Primary high-grade neuroendocrine carcinoma emerging from an adenomatous polyp in the setting of familial adenomatous polyposis

Familial adenomatous polyposis (FAP) is a rare inherited syndrome that is characterised by innumerable adenomas of the colon and rectum, a high risk of colorectal cancer and a variety of extracolonic manifestations. FAP presents as hundreds to thousands of colonic adenomas beginning in adolescence. The syndrome is associated with less than 1% of all colorectal cancer cases, but there is a nearly 100% lifetime risk of colorectal cancer in individuals with FAP. This case demonstrates a 60-year-old man with FAP who developed high-grade neuroendocrine carcinoma with glandular and squamous differentiation, and regional lymph node and liver metastases. Early diagnosis of FAP is of the utmost importance to start screening colonoscopies to assess disease burden, perform polypectomies and to make management decisions. Neuroendocrine carcinomas rarely occur in patients with FAP, and awareness of this association among general medical physicians and pathologists is essential for the diagnosis and care of these patients.

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Rivaroxaban and retropharyngeal haemorrhage

Haemorrhage is a well-known and accepted complication of anticoagulation. A retropharyngeal haemorrhage (RH) is a rare condition that without prompt recognition and management may result in fatal complications. We report a case of RH in a 67-year-old man anticoagulated with rivaroxaban for atrial fibrillation. The patient presented to the emergency department, with a two-day history of atraumatic right-sided neck swelling and associated progressive odynophagia, dysphagia and dysphonia. Rivaroxaban is a potent new oral anticoagulant that has been approved for use by National Institute for Health and Care Excellence (NICE) but still has no approved reversal agent. Despite its rarity, an RH is a potentially life threatening complication of anticoagulation that must be carefully considered. This is especially true for a drug that cannot be easily reversed. We present a discussion of this case presentation with possible differential diagnoses and a review of the literature, and recommend the use of Capp's triad as a diagnostic criterion.

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Abatacept for the Treatment of Systemic Lupus Erythematosus.

Abatacept for the Treatment of Systemic Lupus Erythematosus.

Expert Opin Investig Drugs. 2016 Feb 15;

Authors: Pimentel-Quiroz VR, Alarcón GS, Ugarte-Gil MF

Abstract
INTRODUCTION: Due to improvements in our understanding of the pathogenesis of systemic lupus erythematosus (SLE), several target drugs have been and are being developed. One of the possible targets in SLE is co-stimulation between antigen-presenting cells and T cells. Abatacept is a co-stimulation moderator approved for the treatment of several autoimmune diseases. There is an unmet need for drugs with a better efficacy and safety profile when treating patients with SLE. Areas covered: In this review, the authors discuss the mechanism of action of abatacept including its role in the immune system and glomeruli, and relevant information about its clinical efficacy and safety. Possible explanations for the failure of previous randomized clinical trials are also discussed. Expert opinion: Abatacept has demonstrated efficacy in other autoimmune diseases, but in SLE, randomized clinical trials have failed to achieve their primary outcome. Despite these disappointing results and based on its mechanism of action, abatacept seems to have a role in lupus nephritis and arthritis. This should be corroborated with new trials which hopefully will overcome the design pitfalls of the ones conducted to date.

PMID: 26878310 [PubMed - as supplied by publisher]

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Advances in Antiviral Therapies Targeting Toll-like Receptors.

Advances in Antiviral Therapies Targeting Toll-like Receptors.

Expert Opin Investig Drugs. 2016 Feb 15;

Authors: Shah M, Anwar MA, Kim JH, Choi S

Abstract
INTRODUCTION: Organisms have evolved a rapid and non-specific way to defend themselves via Toll-like receptors (TLRs), which recognize specific signatures present on invading microbes and viruses. Once detected, these receptors flood the cell with cytokines and IFNs that not only help to eradicate the invading viruses but also activate the adaptive immune response. Owing to difficulties in viral detection, a whole class of TLRs is dedicated to sensing viral nucleic acids, while other TLRs detect viral coat proteins and aid in establishing antiviral immunity. To protect humans better, TLRs and their downstream mediators can be used as potential drug targets, which can be either activated or inhibited, to counter viral infections. Areas covered: The current review focuses on TLR-targeting investigational drugs developed to treat viral diseases and virus-induced complications. Expert opinion: TLRs are a good choice for eradicating viral infections because they can fine-tune the immune response. However, TLRs should be exploited carefully, as there have been instances where their activation has led to unwanted responses in terms of both immune and viral activation. Therefore, more focus should be placed on novel drugs that can induce significant and long-term immunity, while concomitantly alleviating side effects.

PMID: 26878224 [PubMed - as supplied by publisher]

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Strategies in early clinical development for the treatment of basic defects of cystic fibrosis.

Strategies in early clinical development for the treatment of basic defects of cystic fibrosis.

Expert Opin Investig Drugs. 2016 Feb 15;

Authors: Dhooghe B, Haaf JB, Noel S, Leal T

Abstract
INTRODUCTION: Twenty six years after the identification of the gene responsible for cystic fibrosis (CF), controversies still surround the pathogenesis of the disease that continues to burden and shorten lives. Therefore, finding effective therapeutic strategies that target the basic defect of CF is crucially needed. Areas covered: This review offers a comprehensive survey of fundamental therapies in early stages of development for the treatment of CF. The first part describes recent strategies targeting the basic defect either at the gene or at the transcript level. The second part summarizes a panel of novel strategies targeting protein repair. The third part reports strategies targeting non-CFTR channels. Expert opinion: Recent major breakthroughs in CF therapy have been made, raising hope to find a cure for CF. Apart from Vertex corrector and potentiator molecules (lumacaftor, ivacaftor, VX-661) and from ataluren, used to correct nonsense mutations, most compounds being currently tested are in very early (I-II) phases of development and definitive clinical results are keenly expected. Among the broad list of molecules and strategies being tested, the QR-010 compound and inhibitors of phosphodiesterase type 5 (sildenafil, vardenafil) could reveal a strong potentiality as therapeutic candidates to cure CF.

PMID: 26878157 [PubMed - as supplied by publisher]

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Genomic and transcriptomic hallmarks of poorly differentiated and anaplastic thyroid cancers.

Genomic and transcriptomic hallmarks of poorly differentiated and anaplastic thyroid cancers.

J Clin Invest. 2016 Feb 15;

Authors: Landa I, Ibrahimpasic T, Boucai L, Sinha R, Knauf JA, Shah RH, Dogan S, Ricarte-Filho JC, Krishnamoorthy GP, Xu B, Schultz N, Berger MF, Sander C, Taylor BS, Ghossein R, Ganly I, Fagin JA

Abstract
BACKGROUND: Poorly differentiated thyroid cancer (PDTC) and anaplastic thyroid cancer (ATC) are rare and frequently lethal tumors that so far have not been subjected to comprehensive genetic characterization.
METHODS: We performed next-generation sequencing of 341 cancer genes from 117 patient-derived PDTCs and ATCs and analyzed the transcriptome of a representative subset of 37 tumors. Results were analyzed in the context of The Cancer Genome Atlas study (TCGA study) of papillary thyroid cancers (PTC).
RESULTS: Compared to PDTCs, ATCs had a greater mutation burden, including a higher frequency of mutations in TP53, TERT promoter, PI3K/AKT/mTOR pathway effectors, SWI/SNF subunits, and histone methyltransferases. BRAF and RAS were the predominant drivers and dictated distinct tropism for nodal versus distant metastases in PDTC. RAS and BRAF sharply distinguished between PDTCs defined by the Turin (PDTC-Turin) versus MSKCC (PDTC-MSK) criteria, respectively. Mutations of EIF1AX, a component of the translational preinitiation complex, were markedly enriched in PDTCs and ATCs and had a striking pattern of co-occurrence with RAS mutations. While TERT promoter mutations were rare and subclonal in PTCs, they were clonal and highly prevalent in advanced cancers. Application of the TCGA-derived BRAF-RAS score (a measure of MAPK transcriptional output) revealed a preserved relationship with BRAF/RAS mutation in PDTCs, whereas ATCs were BRAF-like irrespective of driver mutation.
CONCLUSIONS: These data support a model of tumorigenesis whereby PDTCs and ATCs arise from well-differentiated tumors through the accumulation of key additional genetic abnormalities, many of which have prognostic and possible therapeutic relevance. The widespread genomic disruptions in ATC compared with PDTC underscore their greater virulence and higher mortality.
FUNDING: This work was supported in part by NIH grants CA50706, CA72597, P50-CA72012, P30-CA008748, and 5T32-CA160001; the Lefkovsky Family Foundation; the Society of Memorial Sloan Kettering; the Byrne fund; and Cycle for Survival.

PMID: 26878173 [PubMed - as supplied by publisher]

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Roles for miR-375 in Neuroendocrine Differentiation and Tumor Suppression via Notch Pathway Suppression in Merkel Cell Carcinoma.

Roles for miR-375 in Neuroendocrine Differentiation and Tumor Suppression via Notch Pathway Suppression in Merkel Cell Carcinoma.

Am J Pathol. 2016 Feb 11;

Authors: Abraham KJ, Zhang X, Vidal R, Paré GC, Feilotter HE, Tron VA

Abstract
Dysfunction of key miRNA pathways regulating basic cellular processes is a common driver of many cancers. However, the biological roles and/or clinical applications of such pathways in Merkel cell carcinoma (MCC), a rare but lethal cutaneous neuroendocrine (NE) malignancy, have yet to be determined. Previous work has established that miR-375 is highly expressed in MCC tumors, but its biological role in MCC remains unknown. Herein, we show that elevated miR-375 expression is a specific feature of well-differentiated MCC cell lines that express NE markers. In contrast, miR-375 is strikingly down-regulated in highly aggressive, undifferentiated MCC cell lines. Enforced miR-375 expression in these cells induced NE differentiation, and opposed cancer cell viability, migration, invasion, and survival, pointing to tumor-suppressive roles for miR-375. Mechanistically, miR-375-driven phenotypes were caused by the direct post-transcriptional repression of multiple Notch pathway proteins (Notch 2 and RBPJ) linked to cancer and regulation of cell fate. Thus, we detail a novel molecular axis linking tumor-suppressive miR-375 and Notch with NE differentiation and cancer cell behavior in MCC. Our findings identify miR-375 as a putative regulator of NE differentiation, provide insight into the cell of origin of MCC, and suggest that miR-375 silencing may promote aggressive cancer cell behavior through Notch disinhibition.

PMID: 26877261 [PubMed - as supplied by publisher]

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