Aggressive Biology of Extra-Nodal NK/T Cell Lymphoma: A Case Report.

Extra-nodal NK/T cell lymphoma, nasal type (ENKTL) is a rare and aggressive non-Hodgkin lymphoma primarily seen in Asian and South American populations. Diagnosis involves methods like biopsy and molecular testing, with treatment typically combining systemic and radiation therapy. We present the rare case of a 62-year-old female who was diagnosed with localized ENKTL upon initial presentation of nasal congestion. She was started on radiation therapy and responded favorably at first, with decreased congestion and facial swelling. After five weeks of treatment, she developed significant dysphagia and anorexia, which was initially attributed to being a side effect of chemotherapy. After pausing radiation treatment, her condition worsened until she was hospitalized for obstructive jaundice. CT scans and biopsy confirmed metastasis of the cancer to her pancreas. Her condition rapidly declined until she was ultimately sent to hospice care.

A prospective study to evaluate febrile neutropenia incidence in patients receiving pegfilgrastim on-body injector vs other choices.

PURPOSE: We evaluated the incidence of febrile neutropenia (FN) and related clinical outcomes among patients treated with myelosuppressive chemotherapy for nonmyeloid malignancies who received pegfilgrastim on-body injector (OBI) or other options (Other) for FN prophylaxis. METHODS: In this prospective observational study, adult patients with breast, prostate, or lung cancer, or non-Hodgkin lymphoma at risk for FN were stratified into subgroups based on FN prophylaxis used in the first chemotherapy cycle: pegfilgrastim OBI vs Other (pegfilgrastim or biosimilar pegfilgrastim prefilled syringe, daily filgrastim, or no granulocyte colony-stimulating factor [G-CSF]) for up to 4 planned chemotherapy cycles. RESULTS: This US study enrolled 2575 eligible patients (OBI, 1624; Other, 951). FN incidence was lower in the OBI group (6.4% [95% CI, 5.2-7.6%]) than in the Other group (9.4% [7.5-11.2%]), with a relative risk (RR) of 0.66 (0.47-0.91; p = .006). A decreased risk of dose delays among patients receiving pegfilgrastim OBI vs Other was observed (RR for ≥ 5 days: 0.64 [0.42-0.96], p = .023; RR for ≥ 7 days: 0.62 [0.40-0.91], p = .016). Adherence, defined as G-CSF support for all chemotherapy cycles, was 94.0% (92.9-95.2%) in the OBI group compared with 58.4% (55.2-61.5%) in the Other group. Compliance with pegfilgrastim, defined as administration the day after chemotherapy, was 88.3% in the OBI group and 48.8% in the prefilled syringe group. CONCLUSION: Patients receiving pegfilgrastim OBI had a lower incidence of FN compared with those receiving alternatives. The OBI was associated with improved adherence to and compliance with clinically recommended G-CSF prophylaxis.

A prospective cohort study to evaluate the incidence of febrile neutropenia in patients receiving pegfilgrastim on-body injector versus other options for prophylaxis of febrile neutropenia: breast cancer subgroup analysis.

BACKGROUND: Breast cancer chemotherapy often carries a high risk of febrile neutropenia (FN); guidelines recommend prophylaxis with granulocyte colony-stimulating factor (G-CSF), such as pegfilgrastim. Neulasta® Onpro® on-body injector (OBI) is a delivery device administering pegfilgrastim approximately 27 h after application. METHODS: This prospective study examined patients with breast cancer who received chemotherapy with a high risk of FN, receiving OBI ("OBI") or other options (other G-CSF or none; "other"). The primary endpoint was FN incidence; secondary endpoints included chemotherapy delivery, adherence (G-CSF in all cycles), compliance (G-CSF day after chemotherapy), and FN incidence in patients receiving curative or palliative treatment. RESULTS: A total of 1776 patients with breast cancer were enrolled (OBI, n = 1196; other, n = 580). Across all cycles, FN incidence was lower for OBI (4.4% [95% CI, 3.3-5.6%]) than other (7.4% [5.3-9.6%]). For curative treatment, the FN incidence across all cycles was lower for OBI (4.6% [3.4-5.8%]) than for other (7.1% [5.0-9.3%]). For palliative treatment (OBI, n = 33; other, n = 20), 3 patients (15%) in the other and none in the OBI group had FN. After adjusting for baseline covariates, FN incidence remained lower for OBI (4.6% [3.5-6.1%]) versus other (7.8% [5.7-10.5%]). Adherence was higher for OBI (93.8%) than for other G-CSF (69.8%), as was compliance (90.5 and 53.2%, respectively). Chemotherapy dose delays/reductions were similar for OBI (4.7%/32.3%, respectively) and other (4.7%/30.0%) groups. CONCLUSION: Pegfilgrastim OBI was associated with a lower FN incidence in patients with breast cancer compared to other options for FN prophylaxis. TRIAL REGISTRATION: www. CLINICALTRIALS: gov , NCT02178475, registered 30 June, 2014.

Modeling, synthesis, and biological evaluation of potential retinoid X receptor (RXR) selective agonists: novel analogues of 4-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethynyl]benzoic acid (bexarotene) and (E)-3-(3-(1,2,3,4-tetrahydro-1,1,4,4,6-pentamethylnaphthalen-7-yl)-4-hydroxyphenyl)acrylic acid (CD3254).

Three unreported analogues of 4-[1-(3,5,5,8,8-pentamethyl-5-6-7-8-tetrahydro-2-naphthyl)ethynyl]benzoic acid (1), otherwise known as bexarotene, as well as four novel analogues of (E)-3-(3-(1,2,3,4-tetrahydro-1,1,4,4,6-pentamethylnaphthalen-7-yl)-4-hydroxyphenyl)acrylic acid (CD3254), are described and evaluated for their retinoid X receptor (RXR) selective agonism. Compound 1 has FDA approval as a treatment for cutaneous T-cell lymphoma (CTCL), although treatment with 1 can elicit side-effects by disrupting other RXR-heterodimer receptor pathways. Of the seven modeled novel compounds, all analogues stimulate RXR-regulated transcription in mammalian 2 hybrid and RXRE-mediated assays, possess comparable or elevated biological activity based on EC50 profiles, and retain similar or improved apoptotic activity in CTCL assays compared to 1. All novel compounds demonstrate selectivity for RXR and minimal crossover onto the retinoic acid receptor (RAR) compared to all-trans-retinoic acid, with select analogues also reducing inhibition of other RXR-dependent pathways (e.g., VDR-RXR). Our results demonstrate that further improvements in biological potency and selectivity of bexarotene can be achieved through rational drug design.

Synthesis and biological evaluation of halogenated curcumin analogs as potential nuclear receptor selective agonists.

This report describes the synthesis of analogs of curcumin, and their analysis in acting as nuclear receptor specific agonists. Curcumin (CM), a turmeric-derived bioactive polyphenol found in curry, has recently been identified as a ligand for the vitamin D receptor (VDR), and it is possible that CM exerts some of its bioeffects via direct binding to VDR and/or other proteins in the nuclear receptor superfamily. Using mammalian-two-hybrid (M2H) and vitamin D responsive element (VDRE) biological assay systems, we tested CM and 11 CM synthetic analogs for their ability to activate VDR signaling. The M2H assay revealed that RXR and VDR association was induced by CM and several of its analogs. VDRE-based assays demonstrated that pure curcumin and eight CM analogs activated transcription of a luciferase plasmid at levels approaching that of the endocrine 1,25 dihydroxyvitamin D(3) (1,25D) ligand in human colon cancer cells (HCT-116). Additional experiments were performed in HCT-116 utilizing various nuclear receptors and hormone responsive elements to determine the receptor specificity of curcumin binding. CM did not appear to activate transcription in a glucocorticoid responsive system. However, CM along with several analogs elicited transcriptional activation in retinoic acid and retinoid X receptor (RXR) responsive systems. M2H assays using RXR-RXR, VDR-SRC1 and VDR-DRIP revealed that CM and select analogs stimulate RXR homodimerization and VDR-coactivator interactions. These studies may lead to the discovery of novel curcumin analogs that activate nuclear receptors, including RXR, RAR and VDR, resulting in similar health benefits as those for vitamins A and D, such as lowering the risk of epithelial and colon cancers.

Modeling, synthesis and biological evaluation of potential retinoid X receptor-selective agonists: novel halogenated analogues of 4-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethynyl]benzoic acid (bexarotene).

The synthesis of halogenated analogues of 4-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethynyl]benzoic acid (1), known commonly as bexarotene, and their evaluation for retinoid X receptor (RXR)-specific agonist performance is described. Compound 1 is FDA approved to treat cutaneous T-cell lymphoma (CTCL); however, bexarotene treatment can induce hypothyroidism and elevated triglyceride levels, presumably by disrupting RXR heterodimer pathways for other nuclear receptors. The novel halogenated analogues in this study were modeled and assessed for their ability to bind to RXR and stimulate RXR homodimerization in an RXRE-mediated transcriptional assay as well as an RXR mammalian-2-hybrid assay. In an array of eight novel compounds, four analogues were discovered to promote RXR-mediated transcription with EC(50) values similar to that of 1 and are selective RXR agonists. Our approach also uncovered a periodic trend of increased binding and homodimerization of RXR when substituting a halogen atom for a proton ortho to the carboxylic acid on 1.

The novel gamma secretase inhibitor RO4929097 reduces the tumor initiating potential of melanoma.

Several reports have demonstrated a role for aberrant NOTCH signaling in melanoma genesis and progression, prompting us to explore if targeting this pathway is a valid therapeutic approach against melanoma. We targeted NOTCH signaling using RO4929097, a novel inhibitor of gamma secretase, which is a key component of the enzymatic complex that cleaves and activates NOTCH. The effects of RO4929097 on the oncogenic and stem cell properties of a panel of melanoma cell lines were tested both in vitro and in vivo, using xenograft models. In human primary melanoma cell lines, RO4929097 decreased the levels of NOTCH transcriptional target HES1. This was accompanied by reduced proliferation and impaired ability to form colonies in soft agar and to organize in tridimensional spheres. Moreover, RO4929097 affected the growth of human primary melanoma xenograft in NOD/SCID/IL2gammaR-/- mice and inhibited subsequent tumor formation in a serial xenotransplantation model, suggesting that inhibition of NOTCH signaling suppresses the tumor initiating potential of melanoma cells. In addition, RO4929097 decreased tumor volume and blocked the invasive growth pattern of metastatic melanoma cell lines in vivo. Finally, increased gene expression of NOTCH signaling components correlated with shorter post recurrence survival in metastatic melanoma cases. Our data support NOTCH inhibition as a promising therapeutic strategy against melanoma.

Comparison of arterial and capillary blood gas values in poisoning department assessment.

The aim of this study was to compare simultaneously obtained arterial and capillary blood gas (CBG) values in comatose-poisoned patients presented with stable vital signs. Forty-five adult patients with a diagnosis of coma because of poisoning and stable vital signs were included in this prospective study. With respect to pH, the arterial blood gas (ABG) and CBG values correlated satisfactorily (r(2) = .91) and had an acceptable limit of agreements (LOAs; -0.04 to 0.06). With respect to base excess (BE), the ABG and CBG values correlated well (r(2) = .85), but their 95% LOAs seem too wide to allow substitution (-4.4 to 2.7). PCO(2) (r(2) = .61), HCO(3) (r(2) = .71) and PO(2) (r(2) = .53) correlated less reliably. A capillary PCO(2) of 51.7 mm Hg had a sensitivity of 100% and a specificity of 95.12% for detecting hypercarbia (area under the curve, 0.99; 95% Confidence Interval, 0.90-0.99; p < .0001). In conclusion, CBG analysis for pH may be a reliable substitute for ABG analysis in the initial evaluation of patients presenting with coma and stable vital signs to the poisoning emergency department (PED). Subsequent ABG may be required in patients with capillary PCO(2) > 51.7 mm Hg.

Comparative evaluation of Glasgow Coma Score and gag reflex in predicting aspiration pneumonitis in acute poisoning.

PURPOSE: The purpose of the study was to assess the incidence of aspiration pneumonitis (AP) and its association with gag reflex and Glasgow Coma Score (GCS). MATERIALS AND METHODS: In a retrospective analysis study after prospective data collection, 155 poisoned patients with GCS less than or equal to 12 were evaluated. An assessment of GCS and the quality of gag reflex was made on arrival and recorded. Intubation status before gastrointestinal decontamination was noted. All patients were subsequently followed for developing of AP. RESULTS: The incidence of AP was 15.5%, with significant variance among patients with respect to the gag reflex, GCS, and the performance of intubation. A logistic regression model for predicting AP contained the following predictors: GCS (odds ratio [OR], 0.43; 95% confidence interval [CI], 0.30-0.62), intubation (OR, 0.07; 95% CI, 0.01-0.49), organophosphate ingestion (OR, 1.39; 95% CI, 0.96-2.01), and gastric evacuation (OR, 4.29; 95% CI, 0.94-9.51). In patients with reduced gag reflex, variations in GCS were associated with AP (OR, 0.43; 95% CI, 0.20-0.90), whereas in patients with absent gag reflex, age was the most important predictor of AP (OR, 2.67; 95% CI, 0.99-7.22). CONCLUSIONS: A reduced GCS and a nonintubated trachea are associated with an increased incidence of AP.

Characterization of a fission yeast subunit of an RNA polymerase I essential transcription initiation factor, SpRrn7h/TAF(I)68, that bridges yeast and mammals: association with SpRrn11h and the core ribosomal RNA gene promoter.

Production of eukaryotic ribosomal RNAs (rRNAs) entails sequence-specific recognition of regulatory sequences in the rRNA gene promoter. A putative subunit of the Schizosaccharomyces pombe essential transcription initiation factor for rRNA synthesis has been identified that shares homology with both murine TAF(I)68 and Saccharomyces cerevisiae Rrn7p, subunits of their species' transcription initiation factor. Affinity purified putative SpRrn7h and associated factors, including a putative Rrn11p homolog, SpRrn11h, bear RNA polymerase I transcription initiation factor activity, and recombinant SpRrn7h associates with S. pombe core rDNA promoter sequences. In the first widespread search for putative homologs of SpRrn7h/murine TAF(I)68, and SpRrn11h/murine TAF(I)48, multiple ones were identified across eukaryotes. Analysis of residues conserved between the fission yeast and murine essential initiation factor subunits aided in these identifications. Sequences in the core rRNA gene promoter contributing to transcriptional activation were investigated, including a perfect TATAAA element located at -35.