Frequency of and risk factors for tumor upstaging after wide local excision of primary cutaneous melanoma.

BACKGROUND: Detecting a more advanced stage of the primary melanoma after wide local excision and reconstruction can complicate patient counseling about prognosis, management of surgical margins, and indications for sentinel lymph node biopsy. OBJECTIVE: To identify the frequency of and risk factors associated with upstaging after wide local excision of primary melanoma. METHODS: Retrospective, single center, cross-sectional study of 1332 consecutive in situ to stage T4a melanomas treated with wide local excision. RESULTS: The overall rate of upstaging of melanoma was 3.9% (52/1332). After multivariate analysis, the greatest risk factor for upstaging was anatomic location on the head, neck, hands, feet, genitals, or pretibial leg (odds ratio [OR] 7.06, P < .001) followed by extension of the melanoma to the base of the biopsy specimen (OR 3.42, P < .001); the need for multiple preoperative scouting biopsies (OR 1.89, P = .004); older age (OR 1.03 per year, P = .002); and nonlentigo maligna histologic subtype (OR 3.6, P = .002). LIMITATIONS: This was a single-site, retrospective observational study. CONCLUSIONS: Clinicopathologic characteristics, particularly anatomic location on the head, neck, hands, feet, genitals, or pretibial leg and subtotal diagnostic biopsies, identify melanomas with an increased risk for upstaging.

Risk factors for positive or equivocal margins after wide local excision of 1345 cutaneous melanomas.

BACKGROUND: Positive or equivocal margins after wide local excision (WLE) complicate surgical management of cutaneous melanoma. OBJECTIVE: To identify the frequency of and risk factors for positive or equivocal margins after WLE of cutaneous melanoma. METHODS: Retrospective, single-center, cross-sectional study of 1345 consecutive melanomas treated with WLE. RESULTS: The overall frequency of positive or equivocal margins was 4.2% (56/1345), ranging from 2.2% to 22.6%, depending on the size of the surgical margins, patient characteristics, biopsy history, and the clinicopathology of the melanoma. In descending order, independent risk factors associated with the greatest odds for positive or equivocal margins after multivariate analysis were noncompliance with recommended surgical margins (odds ratio [OR] 5.57, P = .002); anatomic location on the head, neck, hands, feet, genitals, or pretibial leg (OR 5.07, P < .001); histologic regression (OR 2.78, P = .007); in situ melanoma (OR 2.27, P = .011); multiple biopsies at the tumor site before WLE (OR 1.92 [per biopsy], P = .004); and increasing age (OR 1.049 [per year], P < .001). LIMITATIONS: This was a single-site, retrospective observational study. CONCLUSIONS: Clinicopathologic factors, especially location in cosmetically or functionally sensitive areas and noncompliance with recommended surgical margins, identified melanomas at increased risk for positive or equivocal margins after WLE.

Biguanide metformin acts on tau phosphorylation via mTOR/protein phosphatase 2A (PP2A) signaling.

Hyperphosphorylated tau plays an important role in the formation of neurofibrillary tangles in brains of patients with Alzheimer's disease (AD) and related tauopathies and is a crucial factor in the pathogenesis of these disorders. Though diverse kinases have been implicated in tau phosphorylation, protein phosphatase 2A (PP2A) seems to be the major tau phosphatase. Using murine primary neurons from wild-type and human tau transgenic mice, we show that the antidiabetic drug metformin induces PP2A activity and reduces tau phosphorylation at PP2A-dependent epitopes in vitro and in vivo. This tau dephosphorylating potency can be blocked entirely by the PP2A inhibitors okadaic acid and fostriecin, confirming that PP2A is an important mediator of the observed effects. Surprisingly, metformin effects on PP2A activity and tau phosphorylation seem to be independent of AMPK activation, because in our experiments (i) metformin induces PP2A activity before and at lower levels than AMPK activity and (ii) the AMPK activator AICAR does not influence the phosphorylation of tau at the sites analyzed. Affinity chromatography and immunoprecipitation experiments together with PP2A activity assays indicate that metformin interferes with the association of the catalytic subunit of PP2A (PP2Ac) to the so-called MID1-α4 protein complex, which regulates the degradation of PP2Ac and thereby influences PP2A activity. In summary, our data suggest a potential beneficial role of biguanides such as metformin in the prophylaxis and/or therapy of AD.

Interdisciplinary Management of Extramammary Paget's Disease Using Mohs Micrographic Surgery With Frozen Section Cytokeratin-7 Immunostains.

OBJECTIVE: To describe local recurrence rates and patient-reported outcomes when Mohs micrographic surgery with cytokeratin-7 immunostains (MMS-CK7) is included in the interdisciplinary management of extramammary Paget's disease (EMPD) METHODS: A retrospective study was conducted of EMPD treated with MMS-CK7 as part of an interdisciplinary team at an academic medical center between 2009 and 2016. Local recurrence rates and patient-reported outcomes were determined by record review and patient surveys. RESULTS: Twenty tumors in 19 patients were treated using MMS-CK7. After MMS-CK7 defined clear microscopic margins, 75% (15/20) of tumors underwent excision or reconstruction by a surgical colleague. Internal malignancy screening was performed by multiple specialties in 17 patients, with 1 associated malignancy of prostate cancer detected. No local recurrence was detected with a mean follow-up of 75.2 months. Most patients were satisfied with appearance (18/19, 95%) and function (16/19, 84%) after surgery. CONCLUSION: Interdisciplinary teams that include MMS-CK7 can treat EMPD with low local recurrence rates, high patient satisfaction, and thorough internal malignancy screening.

An exceptionally potent inducer of cytoprotective enzymes: elucidation of the structural features that determine inducer potency and reactivity with Keap1.

The Keap1/Nrf2/ARE pathway controls a network of cytoprotective genes that defend against the damaging effects of oxidative and electrophilic stress, and inflammation. Induction of this pathway is a highly effective strategy in combating the risk of cancer and chronic degenerative diseases, including atherosclerosis and neurodegeneration. An acetylenic tricyclic bis(cyano enone) bearing two highly electrophilic Michael acceptors is an extremely potent inducer in cells and in vivo. We demonstrate spectroscopically that both cyano enone functions of the tricyclic molecule react with cysteine residues of Keap1 and activate transcription of cytoprotective genes. Novel monocyclic cyano enones, representing fragments of rings A and C of the tricyclic compound, reveal that the contribution to inducer potency of the ring C Michael acceptor is much greater than that of ring A, and that potency is further enhanced by spatial proximity of an acetylenic function. Critically, the simultaneous presence of two cyano enone functions in rings A and C within a rigid three-ring system results in exceptionally high inducer potency. Detailed understanding of the structural elements that contribute to the reactivity with the protein sensor Keap1 and to high potency of induction is essential for the development of specific and selective lead compounds as clinically relevant chemoprotective agents.

Serum IL-8 and MCP-1 concentration do not identify patients with enlarging contusions after traumatic brain injury.

BACKGROUND: Cerebral contusions contain numerous leukocytes, and a temporal relationship exists among cerebral chemokine expression, leukocyte recruitment, and contusion enlargement. This would suggest a role for chemokines in contusion development. However, it has not been established if serum concentrations of chemokines such as interleukin-8 (IL-8) or monocyte chemoattractant protein-1 (MCP-1) change with contusion enlargement. METHODS: Eighteen adult patients with severe contusional traumatic brain injury, on computerized tomography, were identified. Patients with diffuse injuries or extradural and subdural hematomas associated with mass effect were not included in the study. Daily serum samples were taken for the measurement of IL-8 and MCP-1 concentrations for up to 11 days postinjury. RESULTS: In the patients who died while in intensive care, IL-8 and MCP-1 were significantly greater than in those patients discharged (18 [0-202] vs. 0 [0-156] pg/mL and 498 [339-1,063] vs. 368 [86-11,289] pg/mL for IL-8 and MCP-1, respectively). No difference was seen in serum chemokine levels in patients who deteriorated with contusion enlargement compared with those that did not. The IL-8 and MCP-1 concentrations did not change significantly over time either in the group as a whole or in the subgroup of patients who deteriorated. CONCLUSIONS: These inflammatory mediators may be predictive of a poor outcome in patients with traumatic brain injury in which contusions are the predominant abnormality. However, they do not distinguish those patients who will deteriorate because of contusion enlargement.

Characterisation of the Bax-nucleophosmin interaction: the importance of the Bax C-terminus.

The molecular chaperone nucleophosmin has been identified as a novel Bax binding protein with this interaction proposed to be a key event in the activation and translocation of Bax in mitochondrial dysfunction and apoptotic cell death. Using a proximity assay, we have quantitatively defined the high affinity and saturable interaction between Bax and nucleophosmin indicative of a competitive and specific mechanism. Binding of full length Bax to nucleophosmin was only observed after conformational change was induced using non-ionic detergents (e.g., NP-40). The Bax-nucleophosmin interaction was inhibited by a Bax C-terminal antibody (IC(50) = 1 nM) but minimally affected by antibodies directed against either the N-terminus or alpha-helices 4 and 5. Bcl-2 and p53 inhibited the interaction between full length activated Bax and nucleophosmin. The proximity assay based on the Bax-nucleophosmin interaction was robust and reproducible (Z' = 0.50) facilitating its use for screening a small chemical library. A low molecular weight non-peptide compound, 2-(5-methyl-2-phenyl-1,3-thiazol-4-yl)ethanohydrazide, partially inhibited the Bax-nucleophosmin interaction (IC(50) = 100 nM) and also attenuated UV-induced cell death of HEK293 cells. The present investigations demonstrate the importance of exposure of the C-terminus of Bax for its interaction with nucleophosmin. These protein-protein interaction assays provide a technical approach both for the study of Bax-interacting proteins and for the discovery of novel anti-apoptotic agents.

Advances in small molecules promoting neurotrophic function.

Nerve growth factor (NGF) and other members of the neurotrophin family are critical for the survival and differentiation of neurons and have been implicated in the pathophysiology of numerous disease states. Although the therapeutic potential of neurotrophins has generated much excitement over the past decade, inconvenient pharmacokinetics and adverse side-effect profiles have limited the clinical usefulness of neurotrophic factors themselves. Compounds that mimic neurotrophin signaling and overcome the pharmacokinetic and side-effect barriers may have greater therapeutic potential. Here, we review the progress to date of clinical trials with direct neurotrophin modulators and describe alternative strategies to target (modulate) neurotrophin production and/or their signal transduction pathways. Particular emphasis is placed on small molecules that are able to modulate neurotrophin function in diseases of the nervous system. These alternative strategies show promise in preclinical studies, with some advancing into clinical development. Moreover, the recognition that clinically effective therapeutics, such as antidepressants and immunophilin ligands, can modulate neurotrophin function suggests that the concept of small molecule therapeutics that promote neurotrophic function may still be viable.

Molecular mechanisms of neurite growth with AMPA receptor potentiation.

Positive allosteric modulation of AMPA receptor function has therapeutic potential in a number of psychiatric disorders and neurodegenerative diseases. AMPA receptor potentiators can induce neurite sprouting in vivo. Using a strategy of combined morphological and biochemical analyses, we investigated the effect of the AMPA receptor potentiator LY404187 on neurite growth in the SH-SY5Y human neuroblastoma cell line. LY404187 (0.1-10 microM) increased average neurite length and neurofilament expression when co-administered with s-AMPA. Co-incubation with s-AMPA and LY404187 also increased Trk receptor expression. All actions of LY404187 were sensitive to AMPA receptor blockade by the selective antagonist CNQX (10 microM). Antibody sequestration of BDNF attenuated neurite growth following AMPA receptor potentiator administration, suggesting that LY404187 increases neurite length in vitro by a BDNF mediated mechanism. AMPA receptor potentiation activates multiple intracellular neurochemical cascades and the present report identifies BDNF as one key mediator of the neurotrophic effects of AMPA receptor potentiation.

The odour span task: a novel paradigm for assessing working memory in mice.

Impoverished odour recognition and memory are amongst the earliest symptoms observed in mild cognitive impairment, Alzheimer's disease and schizophrenia, and have been advocated as early disease bio-markers. Although transgenic animals modelling disease pathologies continually emerge, there remains a paucity of tasks to examine olfactory working memory in mice. The present studies describe a mouse odour span task, which assesses the ability to remember increasing numbers of odours. Since caspase-3 is highly expressed throughout the olfactory system, we postulated that mice over-expressing this apoptogenic protein would exhibit impaired performance in the odour span task. Mice over-expressing human caspase-3 (Tg) exhibited age-independent deficits in olfactory working memory (6-18 months) compared with wild-type littermates, requiring longer for task acquisition and exhibiting impaired asymptotic performance, with reduced span lengths, lower accuracy and increased error rates. These impairments appeared to be selective for working memory, as Tg mice had no deficits in odour discriminatory ability or in locomotor measures. Importantly, nicotine, which improves working memory span in man, reversed the deficits exhibited by Tg mice. In conclusion, the mouse odour span task can detect subtle changes in olfactory working memory induced by genetic manipulation and drug administration and therefore should be applied to animal models of neurological disease.

Impaired attention is central to the cognitive deficits observed in alpha 7 deficient mice.

alpha7-Nicotinic acetylcholine receptors (alpha7-nAChR) have been implicated in a range of cognitive deficits in schizophrenia. Therefore we examined alpha7-nAChR knockout (KO), heterozygote (HT) and wildtype (WT) littermate mice in the 5-CSR (a rodent model of sustained attention) and odour span (a novel mouse working memory paradigm) tasks, and related performance to nAChR density. Whilst there was no difference between groups in baseline 5-CSR task performance, alpha7-nAChR KO's exhibited significantly higher omission levels compared to WT mice on increasing the attentional load, with HT mice performing at an intermediate level. Furthermore, alpha7-nAChR KO mice were significantly impaired in the odour span task when compared to WT mice, in a pattern consistent with impaired attention. These behavioural deficits were associated with the loss of alpha7-nAChRs, as alpha4beta2-nAChR density was unaltered in these mice. Thus these studies intimate that the attentional impairment in alpha7-nAChR transgenic mice maybe core to other deficits in cognition.

A systematic comparison of intracellular cyclic AMP and calcium signalling highlights complexities in human VPAC/PAC receptor pharmacology.

VPAC/PAC receptor activation classically results in cyclic-AMP production, with limited reports evaluating calcium signalling. These studies systematically characterise intracellular cyclic-AMP ([cAMP](i)) and calcium ([Ca(2+)](i)) responses in CHO-cells expressing recombinant human (h) VPAC/PAC receptors (hVPAC(1)R, hVPAC(2)R, hPAC(1)R), using two simple, non-radioactive, HT-amenable assays. The rank order of potency (ROP) of the agonists VIP, PACAP-27 and PACAP-38 was similar in both assays for each individual receptor subtype, although potencies (EC(50)) in the [Ca(2+)](i) assay were approximately 100-fold lower. Importantly, this shift was also evident in SHSY-5Y cells endogenously expressing hPAC(1)R. Furthermore, [Ala(11,22,28)]VIP and maxadilan were selective hVPAC(1)R and hPAC(1)R agonists, respectively, and although R3P65 had no demonstrable hVPAC(2)R selectivity, these compounds exhibited comparable reductions in [Ca(2+)](i) EC(50) values. In contrast, PG97-269 and PG99-465, putatively selective hVPAC(1)R and hVPAC(2)R antagonists, respectively, were marginally less potent in [cAMP](i) studies, whereas M65 was equipotent at hPAC(1)R. Moreover, PG99-465 alone increased [cAMP](i) at all three hVPAC/PAC receptor subtypes, with full hVPAC(1)R and hPAC(1)R agonism. With equivalent agonist ROPs generated in both assays, [Ca(2+)](i) signalling provides an alternative approach to examine hVPAC/PAC receptor pharmacology. However, these studies underscore the paucity of receptor selective compounds, complexities in comparing drug potencies across assays, and the pleiotropic nature of VPAC/PAC-receptor signalling.

VIP and PACAP receptor pharmacology: a comparison of intracellular signaling pathways.

VIP/PACAP receptor activation stimulates the production of [cAMP]i and [Ca2+]i by coupling to independent G-protein subunits, although agonist potencies for the different transduction pathways appear to differ. Using CHO-K1 cells stably expressing the human VIP/PACAP receptors (hVPAC1R, hVPAC2R, and hPAC1R), functional assays ([cAMP]i and [Ca2+]i) were established and the receptor pharmacology was characterized with five peptide agonists (VIP, PACAP-27, PACAP-38, [Ala(11,22,28)]VIP, and R3P65). The rank order of potency (ROP) was consistent between assays for the individual receptor subtypes, however, higher agonist concentrations (approximately 100-fold) were required for stimulating [Ca2+]i when compared to [cAMP]i.

Nrf2-Mediated Neuroprotection Against Recurrent Hypoglycemia Is Insufficient to Prevent Cognitive Impairment in a Rodent Model of Type 1 Diabetes.

It remains uncertain whether recurrent nonsevere hypoglycemia (Hypo) results in long-term cognitive impairment in type 1 diabetes (T1D). This study tested the hypothesis that specifically in the T1D state, Hypo leads to cognitive impairment via a pathological response to oxidative stress. Wild-type (Control) and nuclear factor-erythroid 2 p45-related factor 2 (Nrf2) null mice were studied. Eight groups of mice (Control and Nrf2(-/-) ± T1D and ± Hypo) were subject to recurrent, twice-weekly, insulin or saline injections over 4 weeks, after which cognitive function was assessed and brain tissue analyzed. Recurrent moderate hypoglycemia in T1D, but not Control, mice significantly impaired cognitive performance, and this was associated with hippocampal oxidative damage and inflammation despite an enhanced expression of Nrf2 and its target genes Hmox1 and Nqo1 In Nrf2(-/-) mice, both T1D and Hypo independently resulted in impaired cognitive performance, and this was associated with oxidative cell damage and marked inflammation. Together, these data suggest that Hypo induces an Nrf2-dependent antioxidant response in the hippocampus, which counteracts oxidative damage. However, in T1D, this neuroprotective mechanism is insufficient to prevent neuronal oxidative damage, resulting in chronic deficits in working and long-term memory.

Differential profile of Nix upregulation and translocation during hypoxia/ischaemia in vivo versus in vitro.

Nix, a hypoxia-sensitive member of the Bcl-2 family, is upregulated at the mRNA level during hypoxia through induction of a hypoxia-inducible factor-1 alpha (HIF-1 alpha) response element in its promoter sequence. However, the mechanism(s) regulating Nix protein activation remain unclear. The present studies examine Nix protein expression and subcellular distribution in response to hypoxic stimuli in vivo and in culture and to two disparate apoptotic stimuli in vitro. Upregulation and translocation of Nix (by day 5) in hypoxic/serum-deprived CHO-K1 cells, was preceded by Bax activation (by day 4) and caspase-3 processing (by day 2), suggesting that initiation of cell death in vitro is a Nix-independent event. In contrast, an early Nix response (upregulation and translocation to the mitochondria) was observed after 6 h of middle cerebral artery occlusion in the rat. Nix translocation was observed in the ipsilateral cortex and striatum before other histological (infarct development, neuronal loss, apoptotic body formation) or biochemical (Bax activation or caspase-3 cleavage) markers of damage were detected. While fundamental differences between hypoxia/ischaemia in culture and in vivo likely explain the different temporal profiles of Nix, Bax, and caspase-3 activation observed, these studies show that like Bax, mitochondrial accumulation is a common event during Nix activation. These are the first studies to show upregulation and translocation of Nix in the ischaemic brain and suggest Nix to be a novel therapeutic target in ischaemic research. Moreover, Nix upregulation in staurosporine-treated SH-SY5Y cells and dexamethasone-treated A1.1 cells supports a more generalized role for Nix in apoptotic cell death.

Increased expression of macrophage receptor with collagenous structure (MARCO) in mouse cortex following middle cerebral artery occlusion.

Ischaemia induces activation of resident microglia and infiltration of peripheral monocyte/macrophage cells into the central nervous system. The role of scavenger receptors, receptors critical to the recognition and clearance of cell debris, has not been investigated during cerebral ischaemia. MARCO is an inducible member of the scavenger receptor family unique to cells of monocytic lineage and is a cell surface marker that plays a critical role in the differentiation of monocytes to dendritic cells. To understand the role of MARCO in cerebral ischaemia, we investigated its expression in mice following middle cerebral artery (MCA) occlusion. No MARCO mRNA expression was observed in naive mouse brain. There was no significant increase in expression of MARCO mRNA following transient occlusion (60min) of the MCA at any time point up to 24 h. However, a significant, marked increase in MARCO mRNA expression was observed at 24 h in the cortex of mouse brains after a permanent occlusion of the MCA. The increased expression of MARCO mRNA at 24 h after prolonged ischaemia is consistent with its putative role in the clearance of debris and/or degenerating cells after severe ischaemia and supports previous publications showing the presence of dendritic cells around permanently occluded lesions.

Nicotine improves sustained attention in mice: evidence for involvement of the alpha7 nicotinic acetylcholine receptor.

In humans, nicotine has been shown to improve attention in both normal and impaired individuals. Observations in rats reflect some, but not all aspects of the nicotine-induced improvements in humans. To date these findings have not been replicated in mice. To examine the effect of nicotine on sustained attention in mice, we have established a version of the 5-choice serial reaction-time (5-CSR) task with graded levels of difficulty, based upon spatial displacement and a variable intertrial interval. Using this paradigm, microgram doses of nicotine produced a consistent reduction in the level of omissions and an improvement in proportion correct in normal mice. This improvement in sustained attention was made irrespectively of whether mice had previously received nicotine. In an attempt to elucidate which nicotinic acetylcholine receptor (nAChR) subtype(s) mediate this effect, we examined the performance of alpha7 nAChR knockout (KO) mice in the 5-CSR task. alpha7 nAChR KO mice not only acquired the task more slowly than their wild-type littermates, but on attaining asymptotic performance, they exhibited a higher level of omissions. In conclusion, by increasing the level of task difficulty, the performance of mice was maintained at sufficiently low levels to allow a demonstrable improvement in performance upon nicotine administration. Furthermore, as alpha7 KO mice are clearly impaired in the acquisition and asymptotic performance of this task, the alpha7 nAChR may be involved in mediating these effects of nicotine.

Apoptosis is not an invariable component of in vitro models of cortical cerebral ischaemia.

Characterising the mechanisms of cell death following focal cerebral ischaemia has been hampered by a lack of an in vitro assay emulating both the apoptotic and necrotic features observed in vivo. The present study systematically characterised oxygen-glucose-deprivation (OGD) in primary rat cortical neurones to establish a reproducible model with components of both cell-death endpoints. OGD induced a time-dependent reduction in cell viability, with 80% cell death occurring 24 h after 3 h exposure to 0% O2 and 0.5 mM glucose. Indicative of a necrotic component to OGD-induced cell death, N-methyl-D-aspartate (NMDA) receptor inhibition with MK-801 attenuated neuronal loss by 60%. The lack of protection by the caspase inhibitors DEVD-CHO and z-VAD-fmk suggested that under these conditions neurones did not die by an apoptotic mechanism. Moderating the severity of the insult by decreasing OGD exposure to 60 min did not reduce the amount of necrosis, but did induce a small degree of apoptosis (a slight reduction in cell death was observed in the presence of 10 uM DEVD-CHO). In separate experiments purported to enhance the apoptotic component, cells were gradually deprived of O2, exposed to 4% O2 (as opposed to 0%) during the OGD period, or maintained in serum-containing media throughout. While NMDA receptor antagonism significantly reduced cortical cell death under all conditions, a caspase-inhibitor sensitive component of cell death was not uncovered. These studies suggest that OGD of cultured cortical cells models the excitotoxic, but not the apoptotic component of cell death observed in vivo.

Acquired QT interval prolongation and HERG: implications for drug discovery and development.

Putative interactions between the Human Ether-a-go-go Related Gene (HERG), QT interval prolongation and Torsades de Pointes (TdP) are now integral components of any discussion on drug safety. HERG encodes for the inwardly rectifying potassium channel (I(Kr)), which is essential to the maintenance of normal cardiac function. HERG channel mutations are responsible for one form of familial long QT syndrome, a potentially deadly inherited cardiac disorder associated with TdP. Moreover, drug-induced (acquired) QT interval prolongation has been associated with an increase in the incidence of sudden unexplained deaths, with HERG inhibition implicated as the underlying cause. Subsequently, a number of non-cardiovascular drugs which induce QT interval prolongation and/or TdP have been withdrawn. However, a definitive link between HERG, QT interval prolongation and arrhythmogenesis has not been established. Nevertheless, this area is subject to ever increasing regulatory scrutiny. Here we review the relationship between HERG, long QT syndrome and TdP, together with a summary of the associated regulatory issues, and developments in pre-clinical screening.

Comparison of efficacy of oral rofecoxib and ketorolac in controlling early postoperative outpatient orthopedic surgical pain.

We compared the efficacy of rofecoxib and ketorolac in controlling postoperative pain after outpatient surgery. Patients were randomly assigned to receive either rofecoxib or ketorolac preoperatively and every morning for 5 postoperative days. Patients in both groups received oxycodone as needed for breakthrough pain. After 5 postoperative days, patients were asked for information-pain score; number of supplemental analgesics used; and severity of any incision-site bleeding, nausea, or diarrhea. Rofecoxib and ketorolac did not differ on these measures. Rofecoxib and ketorolac are equally effective in controlling postoperative pain.