Real-world outcomes among patients with metastatic colorectal cancer treated first line with a bevacizumab biosimilar (bevacizumab-awwb).

Background: Bevacizumab-awwb (MVASI®) was the first U.S. Food and Drug Administration-approved biosimilar to Avastin® (reference product [RP]) for the treatment of several different types of cancers, including metastatic colorectal cancer (mCRC), an indication approved based on extrapolation. Objectives: Evaluate treatment outcomes in mCRC patients who received first-line (1L) bevacizumab-awwb at treatment initiation or as continuing bevacizumab therapy (switched from RP). Design: A retrospective chart review study. Methods: Adult patients who had a confirmed diagnosis of mCRC (initial presentation of CRC on or after 01 January 2018) and initiated 1L bevacizumab-awwb between 19 July 2019 and 30 April 2020 were identified from the ConcertAI Oncology Dataset. A chart review was conducted to evaluate patient baseline clinical characteristics and effectiveness and tolerability outcomes during the follow-up. Study measures were reported stratified by prior use of RP: (1) naïve patients and (2) switchers (patients who switched to bevacizumab-awwb from RP without advancing the line of therapy). Results: At the end of study period, naïve patients (n = 129) had a median 1L progression-free survival (PFS) of 8.6 months [95% confidence interval (CI), 7.6-9.9] and a 12-month overall survival (OS) probability of 71.4% (95% CI, 61.0-79.5%). Switchers (n = 105) had a median 1L PFS of 14.1 months (95% CI, 12.1-15.8) and a 12-month OS probability of 87.6% (95% CI, 79.1-92.8%). During treatment with bevacizumab-awwb, 20 events of interest (EOIs) were reported in 18 naïve patients (14.0%) and 4 EOIs reported in 4 switchers (3.8%), of which the most commonly reported events were thromboembolic and hemorrhagic events. Most EOIs resulted in emergency department visit and/or treatment hold/discontinuation/switch. None of the EOIs resulted in death. Conclusion: In this real-world cohort of mCRC patients who were treated 1L with a bevacizumab biosimilar (bevacizumab-awwb), the clinical effectiveness and tolerability data were as expected and consistent with previously published findings from real-world studies of bevacizumab RP in mCRC patients.

Real-world use of bevacizumab-awwb, a bevacizumab biosimilar, in US patients with metastatic colorectal cancer.

Aim: Evaluated real world use of bevacizumab-awwb (MVASI®), a bevacizumab biosimilar, for treating metastatic colorectal cancer (mCRC). Materials & methods: Adult mCRC patients who received bevacizumab-awwb during the first year after market availability were identified from the ConcertAI oncology dataset. Results: Of 304 patients, 47% initiated bevacizumab-awwb as reference product (RP) naive patients and 53% received bevacizumab-awwb with prior exposure to RP. Overall, 78% received bevacizumab-awwb as first-line therapy; the proportion was higher (91%) in RP-naive patients. Among RP-experienced patients, 83% were transitioned from RP to bevacizumab-awwb in the same line without disease progression; of those, the majority (83%) were transitioned within 28 days. Conclusion: Early evidence from US oncology practices suggests clinical adoption of bevacizumab-awwb in treating mCRC patients.

Persistence on biologic DMARD monotherapy after achieving rheumatoid arthritis disease control on combination therapy: retrospective analysis of corrona registry data.

Biological disease-modifying antirheumatic drugs (bDMARDs) monotherapy may enhance adherence and decrease adverse events compared to combination therapy with conventional synthetic DMARDs (csDMARDs); however, persistence with bDMARD monotherapy has not been extensively studied. We explore persistence of etanercept monotherapy and monotherapy with other tumor necrosis factor inhibitors (TNFis) among patients first achieving remission/low disease activity (LDA) while on combination therapy with csDMARDs and a TNFi. Using Corrona registry data, the percentage of patients persistent with the index TNFi (etanercept versus other TNFis) over 6 and 12 months was determined. Factors influencing persistence and treatment patterns at 6 and 12 months were examined. Among 617 eligible patients, 56% of 182 patients on etanercept and 45% of 435 patients on other TNFis persisted with monotherapy at 6 months, 46% and 33%, respectively, at 12 months. Across first-line and subsequent biologic DMARDs, etanercept persistence was greater than other TNFi persistence by 10.8% (95% CI 2.1%, 19.6%) at 6 months and 11.4% (95% CI 0.9%, 21.9%) at 12 months. Patients on other TNFis were more likely to require reintroduction of csDMARD after 6 months (45% versus 35% for etanercept). Remission was the key predictor of persistence for both etanercept and other TNFi monotherapies. This retrospective, cohort study of registry data reflecting real-world practice indicates patients who achieve remission/LDA with combination csDMARD and TNFi therapy may successfully transition to TNFi monotherapy. Patients on etanercept monotherapy experienced greater persistence and less frequent reintroduction of a csDMARD than was observed for patients on other TNFi monotherapies.

Persistence of tumor necrosis factor inhibitor or conventional synthetic disease-modifying antirheumatic drug monotherapy or combination therapy in psoriatic arthritis in a real-world setting.

This study described treatment patterns in a psoriatic arthritis (PsA) patient registry for new or ongoing tumor necrosis factor inhibitor (TNFi) monotherapy, conventional synthetic disease-modifying antirheumatic drug (csDMARD) monotherapy, or TNFi/csDMARD combination therapy. This retrospective analysis included adults with PsA who enrolled in the Corrona PsA/spondyloarthritis registry between March 21, 2013 (registry initiation), and January 31, 2017, and received an approved TNFi and/or csDMARD as "existing use" starting before registry entry or "initiated use" starting on/after registry entry. Therapy persistence was defined as index therapy use for ≥ 12 months without a treatment gap of ≥ 30 days. Among the evaluable patients with existing TNFi monotherapy (n = 251), csDMARD monotherapy (n = 225), and combination therapy (n = 214), 93, 87, and 87% were persistent for ≥ 12 months, and another 6, 5, and 5%, respectively, had no change with < 12 months of follow-up after first use. Among evaluable patients who initiated use of TNFi monotherapy (n = 26), csDMARD monotherapy (n = 35), and combination therapy (n = 15), 50, 43, and 53% were persistent for ≥ 12 months, and another 27, 20, and 20%, respectively, had no change with < 12 months of follow-up after first use. After initiation of index therapy, most changes (19-27% of patients) were discontinuation; 4-13% switched biologic therapy during follow-up. The results of this analysis of real-world treatment patterns in a PsA patient registry suggest that nonpersistence for TNFi monotherapy, csDMARD monotherapy, or TNFi/csDMARD combination therapy occurs more commonly after initiation of therapy than in patients with existing therapy. Trial registration: NCT02530268.

Therapy with Biologic Agents After Diagnosis of Solid Malignancies: Results from the Corrona Registry.

OBJECTIVE: Guidelines suggest that rheumatoid arthritis (RA) patients with previously treated solid malignancy may be treated as patients without such history. The recommendation is based on limited evidence, and rheumatologists and patients are frequently hesitant to start or continue biologic therapy after a cancer diagnosis. The objective of this study was to describe biologic use in real-world patients with RA following a malignancy diagnosis. METHODS: RA patients enrolled in the Corrona registry and diagnosed with solid malignancy with at least 1 followup visit within 12 months after diagnosis were included in this analysis. The proportion of patients continuing or initiating biological/targeted synthetic disease-modifying antirheumatic drug (bDMARD/tsDMARD) after diagnosis was estimated. Median time to initiation of bDMARD/tsDMARD after diagnosis was calculated using the Kaplan-Meier method and the proportion initiating biologic treatment in 6-month time intervals was estimated using the life-table method. RESULTS: There were 880 patients who met inclusion criteria with 2585 person-years total followup time postdiagnosis. Of those, 367 (41.7%) were treated with bDMARD/tsDMARD within 12 months preceding malignancy, of whom 270 (30.7%) were taking such agents at first postdiagnosis visit. Forty-four (5%) switched biologic agents within 36 months and an additional 90 patients (10.2%) started a biologic. The majority of bDMARD/tsDMARD initiations during followup was a tumor necrosis factor inhibitor (TNFi; 53.5%). CONCLUSION: In real-world practice, nearly one-third of RA patients with a cancer diagnosis were treated with systemic therapy in the immediate visit after malignancy diagnosis and a considerable percentage of malignancy survivors initiated biologic therapy within 3 years. The majority of bDMARD/tsDMARD initiations post-malignancy diagnosis was a TNFi.

Subsequent Cardiovascular Events Among Patients With Rheumatoid Arthritis, Psoriatic Arthritis, or Psoriasis: Patterns of Disease-Modifying Antirheumatic Drug Treatment.

OBJECTIVE: To examine disease-modifying antirheumatic drug (DMARD) treatments and estimate the risk of a subsequent cardiovascular (CV) event following an initial CV event in patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA), or psoriasis. METHODS: We analyzed data from MarketScan claims databases (January 1, 2006 to June 30, 2015) for adults with RA, PsA, or psoriasis and an initial/index CV event (acute myocardial infarction, stroke, or coronary revascularization) while receiving DMARDs (tumor necrosis factor inhibitor [TNFi] biologic DMARDs [bDMARDs], conventional synthetic DMARDs [csDMARDs], or non-TNFi bDMARDs). We studied DMARD treatment patterns following the index event and rates of subsequent CV events. We used Cox regression to investigate predictors of DMARD discontinuation and risk factors for subsequent CV events. RESULTS: Among 10,254 patients, 15.3% discontinued and 15.5% switched DMARD therapy after the index CV event. Independent predictors of DMARD discontinuation included a psoriasis diagnosis, renal disease, hypertension, heart failure, diabetes mellitus, older age, and baseline csDMARD or non-TNFi bDMARD use (versus TNFi bDMARDs). Rates per 1,000 patient-years of subsequent events were 75.2 (95% confidence interval [95% CI] 54.4-96.0) for patients taking TNFi bDMARDs, 83.6 (95% CI 53.3-113.9) for csDMARDs, and 122.4 (95% CI 60.6-184.3) for non-TNFi bDMARDs. A diagnosis of RA (versus psoriasis) and heart failure at baseline, but not a DMARD pattern after the index event, were independently associated with an increased risk of subsequent CV event. CONCLUSION: In this large nationwide study, nearly one-third of patients with RA, PsA, or psoriasis switched or discontinued DMARD therapy following a CV event. There was no association between DMARD class and the risk of a subsequent CV event.

Retrospective analysis to describe associations between tumor necrosis factor alpha inhibitors and COPD-related hospitalizations.

BACKGROUND: Limited information exists on the impact of tumor necrosis factor inhibition on COPD exacerbations. This retrospective study characterized this impact among COPD patients with underlying autoimmune conditions, exposed to tumor necrosis factor inhibitors (TNFi) and/or non-biologic disease-modifying antirheumatic drugs (DMARDs). PATIENTS AND METHODS: Adult COPD patients with ≥1 diagnosis for rheumatoid arthritis (RA), psoriasis (PsO), psoriatic arthritis (PsA), or ankylosing spondylitis (AS) before or within 6 months following the index COPD diagnosis were identified from the Truven Health MarketScan® databases. Patients were required to have a second claim for RA, PsO, PsA, AS, or DMARD use (biologic or non-biologic) prior to or up to 6 months following the index date. Incidence of COPD-related hospitalizations and emergency room (ER) visits was evaluated in relation to treatment with TNFi and/or DMARDs and other potential risk factors. RESULTS: The study cohort included 40,687 patients (untreated, 37.7%; non-biologic DMARD, 35.4%; TNFi + non-biologic DMARD, 18%; TNFi, 8.8%). The proportion of patients with a COPD-related hospitalization and the incidence of COPD-related hospitalization (per 100 person-years) were lowest in the TNFi cohort (8.6%; 3.54, 95% confidence interval [CI]: 3.16-3.95) and the TNFi + non-biologic DMARD cohort (8.4%; 2.85, 95% CI: 2.63-3.08). In multivariate models, treatment with TNFi + non-biologic DMARD reduced the risk of COPD-related hospitalization or ER visits by 32% relative to non-biologic DMARDs (hazard ratio: 0.68; 95% CI: 0.61-0.75). CONCLUSION: In real-world settings, TNFi monotherapy confers similar risk for COPD-related hospitalization or ER visits as a non-biologic DMARD. Decreased risk was found among those treated with both TNFi and a non-biologic DMARD.

Changes in Healthcare Utilization After Etanercept Initiation in Patients with Rheumatoid Arthritis: A Retrospective Claims Analysis.

INTRODUCTION: Effective treatment for rheumatoid arthritis (RA) may lead to lower overall and RA-related healthcare utilization. We evaluated healthcare utilization before and after initiation of the tumor necrosis factor inhibitor etanercept in patients with moderate to severe RA. METHODS: This retrospective cohort study used data from the MarketScan® claims database. Data from adult patients with RA newly exposed to etanercept between January 1, 2010 and December 31, 2013 were analyzed. Patients had at least one inpatient or outpatient claim for RA and at least one claim for etanercept (first claim was index date). Etanercept compliance was determined on the basis of proportion of days covered (PDC). Primary outcome was change in overall and RA-related healthcare utilization in the year before and year after etanercept initiation. McNemar's test and paired t test, respectively, were used to determine statistical significance for dichotomous and continuous variables. RESULTS: Data from 6737 patients were analyzed; mean age was 49.8 years and 77.3% were female. Overall outpatient services, office visits, outpatient hospital services, laboratory visits, and emergency department visits were significantly lower in the post-index period compared to pre-index. RA-related pharmacotherapy use (oral corticosteroids, opioid analgesics, nonsteroidal anti-inflammatory drugs, and nonbiologic disease-modifying antirheumatic drugs) was significantly lower in the post-index period compared to pre-index. Rates of RA-related total joint arthroplasty, joint reconstructions, and soft tissue procedures were similar in pre-index and post-index periods. High etanercept compliance (PDC ≥80%) was associated with significantly lower rates of RA-related outpatient services, office visits, diagnostic imaging studies, and joint reconstructions compared with noncompliance. CONCLUSION: Overall healthcare utilization decreased after etanercept initiation. Patients who were most compliant with etanercept had significantly lower utilization than less compliant patients. FUNDING: Amgen, Inc.

Dose relationship between oral glucocorticoids and tumor necrosis factor inhibitors and the risk of hospitalized infectious events among patients with rheumatoid arthritis.

The objective of this study was to evaluate the impact of oral glucocorticoid (GC) dose on rates of hospitalized infectious events (HIEs) among RA patients newly exposed to tumor necrosis factor inhibitor (TNFi) therapy. This retrospective cohort study used data from the MarketScan claims database. Incident and prevalent adult RA patients newly exposed to TNFi therapy were identified and assigned to three cohorts: no GC, low-dose GC (≤7.5 mg), and high-dose GC (>7.5 mg); patients could contribute exposure time to multiple cohorts if they changed dose or discontinued GC. The primary outcome was estimated incidence rate (IR) of HIEs per 100 patient-years of GC exposure. A total of 40,933 eligible patients were identified (mean age 53.0 years; 77.4% female). HIE risk increased with increasing GC dose: the IR [95% confidence interval (CI)] was 3.9 (3.63-4.13) for no GC; 6.4 (5.68-7.16) for low-dose GC; and 13.3 (11.9-15.5) for high-dose GC. Adjusted rate ratios (95% CI) were 1.4 (1.21-1.60) for low-dose vs no GC; 2.8 (2.32-3.34) for high-dose vs no GC, and 2.0 (1.66-2.45) for high-dose vs low-dose GC. The risk of HIEs increased with increasing age. HIE risk did not increase with longer exposure to GCs. Oral GCs, regardless of dose, significantly increased the risk of HIEs among RA patients newly initiating TNFi therapy. Steroid dosing must be considered when assessing infection risk in treatment decisions for RA patients.

Changes in Treatment Patterns in Patients with Psoriatic Arthritis Initiating Biologic and Nonbiologic Therapy in a Clinical Registry.

OBJECTIVE: Treatment options for psoriatic arthritis (PsA) have increased and improved in the past decade; treatment patterns in PsA remain poorly understood. Understanding current practices would aid in treatment management of patients with PsA. METHODS: This observational study was based on data from the Corrona registry of adult patients with PsA in North America collected between January 1, 2004, and December 31, 2012. Patients were divided among 3 therapy cohorts: tumor necrosis factor inhibitor (TNFi) monotherapy, methotrexate (MTX) monotherapy, and TNFi and MTX combination therapy. Patients were further divided among 3 study periods to understand changes over time: 2004-2006, 2007-2009, and 2010-2012. Data were collected on persistence, discontinuation, restarting, switching, adding/dropping therapy, and dose stretching. RESULTS: This study included 520 patients: 190 TNFi monotherapy, 217 MTX monotherapy, and 113 combination therapy; 110 from 2004 to 2006, 192 from 2007 to 2009, and 218 from 2010 to 2012. Over time, the proportion of patients initiating TNFi monotherapy decreased, while the proportion initiating combination therapy remained constant. The percentage of patients who were persistent decreased over time across all therapy cohorts, but remained higher in TNFi monotherapy than in other cohorts. Duration of persistence decreased over time. Patients initiating MTX monotherapy were more likely than their TNFi counterparts to add therapy. CONCLUSION: Treatment patterns in patients with PsA have changed from 2004 to 2012. Physicians are not more likely to initiate TNFi monotherapy, although clinical evidence supporting its effectiveness has increased over this study period, and patients remain more persistent with it.

Incidence and Prevalence of Cardiovascular Risk Factors Among Patients With Rheumatoid Arthritis, Psoriasis, or Psoriatic Arthritis.

OBJECTIVE: To estimate prevalence and incidence of cardiovascular (CV) risk factors of hypertension, diabetes mellitus, hyperlipidemia, and obesity in patients with rheumatoid arthritis (RA), psoriasis, or psoriatic arthritis (PsA). METHODS: Patients with RA, psoriasis, or PsA were identified based on medical and pharmacy claims from the MarketScan claims databases from January 1, 2002 through December 31, 2014. Primary outcomes included age- and sex-standardized prevalence of CV risk factors during the 12 months preceding diagnosis date and incidence rates per 1,000 patient-years, with 95% confidence intervals (95% CIs) during followup. RESULTS: Prevalence for RA, psoriasis, and PsA cohorts for hypertension was 18.6% (95% CI 18.3-18.8), 16.6% (95% CI 16.3-17.0), and 19.9% (95% CI 19.4-20.4), respectively; for diabetes mellitus 6.2% (95% CI 6.1-6.4), 6.3% (95% CI 6.0-6.5), and 7.8% (95% CI 7.4-8.2); for hyperlipidemia 9.9% (95% CI 9.7-10.1), 10.4% (95% CI 10.2-10.7), and 11.6% (95% CI 11.2-12.0); and for obesity 4.4% (95% CI 4.2-4.6), 3.8% (95% CI 3.5-4.0), and 6.0% (95% CI 5.6-6.5). Incidence rates per 1,000 patient-years during followup for RA, psoriasis, and PsA cohorts, respectively, for hypertension were 74.0 (95% CI 72.5-75.5), 68.2 (95% CI 65.9-70.4), and 79.8 (95% CI 76.3-83.3); for diabetes mellitus 10.6 (95% CI 10.1-11.1), 13.0 (95% CI 12.1-13.8), and 14.7 (95% CI 13.5-16.0); for hyperlipidemia 40.3 (95% CI 39.4-41.3), 47.1 (95% CI 45.4-48.7), and 52.0 (95% CI 49.6-54.3); and for obesity 24.4 (95% CI 23.4-25.4), 26.4 (95% CI 25.0-27.8), and 32.9 (95% CI 30.6-35.2). CONCLUSION: Patients with RA, psoriasis, and PsA have high prevalence and incidence of CV risk factors, suggesting the need for risk factor monitoring of these patients.

Risk of Subsequent Infection Among Patients Receiving Tumor Necrosis Factor Inhibitors and Other Disease-Modifying Antirheumatic Drugs.

OBJECTIVE: To describe the incidence of subsequent serious infections in patients who received systemic drug therapy after an initial serious infection. METHODS: Patients with rheumatic conditions (rheumatoid arthritis [RA], psoriatic arthritis, ankylosing spondylitis) or psoriasis who experienced a serious infection between January 1, 2006 and December 31, 2011 were identified in a claims database. Patients were required to be continuously enrolled in the Truven Health Analytics MarketScan Research Database for 12 months prior to and at least 60 days after the date of discharge or the end of intravenous antibiotic therapy for the index serious infection. Subsequent serious infection incidence rates per 100 patient-years with 95% confidence intervals (95% CIs) were calculated for up to 18 months post-index, starting 60 days post-index. Cox proportional hazards models were used to adjust for baseline demographic and clinical characteristics, treatment duration, and changes during followup. RESULTS: Among the 21,699 patients who met the inclusion criteria, the majority (84.3%) had RA. Patients who received tumor necrosis factor (TNF) inhibitor therapy after their index infection had a lower rate of subsequent serious infections (18.1 per 100 patient-years for those treated with a TNF inhibitor alone and 17.3 per 100 patient-years for those treated with a TNF inhibitor plus a nonbiologic disease-modifying antirheumatic drug [DMARD]) compared with those treated with a nonbiologic DMARD alone (21.4 per 100 patient-years). Etanercept, either alone (adjusted hazard ratio [HR] 0.87, 95% CI 0.77-0.99) or in combination with a nonbiologic DMARD (adjusted HR 0.76, 95% CI 0.66-0.88), and infliximab (only in combination with a nonbiologic DMARD) (adjusted HR 0.80, 95% CI 0.67-0.95) were associated with a significantly lower risk of subsequent serious infections compared with a nonbiologic DMARD alone. CONCLUSION: We did not observe an increased risk of subsequent infection in patients who received TNF inhibitor treatment following a serious infection. The risk of a subsequent serious infection was lower in patients treated with both a TNF inhibitor and a nonbiologic DMARD compared with that in patients treated with a nonbiologic DMARD alone.

OBSERVE-5: observational postmarketing safety surveillance registry of etanercept for the treatment of psoriasis final 5-year results.

BACKGROUND: OBSERVE-5 was a 5-year Food and Drug Administration-mandated surveillance registry of patients with psoriasis. OBJECTIVE: We sought to assess long-term etanercept safety and effectiveness. METHODS: Patients with moderate to severe psoriasis enrolled; a single baseline dose of etanercept was required. Key outcome measures included serious adverse events, serious infectious events, events of medical interest, psoriasis-affected body surface area, physician global assessment score, and Dermatology Life Quality Index score. Safety outcomes were assessed relative to data from the MarketScan database. RESULTS: For 2510 patients, 5-year cumulative incidence was 22.2% (95% confidence interval [CI] 20.3%-24.2%) for serious adverse events; 6.5% (95% CI 5.4%-7.7%) for serious infectious events; 3.2% (95% CI 2.3%-4.1%) for malignancies excluding nonmelanoma skin cancer; 3.6% (95% CI 2.7%-4.5%) for nonmelanoma skin cancer; 2.8% (95% CI 2.0%-3.6%) for coronary artery disease; 0.7% (95% CI 0.3%-1.2%) for psoriasis worsening; 0.2% (95% CI 0.0%-0.4%) for central nervous system demyelinating disorder; 0.1% (95% CI 0.0%-0.3%) for lymphoma and for tuberculosis; and 0.1% (95% CI 0.0%-0.2%) for opportunistic infection and for lupus; 55 fatal events were reported. Rates of malignancies, lymphomas, nonmelanoma skin cancer, and hospitalization-associated infections were not higher than expected relative to administrative claims data. The percentage of patients rated as clear/almost clear was 12% at baseline, which increased to 51% at month 6 and remained relatively stable throughout 5 years. LIMITATIONS: No internal comparator group was included; rare events may not have been detected. CONCLUSION: No new safety signals were observed with long-term, real-world etanercept use.

The effect of delay time between primary melanoma biopsy and sentinel lymph node dissection on sentinel node status, recurrence, and survival.

For primary melanoma, there is a delay between the initial skin biopsy and sentinel lymph node dissection, which may cause anxiety for the patient. The consequences of this delay on disease progression are unknown. The goal of this study was to determine whether delay time for sentinel node dissection from the initial cutaneous melanoma biopsy affects patient outcomes. A retrospective analysis of 492 patients with melanoma who underwent a sentinel node dissection between 1993 and 1999 was carried out. The endpoints assessed were sentinel node tumor status, recurrence, and mortality. Time to sentinel node dissection was compared between patients with positive and negative sentinel nodes. Long-term survival and recurrence were evaluated in relation to the time between the cutaneous biopsy and the sentinel node dissection (delay time), comparing less than 40 days with at least 40 days. In total, 15.9% of patients had positive sentinel nodes. The median follow-up was 11.7 years. Positive sentinel node patients had a median delay of 35 days between the primary melanoma biopsy and the sentinel node dissection compared with 41 days for negative sentinel node patients (P=0.5). Kaplan-Meier survival curves showed that a delay time of less than 40 days versus at least 40 days was not related to recurrence of melanoma (log-rank P=0.13) or overall survival (log-rank P=0.14). On multivariate analysis of age, thickness, ulceration, and sentinel node status, there was no difference in disease-free survival (P=0.58) or overall survival (P=0.53) between the less than 40 days and the at least 40 days groups. A modest delay in sentinel node dissection from the initial melanoma biopsy does not adversely affect sentinel node status, recurrence, nor survival.

Prognosis and determinants of outcome following locoregional or distant recurrence in patients with cutaneous melanoma.

OBJECTIVE: Information on prognosis for patients with cutaneous melanoma after locoregional or distant recurrence is sparse and controversial. The aim of this study was to analyze factors influencing outcome after the development of a first relapse. METHODS: Information was extracted from the Sydney Melanoma Unit database for 873 melanoma patients with American Joint Committee on Cancer (AJCC) Stage I and II disease treated between 1960 and 2002 who relapsed following treatment of their primary melanoma. Clinical and pathologic factors predicting survival were analyzed using the Cox proportional hazards regression model. RESULTS: Initial presentation of recurrence was local: 95 patients (10.9%), in transit: 86 patients (9.9%), regional lymph node: 300 patients (34.4%), and distant: 392 patients (44.9%). Independent prognostic factors for survival of the 481 patients with only locoregional recurrence were type of recurrence, primary tumor ulceration, and patient age. Predictors for longer survival in the 392 patients with distant metastasis at the time of first presentation with recurrence were lung vs other sites and diagnosis of relapse after 1990 compared with diagnosis before 1980. CONCLUSIONS: The type of recurrence is the most important prognostic factor in melanoma patients who relapse. Primary tumor ulceration is the most important pathologic predictor. The results of this study suggest that management of distant metastases may have improved over the last 25 years, but many confounders and improved staging techniques make assessment of this unreliable.

Impact of multiple lymphatic channel drainage to a single nodal basin on outcomes in melanoma.

OBJECTIVE: To determine the impact of multiple lymphatic channels (MLCs) on outcome in melanoma. DESIGN: Retrospective cohort study. SETTING: Academic tertiary care center. PATIENTS: Of 1198 consecutive selective sentinel lymphadenectomies performed from 1995 to 2000 for primary invasive melanoma, 502 patients were identified with extremity or truncal melanoma that drained to a single nodal basin. Three cohorts were formed based on lymphatic channels (none, single, and multiple). Tumors with drainage to multiple nodal basins as well as all head and neck tumors were excluded. MAIN OUTCOME MEASURES: Multiple variables, including patterns of lymphatic drainage, were analyzed for impact on disease-free and overall survival. RESULTS: Demographics were similar among groups, with a median follow-up of 5.6 years. Univariate analysis revealed MLCs as an independent risk factor for both disease-free (P = .04) and overall survival (P = .003). Multivariate analysis confirmed that tumor depth, sentinel lymph node status, and MLCs were risk factors for both disease-free and overall survival. Kaplan-Meier analysis showed worse survival in the MLCs group. CONCLUSIONS: Our study reveals that MLCs are an independent risk factor for recurrence and mortality in melanoma. Multiple lymphatic channels may facilitate the process of metastasis.

Detection of first relapse in cutaneous melanoma patients: implications for the formulation of evidence-based follow-up guidelines.

BACKGROUND: The value of follow-up surveillance for patients with cutaneous melanoma remains uncertain. In this prospective study the frequency of detection of first melanoma recurrence (FMR) by patient or doctor was analyzed to assist in the future design of evidence-based follow-up guidelines. METHODS: Patients who had a recurrence of a previously treated American Joint Committee on Cancer (AJCC) stage I-III primary melanoma (PM) were interviewed to ascertain how their PM and FMR were detected. Factors predicting the detection of PM and FMR were analyzed. RESULTS: The study group comprised 211 patients. In 168 patients, information on detection of their PM was available; 102 PMs (61%) were detected by the patient and 18 (11%) by their partner. Higher AJCC stage, visible location for the patient, and female sex were independent predictive factors for patient-detected PM (P = .03, .002, and .02 respectively). The FMR type was local in 28 (13%), in transit in 35 (17%), in regional lymph nodes in 97 (46%), and distant in 51 (24%). Seventy-three percent of all FMRs were detected by the patient. The presence of a symptom was the only independent predictor of a patient-detected FMR (P < .0001). There was no statistically significant survival difference between the patient-detected and doctor-detected FMRs. CONCLUSIONS: Three-quarters of FMRs were detected by patients or their partners, and it should be possible to improve this rate even further by better education. More frequent follow-up visits are thus unlikely to be valuable. Reductions in follow-up frequency may therefore be safe and economically responsible.

Promotion of acellular dermal matrix resolution in vitro by matrix metalloproteinase-2.

OBJECTIVE: To determine whether acellular human dermis is degraded by matrix metalloproteinases (MMPs), a large class of matrix-degrading enzymes. METHODS: The degradation of acellular human dermis specimens was evaluated in vitro. Wild-type murine fibroblasts with a broad-spectrum MMP inhibitor, GM6001, and MMP-2-deficient fibroblasts were placed on the basement membrane and dermal surfaces of acellular human dermis. Matrix degradation and fibroblast infiltration into the matrix were assessed after a 20-day incubation period. RESULTS: The basement membrane thickness of the specimens cultured with wild-type fibroblasts was significantly less than that of specimens cultured with GM6001 (P<.001), and the infiltration of fibroblasts into the dermal surface was limited by the addition of GM6001 (P=.002). To determine whether MMP-2 was involved in this in vitro phenotype, MMP-2-deficient fibroblasts were assessed in comparison with wild-type fibroblasts. Wild-type fibroblasts degraded the basement membrane surface (P<.001) and infiltrated the dermal surface (P = .003) more efficiently than did MMP-2-deficient fibroblasts. CONCLUSIONS: The results from our in vitro experiments suggest that MMPs and specifically MMP-2 may play an important role in the resorption of acellular human dermis. Addition of MMP inhibitors to implanted dermal matrices may slow fibroblast infiltration and improve their longevity in vivo.

Brief communication: Glomerulonephritis in patients with hepatitis C cirrhosis undergoing liver transplantation.

BACKGROUND: Patients infected with hepatitis C virus (HCV) frequently develop renal failure after liver transplantation. OBJECTIVE: To describe renal histologic characteristics and concomitant clinical features in HCV-infected patients with end-stage cirrhosis. DESIGN: Case series. SETTING: Single-center liver transplant program in the United States. PATIENTS: 30 patients who received liver transplants for HCV-induced cirrhosis. INTERVENTION: Kidney biopsy during liver engraftment. MEASUREMENTS: Clinical data and laboratory tests of renal function within 6 months before liver transplantation. RESULTS: Twenty-five patients had immune-complex glomerulonephritis: membranoproliferative glomerulonephritis type 1 (n = 12), IgA nephropathy (n = 7), and mesangial glomerulonephritis (n = 6). Of these patients, 10 had normal serum creatinine levels, normal urinalysis results, and normal quantitative proteinuria. For 5 others, the only renal abnormality was an increased serum creatinine level. No patient had cryoglobulins in the blood or kidney. LIMITATIONS: This small observational study did not include patients with nonviral cirrhosis and did not document post-transplantation outcomes. CONCLUSIONS: Immune-complex glomerulonephritis was common in patients with end-stage HCV-induced cirrhosis and was often clinically silent. Its potential to cause renal failure after liver transplantation may be underappreciated.

Impact of sentinel node status and other risk factors on the clinical outcome of head and neck melanoma patients.

OBJECTIVE: To determine the impact of sentinel lymph node (SLN) status and other risk factors on recurrence and overall survival in head and neck melanoma patients. DESIGN: The SLN Working Group, based in San Francisco, Calif, with its 11 member centers, the John Wayne Cancer Institute, and The University of Texas M. D. Anderson Cancer Center pooled data on 629 primary head and neck melanoma patients who had selective sentinel lymphadenectomy. A total of 614 subjects were analyzable. All centers obtained internal review board approval and adhered to the Health Insurance Portability and Accountability Act of 1996 regulations. A Cox proportional hazards model was used to identify factors associated with overall and disease-free survival. SETTING: Tertiary care medical centers. MAIN OUTCOME MEASURE: Clinical outcome of head and neck melanoma patients undergoing selective sentinel lymphadenectomy. RESULTS: Overall, 10.1% (n = 62) of the subjects had at least 1 positive node. Subjects with positive SLN status had significantly thicker tumors (mean thickness, 2.8 vs 2.1 mm; P < .001), and were more likely to have ulcerated tumors (P = .004). During the median follow-up of 3.3 years, the overall mortality from head and neck melanoma was 10%, with more than 20% experiencing at least 1 recurrence. Multivariate analysis showed that tumor site was an independent predictor of mortality; location on the scalp had a more than 3-fold (P < .001) greater mortality than tumors on the face. Tumor thickness was also an independent predictor of overall survival, and SLN status was the most important predictor of disease-free survival in the multivariate model (P < .001). Tumors on the scalp had the highest rate of recurrence, while those on the neck had the lowest. Tumor ulceration was the significant predictor of time to recurrence or disease-free survival (P < .001). CONCLUSION: In this multicenter study, SLN status and other risk factors have an effect on recurrence and/or overall survival.