Sinonasal Malignant Melanoma Variant: A Case Report.

Sinonasal malignant melanoma (SMM) is a rare malignant tumour among head and neck cancers predominantly found in adults 60 years and above. The commonly reported symptoms for sinonasal tumour lesions are nasal obstruction and recurrent, painless epistaxis as the symptoms are non-specific and can delay the diagnosis. Moreover, melanoma has a poor prognosis regardless of its location. We report an 86-year-old female patient presenting with recurrent, painless epistaxis from the nasal cavity. Anterior rhinoscopic examination revealed a bluish-black, bleeding mass completely obstructing the left nasal nare. Contrast-enhanced computed tomography of the nasal cavity and sinus region showed a polypoidal soft tissue attenuation with heterogeneous enhancement completely filling the left nasal cavity. The patient underwent endoscopic excision. Histopathology of the specimen showed a small, round and blue cell tumour which immunohistochemistry found to be positive for S100 and HMB 45. After surgical resection, the patient received chemotherapy and radiotherapy. Sinonasal malignant melanoma is a rare, aggressive tumour that has a very poor prognosis. Contrast-enhanced computed tomography of the nasal cavity and paranasal sinuses is the imaging modality of choice which reveals the enhancing mass. There is no optimal management strategy for SMM. Surgical resection is the first-line treatment but is limited due to the complex anatomy of the sinonasal region.

Inhibition of WNT signaling attenuates self-renewal of SHH-subgroup medulloblastoma.

The SMOOTHENED inhibitor vismodegib is FDA approved for advanced basal cell carcinoma (BCC), and shows promise in clinical trials for SONIC HEDGEHOG (SHH)-subgroup medulloblastoma (MB) patients. Clinical experience with BCC patients shows that continuous exposure to vismodegib is necessary to prevent tumor recurrence, suggesting the existence of a vismodegib-resistant reservoir of tumor-propagating cells. We isolated such tumor-propagating cells from a mouse model of SHH-subgroup MB and grew them as sphere cultures. These cultures were enriched for the MB progenitor marker SOX2 and formed tumors in vivo. Moreover, while their ability to self-renew was resistant to SHH inhibitors, as has been previously suggested, this self-renewal was instead WNT-dependent. We show here that loss of Trp53 activates canonical WNT signaling in these SOX2-enriched cultures. Importantly, a small molecule WNT inhibitor was able to reduce the propagation and growth of SHH-subgroup MB in vivo, in an on-target manner, leading to increased survival. Our results imply that the tumor-propagating cells driving the growth of bulk SHH-dependent MB are themselves WNT dependent. Further, our data suggest combination therapy with WNT and SHH inhibitors as a therapeutic strategy in patients with SHH-subgroup MB, in order to decrease the tumor recurrence commonly observed in patients treated with vismodegib.

[Genomic techniques used in uveal melanoma: a literature review]. / Techniques d'analyse génomique du mélanome uvéal: une revue bibliographique.

Genome study and expression profiling of the tumor seem to be the most significant biologic prognostic factor in uveal melanoma. Many cytogenetic and molecular tests are reported; our aim was to assess their ability to detect high metastatic risk patients through a literature review. Standard karyotyping, fluorescence in situ hybridization and microsatellite analysis are not adequate. DNA-based genome techniques must analyse the entire genome (comparative genomic hybridization [CGH]) and, optimally, detect chromosome 3 isodisomy ("single-nucleotid polymorphism" SNP-array). Multiplex ligation-dependent probe amplification (MLPA) is less expensive than array-CGH, but its interpretation may be delicate. Gene expression profiling is the most accurate molecular test for predicting metastatic death in patient with uveal melanoma even if it remains a costly technique. These prognostic tests could be useful to identify high-risk patients in future adjuvant therapy protocols.

[Genomic profiling by comparative genomic hybridization: analysis of ten enucleated uveal melanoma cases]. / Apport de l'analyse par hybridation comparative génomique dans le mélanome uvéal : étude de dix cas énucléés.

AIM: To detect major chromosomal aberrations from enucleated uveal melanoma and relate them to hepatic metastasis and survival. PATIENTS AND METHODS: Ten uveal melanomas enucleated between 2005 and 2008 in the Lyon Croix-Rousse Hospital were retrospectively analyzed using a 19 000-clone comparative genomic hybridization microarray. RESULTS: The most frequent imbalances were the loss of chromosome 3 (8/10), gain of the 8q arm (7/10) or the entire chromosome 8 (2/10), and gain of the 6p arm (2/10). Most metastatic tumors (6/7) and all cases of death (5/5) concerned melanoma with monosomy 3 and gain of the 8q arm. DISCUSSION AND CONCLUSION: Genome-wide array comparative genomic hybridization is a reliable tool for identifying uveal melanoma genomic imbalances. Gains of the 8q arm with monosomy 3 are frequent and are strongly associated with poor outcome. Gains of the 6p arm are rare and have a better prognosis. There is a mutually exclusive relationship between monosomy 3 and chromosome 6 abnormalities in our study. These results confirm previously published reports.

Comparing the efficacy in providing instant relief of dentin hypersensitivity of a new toothpaste containing 8.0% arginine, calcium carbonate, and 1450 ppm fluoride to a benchmark desensitizing toothpaste containing 2% potassium ion and 1450 ppm fluoride, and to a control toothpaste with 1450 ppm fluoride: a three-day clinical study in Mississauga, Canada.

OBJECTIVE: The objective of this double-blind, randomized, parallel-design clinical study was to compare the efficacy in reducing dentin hypersensitivity of a novel toothpaste containing 8.0% arginine, calcium carbonate, and 1450 ppm fluoride to a benchmark desensitizing toothpaste containing 2% potassium ion and 1450 ppm fluoride, and to a control toothpaste containing 1450 ppm fluoride, instantly after a single direct topical self-application using a fingertip, and after subsequent brushing twice daily for three days. METHODS: Qualifying subjects from the Mississauga, Canada area who presented two hypersensitive teeth with a tactile hypersensitivity score (Yeaple Probe) between 10 and 50 grams of force, and an air blast hypersensitivity score of 2 or 3 (Schiff Sensitivity Scale) participated in this study. The first phase of the study consisted of a single topical application of the assigned product directly onto the hypersensitive surface of each of the two baseline-designated hypersensitive teeth. Study subjects applied a pea-size amount of their assigned toothpaste onto the hypersensitive surface of each tooth, and massaged each surface for one minute. The second phase of the study consisted of twice-daily at-home brushing with the assigned toothpaste for three days. Dentin hypersensitivity assessments, as well as examinations of oral hard and soft tissues, were conducted at baseline, immediately after direct topical application, and after three days of product use. RESULTS: One-hundred and twenty subjects complied with the protocol and completed the study. Relative to the desensitizing toothpaste and the control toothpaste groups, the 8.0% arginine toothpaste group exhibited statistically significant (p < 0.05) reductions in dentin hypersensitivity on both tactile and air blast measures immediately after completion of the first phase of the study. Reductions in sensitivity for the 8.0% arginine toothpaste, compared to the benchmark desensitizing toothpaste and the control toothpaste, were 130.7% and 139.5% (tactile), and 43.8.0% and 49.6% (air blast), respectively. Relative to the benchmark desensitizing toothpaste and control toothpaste groups, the 8.0% arginine group also exhibited statistically significantly (p < 0.05) reductions in sensitivity after completion of the second phase of the study, of 104.9% and 136.1% (tactile), and 44.5% and 53.2% (air blast), respectively. There was no loss of the instant relief effects in the 8.0% arginine group after the brushing period. CONCLUSION: A single fingertip topical self-application of the 8.0% arginine-calcium carbonate toothpaste directly onto the hypersensitive surface of teeth provides significant immediate improvements in dentin hypersensitivity relative to an identical application of the control toothpaste and to the benchmark potassium-based desensitizing toothpaste. Significant improvements in dentin hypersensitivity were also demonstrated after three days of brushing with the 8.0% arginine-calcium carbonate toothpaste, subsequent to the single topical self-application of the product, relative to an identical application of the control toothpaste and to the benchmark potassium-based desensitizing toothpaste. The improvement demonstrated by the 8.0% arginine toothpaste after direct application was maintained after three days of twice-daily brushing.

Biphasic insulin aspart 30 treatment improves glycaemic control in patients with type 2 diabetes in a clinical practice setting: experience from the PRESENT study.

AIM: The Physicians' Routine Evaluation of Safety and Efficacy of NovoMix 30 Therapy (PRESENT) study aims to assess the safety and efficacy of biphasic insulin aspart 30 (BIAsp 30) in patients with type 2 diabetes mellitus in routine clinical practice. METHODS: This was a 6-month, prospective, multinational, multiethnic observational study involving 21 977 patients from 13 countries (India, Iraq, Jordan, Kuwait, Lebanon, Qatar, Romania, Russia, Saudi Arabia, South Africa, South Korea, Turkey and the United Arab Emirates). The patients were transferred to BIAsp 30 with or without oral antidiabetic drugs (OADs) from prior treatment with OAD (n = 8583), insulin (n = 5942), OAD + insulin (n = 4673) or diet (i.e. treatment naive) (n = 1707). One thousand and seventy-two patients had incomplete or no information on previous treatment. RESULTS: At 3 and 6 months, significant reductions from baseline were observed in the mean haemoglobin A(1c) (HbA(1c)) (-1.33 and -1.81%), fasting plasma glucose (-3.02 and -3.74 mmol/l) and postprandial plasma glucose (-4.76 and -5.82 mmol/l) (p < 0.001). A significantly greater proportion of patients achieved target HbA(1c) of less than 7% at 3 months (15.3%) and 6 months (27.7%) compared with baseline (4.8%) (p < 0.001). Overall, the mean HbA(1c) at 6 months was lowered in patients regardless of prior treatment: -2.15% (OAD), -1.45% (insulin), -1.47% (OAD + insulin) and -2.35% (treatment naive). In the overall cohort, the rate of total hypoglycaemia was reduced from 5.4 events per patient-year at baseline to 2.2 events per patient-year at study end (p < 0.001). Among prior treatment subgroups, the rates of total hypoglycaemia were reduced from 2.5 to 2.1 events per patient-year in the OAD group, from 9.6 to 2.2 events per patient-year in the insulin group and from 7.6 to 2.5 events per patient-year in the OAD + insulin group but were increased from 1.0 to 1.8 events per patient-year in the treatment-naive group (p < 0.001). There were 444 adverse drug reactions (ADRs), including 13 serious ADRs: lipodystrophy (three events), symptoms of generalized hypersensitivity (two events), acute painful neuropathy (one event), worsening of diabetic retinopathy (one event), oedema (one event) and unspecified ADRs (five events). CONCLUSION: The use of BIAsp 30 monotherapy or in combination with OADs in clinical practice was effective and safe in patients with poorly controlled type 2 diabetes mellitus.

Systemic bevacizumab for retinal angiomatous proliferation associated with retinal pigment epithelial detachment.

PURPOSE: To report the off-label use of systemic bevacizumab in a patient with stage 3 retinal angiomatous proliferation (RAP) associated with a vascularized pigmented epithelium detachment (PED). METHODS: Interventional case report. RESULTS: The patient was treated with systemic bevacizumab after obtaining fully informed consent. At 3 months post-treatment, the authors observed an improvement of one line (seven letters) in visual acuity and total regression of the PED on ocular coherence tomography. No adverse effects were observed. CONCLUSIONS: Systemic bevacizumab therapy appears to be safe and effective in the treatment of RAP associated with PED during this short follow-up period of 3 months. The authors recommend a large trial with long-term follow-up to confirm the promising results and evaluate the occurrence of adverse effects associated with systemic bevacizumab.

Transferring type 2 diabetes patients with uncontrolled glycaemia from biphasic human insulin to biphasic insulin aspart 30: experiences from the PRESENT study.

AIM: The Physician's Routine Evaluation of Safety and Efficacy of NovoMix* 30 Therapy (PRESENT) aims to assess the safety and efficacy of biphasic insulin aspart (BIAsp30) used in routine clinical practice. METHODS: This was a large, multi-national, multi-centre, prospective, 6-month study in type 2 diabetes mellitus patients who were prescribed BIAsp30. Efficacy endpoints included changes in HbA(1c), fasting plasma glucose (FPG), postprandial plasma glucose (PPPG), and proportion who achieved target HbA(1c) < 7%. Changes from baseline were analysed using paired t-test. Safety endpoints were incidence and rate of hypoglycaemic episodes. A subgroup of patients previously uncontrolled (HbA(1c) > or = 7.0%) on biphasic human insulin (BHI) were analysed. RESULTS: Glycaemia improved significantly (mean +/- SD): HbA(1c) by 1.58 +/- 1.69% points (from 9.32 +/- 1.64% to 7.70 +/- 1.29%), FPG by 2.92 +/- 3.71 mmol/L and PPPG by 4.75 +/- 4.87 mmol/L. The incidence of hypoglycaemic episodes decreased over time, from 38.7% (baseline) to 20.8% (6 months). Episodes were mostly minor (reduced from 37.7 to 20.6% at 6 months), occurring during the day (reduced from 31.5 to 17.1% at 6 months). Major episodes were less frequently reported (reduced from 5.0 to 0.4% at 6 months). The rate of hypoglycaemia (episodes/patient year) from baseline to end of study decreased over time for overall (8.9-2.2), major (0.7-0.1), minor (8.2-2.2) and nocturnal (2.9-0.5) episodes. CONCLUSIONS: In this observational study, in the type 2 diabetes mellitus patients who were poorly controlled on BHI, glycaemia improved when transferred to BIAsp30, and a lower incidence or rate of hypoglycaemia was observed in these patients.

[Ring melanoma revealed by spontaneous hyphema]. / Mélanome annulaire révélé par un hyphéma spontané.

INTRODUCTION: Ring melanoma is a rare form of uveal melanoma characterized by the circumferential involvement of the ciliary body. Unilateral chronic and refractory glaucoma is a classic circumstance of diagnosis. OBSERVATION: We report a case of ring melanoma revealed by acute intraocular hypertonia secondary to spontaneous hyphema. Iris and iridocorneal angle were diffusely invaded by the tumor. The fundus was masked but B-scan ultrasonography revealed a voluminous ciliochoroidal tumor. The patient had been enucleated. Pathological examination confirmed the diagnosis of ring melanoma. The tumor involved angle structures. The patient died 1 year later because of metastasis. DISCUSSION: Acute or chronic ocular hypertonia is a classic but rare circumstance of uveal melanoma diagnosis. Many mechanisms exist: neovascular glaucoma, secondary angle closure, involvement of angle structures, and trabecular obstruction by tumor cells or pigment. Acute intraocular hypertonia secondary to hyphema is more exceptional. Our observation highlights that apart from the classic situation of acute angle closure glaucoma, intraocular hypertonia requires meticulous fundus examination, if necessary using B-scan ultrasonography.

[Endophthalmitis after plana vitrectomy: incidence, microbiology, and visual outcome]. / Endophtalmies après vitrectomie postérieure: incidence, micro-organismes et devenir visuel.

INTRODUCTION: The aim of this retrospective study was to analyze incidence, microorganisms, and final visual acuity after pars plana vitrectomy. METHODS: Data on all patients with endophthalmitis after pars plana vitrectomy performed at Croix-Rousse Hospital, Lyon, France, between 1994 and 2004 were analyzed. RESULTS: Among 1632 posterior vitrectomies done over an 11-year period, 14 cases of endophthalmitis occurred (0.86%). Half of the patients were diabetic with poor glycemic control. The most frequent microorganism was negative coagulase Staphylococcus. One case of Bacillus cereus was noted. On the whole, visual prognosis was poor: final visual acuity never exceeded 20/200 in the best cases. The final visual acuity depended on the initial pathology requiring vitrectomy. One eye was enucleated because of phthisis. DISCUSSION: Historically, the incidence of endophthalmitis after vitrectomy is approximately 0.05%. It was higher in our series probably because of the high number of diabetic patients with poor glycemic control. Final visual acuity after pars plana vitrectomy in current series is low. Nevertheless it must be compared with the visual acuity before the vitrectomy because it depends greatly on the causal pathology which is very disabling. CONCLUSION: Endophthalmitis after pars plana vitrectomy is a serious complication. Prophylaxis is still the best treatment.

[Persistent unsealed sclerotomy after intravitreal injection of triamcinolone acetonide with a 30-gauge needle]. / Béance persistante de la sclérotomie après injection intravitréenne de triamcinolone à l'aide d'une aiguille de 30-gauges.

We report the case of a persistent unsealed sclerotomy following intravitreous injection of triamcinolone through the pars plana using a 30-gauge needle. The injection was made for the treatment of diabetic macular edema. The eye had been treated 9 months before by pars plana vitrectomy and pan retinal photocoagulation for vitreous hemorrhage complicating diabetic proliferative retinopathy. Five days after injection, the patient presented with severe hypotony and chemosis. A conjunctival Seidel was noted at the site of injection. Surgical exploration revealed a punctiform scleral wound without vitreous incarceration, which was closed with a 10-0 nylon suture. No other complication occurred. Our observation highlights that in spite of its simplicity, intravitreous injection of triamcinolone is an invasive procedure that requires rigorous follow-up. In vitrectomized eyes, the higher risk of unsealed scleral wound after intravitreous injection should encourage this injection to be made in a site where no sclerotomy usually occurs. The 6'o-clock meridian could be a good location.

Mitotic phosphorylation of rab4 prevents binding to a specific receptor on endosome membranes.

Phosphorylation of the monomeric GTPase rab4 in mitotic cells leads to its relocalization from endosome membranes to the cytosol. To determine the mechanism underlying this change in distribution, we established an in vitro assay that reconstituted specific binding of rab4 when endosome-containing membranes were incubated with rab4 complexed with its cytosolic chaperone, GDP dissociation inhibitor (GDI). rab4 was found to bind to a saturable receptor associated with highly purified endosomes. Membrane binding and nucleotide exchange were physically distinct, since an active soluble fragment of the rab4 receptor, but not rab4 nucleotide exchange activity, could be released from membranes by elastase cleavage. Interestingly, the soluble fragment could be used to fully reconstitute rab4 membrane binding. In vitro phosphorylation of rab4 by cdc2/cyclin B kinase did not affect formation of rab4-GDI complexes, but did completely inhibit rab4 binding to its receptor. In contrast, in vitro phosphorylation of membranes did not result in the dissociation of bound rab4, nor were mitotic membranes deficient with respect to binding non-phosphorylated rab4. Thus, mitotic cells appear to accumulate rab4 in the cytosol by phosphorylating rab4 during the soluble phase of its normal activity cycle, thereby preventing membrane attachment.

Isolation of a preadipocyte cell line from rat bone marrow and differentiation to adipocytes.

A unique population of rat adipocyte precursor cells was derived from normal rat bone marrow. The epitheloid-like preadipocytes were isolated from a mixed culture of bone marrow cells by a combination of differential trypsinization, enrichment by Ficoll gradient centrifugation, and differential seeding. This cell line, designated RBM-Ad, can be fully differentiated into multilocular adipocytes morphologically resembling brown adipose tissue. No changes in the differentiation pattern are observed during propagation of these cells, and they have been successfully carried and differentiated up to passage 49. Histological staining of differentiated cells with Sudan black, Sudan IV, and oil red O indicates the presence of lipids in intracellular vesicles. The nonselective beta-adrenergic agonist isoproterenol stimulates adenylyl cyclase activity in both preadipocytes and differentiated adipocytes. In contrast, BRL-37344, a beta 3-adrenergic receptor-specific agonist, stimulates adenylyl cyclase activity and glycerol release in differentiated adipocytes, but not preadipocytes. In addition, differentiated adipocytes contain messenger RNA encoding the brown adipose-specific protein, thermogenin. Thus, this rat preadipocyte cell line can be differentiated into adipocytes that histologically and functionally resemble brown adipose tissue.

Model of human chorionic gonadotropin and lutropin receptor interaction that explains signal transduction of the glycoprotein hormones.

The goal of these studies was to devise a model that explains how human chorionic gonadotropin (hCG) interacts with lutropin (LH) receptors to elicit a hormone signal. Here we show that alpha-subunit residues near the N terminus, the exposed surface of the cysteine knot, and portions of the first and third loops most distant from the beta-subunit interface were recognized by antibodies that bound to hCG-receptor complexes. These observations were combined with similar data obtained for the beta-subunit (Cosowsky, L., Rao, S.N.V., Macdonald, G.J., Papkoff, H., Campbell, R.K., and Moyle, W.R. (1995) J. Biol. Chem. 270, 20011-20019), information on residues of hCG that can be changed without disrupting hormone function, the crystal structure of deglycosylated hCG, and the crystal structure of a leucine-repeat protein to devise a model of hCG-receptor interaction. This model suggest that the extracellular domain of the LH receptor is "U-" or "J"-shaped and makes several contacts with the transmembrane domain. High affinity hormone binding results from interactions between residues in the curved portion of the extracellular domain of the receptor and the groove in the hormone formed by the apposition of the second alpha-subunit loop and the first and third beta-subunit loops. Most of the remainder of the hormone is found in the large space between the arms of the extracellular domain and makes few, if any, additional specific contacts with the receptor needed for high affinity binding. Signal transduction is caused by steric or other influences of the hormone on the distance between the arms of the extracellular domain, an effect augmented by the oligosaccharides. Because the extracellular domain is coupled at multiple sites to the transmembrane domain, the change in conformation of the extracellular domain is relayed to the transmembrane domain and subsequently to the cytoplasmic surface of the plasma membrane. While the model does not require the hormone to contact the transmembrane domain to initiate signal transduction, small portions of both subunits may be near the transmembrane domain and assist in initiating the hormonal signal. This is the first model that is consistent with all known information on the activity of the gonadotropins including the amounts of the hormone that are exposed in the hormone-receptor complex, the apparent lack of specific contacts between much of the hormone and the receptor, and the roles of the oligosaccharides in signal transduction.(ABSTRACT TRUNCATED AT 400 WORDS)