Should Oral Corticosteroids be Used in Medical Therapy for Chronic Rhinosinusitis? A Risk Analysis.

OBJECTIVES: Oral corticosteroid (OCS) as a part of appropriate medical therapy (AMT) (formerly maximal medical therapy) in chronic rhinosinusitis remains controversial. While the risks of OCS are well known, the benefit remains unclear due the absence of a standardized prescribing regimen. Consequently, it is difficult to characterize whether the risks of OCS and its ability to avert endoscopic sinus surgery (ESS) are helpful in AMT. When OCS is highly effective at averting surgery, the lesser risks of OCS would be justified because it can avoid the greater risks of ESS. When OCS is poorly effective at averting ESS, the risks of OCS would not be justified because many patients will be exposed to both risks. This study seeks to identify the threshold effectiveness of OCS at averting ESS that would minimize risk exposure to patients. METHODS: A probabilistic risks-based decision analysis was constructed from literature reported incidences and impacts of adverse events of OCS and ESS. Monte Carlo analysis was performed to identify the minimum effectiveness required to avoid further intervention (MERAFI) for chronic sinusitis without nasal polyp (CRSsNP) and chronic sinusitis with nasal polyp (CRSwNP). RESULTS: The analysis showed MERAFI results of 20.8% (95% CI 20.7-20.9%) for CRSsNP and 16.8% (95% CI 16.7-16.9%) for CRSwNP. CONCLUSIONS: Given reported OCS effectiveness in the range of 34-71% in CRSsNP and 46-63% in CRSwNP, this analysis suggests that the inclusion of OCS in AMT may be the lower risk strategy. LEVEL OF EVIDENCE: N/A Laryngoscope, 131:473-481, 2021.

CSO (Canadian Society of Otolaryngology - Head & Neck Surgery) position paper on rhinologic and skull base surgery during the COVID-19 pandemic.

Healthcare services in many countries have been partially or completely disrupted by the Coronavirus (COVID-19) pandemic since its onset in the end of 2019. Amongst the most impacted are the elective medical and surgical services in order to conserve resources to care for COVID-19 patients. As the number of infected patients decrease across Canada, elective surgeries are being restarted in a staged manner. Since Otolaryngologists - Head & Neck Surgeons manage surgical diseases of the upper aerodigestive tract where the highest viral load reside, it is imperative that these surgeries resume in a safe manner. The aim of this document is to compile the current best evidence available and provide expert consensus on the safe restart of rhinologic and skull base surgeries while discussing the pre-operative, intra-operative, and post-operative care and tips. Risk assessment, patient selection, case triage, and pre-operative COVID-19 testing will be analyzed and discussed. These guidelines will also consider the optimal use of personal protective equipment for specific cases, general and specific operative room precautions, and practical tips of intra-operative maneuvers to optimize patient and provider safety. Given that the literature surrounding COVID-19 is rapidly evolving, these recommendations will serve to start our specialty back into elective rhinologic surgeries over the next months and they may change as we learn more about this disease.

Developing a laddered algorithm for the management of intractable epistaxis: a risk analysis.

IMPORTANCE: For patients with epistaxis in whom initial interventions, such as anterior packing and cauterization, had failed, options including prolonged posterior packing, transnasal endoscopic sphenopalatine artery ligation (TESPAL), and embolization are available. However, it is unclear which interventions should be attempted and in which order. While cost-effectiveness analyses have suggested that TESPAL is the most responsible use of health care resources, physicians must also consider patient risk to maintain a patient-centered decision-making process. OBJECTIVE: To quantify the risk associated with the management of intractable epistaxis. DESIGN AND SETTING: A risk analysis was performed using literature-reported probabilities of treatment failure and adverse event likelihoods in an emergency department and otolaryngology hospital admissions setting. The literature search included articles from 1980 to May 2014. The analysis was modeled for a 50-year-old man with no other medical comorbidities. Severities of complications were modeled based on Environmental Protection Agency recommendations, and health state utilities were monetized based on a willingness to pay $22 500 per quality-adjusted life-year. Six management strategies were developed using posterior packing, TESPAL, and embolization in various sequences (P, T, and E, respectively). MAIN OUTCOMES AND MEASURES: Total risk associated with each algorithm quantified in US dollars. RESULTS: Algorithms involving posterior packing and TESPAL as first-line interventions were found to be similarly low risk. The lowest-risk approaches were P-T-E ($2437.99 [range, $1482.83-$6976.40]), T-P-E ($2840.65 [range, $1136.89-$8604.97]), and T-E-P ($2867.82 [range, $1141.05-$9833.96]). Embolization as a first-line treatment raised the total risk significantly owing to the risk of cerebrovascular events (E-T-P, $11 945.42 [range, $3911.43-$31 847.00]; and E-P-T, $11 945.71 [range, $3919.91-$31 767.66]). CONCLUSIONS AND RELEVANCE: Laddered approaches using TESPAL and posterior packing appear to provide the lowest risk. Combining risk and cost-effectiveness perspectives, we recommend a laddered approach to intractable epistaxis with TESPAL first, followed by either embolization or posterior packing.

Cost-effectiveness analysis of endoscopic sphenopalatine artery ligation vs arterial embolization for intractable epistaxis.

IMPORTANCE: Intractable epistaxis is a common otolaryngology emergency. Transnasal endoscopic sphenopalatine artery ligation (TESPAL) and endovascular arterial embolization both provide excellent success rates, and therefore the decision to choose one over the other can be challenging. OBJECTIVE: To aid in decision making by evaluating the cost-effectiveness of TESPAL vs endovascular arterial embolization for intractable epistaxis. DESIGN, SETTING, AND PARTICIPANTS: Economic evaluation using a decision tree model with a 14-day time horizon for emergency department consultations for patients with intractable epistaxis defined as persistent bleeding despite bilateral anterior nasal packing. The economic perspective was the health care third-party payer. Effectiveness and probability data were obtained from the published medical literature. Costs were obtained from the published literature, the Centers for Medicare & Medicaid Services database, and the Healthcare Cost and Utilization Project database. Multiple sensitivity analyses were performed, including a probabilistic sensitivity analysis. Comparative treatment groups were (1) TESPAL and (2) embolization. INTERVENTIONS: TESPAL and endovascular arterial embolization. MAIN OUTCOME AND MEASURES: The primary outcome was the incremental cost-effectiveness ratio (ICER) for successful control of epistaxis. RESULTS: The reference case demonstrated that the embolization strategy was more effective but more costly compared with the TESPAL strategy: $22,324.70 per 0.70 effectiveness compared with $12,484.14 per 0.68 of effectiveness, respectively. The embolization vs TESPAL ICER was $492,028, which is higher than any willingness to pay (WTP), suggesting that TESPAL is the cost-effective decision. The sensitivity analysis demonstrated a 77.6% and 73.7% certainty that the TESPAL strategy is cost-effective at WTP thresholds of $10,000 and $50,000, respectively. CONCLUSIONS AND RELEVANCE: Results from this economic evaluation suggest that when both TESPAL and arterial embolization are viable options (based on patient and institutional factors), TESPAL is the more cost-effective treatment strategy for patients with intractable epistaxis.

When do the risks of repeated courses of corticosteroids exceed the risks of surgery?

BACKGROUND: The management of chronic rhinosinusitis with nasal polyposis (CRSwNP) becomes unclear when patients require multiple courses of corticosteroids to maintain quality of life. Repeated courses of corticosteroids carry increased risks to patients. Although endoscopic sinus surgery (ESS) is an effective therapeutic modality, it also carries inherent risks. This study aims to identify the threshold at which the risks of repeated courses of corticosteroid exceed the risks of surgery. METHODS: An evidence-based risk analysis was simulated using literature-reported complication rates, quality of life changes, and Medicare costs. Simulations were performed from the Medicare patient perspective, societal perspective, and the universal healthcare patient perspective. RESULTS: All 3 simulations demonstrate a breakeven threshold favoring surgery over medical therapy when patients require oral corticosteroids (OCS) more often than once every 2 years in CRSwNP, once per year in CRSwNP/asthma, or twice per year for Samter's triad patients. CONCLUSION: This represents the first rationalized evidence-based analysis for when surgery should be considered in place of repeated courses of oral corticosteroids. This threshold provides a guide for otolaryngologists to use when making clinical decisions with patients.

Primary care and upfront computed tomography scanning in the diagnosis of chronic rhinosinusitis: a cost-based decision analysis.

OBJECTIVES/HYPOTHESIS: To diagnose chronic rhinosinusitis (CRS), current guidelines require either endoscopic or computed tomography (CT) findings of sinus disease. To a primary care physician, this means a referral to an otolaryngologist or obtaining a CT scan. Unfortunately, the sensitivity of endoscopy for detecting CRS is low, and examination by the Otolaryngologist may not yield a definitive diagnosis. This leaves CT scanning. However, this is contradicted by recommendations to limit CT scanning for only preoperative planning purposes due to cost concerns. This study aims to provide an evidence-based cost-efficient recommendation for primary care practice. STUDY DESIGN: Health care economics-based decision analysis model. METHODS: A cost-based decision analysis based on literature-reported probabilities and Medicare costs was constructed for two scenarios: 1) primary care physicians who are comfortable initiating first-line treatment for chronic rhinosinusitis, rhinitis, and atypical facial pain; and 2) primary care physicians who are less comfortable with medical management of these conditions. RESULTS: Under both scenarios and the extremes of sensitivity analysis, upfront CT scanning provides cost-efficient diagnosis over presuming a diagnosis of chronic rhinosinusitis. Primary care physicians who attempt first-line treatment can expect $503 (range = $296-$761) saved per patient. Meanwhile, primary care physicians who prefer to refer may expect $326 (range = $299-$353) saved per patient. CONCLUSIONS: In all scenarios, confirming diagnosis with CT scanning prior to treatment or referral is more cost-efficient than presuming a diagnosis of CRS based on symptoms alone.

Effect of symptom-based risk stratification on the costs of managing patients with chronic rhinosinusitis symptoms.

BACKGROUND: Current symptom criteria poorly predict a diagnosis of chronic rhinosinusitis (CRS) resulting in excessive treatment of patients with presumed CRS. The objective of this study was analyze the positive predictive value of individual symptoms, or symptoms in combination, in patients with CRS symptoms and examine the costs of the subsequent diagnostic algorithm using a decision tree-based cost analysis. METHODS: We analyzed previously collected patient-reported symptoms from a cross-sectional study of patients who had received a computed tomography (CT) scan of their sinuses at a tertiary care otolaryngology clinic for evaluation of CRS symptoms to calculate the positive predictive value of individual symptoms. Classification and regression tree (CART) analysis then optimized combinations of symptoms and thresholds to identify CRS patients. The calculated positive predictive values were applied to a previously developed decision tree that compared an upfront CT (uCT) algorithm against an empiric medical therapy (EMT) algorithm with further analysis that considered the availability of point of care (POC) imaging. RESULTS: The positive predictive value of individual symptoms ranged from 0.21 for patients reporting forehead pain and to 0.69 for patients reporting hyposmia. The CART model constructed a dichotomous model based on forehead pain, maxillary pain, hyposmia, nasal discharge, and facial pain (C-statistic 0.83). If POC CT were available, median costs ($64-$415) favored using the upfront CT for all individual symptoms. If POC CT was unavailable, median costs favored uCT for most symptoms except intercanthal pain (-$15), hyposmia (-$100), and discolored nasal discharge (-$24), although these symptoms became equivocal on cost sensitivity analysis. The three-tiered CART model could subcategorize patients into tiers where uCT was always favorable (median costs: $332-$504) and others for which EMT was always favorable (median costs -$121 to -$275). The uCT algorithm was always more costly if the nasal endoscopy was positive. CONCLUSION: Among patients with classic CRS symptoms, the frequency of individual symptoms varied the likelihood of a CRS diagnosis marginally. Only hyposmia, the absence of facial pain, and discolored discharge sufficiently increased the likelihood of diagnosis to potentially make EMT less costly. The development of an evidence-based, multisymptom-based risk stratification model could substantially affect the management costs of the subsequent diagnostic algorithm.

Patient level decision making in recurrent acute rhinosinusitis: a cost-benefit threshold for surgery.

OBJECTIVES/HYPOTHESIS: A previous effort to identify the threshold for surgery in recurrent acute rhinosinsutis (RARS) was made based on workforce productivity. While this macroeconomic approach is useful for population-level decision making, patient-level decision making is variable and driven by personal and financial implications. This microeconomic study seeks to identify threshold levels of infection where surgery becomes worthwhile to patients based on costs, lost income, and quality of life. STUDY DESIGN: Cost-Benefit Breakeven Analysis. METHODS: A breakeven analysis was constructed from literature reported medical and surgical response rates, change in quality of life as a result of intervention, and costs to patients. RESULTS: A breakeven threshold occurs when patients suffer from 1.3-2.8 episodes per year under the conservative assumption that the effects of surgery do not extend beyond 19 months--the longest outcomes reported. DISCUSSION: Due to possible confusion with URTIs, we have adopted an approach similar to that advocated by the Rhinosinusitis Task Force. Given the average number of URTIs suffered by adults annually is 1.4-2.3. We suggest adding this to the threshold number of episodes calculated in the present model. Under the most conservative assumptions, this suggests that patients should consider surgery when suffering from five or more episodes per year.

The effect of low-fidelity endoscopic sinus surgery simulators on surgical skill.

BACKGROUND: Surgical training models are being increasingly used to provide an environment for surgical trainees to improve their skills without risk to patients. This study uses previously validated, inexpensive, low-fidelity training models to determine how pretraining affects endoscopic sinus surgery (ESS) skills. METHODS: Fourteen Otolaryngology residents were randomized to 1 of 2 groups that were stratified for training level. The first group took part in a pretraining session where they practiced on all 5 different modules whereas the second group did not receive any pretraining. The following day, all participants took part in a cadaveric ESS course. Participants were instructed to complete a set of tasks and their performances were videotaped. The videos were then evaluated using a Global Rating Scale (GRS) and a Task-Specific Checklist (TSC). The performances of those who trained using the models were compared to the performances of those who did not. RESULTS: The intervention (pretraining) group performed better than the nonintervention (no pretraining) group on the cadaveric ESS tasks (p < 0.05). As well, there was a statistical difference between the senior residents who had the pretraining with the simulator models performing better than those who did not. CONCLUSION: The modules appear to have made a positive impact on ESS skills. These low-cost, easily-constructed training modules have the potential to be integrated into Otolaryngology-Head and Neck Surgery resident training. Assessment of long-term training effects with a larger number of participants is planned for future studies.

Establishing a threshold for surgery in recurrent acute rhinosinusitis: a productivity-based analysis.

OBJECTIVE: Treatment of recurrent acute rhinosinusitis (RARS) has 2 effective modalities: medical therapy with exacerbations or surgery to reduce the frequency and severity of infections. However, it is unclear when one therapy should be recommended over the other. This study seeks to identify a threshold number of infections where the morbidity of surgery is offset by the morbidity of RARS. STUDY DESIGN: Health economic breakeven threshold analysis. SETTING: Clinical otolaryngology practice. SUBJECTS: None. METHODS: A model of productivity was constructed to simulate the first 1 to 3 years after surgery using literature reported rates of medical and surgical response rates, quality of life, and productivity. RESULTS: Based on lost productivity, the lost time for the postoperative period balances out when patients suffer from 4 episodes per year (range, 1.8-12.8). CONCLUSION: Because of possible confusion with upper respiratory tract infections (URTIs), the authors have adopted an approach similar to that adopted by the Rhinosinusitis Task Force (RTF). Given the average number of URTIs suffered by adults annually is 1.4 to 2.3, they suggest adding 2 to the threshold number of episodes similar to the RTF guideline for RARS. From a productivity perspective, surgical intervention may be a viable consideration if patients have suffered from 6 episodes per year. However, the effects of surgery are expected to last longer than the 19 months observed in the literature, implying that the breakeven threshold is likely lower than projected. Discussion with the patient must include a rational consideration of the burden of disease, overall patient quality of life, and risks of surgery.

Upfront computed tomography scanning is more cost-beneficial than empiric medical therapy in the initial management of chronic rhinosinusitis.

BACKGROUND: Current treatment algorithms for patients with symptoms of chronic rhinosinusitis (CRS) recommend a trial of empiric medical therapy prior to obtaining a sinus computed tomography (CT) scan, even in cases of negative nasal endoscopy. This empiric approach evolved in an era when same day conventional CT was both impractical and economically irresponsible. The objective of this work was to determine whether upfront CT scanning is more cost-beneficial than empiric medical therapy for patients presenting with CRS symptoms but negative endoscopic findings. METHODS: A Markov economic model was employed. Medication costs, CT costs, treatment response rates, and treatment associated adverse event rates were included as model parameters. Treatment cost values were derived from Medicare. RESULTS: There is a clear cost advantage to the upfront CT algorithm over empiric therapy regardless of the availability of point-of-care CT scanning (POC-CT). This advantage persists during the sensitivity analysis when costs and response rates are fully biased toward empiric therapy. If POC-CT is available, upfront CT can save $320.50 per patient (range, $138.5-671.5). When POC-CT CT is unavailable, upfront CT savings persist at $296.60 (range, $106.09-655.40). CONCLUSION: In patients meeting symptom criteria for CRS but without endoscopic evidence of inflammation, upfront CT scanning is more cost-beneficial than empiric medical therapy. Adopting upfront CT scanning can save the U.S. healthcare system $1.2 billion dollars per year. Further, POC-CT can offer same day diagnosis, facilitate prompt treatment, and decrease unnecessary antibiotic prescriptions.

Osteomeatal complex obstruction is not associated with adjacent sinus disease in chronic rhinosinusitis with polyps.

BACKGROUND: It is universally accepted that osteomeatal complex (OMC) disease is linked to the subsequent development of chronic rhinosinusitis without nasal polyps (CRSsNPs) via postobstructive mechanisms. The role of OMC obstruction in the pathogenesis of CRSwNPs is less clear. This study was designed to identify if there is an association between OMC obstruction and inflammation of the adjacent sinuses, when patients are stratified by polyp status. This is a follow-up and expanded series of a previous pilot study from our group. METHOD: CT scans of 144 patients with CRSsNPs and 123 patients with CRS with nasal polyps (CRSwNPs) were evaluated for each sinus and OMC. Patients had no previous surgeries for NPs. CT scans were obtained after a trial of maximal medical therapy. RESULTS: Increasing OMC involvement was associated with increasing Lund-Mackay score for both CRSsNPs and CRSwNPs. In CRSsNP patients, OMC status significantly correlated with adjacent sinus status (p << 0.0001). Meanwhile in CRSwNPs, OMC status does not correlate with adjacent sinus status (p = 0.328). CONCLUSION: OMC obstruction in the setting of CRSwNP may be a barometer of the overall disease process, but in this scenario, paranasal sinus inflammation can not be classified as a postobstructive phenomenon. These findings question the role of minimally invasive procedures in the management of CRSwNPs.

Advancements in computed tomography management of chronic rhinosinusitis.

BACKGROUND: Advances in cone beam computed tomography (CBCT) technology have allowed for reduction in radiation dosages as well as the miniaturization of CT scanner units. This has given rise to new applications for CT scanning, including point-of-care (POC) in-office and intraoperative applications. METHODS: A review of recent changes to radiological modalities as applied to otolaryngology-head and neck surgery was performed. A discussion of the physics, applications, and role of diagnostic imaging in the evaluation of chronic rhinosinusitis (CRS) is conducted. RESULTS: The adaptation of cone beam technology has allowed for the practical implementation of CT scanning at the bedside, be it in the clinic or operating room setting. CONCLUSION: Given their relative low cost, ease of storage, and low-dose radiation exposure, POC-CT scanners have become an indispensable tool in the diagnosis and treatment of CRS. In the setting of increasing antibiotic costs, overtreatment with antibiotics, and fewer required return visits, POC-CT challenges the conventional role of empiric medical therapy before progression to imaging for the diagnosis of CRS.

Effect of endoscopic sinus surgery on pulmonary function and microbial pathogens in a pediatric population with cystic fibrosis.

OBJECTIVE: To assess whether improvements in pulmonary function and microbial pathogenic findings can be achieved by endoscopic sinus surgery in a pediatric population with cystic fibrosis. DESIGN: Retrospective medical record review. SETTING: Academic research. PATIENTS: Forty-one patients with cystic fibrosis who had undergone endoscopic sinus surgery at a single tertiary academic pediatric otolaryngology practice. MAIN OUTCOME MEASURES: Changes in pulmonary function test values or respiratory tract microbial pathogens after endoscopic sinus surgery were examined. RESULTS: Endoscopic sinus surgery did not improve pulmonary function test results in this population. Examination of respiratory tract microbial colonization showed that endoscopic sinus surgery did not affect microbial pathogens. The most common organisms isolated were Staphylococcus aureus and Pseudomonas aeruginosa. CONCLUSION: The lack of effect of endoscopic sinus surgery on pulmonary function test results and respiratory tract microbial pathogens in our study highlights the need for prospective assessments of postoperative quality-of-life improvement and of adjunct medical therapy efficacy.

Bilateral simultaneous cochlear implantation in children: our first 50 cases.

OBJECTIVES/HYPOTHESIS: To assess the safety and surgical technique of bilateral simultaneous cochlear implantation in children. STUDY DESIGN: Prospective case series at a tertiary academic pediatric hospital. METHODS: Surgical times, complications, and patient outcomes are reported from the first 50 consecutive simultaneous cochlear implants performed at the Hospital for Sick Children between 2005 and 2008. These results were compared to the same measures in a group of sequentially implanted children consecutively implanted from 2001 to 2008. RESULTS: The group of children receiving simultaneous bilateral cochlear implants showed no difference in complications, length of hospital stay, or use of analgesia and antiemetics compared with children receiving single implants. The simultaneously implanted children had a reduced cumulative surgical time and hospital stay than is required for bilateral implantation performed sequentially. CONCLUSIONS: Bilateral simultaneous cochlear implantation in this series of children was safe and required no significant increase in surgical time and hospital stay compared with unilateral procedures.

Electrogustometric assessment of taste after otologic surgery in children.

OBJECTIVES/HYPOTHESIS: Long term taste dysfunction after otologic surgery has never been characterized in children. The aim of this study is to determine the rates of gustatory dysfunction in normal and postotologic surgery in children. STUDY DESIGN: Cross-sectional study. METHODS: One hundred sixty children visiting a tertiary pediatric otolaryngology clinic, 4 to 18 years of age, were recruited. Surgical groups included patients who had undergone tympanoplasty, combined approach mastoidectomy, modified radical mastoidectomy, and unilateral and bilateral cochlear implantation. They were then tested using a Rion TR-06 electrogustometer (Sensonics, Inc., Haddon Heights, NJ) using a standardized protocol to assess chorda tympani nerve function. An abnormal gustometry result was defined as any recording of > or =16 dB or a difference of 6 dB between ears. RESULTS: The control group had a 9% (5/61) abnormal electrogustometric threshold rate. Rates of dysfunction after surgery were: tympanoplasty (27%, 4/15), combined approach mastoidectomy (30%, 11/29), modified radical mastoidectomy (50%, 4/8). Unilateral cochlear implantation yielded a 26% (7/27) per ear risk of dysfunction, whereas bilateral cochlear implantation had a 5% (2/40) per ear risk. CONCLUSIONS: There is a 9% baseline level of electrogustometric abnormality in the pediatric population, which suggests a subclinical level of gustatory dysfunction. Normal electrogustometry was found in 50% of children after modified radical mastoidectomy, suggesting a degree of neural regenerative capacity. Finally, cochlear implantation, using newer surgical techniques (in the bilateral cochlear implant group) has a low risk for causing gustatory dysfunction, reducing concerns over the safety profile of bilateral cochlear implantation.

Construct validation of a low-fidelity endoscopic sinus surgery simulator.

BACKGROUND: Before a simulator becomes widely accepted, it must be relevant, affordable, and accessible. We have developed a low-cost model emphasizing the basic skills required for endoscopic sinus surgery (ESS). It is noninvasive, free from risk of infection, and an excellent low-pressure learning opportunity. The current study was designed to assess the construct validity of our simulator. METHODS: We conducted a stratified randomized crossover-control study. Otolaryngology residents, fellows, and faculty performed predetermined tasks on the model or cadaver, and then switched. Evaluation included hand motion analysis, task time, and blinded expert review. RESULTS: Sixteen subjects at various levels of training participated. Cadaver performance correlated well with level of training and previous experience with ESS. However, model performance did not demonstrate statistically significant correlation. CONCLUSION: Our model was unable to demonstrate clear construct validity at this time. Materials and structural modifications are in progress. Pending further validation, its low-cost construction possesses potential for integration into otolaryngology residency curricula. Assessment of the simulator's ability to improve surgical skill is also planned.

Interleukin-8 secreted by endothelial cells induces chemotaxis of melanoma cells through the chemokine receptor CXCR1.

There is increasing evidence that both cell adhesion molecules and soluble factors are involved in tumor metastasis. We have found that endothelial cells secrete chemoattractants that can induce melanoma cell chemotaxis. Protein separation on an ion-exchange column shows the association of IL-8 with fractions that contain the chemoattractant activity. This activity is completely lost from the conditioned medium after immunoprecipitation with anti-IL-8 antibodies, indicating that IL-8 is the major melanoma chemoattractant secreted by endothelial cells. IL-877, the predominant endothelial IL-8 isoform that contains 77 amino acids, is found to be twice as potent as the more common 72-amino acid isoform IL-872. Antibody inhibition studies indicate that the chemotactic response of melanoma cells is mediated by the CXC-chemokine receptor CXCR1 and not by the more promiscuous CXCR2. When stimulated by tumor necrosis factor alpha, the nonresponsive WM35 melanoma cells synthesize a higher level of CXCR1 and become chemotactic toward interleukin (IL)-8. Pretreatment of cells with pertussis toxin nullifies their chemotactic response, suggesting the involvement of G proteins. Antibodies against either IL-8 or CXCR1 inhibit melanoma transendothelial migration in a coculture assay by 30%. These results are consistent with a role for IL-8-induced chemotaxis in the transendothelial migration of melanoma cells.