Nicotinamide for Skin-Cancer Chemoprevention in Transplant Recipients.

BACKGROUND: Immunosuppressed organ-transplant recipients have an increased incidence of, and mortality from, skin cancer. Nicotinamide (vitamin B3) enhances the repair of ultraviolet (UV) radiation-induced DNA damage, reduces the cutaneous immunosuppressive effects of UV radiation, and reduces the incidence of keratinocyte cancers (including squamous-cell and basal-cell carcinomas) and actinic keratoses among high-risk immunocompetent patients. Whether oral nicotinamide is useful for skin-cancer chemoprevention in organ-transplant recipients is unclear. METHODS: In this phase 3 trial, we randomly assigned, in a 1:1 ratio, organ-transplant recipients who had had at least two keratinocyte cancers in the past 5 years to receive 500 mg of nicotinamide or placebo twice daily for 12 months. Participants were examined for skin lesions by dermatologists at 3-month intervals for 12 months. The primary end point was the number of new keratinocyte cancers during the 12-month intervention period. Secondary end points included the numbers of squamous-cell and basal-cell carcinomas during the 12-month intervention period, the number of actinic keratoses until 6 months after randomization, safety, and quality of life. RESULTS: A total of 158 participants were enrolled, with 79 assigned to the nicotinamide group and 79 to the placebo group. The trial was stopped early owing to poor recruitment. At 12 months, there were 207 new keratinocyte cancers in the nicotinamide group and 210 in the placebo group (rate ratio, 1.0; 95% confidence interval, 0.8 to 1.3; P = 0.96). No significant between-group differences in squamous-cell and basal-cell carcinoma counts, actinic keratosis counts, or quality-of-life scores were observed. Adverse events and changes in blood or urine laboratory variables were similar in the two groups. CONCLUSIONS: In this 12-month, placebo-controlled trial, oral nicotinamide therapy did not lead to lower numbers of keratinocyte cancers or actinic keratoses in immunosuppressed solid-organ transplant recipients. (Funded by the National Health and Medical Research Council; ONTRANS Australian New Zealand Clinical Trials Registry number, ACTRN12617000599370.).

Clinical and dermoscopic features of nail unit melanoma in an Australian nail clinic cohort.

Nail unit melanoma carries diagnostic challenges conferring with its poor prognosis. This audit aims to characterise both clinical and dermoscopic features of nail unit malignant lesions and compare them with biopsied benign lesions. It focuses on informing future practice by aiding in the stratification and recognition of malignant diagnostic patterns in the Australian context.

Clinical and histopathological features of onychopapilloma in an Australian setting: A case series of 50 patients.

Onychopapilloma is an uncommon tumour of the nailbed and the distal nail matrix. To date, only 19 case reports and case series have been reported in the literature. This article includes literature review on all reported cases and provides the first case series of onychopapilloma in an Australian population, evaluating the clinical features and histopathological diagnosis of patients with onychopapilloma in an Australian subspecialty nail clinic.

Effect of incorporation of pumpkin (Cucurbita moshchata) powder and guar gum on the rheological properties of wheat flour.

The present study was carried out to study the effect of incorporation of fibre rich pumpkin powder and guar gum on the farinographic characteristics of wheat flour. The flour and pumpkin powder were assessed for proximate composition, total dietary fibre, minerals and ß-carotene. Pumpkin powder contained appreciable amount of fibre, minerals and ß-carotene. The effects of incorporation of different levels of pumpkin powder and guar gum along with pumpkin powder on farinographic characteristics were studied. Dough development time, dough stability, time to break down and farinograph quality number increased whereas mixing tolerance index decreased with incorporation of pumpkin powder (> 5 %) and guar gum (1.0 and 1.5 %) along with pumpkin powder in the flour. Resistance to extension as well as extensibility of dough prepared increased significantly by adding pumpkin powder (5-15 %) whereas increase in resistance to extension only was noticed with inclusion of guar gum (0.5-1.5 %) to flour containing 5 % pumpkin powder. Results indicated that pumpkin can be processed to powder that can be utilized with guar gum for value addition.

BRAF mutation testing for patients diagnosed with stage III or stage IV melanoma: practical guidance for the Australian setting.

Targeted therapy (BRAF inhibitor plus MEK inhibitor) is now among the possible treatment options for patients with BRAF mutation-positive stage III or stage IV melanoma. This makes prompt BRAF mutation testing an important step in the management of patients diagnosed with stage III or IV melanoma; one that can help better ensure that the optimal choice of systemic treatment is initiated with minimal delay. This article offers guidance about when and how BRAF mutation testing should be conducted when patients are diagnosed with melanoma in Australia. Notably, it recommends that pathologists reflexively order BRAF mutation testing whenever a patient is found to have American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) stage III or IV melanoma (i.e., any metastatic spread beyond the primary tumour) and that patient's BRAF mutation status is hitherto unknown, even if BRAF mutation testing has not been specifically requested by the treating clinician (in Australia, Medicare-subsidised BRAFV600 mutation testing does not need to be requested by the treating clinician). When performed in centres with appropriate expertise and experience, immunohistochemistry (IHC) using the anti-BRAF V600E monoclonal antibody (VE1) can be a highly sensitive and specific means of detecting BRAFV600E mutations, and may be used as a rapid and relatively inexpensive initial screening test. However, VE1 immunostaining can be technically challenging and difficult to interpret, particularly in heavily pigmented tumours; melanomas with weak, moderate or focal BRAFV600E immunostaining should be regarded as equivocal. It must also be remembered that other activating BRAFV600 mutations (including BRAFV600K), which account for ∼10-20% of BRAFV600 mutations, are not detected with currently available IHC antibodies. For these reasons, if available and practicable, we recommend that DNA-based BRAF mutation testing always be performed, regardless of whether IHC-based testing is also conducted. Advice about tissue/specimen selection for BRAF mutation testing of patients diagnosed with stage III or IV melanoma is also offered in this article; and potential pitfalls when interpreting BRAF mutation tests are highlighted.

Recurrent phyllodes tumor of the breast: defining the role for skin-sparing mastectomy and autologous reconstruction.

Phyllodes tumors (PTs) are uncommon fibroepithelial tumors of the breast, noteworthy for their difficult excisions and high recurrence rates. In the setting of recurrence, there is no consensus in the literature as to the extent of excision or the impact on reconstructive options. Breast-conserving surgery and simple mastectomy have each been described with mixed reports. Despite a shift toward the selective use of skin-sparing mastectomy and nipple-areola complex-sparing mastectomy in breast carcinoma, neither the role for these techniques nor the role for breast reconstruction in recurrent PT has been described. A case report is presented demonstrating the utility of skin-sparing mastectomy and autologous breast reconstruction for locally recurrent PT of the breast, with a literature review of management options in this setting presented. The case presented highlights an appropriate setting for autologous microsurgical reconstruction of the breast in recurrent PT. The literature review highlights a lack of any published management consensus, with only the role for mastectomy suggested for recurrent high-grade or malignant lesions. A potential management algorithm is thus presented. Skin-sparing mastectomy, particularly for intermediate-grade lesions, may allow wider resections while enabling aesthetically pleasing reconstructive options without affecting recurrence rates.

Complex interactions amongst N-cadherin, DLAR, and Liprin-alpha regulate Drosophila photoreceptor axon targeting.

The formation of stable adhesive contacts between pre- and post-synaptic neurons represents the initial step in synapse assembly. The cell adhesion molecule N-cadherin, the receptor tyrosine phosphatase DLAR, and the scaffolding molecule Liprin-alpha play critical, evolutionarily conserved roles in this process. However, how these proteins signal to the growth cone and are themselves regulated remains poorly understood. Using Drosophila photoreceptors (R cells) as a model, we evaluate genetic and physical interactions among these three proteins. We demonstrate that DLAR function in this context is independent of phosphatase activity but requires interactions mediated by its intracellular domain. Genetic studies reveal both positive and, surprisingly, inhibitory interactions amongst all three genes. These observations are corroborated by biochemical studies demonstrating that DLAR physically associates via its phosphatase domain with N-cadherin in Drosophila embryos. Together, these data demonstrate that N-cadherin, DLAR, and Liprin-alpha function in a complex to regulate adhesive interactions between pre- and post-synaptic cells and provide a novel mechanism for controlling the activity of Liprin-alpha in the developing growth cone.

Congenital achiasma and see-saw nystagmus in VACTERL syndrome.

A 29-year-old man with vertebral defects, anal atresia, cardiac defects, tracheoesophageal fistula, renal defects, and limb defects (VACTERL) presented with headache, photophobia, and worsening nystagmus. He had near-normal visual acuity and visual fields, absent stereopsis, and see-saw nystagmus. Brain MRI revealed a thin remnant of the optic chiasm but normal-sized optic nerves. Functional MRI during monocular visual stimulation demonstrated non-crossing of the visual evoked responses in the occipital cortex, confirming achiasma. These findings have not previously been reported in VACTERL.

Drosophila N-cadherin mediates an attractive interaction between photoreceptor axons and their targets.

Classical cadherins have been proposed to mediate interactions between pre- and postsynaptic cells that are necessary for synapse formation. We provide the first direct, genetic evidence in favor of this model by examining the role of N-cadherin in controlling the pattern of synaptic connections made by photoreceptor axons in Drosophila. N-cadherin is required in both individual photoreceptors and their target neurons for photoreceptor axon extension. Cell-by-cell reconstruction of wild-type photoreceptor axons extending within mosaic patches of mutant target cells shows that N-cadherin mediates attractive interactions between photoreceptors and their targets. This interaction is not limited to those cells that will become the synaptic partners of photoreceptors. Multiple N-cadherin isoforms are produced, but single isoforms can substitute for endogenous N-cadherin activity. We propose that N-cadherin mediates a homophilic, attractive interaction between photoreceptor growth cones and their targets that precedes synaptic partner choice.

Metastasis-Associated Gene Expression Changes Predict Poor Outcomes in Patients with Dukes Stage B and C Colorectal Cancer.

PURPOSE: Colorectal cancer prognosis is currently predicted from pathologic staging, providing limited discrimination for Dukes stage B and C disease. Additional markers for outcome are required to help guide therapy selection for individual patients. EXPERIMENTAL DESIGN: A multisite single-platform microarray study was done on 553 colorectal cancers. Gene expression changes were identified between stage A and D tumors (three training sets) and assessed as a prognosis signature in stage B and C tumors (independent test and external validation sets). RESULTS: One hundred twenty-eight genes showed reproducible expression changes between three sets of stage A and D cancers. Using consistent genes, stage B and C cancers clustered into two groups resembling early-stage and metastatic tumors. A Prediction Analysis of Microarray algorithm was developed to classify individual intermediate-stage cancers into stage A-like/good prognosis or stage D-like/poor prognosis types. For stage B patients, the treatment adjusted hazard ratio for 6-year recurrence in individuals with stage D-like cancers was 10.3 (95% confidence interval, 1.3-80.0; P = 0.011). For stage C patients, the adjusted hazard ratio was 2.9 (95% confidence interval, 1.1-7.6; P = 0.016). Similar results were obtained for an external set of stage B and C patients. The prognosis signature was enriched for downregulated immune response genes and upregulated cell signaling and extracellular matrix genes. Accordingly, sparse tumor infiltration with mononuclear chronic inflammatory cells was associated with poor outcome in independent patients. CONCLUSIONS: Metastasis-associated gene expression changes can be used to refine traditional outcome prediction, providing a rational approach for tailoring treatments to subsets of patients. (Clin Cancer Res 2009;15(24):7642-51).

Liprin-alpha is required for photoreceptor target selection in Drosophila.

Classical cadherin-mediated interactions between axons and dendrites are critical to target selection and synapse assembly. However, the molecular mechanisms by which these interactions are controlled are incompletely understood. In the Drosophila visual system, N-cadherin is required in both photoreceptor (R cell) axons and their targets to mediate stabilizing interactions required for R cell target selection. Here we identify the scaffolding protein Liprin-alpha as a critical component in this process. We isolated mutations in Liprin-alpha in a genetic screen for mutations affecting the pattern of synaptic connections made by R1-R6 photoreceptors. Using eye-specific mosaics, we demonstrate a previously undescribed, axonal function for Liprin-alpha in target selection: Liprin-alpha is required to be cell-autonomous in all subtypes of R1-R6 cells for their axons to reach their targets. Because Liprin-alpha, the receptor tyrosine phosphatase LAR, and N-cadherin share qualitatively similar mutant phenotypes in R1-R6 cells and are coexpressed in R cells and their synaptic targets, we infer that these three genes act at the same step in the targeting process. However, unlike N-cadherin, neither Liprin-alpha nor LAR is required postsynaptically for R cells to project to their correct targets. Thus, these two proteins, unlike N-cadherin, are functionally asymmetric between axons and dendrites. We propose that the adhesive mechanisms that link pre- and postsynaptic cells before synapse formation may be differentially regulated in these two compartments.

The mechanisms and molecules that connect photoreceptor axons to their targets in Drosophila.

The development of the Drosophila visual system provides a framework for investigating how circuits assemble. A sequence of reciprocal interactions amongst photoreceptors, target neurons and glia creates a precise pattern of connections while reducing the complexity of the targeting process. Both afferent-afferent and afferent-target interactions are required for photoreceptor (R cell) axons to select appropriate synaptic partners. With the identification of some critical cell adhesion and signaling molecules, the logic by which axons make choices amongst alternate synaptic partners is becoming clear. These studies also provide an opportunity to examine the molecular basis of neural circuit evolution.

An isoform-specific allele of Drosophila N-cadherin disrupts a late step of R7 targeting.

Drosophila N-cadherin is required for the formation of precise patterns of connections in the fly brain. Alternative splicing is predicted to give rise to 12 N-cadherin isoforms. We identified an N-cadherin allele, N-cad(18Astop), that eliminates the six isoforms containing alternative exon 18A and demonstrate that it strongly disrupts the connections of R7 photoreceptor neurons. During the first half of pupal development, N-cadherin is required for R7 growth cones to terminate within a temporary target layer in the medulla. N-cadherin isoforms containing exon 18B are sufficient for this initial targeting. By contrast, 18A isoforms are preferentially expressed in R7 during the second half of pupal development and are necessary for R7 to terminate in the appropriate synaptic layer in the medulla neuropil. Transgene rescue experiments suggest that differences in isoform expression, rather than biochemical differences between isoforms, underlie the 18A isoform requirement in R7 neurons.