An Update on Grading of Salivary Gland Carcinomas

Histologic grade is a significant predictor of outcome in salivary gland carcinomas. However, the sheer variety of tumor type and the rarity of these tumors pose challenges to devising highly predictive grading schemes. As our knowledge base has evolved, it is clear that carcinoma ex pleomorphic adenoma is not automatically a high grade tumor as is traditionally suggested. These tumors should be further qualified as to type/grade of carcinoma and extent, since intracapsular and minimally invasive carcinomas ex pleomorphic adenoma behave favorably. The two carcinoma types for which grading schemes are common include adenoid cystic carcinoma and mucoepidermoid carcinoma. Adenoid cystic carcinomas are graded based solely on pattern with solid components portending a worse prognosis. Occasionally, adenoid cystic carcinomas may undergo transformation to pleomorphic high grade carcinomas. This feature confers a high propensity for lymph node metastasis and should thus be reported to alert the clinical team. Mucoepidermoid carcinomas are graded in a three tier fashion based on a constellation of features including cystic component, border, mitoses, anaplasia, and perineural invasion among others. All grading schemes are somewhat cumbersome, intimidating and occasionally ambiguous, but evidence suggests that using a scheme consistently shows greater reproducibility than using an intuitive approach. The intermediate grade category demonstrates the most variability between grading systems and thus the most controversy in management. In the AFIP system intermediate grade tumors cluster with high grade tumors, while in the Brandwein system, they cluster with low grade tumors

Multiple reassortment events in the evolutionary history of H1N1 influenza A virus since 1918

The H1N1 subtype of influenza A virus has caused substantial morbidity and mortality in humans, first documented in the global pandemic of 1918 and continuing to the present day. Despite this disease burden, the evolutionary history of the A/H1N1 virus is not well understood, particularly whether there is a virological basis for several notable epidemics of unusual severity in the 1940s and 1950s. Using a data set of 71 representative complete genome sequences sampled between 1918 and 2006, we show that segmental reassortment has played an important role in the genomic evolution of A/H1N1 since 1918. Specifically, we demonstrate that an A/H1N1 isolate from the 1947 epidemic acquired novel PB2 and HA genes through intra-subtype reassortment, which may explain the abrupt antigenic evolution of this virus. Similarly, the 1951 influenza epidemic may also have been associated with reassortant A/H1N1 viruses. Intra-subtype reassortment therefore appears to be a more important process in the evolution and epidemiology of H1N1 influenza A virus than previously realized

Acinic cell carcinoma in pregnancy: a case report and review of the literature

<p>Abstract</p> <p>Introduction</p> <p>We report an observational study on the etiology and recurrence of acinic cell carcinoma of the parotid gland that seemed to be related to pregnancy. The medical literature has never reported such an association; therefore, our case report is probably the first to mention this observation.</p> <p>Case presentation</p> <p>This report is of a 25-year-old Arabic female patient from the United Arab Emirates, who, during her first pregnancy, developed acinic cell carcinoma of the right parotid gland that was managed with surgical excision in the form of superficial parotidectomy. During her second pregnancy, which occurred four years later, she had a recurrence of the same malignant neoplasm associated with ipsilateral malignant cervical lymphadenopathy. The patient was managed with total parotidectomy and neck dissection, as well as postoperative adjuvant radiotherapy. Our observation on this particular case of acinic cell carcinoma is that the initial onset of her neoplasm was during her first pregnancy, and the recurrence of the same malignant disease was during a subsequent pregnancy. This chronologic association raised our suspicion that there might be a possible etiologic effect of pregnancy or its associated hormonal or physiologic changes or both on the pathogenesis or etiology of acinic cell carcinoma.</p> <p>Conclusion</p> <p>Some association might exist between pregnancy and the pathogenesis or etiology of acinic cell carcinoma.</p

Progress in Understanding and Treating SCN2A-Mediated Disorders

Advances in gene discovery for neurodevelopmental disorders have identified SCN2A dysfunction as a leading cause of infantile seizures, autism spectrum disorder, and intellectual disability. SCN2A encodes the neuronal sodium channel NaV1.2. Functional assays demonstrate strong correlation between genotype and phenotype. This insight can help guide therapeutic decisions and raises the possibility that ligands that selectively enhance or diminish channel function may improve symptoms. The well-defined function of sodium channels makes SCN2A an important test case for investigating the neurobiology of neurodevelopmental disorders more generally. Here, we discuss the progress made, through the concerted efforts of a diverse group of academic and industry scientists as well as policy advocates, in understanding and treating SCN2A-related disorders

Combined treatment of malignant salivary gland tumours with intensity-modulated radiation therapy (IMRT) and carbon ions: COSMIC

<p>Abstract</p> <p>Background</p> <p>Local control in malignant salivary gland tumours is dose dependent. High local control rates in adenoid cystic carcinomas could be achieved by highly conformal radiotherapy techniques and particle (neutron/carbon ion) therapy. Considering high doses are needed to achieve local control, all malignant salivary gland tumours probably profit from the use of particle therapy, which in case of carbon ion treatment, has been shown to be accompanied by only mild side-effects.</p> <p>Methods/design</p> <p>The COSMIC trial is a prospective, mono-centric, phase II trial evaluating toxicity (primary endpoint: mucositis ≥ CTCAE°3) and efficacy (secondary endpoint: local control, disease-free survival) in the combined treatment with IMRT and carbon ion boost in 54 patients with histologically proved (≥R1-resected, inoperable or Pn+) salivary gland malignancies. Patients receive 24 GyE carbon ions (8 fractions) and IMRT (50 Gy at 2.0 Gy/fraction).</p> <p>Discussion</p> <p>The primary objective of COSMIC is to evaluate toxicity and feasibility of the proposed treatment in all salivary gland malignancies.</p> <p>Trial Registration</p> <p>Clinical trial identifier NCT 01154270</p

ANDES: Statistical tools for the ANalyses of DEep Sequencing

<p>Abstract</p> <p>Background</p> <p>The advancements in DNA sequencing technologies have allowed researchers to progress from the analyses of a single organism towards the deep sequencing of a sample of organisms. With sufficient sequencing depth, it is now possible to detect subtle variations between members of the same species, or between mixed species with shared biomarkers, such as the 16S rRNA gene. However, traditional sequencing analyses of samples from largely homogeneous populations are often still based on multiple sequence alignments (MSA), where each sequence is placed along a separate row and similarities between aligned bases can be followed down each column. While this visual format is intuitive for a small set of aligned sequences, the representation quickly becomes cumbersome as sequencing depths cover loci hundreds or thousands of reads deep.</p> <p>Findings</p> <p>We have developed ANDES, a software library and a suite of applications, written in Perl and R, for the statistical ANalyses of DEep Sequencing. The fundamental data structure underlying ANDES is the position profile, which contains the nucleotide distributions for each genomic position resultant from a multiple sequence alignment (MSA). Tools include the root mean square deviation (RMSD) plot, which allows for the visual comparison of multiple samples on a position-by-position basis, and the computation of base conversion frequencies (transition/transversion rates), variation (Shannon entropy), inter-sample clustering and visualization (dendrogram and multidimensional scaling (MDS) plot), threshold-driven consensus sequence generation and polymorphism detection, and the estimation of empirically determined sequencing quality values.</p> <p>Conclusions</p> <p>As new sequencing technologies evolve, deep sequencing will become increasingly cost-efficient and the inter and intra-sample comparisons of largely homogeneous sequences will become more common. We have provided a software package and demonstrated its application on various empirically-derived datasets. Investigators may download the software from Sourceforge at <url>https://sourceforge.net/projects/andestools</url>.</p

DNA aneuploidy as a topographic malignant transformation pattern in a pleomorphic adenoma of long-term evolution: a case report

<p>Abstract</p> <p>Introduction</p> <p>We present a case of long-term evolution of a submandibular pleomorphic adenoma. There is little information about topographic malignant transformation patterns of pleomorphic adenomas.</p> <p>Case presentation</p> <p>We extensively analyze a giant submandibular mixed tumor of 25-year evolution in a 57-year-old Caucasian woman. Deoxyribonucleic acid ploidy was evaluated in different superficial and deep areas using flow cytometry analysis and correlated with pathological and immunohistochemical characteristics. Superficial areas exhibited a typical histological pleomorphic adenoma pattern and were deoxyribonucleic acid diploid. Deep samples showed deoxyribonucleic acid aneuploidy, atypical histological benign features and expression of markers involved at an early-stage of malignant transformation, such as tumor protein 53 and antigen Ki67.</p> <p>Conclusion</p> <p>These findings revealed that deep tumor compartments may be involved in the initial stages of malignant transformation. Deoxyribonucleic acid ploidy analysis may provide an additional diagnosis tool and indicate 'uncertain' areas that require careful study to avoid diagnostic errors. Larger studies are needed to confirm our results and to evaluate the usefulness of the technique.</p

Combined treatment of adenoid cystic carcinoma with cetuximab and IMRT plus C12 heavy ion boost: ACCEPT [ACC, Erbitux® and particle therapy]

<p>Abstract</p> <p>Background</p> <p>Local control in adjuvant/definitive RT of adenoid cystic carcinoma (ACC) is largely dose-dependent leading to the establishment of particle therapy in this indication. However, even modern techniques leave space for improvement of local control by intensification of local treatment. Radiation sensitization by exploitation of high EGFR-expression in ACC with the EGFR receptor antibody cetuximab seems promising.</p> <p>Methods/design</p> <p>The ACCEPT trial is a prospective, mono-centric, phase I/II trial evaluating toxicity (primary endpoint: acute and late effects) and efficacy (secondary endpoint: local control, distant control, disease-free survival, overall survival) of the combined treatment with IMRT/carbon ion boost and weekly cetuximab in 49 patients with histologically proven (≥R1-resected, inoperable or Pn+) ACC. Patients receive 18 GyE carbon ions (6 fractions) and 54 Gy IMRT (2.0 Gy/fraction) in combination with weekly cetuximab throughout radiotherapy.</p> <p>Discussion</p> <p>The primary objective of ACCEPT is to evaluate toxicity and feasibility of cetuximab and particle therapy in adenoid cystic carcinoma.</p> <p>Trial Registration</p> <p>Clinical Trial Identifier: <a href="http://www.clinicaltrials.gov/ct2/show/NCT01192087">NCT 01192087</a></p> <p>EudraCT number: 2010 - 022425 - 15</p

Knock-Down of Core Proteins Regulating MicroRNA Biogenesis Has No Effect on Sensitivity of Lung Cancer Cells to Ionizing Radiation

Recent studies underline the important role of microRNAs (miRNA) in the development of lung cancer. The main regulators of miRNA biogenesis are the ribonucleases Drosha, Dicer and Ago2. Here the role of core proteins of miRNA biogenesis machinery in the response of human non-small and small cell lung carcinoma cell lines to treatment with ionizing radiation was assessed. We found that Drosha and Dicer were expressed at higher levels in radioresistant but not in sensitive cell lines. However, down-regulation of either Dicer or Drosha had no effect on the sensitivity of cells to irradiation. Elimination of components of the RNA-induced silencing complex Ago2 and Tudor staphylococcal nuclease also did not sensitize cells to the same treatment. Thus, modulation of miRNA biogenesis machinery is not sufficient to increase the radiosensitivity of lung tumors and other strategies are required to combat lung cancer