.1% for riboflavin, and 43.5% for folate and the proportions of cancer survivors above the ULs were 3.3% for iron, and 2.3% for vitamin A. For female cancer survivors, education above an elementary school level, moderate physical activity, low vegetable intake, and high circulating vitamin D levels were associated with supplement use. For male cancer survivors, living in an urban area, no consumption of alcohol, and lower energy intake, were associated with supplement use.

Conclusions

Korean cancer survivors have higher rate of dietary supplement use and higher contribution from supplements to total nutrient intake than cancer-free individuals. Demographic and lifestyle factors were associated with supplement use among cancer survivors.

from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2pLyaxF

Expitope 2.0: a tool to assess immunotherapeutic antigens for their potential cross-reactivity against naturally expressed proteins in human tissues

Abstract

Background

Adoptive immunotherapy offers great potential for treating many types of cancer but its clinical application is hampered by cross-reactive T cell responses in healthy human tissues, representing serious safety risks for patients. We previously developed a computational tool called Expitope for assessing cross-reactivity (CR) of antigens based on tissue-specific gene expression. However, transcript abundance only indirectly indicates protein expression. The recent availability of proteome-wide human protein abundance information now facilitates a more direct approach for CR prediction. Here we present a new version 2.0 of Expitope, which computes all naturally possible epitopes of a peptide sequence and the corresponding CR indices using both protein and transcript abundance levels weighted by a proposed hierarchy of importance of various human tissues.

Results

We tested the tool in two case studies: The first study quantitatively assessed the potential CR of the epitopes used for cancer immunotherapy. The second study evaluated HLA-A*02:01-restricted epitopes obtained from the Immune Epitope Database for different disease groups and demonstrated for the first time that there is a high variation in the background CR depending on the disease state of the host: compared to a healthy individual the CR index is on average two-fold higher for the autoimmune state, and five-fold higher for the cancer state.

Conclusions

The ability to predict potential side effects in normal tissues helps in the development and selection of safer antigens, enabling more successful immunotherapy of cancer and other diseases.

from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2E5Ujd5

Invasive micropapillary carcinoma of the breast overexpresses MUC4 and is associated with poor outcome to adjuvant trastuzumab in HER2-positive breast cancer

Abstract

Background

Invasive micropapillary carcinoma of the breast (IMPC) is a histological tumor variant that occurs with low frequency characterized by an inside-out formation of tumor clusters with a pseudopapillary arrangement. IMPC is an aggressive tumor with poor clinical outcome. In addition, this histological subtype usually expresses human epidermal growth factor receptor 2 (HER2) which also correlates with a more aggressive tumor. In this work we studied the clinical significance of IMPC in HER2-positive breast cancer patients treated with adjuvant trastuzumab. We also analyzed mucin 4 (MUC4) expression as a novel biomarker to identify IMPC.

Methods

We retrospectively studied 86 HER2-positive breast cancer patients treated with trastuzumab and chemotherapy in the adjuvant setting. We explored the association of the IMPC component with clinicopathological parameters at diagnosis and its prognostic value. We compared MUC4 expression in IMPC with respect to other histological breast cancer subtypes by immunohistochemistry.

Results

IMPC, either as a pure entity or associated with invasive ductal carcinoma (IDC), was present in 18.6% of HER2-positive cases. It was positively correlated with estrogen receptor expression and tumor size and inversely correlated with patient's age. Disease-free survival was significantly lower in patients with IMPC (hazard ratio = 2.6; 95%, confidence interval 1.1–6.1, P = 0.0340). MUC4, a glycoprotein associated with metastasis, was strongly expressed in all IMPC cases tested. IMPC appeared as the histological breast cancer subtype with the highest MUC4 expression compared to IDC, lobular and mucinous carcinoma.

Conclusion

In HER2-positive breast cancer, the presence of IMPC should be carefully examined. As it is often not informed, because it is relatively difficult to identify or altogether overlooked, we propose MUC4 expression as a useful biomarker to highlight IMPC presence. Patients with MUC4-positive tumors with IMPC component should be more frequently monitored and/or receive additional therapies.

from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2pM7FYL

Does vagus nerve stimulation influence pregnancy outcomes?

Publication date: Available online 27 December 2017
Source:Brain Stimulation
Author(s): Anne Sabers, Line Buchgreitz, Winfried Neuhuber




from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2E1U4zE

Chronic deep brain stimulation normalizes scalp EEG activity in isolated dystonia

Publication date: February 2018
Source:Clinical Neurophysiology, Volume 129, Issue 2
Author(s): Svjetlana Miocinovic, Andrew Miller, Nicole C. Swann, Jill L. Ostrem, Philip A. Starr
ObjectiveTo investigate cortical activity using scalp EEG in patients with isolated dystonia treated with chronic deep brain stimulation (DBS), on and off stimulation.MethodsWe analyzed 64-channel scalp EEG in 12 isolated dystonia patients treated with chronic DBS (7 generalized, 5 cervical/segmental; 7 globus pallidus (GP), 5 subthalamic nucleus (STN)), and 20 healthy age-matched controls. Recordings during rest and movement task, and clinical motor scores, were collected with DBS-on and during a 90-min DBS washout.ResultsResting state alpha power in the dominant (or contralateral to more dystonic side) motor cortex channel during DBS was comparable to healthy controls, but it increased when DBS was stopped. Resting state and movement-related alpha coherence between bilateral motor cortex channels was increased off DBS.ConclusionsChronic DBS reduces exaggerated alpha oscillations and interhemispheric alpha coherence in the motor cortex of patients with isolated dystonia.SignificanceThese findings complement related studies in Parkinson's disease and support the view that network desynchronization is a prominent mechanism of DBS in movement disorders.



from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2BYPPaK

The effect of increased intracranial EEG sampling rates in clinical practice

Publication date: February 2018
Source:Clinical Neurophysiology, Volume 129, Issue 2
Author(s): Kathryn A. Davis, Seth P. Devries, Abba Krieger, Temenuzhka Mihaylova, Daniela Minecan, Brian Litt, Joost B. Wagenaar, William C. Stacey
ObjectiveRecent research suggests that high frequency intracranial EEG (iEEG) may improve localization of epileptic networks. This study aims to determine whether recording macroelectrode iEEG with higher sampling rates improves seizure localization in clinical practice.Methods14 iEEG seizures from 10 patients recorded with >2000 Hz sampling rate were downsampled to four sampling rates: 100, 200, 500, 1000 Hz. In the 56 seizures, seizure onset time and location was marked by 5 independent, blinded EEG experts.ResultsWhen reading iEEG under clinical conditions, there was no consistent difference in time or localization of seizure onset or number of electrodes involved in the seizure onset zone with sampling rates varying from 100 to 1000 Hz. Stratification of patients by outcome did not improve with higher sampling rate.ConclusionWhen utilizing standard clinical protocols, there was no benefit to acquiring iEEGs with sampling rate >100 Hz. Significant variability was noted in EEG marking both within and between individual expert EEG readers.SignificanceAlthough commercial equipment is capable of sampling much faster than 100 Hz, tools allowing visualization of subtle high frequency activity such as HFOs will be required to improve patient care. Quantitative methods may decrease reader variability, and potentially improve patient outcomes.



from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2zEj7Wg

Fasciculation potentials and decremental responses in amyotrophic lateral sclerosis

Publication date: February 2018
Source:Clinical Neurophysiology, Volume 129, Issue 2
Author(s): Yosuke Miyaji, Yuki Hatanaka, Mana Higashihara, Takamichi Kanbayashi, Fumiaki Tanaka, Masahiro Sonoo
ObjectiveThe positive correlation between fasciculation potentials (FPs) and decremental responses in repetitive nerve stimulation test (RNS) in amyotrophic lateral sclerosis (ALS) patients has been described based on only one past study. We revisited this issue.MethodsSubjects consisted of 30 prospectively-enrolled ALS patients on whom both needle EMG and RNS were conducted in the same trapezius muscle. Fasciculation potentials (FPs) were identified off-line from the restored 3-min signal. Firing rate of FPs (FR-FP) per minute was calculated from the total count of FPs of different origins. Correlations between FR-FP, decremental percentage (Decr%) and the amplitude of the initial compound muscle action potential (CMAPamp) in RNS were investigated.ResultsThere was no correlation between FR-FP and Decr% (r = 0.03) or between FR-FP and CMAPamp (r = 0.04). A significant negative correlation was observed between CMAPamp and Decr% (r = −0.56, P < .005).ConclusionFPs are not correlated with the decremental response in RNS.SignificanceThe underlying mechanism for FPs and decremental responses in ALS must be different and unrelated to each other.



from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2C1YEkp

Nerve ultrasound in neurofibromatosis type 1: A follow-up study

Publication date: February 2018
Source:Clinical Neurophysiology, Volume 129, Issue 2
Author(s): Johan A. Telleman, Menno D. Stellingwerff, Geert J. Brekelmans, Leo H. Visser
ObjectiveTo investigate development of sonographic abnormalities and applications of high-resolution ultrasonography (HRUS) in neurofibromatosis type 1 (NF1).MethodsSixteen asymptomatic or minimally symptomatic NF1 patients underwent HRUS at inclusion and 1 year follow-up. Upper and lower extremity nerves were investigated. Peripheral nerve involvement was graded.ResultsPlexiform neurofibromas (PNFs) were found in 7 patients (43.8%) at inclusion and 10 (62.5%) at follow-up. All initially identified PNFs were also found at follow-up; additional PNFs were found by extended longitudinal assessment at follow-up. All 3 patients with minor and 7 patients with severe peripheral nerve involvement had similar involvement at follow-up. Mean nerve size change was −0.2 mm² (±1.6) and 0.3 mm² (±6.2) in patients with minor and severe involvement. Mean PNF size change was −0.1 mm² (±9.9).ConclusionsHRUS allows qualitative assessment of peripheral nerves, which makes it advantageous as initial imaging technique in suspected neuropathy. Patients with minimal nerve involvement remained so, and might therefore require less follow-up for malignant peripheral nerve sheath tumor (MPNSTs) development. Measured change in PNF size was highly variable. Repeating an extensive standardized HRUS protocol during follow-up thus seems less useful to screen for MPNSTs.SignificanceHRUS has potential applications as diagnostic and screening tool in NF1.



from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2zDreCh

Correlations between MUNIX and adapted multiple point stimulation MUNE methods

Publication date: February 2018
Source:Clinical Neurophysiology, Volume 129, Issue 2
Author(s): Karim Benmouna, Christophe Milants, François Charles Wang
ObjectiveThe aim of this study was to evaluate how the motor unit number index (MUNIX) is related to the adapted multiple point stimulation (AMPS) technique.MethodsMUNIX and AMPS technique were prospectively performed on thenar muscles in 20 consecutive patients referred to our neurophysiological laboratory with the clinical diagnosis of a possible motoneurone disorder (MND). The clinical and paraclinical assessment confirmed the diagnosis of MND in 13 out of 20 patients, amyotrophic lateral sclerosis (ALS) in 9 (with MND group). In the other 7 patients, there were neither evidence of MND, nor of any peripheral nervous system disease (without MND group).ResultsAMPS and MUNIX data were significantly (p < 0.001) lower in patients with MND than in patients without MND. There was a strong significant positive linear correlation between AMPS and MUNIX values (n = 20; R = 0.83; p < 0.01).ConclusionBoth MUNIX and AMPS methods could serve as a reliable marker to document the motor unit loss.SignificanceThe present paper constitutes one more clue of MUNIX reliability.



from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2C17i2o

Detecting sub-second changes in brain activation patterns during interictal epileptic spike using simultaneous EEG-fMRI

Publication date: February 2018
Source:Clinical Neurophysiology, Volume 129, Issue 2
Author(s): Epifanio Bagarinao, Satoshi Maesawa, Yuji Ito, Naotaka Usui, Jun Natsume, Hirohisa Watanabe, Minoru Hoshiyama, Toshihiko Wakabayashi, Gen Sobue, Shinji Naganawa, Haruo Isoda
ObjectiveEpileptic spikes are associated with rapidly changing brain activation involving the epileptic foci and other brain regions in the "epileptic network". We aim to resolve these activation changes using simultaneous electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) recordings.MethodsSimultaneous EEG-fMRI recordings from 9 patients with epilepsy were used in the analysis. Our method employed the whole scalp EEG data to generate regressors for the analysis of fMRI data using the general linear model.ResultsWe were able to resolve, with milliseconds temporal resolution, changes in activation patterns involving suspected epileptic foci and other brain regions in the epileptic network during spike and slow wave. Using summary maps (called SSWAS maps) which show the activation frequency of voxels, we found that suspected epileptic foci tend to be significantly active during this interval. SSWAS maps also enabled the detection of the epileptic foci in 4 of 5 patients where the conventional event-timing-based analysis failed to identify.ConclusionThese findings demonstrated the efficacy of the method and the potential application of SSWAS maps to identify epileptic foci.SignificanceThe method could help resolve activation changes during epileptic spike and could provide insights into the underlying pathophysiology of these changes.



from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2C1XXaH

Impact of FHIT loss on the translation of cancer-associated mRNAs

Abstract

Background

FHIT is a genome caretaker/tumor suppressor that is silenced in >50% of cancers. Although it was identified more than 20 years ago, questions remain as to how FHIT loss contributes to cancer, and conversely, how FHIT acts to maintain genome integrity and suppress malignancy. Fhit belongs to the histidine triad family of enzymes that catalyze the degradation of nucleoside 5′,5′-triphosphates, including the m⁷GpppN 'caps' that are generated when mRNAs undergo 3′-5′ decay. This raised the possibility that Fhit loss might affect changes in the translation of cancer-associated mRNAs, possibly as a consequence of increased intracellular concentrations of these molecules.

Results

Ribosome profiling identified several hundred mRNAs for which coding region ribosome occupancy changed as a function of Fhit expression. While many of these changes could be explained by changes in mRNA steady-state, a subset of these showed changes in translation efficiency as a function of Fhit expression. The onset of malignancy has been linked to changes in 5'-UTR ribosome occupancy and this analysis also identified ribosome binding to 5′-untranslated regions (UTRs) of a number of cancer-associated mRNAs. 5'-UTR ribosome occupancy of these mRNAs differed between Fhit-negative and Fhit-positive cells, and in some cases these differences correlated with differences in coding region ribosome occupancy.

Conclusions

In summary, these findings show Fhit expression impacts the translation of a number of cancer associated genes, and they support the hypothesis that Fhit's genome protective/tumor suppressor function is associated with post-transcriptional changes in expression of genes whose dysregulation contributes to malignancy.

from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2ChmOnO

The changing face of clinical trials in the personalized medicine and immuno-oncology era: report from the international congress on clinical trials in Oncology & Hemato-Oncology (ICTO 2017)

Abstract

In the past decade, the oncology community has witnessed major advances in the understanding of cancer biology and major breakthroughs in several different therapeutic areas, from solid tumors to hematological malignancies; moreover, the advent of effective immunotherapy approaches, such as immune-checkpoint blockade, is revolutionizing treatment algorithms in almost all oncology disease areas. As knowledge evolves and new weapons emerge in the "war against cancer", clinical and translational research need to adapt to a rapidly changing environment to effectively translate novel concepts into sustainable and accessible therapeutic options for cancer patients.

With this in mind, translational cancer researchers, oncology professionals, treatment experts, CRO and industry leaders, as well as patient representatives gathered in London, 16-17 March 2017, for The International Congress on Clinical Trials in Oncology and Hemato-Oncology (ICTO2017), to discuss the changing face of oncology clinical trials in the new era of personalized medicine and immuno-oncology. A wide range of topics, including clinical trial design in immuno-oncology, biomarker-oriented drug development paths, statistical design and endpoint selection, challenges in the design and conduct of personalized medicine clinical trials, risk-based monitoring, financing and reimbursement, as well as best operational practices, were discussed in an open, highly interactive format, favoring networking among all relevant stakeholders. The most relevant data, approaches and issues emerged and discussed during the conference are summarized in this report.

from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2pJJPx4

Effective radiotherapeutic treatment intensification in patients with pancreatic cancer: higher doses alone, higher RBE or both?

Abstract

Pancreatic cancer, especially in case of locally advanced stage has a poor prognosis. Radiotherapy in general can lead to tumor volume reduction, but further improvements, such as ion beam therapy have to be promoted in order to enable dose escalation, which in turn results in better local control rates and downsizing of the tumor itself. Ion beam therapy with its highly promising physical properties is also accompanied by distinct inter- and intrafractional challenges in case of robustness. First clinical results are promising, but further research in motion mitigation and biological treatment planning is necessary, in order to determine the best clinical rationales and conditions of ion beam therapy of pancreatic cancer. This review summarizes the current knowledge and studies on ion beam therapy of pancreatic cancer.

from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2BMQ98v

Desmoplastic Small Round Cell Tumor: A Rare Case of Extraluminal Bowel Obstruction and Review of the Literature

from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2zD2ZUN

Docosahexaenoic acid reduces sterol regulatory element binding protein-1 and fatty acid synthase expression and inhibits cell proliferation by inhibiting pAkt signaling in a human breast cancer MCF-7 cell line

Abstract

Background

Fatty acid synthase (FASN), the major enzyme in de novo fatty acid synthesis, is highly expressed in breast cancer and its expression is reduced by polyunsaturated fatty acids (PUFAs) in liver. We previously found a positive association between rat mammary tumor levels of the n-6 PUFA arachidonic acid (AA) and tumor weight. We examined the roles of the major n-3 PUFA, docosahexaenoic acid (DHA, 22:6n-3), and the major n-6 PUFA, AA, in FASN expression in, and proliferation of, human breast cancer MCF-7 cells.

Methods

The cells were treated for 48 h with BSA or 60 μM BSA-bound DHA, AA, or oleic acid (OA, 18:1n-9), then were incubated with or without estradiol or insulin. Western blot and ³H–thymidine incorporation assay were used to determine the role of DHA on FASN regulation and MCF-7 cell proliferation.

Results

DHA, but neither AA nor OA, inhibits estradiol-induced and insulin-induced expression of the precursor of sterol regulatory element binding protein-1 (p-SREBP-1), its mature form (m-SREBP-1), and FASN. Estradiol or insulin stimulation increased the pAkt/Akt and pS6/S6 ratios, expression of p-SREBP-1, m-SREBP-1, and FASN, and cell proliferation, and these effects were decreased by DHA. The DHA-induced decrease in FASN expression resulted from reduced pAkt/Akt signaling and not pERK1/2/ERK1/2 signaling. In addition, DHA enhanced the inhibitory effect of LY294002 on pAkt signaling and expression of p-SREBP-1, m-SREBP-1, and FASN. However, addition of rapamycin, an inhibitor of the mTOR signaling pathways, 1 h before addition of estradiol or insulin increased the pAkt/Akt ratio and FASN expression, and this effect was inhibited by addition of DHA 48 h before rapamycin.

Conclusion

We conclude that, in MCF-7 cells, DHA inhibits pAKT signaling and thus expression of p-SREBP-1, m-SREBP-1, and FASN and cell proliferation.

from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2l8y7ae

Chromosomal instability induced by increased BIRC5 /Survivin levels affects tumorigenicity of glioma cells

Abstract

Background

Survivin, belonging to the inhibitor of apoptosis (IAP) gene family, is abundantly expressed in tumors. It has been hypothesized that Survivin facilitates carcinogenesis by inhibition of apoptosis resulting in improved survival of tumorigenic progeny. Additionally, Survivin plays an essential role during mitosis. Together with its molecular partners Aurora B, Borealin and inner centromere protein it secures bipolar chromosome segregation. However, whether increased Survivin levels contribute to progression of tumors by inducing chromosomal instability remains unclear.

Methods

We overexpressed Survivin in U251-MG, SVGp12, U87-MG, HCT116 and p53-deficient U87-MG^shp53 and HCT116^p53−/− cells. The resulting phenotype was investigated by FACS-assisted cell cycle analysis, Western Blot analysis, confocal laser scan microscopy, proliferation assays, spectral karyotyping and in a U251-MG xenograft model using immune-deficient mice.

Results

Overexpression of Survivin affected cells with knockdown of p53, cells harboring mutant p53 and SV40 large T antigen, respectively, resulting in the increase of cell fractions harboring 4n and >4n DNA contents. Increased γH2AX levels, indicative of DNA damage were monitored in all Survivin-transduced cell lines, but only in p53 wild type cells this was accompanied by an attenuated S-phase entry and activation of p21^waf/cip. Overexpression of Survivin caused a DNA damage response characterized by increased appearance pDNA-PKcs foci in cell nuclei and elevated levels of pATM S1981 and pCHK2 T68. Additionally, evolving structural chromosomal aberrations in U251-MG cells transduced with Survivin indicated a DNA-repair by non-homologous end joining recombination. Subcutaneous transplantation of U251-MG cells overexpressing Survivin and mycN instead of mycN oncogene alone generated tumors with shortened latency and decreased apoptosis. Subsequent SKY-analysis of Survivin/mycN-tumors revealed an increase in structural chromosomal aberrations in cells when compared to mycN-tumors.

Conclusions

Our data suggest that increased Survivin levels promote adaptive evolution of tumors through combining induction of genetic heterogeneity with inhibition of apoptosis.

from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2liIHuQ

Prediction of survival after neoadjuvant chemotherapy for breast cancer by evaluation of tumor-infiltrating lymphocytes and residual cancer burden

Abstract

Background

The tumor immune environment not only modulates the effects of immunotherapy, but also the effects of other anticancer drugs and treatment outcomes. These immune responses can be evaluated with tumor-infiltrating lymphocytes (TILs), which has frequently been verified clinically. On the other hand, residual cancer burden (RCB) evaluation has been shown to be a useful predictor of survival after neoadjuvant chemotherapy (NAC). In this study, RCB and TILs evaluations were combined to produce an indicator that we have termed "RCB-TILs", and its clinical application to NAC for breast cancer was verified by subtype-stratified analysis.

Methods

A total of 177 patients with breast cancer were treated with NAC. The correlation between RCB and TILs evaluated according to the standard method, and prognosis, including the efficacy of NAC, was investigated retrospectively. The RCB and TILs evaluations were combined to create the "RCB-TILs". Patients who were RCB-positive and had high TILs were considered RCB-TILs-positive, and all other combinations were RCB-TILs-negative.

Results

On multivariable analysis, being RCB-TILs-positive was an independent factor for recurrence after NAC in all patients (p < 0.001, hazard ratio = 0.048), triple-negative breast cancer (TNBC) patients (p = 0.018, hazard ratio = 0.041), HER2-positive breast cancer (HER2BC) patients (p = 0.036, hazard ratio = 0.134), and hormone receptor-positive breast cancer (HRBC) patients (p = 0.002, hazard ratio = 0.081).

Conclusions

The results of the present study suggest that RCB-TILs is a significant predictor for breast cancer recurrence after NAC and may be a more sensitive indicator than TILs alone.

from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2l9I1IV