Merkel Cell Carcinoma.

Merkel cell carcinoma (MCC) is a rare and aggressive neuroendocrine skin cancer that is highly radiosensitive and immunogenic. Immunotherapy is the primary treatment of advanced disease, and immune checkpoint inhibitors show promise as neoadjuvant or adjuvant therapy in patients with high-risk resectable MCC. Emerging biomarkers of tumor burden are becoming increasingly important in identifying high-risk patients and in post-treatment surveillance. Further research is needed to determine the optimal duration of anti-PD-(L)1 treatment and second-line options for patients with MCC refractory to immunotherapy. This review covers the characteristics and management of MCC including recent innovations and areas of active investigation.

Greener Operations: a James Lind Alliance Priority Setting Partnership to define research priorities in environmentally sustainable perioperative practice through a structured consensus approach.

OBJECTIVES: To agree on the 'top 10' research priorities for environmentally sustainable perioperative practice. DESIGN: Surveys and literature review; final consensus workshop using a nominal group technique. SETTING: UK-based setting. PARTICIPANTS: Healthcare professionals, patients, carers and the public. OUTCOME MEASURES: Initial survey-suggested research questions; interim survey-shortlist of 'indicative' questions (the 20 most frequently nominated by patients, carers and the public, and healthcare professionals); final workshop-ranked research priorities. RESULTS: Initial survey-1926 suggestions by 296 respondents, refined into 60 indicative questions. Interim survey-325 respondents. Final workshop-21 participants agreed the 'top 10': (1) How can more sustainable reusable equipment safely be used during and around the time of an operation? (2) How can healthcare organisations more sustainably procure (obtain) medicines, equipment and items used during and around the time of an operation? (3) How can healthcare professionals who deliver care during and around the time of an operation be encouraged to adopt sustainable actions in practice? (4) Can more efficient use of operating theatres and associated practices reduce the environmental impact of operations? (5) How can the amount of waste generated during and around the time of an operation be minimised? (6) How do we measure and compare the short-term and long-term environmental impacts of surgical and non-surgical treatments for the same condition? (7) What is the environmental impact of different anaesthetic techniques (eg, different types of general, regional and local anaesthesia) used for the same operation? (8) How should the environmental impact of an operation be weighed against its clinical outcomes and financial costs? (9) How can environmental sustainability be incorporated into the organisational management of operating theatres? (10) What are the most sustainable forms of effective infection prevention and control used around the time of an operation (eg, personal protective equipment, drapes, clean air ventilation)? CONCLUSIONS: A broad range of 'end-users' have identified research priorities for sustainable perioperative care.

A Case of Acute Myeloid Leukemia-Associated Necrotizing Sweet Syndrome.

Sweet syndrome (SS), or acute febrile neutrophilic dermatosis, is a rare painful skin condition that is characterized by hyperpyrexia, peripheral blood and skin neutrophilia, and edematous skin lesions. Necrotizing SS (NSS) is a severe and locally aggressive condition that histopathologically resembles a necrotizing soft tissue infection. As opposed to necrotizing soft tissue infections, NSS responds to systemic steroids. SS is divided into three subtypes: classical SS, malignancy-associated SS, and drug-induced SS. Within the malignancy-associated SS subtype, both solid tumor and hematologic malignancies have been precursors to developing SS. Here, we present a case of acute myeloid leukemia-associated NSS.

A Histologic Timeline of a Delayed Hypersensitivity Reaction after the COVID-19 Pfizer Booster.

A 54-year-old man presented with worsening bilateral rashes on legs and arms 7 days after receiving his BNT162b2 mRNA COVID-19 (Pfizer) vaccine booster. He developed burning on his palms about 5 days after receiving the booster. On day 6, he observed significant edema on his fingers and palms in addition to thin erythematous papules on his forearms. On day 7, he developed edema on his bilateral dorsal feet, and thin erythematous plaques on his shins. He stated that the rashes were pruritic. He had no rashes following the first two doses of the Pfizer vaccine. He denied having any history of skin disease, autoimmune disease, or allergies. Physical examination revealed multiple thin erythematous papules coalescing into thin plaques on his flexor forearms, and thin erythematous plaques on his dorsal feet (Figure 1). Three 4-mm punch biopsies were performed on his left flexor forearm. The biopsies were carried out at papules present for different lengths of time. Papules at biopsy sites "A," "B," and "C" were present for approximately 24-36 hours, 12-18 hours, and 3-6 hours, respectively (Figure 1).

FTO Plays an Oncogenic Role in Acute Myeloid Leukemia as a N6-Methyladenosine RNA Demethylase.

N6-Methyladenosine (m6A) represents the most prevalent internal modification in mammalian mRNAs. Despite its functional importance in various fundamental bioprocesses, the studies of m6A in cancer have been limited. Here we show that FTO, as an m6A demethylase, plays a critical oncogenic role in acute myeloid leukemia (AML). FTO is highly expressed in AMLs with t(11q23)/MLL rearrangements, t(15;17)/PML-RARA, FLT3-ITD, and/or NPM1 mutations. FTO enhances leukemic oncogene-mediated cell transformation and leukemogenesis, and inhibits all-trans-retinoic acid (ATRA)-induced AML cell differentiation, through regulating expression of targets such as ASB2 and RARA by reducing m6A levels in these mRNA transcripts. Collectively, our study demonstrates the functional importance of the m6A methylation and the corresponding proteins in cancer, and provides profound insights into leukemogenesis and drug response.

Eradication of Acute Myeloid Leukemia with FLT3 Ligand-Targeted miR-150 Nanoparticles.

Acute myeloid leukemia (AML) is a common and fatal form of hematopoietic malignancy. Overexpression and/or mutations of FLT3 have been shown to occur in the majority of cases of AML. Our analysis of a large-scale AML patient cohort (N = 562) indicates that FLT3 is particularly highly expressed in some subtypes of AML, such as AML with t(11q23)/MLL-rearrangements or FLT3-ITD. Such AML subtypes are known to be associated with unfavorable prognosis. To treat FLT3-overexpressing AML, we developed a novel targeted nanoparticle system: FLT3 ligand (FLT3L)-conjugated G7 poly(amidoamine) (PAMAM) nanosized dendriplex encapsulating miR-150, a pivotal tumor suppressor and negative regulator of FLT3 We show that the FLT3L-guided miR-150 nanoparticles selectively and efficiently target FLT3-overexpressing AML cells and significantly inhibit viability/growth and promote apoptosis of the AML cells. Our proof-of-concept animal model studies demonstrate that the FLT3L-guided miR-150 nanoparticles tend to concentrate in bone marrow, and significantly inhibit progression of FLT3-overexpressing AML in vivo, while exhibiting no obvious side effects on normal hematopoiesis. Collectively, we have developed a novel targeted therapeutic strategy, using FLT3L-guided miR-150-based nanoparticles, to treat FLT3-overexpressing AML with high efficacy and minimal side effects. Cancer Res; 76(15); 4470-80. ©2016 AACR.

miR-22 has a potent anti-tumour role with therapeutic potential in acute myeloid leukaemia.

MicroRNAs are subject to precise regulation and have key roles in tumorigenesis. In contrast to the oncogenic role of miR-22 reported in myelodysplastic syndrome (MDS) and breast cancer, here we show that miR-22 is an essential anti-tumour gatekeeper in de novo acute myeloid leukaemia (AML) where it is significantly downregulated. Forced expression of miR-22 significantly suppresses leukaemic cell viability and growth in vitro, and substantially inhibits leukaemia development and maintenance in vivo. Mechanistically, miR-22 targets multiple oncogenes, including CRTC1, FLT3 and MYCBP, and thus represses the CREB and MYC pathways. The downregulation of miR-22 in AML is caused by TET1/GFI1/EZH2/SIN3A-mediated epigenetic repression and/or DNA copy-number loss. Furthermore, nanoparticles carrying miR-22 oligos significantly inhibit leukaemia progression in vivo. Together, our study uncovers a TET1/GFI1/EZH2/SIN3A/miR-22/CREB-MYC signalling circuit and thereby provides insights into epigenetic/genetic mechanisms underlying the pathogenesis of AML, and also highlights the clinical potential of miR-22-based AML therapy.

Wilms' tumor 1-associating protein regulates the proliferation of vascular smooth muscle cells.

Smooth muscle cells (SMCs) are called on to proliferate during vascular restructuring but must return to a nonproliferative state if remodeling is to appropriately terminate. To identify mediators of the reacquisition of replicative quiescence, we undertook gene expression screening in a uniquely plastic human SMC line. As proliferating SMCs shifted to a contractile and nonproliferative state, expression of TIMP-3, Axl, and KIAA0098 decreased whereas expression of complement C1s, cathepsin B, cellular repressor of E1A-activated genes increased. Wilms' tumor 1-associating protein (WTAP), a nuclear constituent of unknown function, was also upregulated as SMCs became nonproliferative. Furthermore, WTAP in the intima of injured arteries was substantially upregulated in the late stages of repair. Introduction of WTAP complementary DNA into human SMCs inhibited their proliferation, with a corresponding decrease in DNA synthesis and an increase in apoptosis. Knocking down endogenous WTAP increased SMC proliferation, because of increased DNA synthesis and G(1)/S phase transition, together with reduced apoptosis. WTAP was found to associate with the Wilms' tumor-1 protein in human SMCs and WTAP overexpression inhibited the binding of WT1 to an oligonucleotide containing a consensus WT1 binding site, whereas WTAP knockdown accentuated this interaction. Expression of the WT1 target genes, amphiregulin and Bcl-2, was suppressed in WTAP-overexpressing SMCs and increased in WTAP-deficient SMCs. Moreover, exogenous amphiregulin rescued the antiproliferative effect of WTAP. These findings identify WTAP as a novel regulator of the cell cycle and cell survival and implicate a WTAP-WT1 axis as a novel pathway for controlling vascular SMC phenotype.