Neoplastic infiltration of the sphenoid wing: a rare manifestation of metastatic colorectal cancer

Atypical patterns of metastatic spread from colorectal primary tumors are often misdiagnosed, with potential implications for the clinical outcome. Metastatic diffusion to the splanchnocranium is extremely rare in colorectal cancer. A histological proof of diagnosis is rarely obtained and therapeutic management is a challenge. We describe the case of a 46-year-old patient who presented with a radiologically proven sphenoid wing metastasis. The patient presented with left-sided exophthalmos while receiving systemic chemotherapy for relapsed high-risk colorectal cancer. A left sphenoid wing metastasis was proven by a head computed tomography scan. A metastatic spread to the sino-nasal tract is regarded as a poor prognosis determinant in colorectal cancer and presents a unique set of diagnostic and therapeutic challenges. The compression of noble structures such as the optic nerve holds serious implications in terms of quality of life but there is insufficient evidence clarifying whether radiotherapy or surgery represent the best option for these patients, leaving the therapeutic plan to be decided case by case.     

Activity of aspirin analogues and vanillin in a human colorectal cancer cell line

Colorectal cancer is the third most common cancer and is associated with significant morbidity and mortality. Epidemiological and animal studies indicate that regular acetylsalicylic acid (aspirin) intake is associated with a reduction in the incidence of colorectal cancer. Acetylsalicylic acid (ASA) has also been shown to inhibit colorectal cancer cell proliferation in?vitro. The molecular basis for this specific cytotoxicity is an area of considerable debate. To investigate the toxicity of salicylates, the sensitivity of the DNA mismatch repair proficient SW480 human colorectal cancer cell line to four categories of compounds with varying degrees of structural similarity to acetylsalicylic acid was tested. These compounds were: i) salicylic acid analogues with substituents at the 5-position; ii) ASA analogues with extended chain lengths in the acyl group; iii) vanillin (4-hydroxy-3-methoxybenzaldehyde; and iv) bis(2-carboxyphenyl) succinate (BCS) and structurally similar derivatives thereof. It was found that compounds with amino and acetamido substituents at the salicylate 5-position were less toxic than ASA itself. Modifications to the length of the hydrocarbon chain in the acyl groups of ASA analogues also marginally reduced toxicity. Vanillin exhibited relatively limited toxicity against the SW480 colorectal cancer cell line. Commercially available and in-house synthesised BCS (diaspirin) were notably more inhibitory to cell growth than ASA itself, yet retained substantial specificity against colorectal cancer cell lines vs. non-colorectal cancer cell lines. BCS and ASA were toxic to SW480 cells through initiation of necrotic and apoptotic pathways. Fumaroyldiaspirin and benzoylaspirin exhibited greater toxicity than ASA against the SW480 cell line. A novel method for synthesis of BCS, a compound that has erratic commercial availability, is described. We propose that the anti-inflammatory and anticancer capacity of BCS and the other analogues described herein is worthy of investigation.     

20-Hydroxyeicosatetraenoic acid stimulates nuclear factor-kappaB activation and the production of inflammatory cytokines in human endothelial cells

Endothelial dysfunction is associated with endothelial cell activation, i.e., up-regulation of surface cell adhesion molecules and the release of proinflammatory cytokines. 20-Hydroxyeicosatetraenoic acid (HETE), a major vasoactive eicosanoid in the microcirculation, has been implicated in the regulation of endothelial cell function through its angiogenic and pro-oxidative properties. We examined the effects of 20-HETE on endothelial cell activation in vitro. Cells transduced with adenovirus containing either CYP4A1 or CYP4A2 produced higher levels of 20-HETE, and they demonstrated increased expression levels of the adhesion molecule intercellular adhesion molecule (ICAM) (4-7-fold) and the oxidative stress marker 3-nitrotyrosine (2-3-fold) compared with cells transduced with control adenovirus. Treatment of cells with 20-HETE markedly increased levels of prostaglandin (PG) E(2) and 8-epi-isoprostane PGF(2alpha), commonly used markers of activation and oxidative stress, and most prominently, interleukin-8, a potent neutrophil chemotactic factor whose overproduction by the endothelium is a key feature of vascular injury. 20-HETE at nanomolar concentrations increased inhibitor of nuclear factor-kappaB phosphorylation by 2 to 5-fold within 5 min, which was followed with increased nuclear translocation of nuclear factor-kappaB (NF-kappaB). Likewise, 20-HETE activated the mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) pathway by stimulating phosphorylation of ERK1/2. Inhibition of NF-kappaB activation and inhibition of ERK1/2 phosphorylation inhibited 20-HETE-induced ICAM expression. It seems that 20-HETE triggers NF-kappaB and MAPK/ERK activation and that both signaling pathways participate in the cellular mechanisms by which 20-HETE activates vascular endothelial cells.     

Convergence of nociceptive information in the forebrain of female rats: reproductive organ response variations with stage of estrus

Neurons in the preoptic area (POA) of the hypothalamus and the bed nucleus of stria terminalis (BST) play an important role in the neuroendocrine control of the reproductive cycle, mating behaviors and nociception. Single unit extracellular recordings were performed in the POA and BST region of 20 urethane anesthetized female rats during either the proestrus (elevated levels of estrogen/progesterone) or metestrus (low circulating hormones) stage of the estrous cycle. A total of 118 neurons in the POA and 65 neurons in the BST responded to the search stimuli, bilateral electrical stimulation of the viscerocutaneous branch of the pelvic nerve and/or sensory branch of the pudendal nerve (i.e., dorsal nerve of clitoris). Most of the neurons responding to the electrical search stimuli received a high degree of somatovisceral convergence, including inputs from the abdominal branches of the vagus, cervix, vagina, colon and skin territories on the perineum and trunk. Mean neuronal response thresholds for vaginal and cervical stimulation but not colon distention were significantly higher for animals tested during proestrus. Also, there was a shift in POA and BST neuronal responsiveness towards more inhibition and less excitation during proestrus for a variety of somatovisceral inputs. These data demonstrate that the changes in hormonal status affect the properties of POA and BST neurons, which likely relates not only to the functional importance of these inputs for reproductive behaviors but also for nociceptive processing as well.     

Comparison of reconstructive procedures in primary versus secondary mandibular reconstruction

BACKGROUND: Few reports have compared reconstructive outcomes of primary versus secondary mandibular reconstruction. METHODS: A retrospective chart review was performed on 149 patients following primary (n = 110) and secondary reconstruction (n = 39). RESULTS: There was no statistically significant difference in patient demographics between the 2 groups. The secondary reconstruction mandibular defects were more extensive; significantly more involved the condyle or the central portion of the mandible. The vascularized fibular flap was most commonly used (primary 82%, secondary 69%). The overall complication rate was similar in both groups. There was no statistical difference in the frequency of complications between the primary or secondary reconstruction groups (acute, p = .40; late, p = .17). CONCLUSIONS: Success in secondary mandibular reconstruction could be achieved utilizing a range of osseous free flaps, and there was no increased rate of complications compared with primary mandibular reconstructions.     

An economic evaluation of oxaliplatin for the adjuvant treatment of colon cancer in the United Kingdom (UK)

The MOSAIC study was the first trial to show a statistically significant disease-free survival benefit for a treatment regimen for stage III colon cancer in the adjuvant setting. At 4 years, there was a 25% reduction in the risk of disease recurrence in these patients for the combination of oxaliplatin/5-FU/FA compared with 5-FU/FA alone (p=0.002). This analysis evaluates the long-term cost effectiveness of oxaliplatin given in combination with 5-FU/FA from the perspective of the NHS in the United Kingdom (UK). The cost per quality-adjusted life-year gained over a lifetime was calculated using patient level data from the MOSAIC trial. Trial data were available for a median of 4 years of follow-up, these data were then extrapolated to a lifetime horizon. The estimated incremental lifetime cost per quality-adjusted life-year of oxaliplatin/5-FU/FA compared with 5-FU/FA alone in patients with stage III postoperative colon cancer is pound 4805. This compares favourably with other accepted interventions in oncology.     

Determinants of renal functional outcome in lupus nephritis: a single centre retrospective study

Background: Lupus nephritis (LN) is a rare disease but is thestrongest predictor of poor outcome in patients with SystemicLupus Erythematosis (SLE). It is associated with significantmorbidity, with 10–20% of patients developing end stagerenal failure. As there is a paucity of randomized clinicaltrial data in LN, and no consistent literature regarding baselinefactors that predict renal outcome, we were prompted to analyseour centre's complete experience of managing LN. Methods: A retrospective analysis was undertaken of all patientspresenting to our renal centre with biopsy proven LN from 1979–2003.Patients were divided into two categories, those with stableor deteriorating renal function over time. Baseline parameterswere correlated with renal outcome. Results: Complete clinical records were available for 45 (40female) patients. Mean (SD) age of onset of SLE was 32 ±14 years, and mean age onset of LN was 36 ± 13 years.Patients were followed up for an average of 74 ± 56 months.Four patients (9%) had WHO Class II LN, 11 (24%) WHO Class IIIand there were 15 (33%) each in Class IV and V, respectivelyon renal biopsy. Five (11%) patients presented with acute renalfailure and all had proliferative changes on biopsy. The chiefarbiters of renal functional deterioration over follow up werelonger time to development of LN (P = 0.04), a high plateletcount and worse baseline renal function (both P = 0.05). Therewas a trend relating low haemoglobin or membranous histologyto poor renal outcome, and Class IV histology to better outcome. Conclusion: The study has identified that longer time to developmentof LN, high platelet count and poorer renal function at baselinesuggest a worse renal outcome in LN. The study was small butLN is a rare condition. A combination of factors is likely toinfluence renal outcome in LN and larger prospective trialsare required to ascertain consistent baseline prognostic markers.