Marcella M. Johnson

Frequency and risk factors associated with osteonecrosis of the jaw in cancer patients treated with intravenous bisphosphonates.

Introduction: Osteonecrosis of the jaw (ONJ) has been reported in patients treated with bisphosphonates. The incidence and risk factors associated with this disorder have not been clearly defined.

Hepatic arterial embolization and chemoembolization for the treatment of patients with metastatic neuroendocrine tumors: variables affecting response rates and survival.

The objective of this study was to determine the prognostic variables that influence response and survival in patients with metastatic neuroendocrine tumors who are treated with hepatic arterial embolization (HAE) or chemoembolization (HACE).

Differential Time to Positivity: A Useful Method for Diagnosing Catheter-Related Bloodstream Infections

Context Diagnosing central venous catheterrelated bloodstream infections may be difficult. Contribution This prospective study from a tertiary care cancer center examined 191 infections with the same organism detected from simultaneously drawn central and peripheral blood cultures. Catheter-tip colonization or quantitative blood cultures defined catheter-related bloodstream infection. When the culture drawn from the catheter became positive at least 120 minutes earlier than the peripherally drawn culture, the odds of catheter-related bloodstream infection increased by a factor of 5.9. Implications Differential time to positivity of at least 120 minutes between centrally and peripherally drawn blood cultures helps diagnose catheter-related bloodstream infection. The Editors Catheter-related bloodstream infections are a common type of nosocomial bloodstream infections and are associated with the use of central venous catheters (1, 2). Kluger and Maki (3) estimated that more than 200 000 cases of catheter-related bloodstream infections occur annually in the United States, with an attributable mortality rate of 12% to 25% (3). However, despite their high frequency of occurrence and seriousness, such infections are often difficult to diagnose. Clinical manifestations of this type of infection, such as fever and chills, are sensitive but not specific for a diagnosis, whereas other manifestations, suchas catheter-site inflammation, are specific but not sensitive. For the past 25 years, semiquantitative (for example, the roll-plate technique) and quantitative (for example, sonication) methods of catheter culture have been used to establish the diagnosis of catheter-related bloodstream infection (4-6). However, because taking catheter cultures requires the removal or exchange of the catheter, it only minimally affects management of the infection (7). To avoid unnecessary removal of the central venous catheter, some researchers have suggested taking simultaneous quantitative blood cultures from the catheter and the peripheral vein (8, 9). This method has been limited because quantitative blood cultures are labor intensive and costly and therefore are not widely used in clinical microbiology laboratories. Recently, Blot and colleagues (10, 11) reported that the measurement of differential time to positivity between blood cultures drawn through the central venous catheter and those drawn from the peripheral vein is highly diagnostic of catheter-related bloodstream infection in patients with long-term catheters. The differential time to positivity was defined as the difference in the time it took for a blood culture drawn through the central venous catheter and a culture drawn from a peripheral vein to become positive. Other investigators did not show that this method is highly diagnostic of catheter-related bloodstream infection in patients with short-term (<30 days of dwell time) catheters. However, all of the studies reported so far have included a very small number of evaluable patients who had positive simultaneous blood cultures from both the central venous catheter and the peripheral vein (12-14). To investigate the diagnostic usefulness of differential time to positivity, we decided a priori to follow for a year patients who grew the same organism from blood cultures drawn simultaneously through the central venous catheter and peripheral vein. We hypothesized that the diagnostic utility of differential time to positivity would differ between patients who had short-term catheters and those who had long-term catheters. Methods Patients The study took place at the University of Texas M.D. Anderson Cancer Center, in Houston, Texas, between 1 September 1999 and 1 November 2000. We evaluated the results of all blood cultures drawn simultaneously from the central venous catheter and peripheral vein and prospectively followed patients who had positive simultaneous blood cultures that grew the same organisms. Information obtained on these patients included age, sex, underlying disease, duration of hospitalization, duration of stay in the intensive care unit, history of bone marrow transplantation, type of catheter, number of catheter lumen, catheter insertion site, and duration of catheterization. We also evaluated patients for neutropenia, thrombocytopenia, concomitant infections, therapy with antimicrobial agents, and outcome of infections. Definitions and Diagnosis We defined differential time to positivity as the difference in time needed for blood cultures drawn simultaneously through the central venous catheter and from a peripheral vein to become positive. As in previous studies, differential time to positivity was considered positive (that is, suggestive of catheter-related bloodstream infection) if the blood culture drawn through the central venous catheter became positive at least 120 minutes earlier than a positive culture drawn simultaneously from a peripheral vein. Significant colonization of the catheter tip was defined as a positive semiquantitative catheter culture by the roll-plate method, whereby at least 15 colony-forming units (CFUs) of an organism were cultured from the catheter tip (4). We used 3 definitions of catheter-related bloodstream infection in this study to evaluate the diagnostic accuracy of differential time to positivity. All of the definitions included the presence of clinical signs and symptoms of bacteremia, such as fever and chills, in the absence of sources for the bacteremia other than the catheter. The definitions were as follows: 1. Composite definition of catheter-related bloodstream infection as defined by the recent Infectious Disease Society of America (IDSA) guidelines (15): Positive simultaneous blood cultures from the central venous catheter and peripheral vein yielding the same organism in the presence of either significant catheter-tip colonization with 15 CFUs or more of the same organism (same species and antibiogram) isolated from the blood cultures, or simultaneous quantitative blood cultures in which the number of CFUs isolated from the blood drawn through the central venous catheter was at least 5-fold greater than the number isolated from blood drawn percutaneously. 2. Partial definition based on simultaneous quantitative blood cultures: The presence of at least 5 times the number of CFUs from the central venous catheter blood culture compared with that the number from the peripheral vein blood culture. 3. Partial definition based on semiquantitative catheter culture: Catheter-tip culture with at least 15 CFUs of the same organism isolated from the peripheral vein blood culture. A bloodstream infection originating from a noncatheter source was defined as one with positive blood cultures from the central venous catheter and peripheral vein that did not fulfill any of the criteria of quantitative catheter-related bloodstream infection or tip culturebased bloodstream infection, as defined earlier. Evaluable cases of bloodstream infection were those with positive simultaneous blood cultures of the same organisms from the central venous catheter and peripheral vein, in which it was possible to determine the source of the bloodstream infection (catheter or otherwise) on the basis of the definitions outlined earlier. Short-term central venous catheters were those with a dwell time of less than 30 days, and long-term central venous catheters were those with a dwell time of 30 days or more. The principal investigator determined whether infections were catheter related and had no knowledge of differential time to positivity at the time of adjudication of the reference standard definitions. Culture Techniques After rigorous antiseptic cleansing of the skin and the hub with 70% alcohol, we drew quantitative and qualitative blood cultures from the peripheral vein and central venous catheter hub simultaneously (maximum of 15 minutes apart). From the central venous catheter, we drew 7 to 10 mL of blood and then discarded the sample to avoid contamination with previously administered agents that could have antimicrobial activity. We subsequently drew 20 mL of blood through the central venous catheter and divided the sample into 2 portions. We placed 10 mL in isolator tubes (isolator 10, Wampole, Cranbury, New Jersey) for quantitative culturing by using the lysis centrifugation method, as described elsewhere (16). Another 10 mL of blood was placed in a regular aerobic blood culture bottle (aerobic 26+, Becton Dickinson DIS, Sparks, Maryland). We also drew 20 mL of blood percutaneously and processed the sample in the same manner as the blood culture from the central venous catheter. All blood culture bottles were taken promptly to the microbiology laboratory and placed in an automatic culture detector (Bactec 9240, Bactec Plus Aerobic/F, Becton Dickinson DIS, Sparks, Maryland), which records culture positivity every 15 minutes according to changes in fluorescence related to microbial growth. Catheters were removed aseptically, at the discretion of primary care physicians, if they were no longer needed or if infection was suspected. A 5-cm segment of the removed catheter tip was aseptically cut and delivered to the microbiology laboratory for culture by the semiquantitative roll-plate method (4). Statistical Analysis We divided the study sample into 2 groups, those with catheter-related bloodstream infection and those without, on basis of the composite definition of catheter-related bloodstream infection according to IDSA guidelines (15). We determined the significance of the differences between the 2 study groups using the chi-square test or the Fisher exact test, as appropriate, for categorical variables. The Student t-test or MannWhitney test was used for continuous variables. All P values were based on 2-tailed tests (level of significance, P 0.05). Sensitivity, specificity, and likelihood ratios, along with associated 95% CIs, were determined for differential time to positivity o

Prognostic Significance of Mitotic Rate in Localized Primary Cutaneous Melanoma: An Analysis of Patients in the Multi-Institutional American Joint Committee on Cancer Melanoma Staging Database

PURPOSE The aim of this study was to assess the independent prognostic value of primary tumor mitotic rate compared with other clinical and pathologic features of stages I and II melanoma. METHODS From the American Joint Committee on Cancer (AJCC) melanoma staging database, information was extracted for 13,296 patients with stages I and II disease who had mitotic rate data available. RESULTS Survival times declined as mitotic rate increased. Ten-year survival ranged from 93% for patients whose tumors had 0 mitosis/mm(2) to 48% for those with ≥ 20/mm(2) (P < .001). Mean number of mitoses/mm(2) increased as the primary melanomas became thicker (1.0 for melanomas ≤ 1 mm, 3.5 for 1.01 to 2.0 mm, 7.3 for 3.01 to 4.0 mm, and 9.6 for > 8 mm). Ulceration was also associated with a higher mitotic rate; 59% of ulcerated melanomas had ≥ 5 mitoses/mm(2) compared with 16% of nonulcerated melanomas (P < .001). In a multivariate analysis of 10,233 patients, the independent predictive factors for survival in order of statistical significance were as follows: tumor thickness (χ(2) = 104.9; P < .001), mitotic rate (χ(2) = 67.0; P < .001), patient age (χ(2) = 48.2; P < .001), ulceration (χ(2) = 46.4; P < .001), anatomic site (χ(2) = 34.6; P < .001), and patient sex (χ(2) = 33.9; P < .001). Clark level of invasion was not an independent predictor of survival (χ(2) = 3.2; P = .37). CONCLUSION A high mitotic rate in a primary melanoma is associated with a lower survival probability. Among the independent predictors of melanoma-specific survival, mitotic rate was the strongest prognostic factor after tumor thickness.

Phase II trial of imatinib mesylate in patients with metastatic melanoma

Metastatic melanoma cells express a number of protein tyrosine kinases (PTKs) that are considered to be targets for imatinib. We conducted a phase II trial of imatinib in patients with metastatic melanoma expressing at least one of these PTKs. Twenty-one patients whose tumours expressed at least one PTK (c-kit, platelet-derived growth factor receptors, c-abl, or abl-related gene) were treated with 400 mg of imatinib twice daily. One patient with metastatic acral lentiginous melanoma, containing the highest c-kit expression among all patients, had dramatic improvement on positron emission tomographic scan at 6 weeks and had a partial response lasting 12.8 months. The responder had a substantial increase in tumour and endothelial cell apoptosis at 2 weeks of treatment. Imatinib was fairly well tolerated: no patient required treatment discontinuation because of toxicity. Fatigue and oedema were the only grade 3 or 4 toxicities that occurred in more than 10% of the patients. Imatinib at the studied dose had minimal clinical efficacy as a single-agent therapy for metastatic melanoma. However, based on the characteristics of the responding tumour in our study, clinical activity of imatinib, specifically in patients with melanoma with certain c-kit aberrations, should be examined.

Clinical Risk Factors for Malignancy and Overall Survival in Patients with Pheochromocytomas and Sympathetic Paragangliomas: Primary Tumor Size and Primary Tumor Location as Prognostic Indicators

CONTEXT Pheochromocytomas and sympathetic paragangliomas are rare neuroendocrine tumors for which no precise histological or molecular markers have been identified to differentiate benign from malignant tumors. OBJECTIVE The aim was to determine whether primary tumor location and size are associated with malignancy and decreased survival. DESIGN AND SETTING We performed a retrospective chart review of patients with either pheochromocytoma or sympathetic paraganglioma. PATIENTS The study group comprised 371 patients. MAIN OUTCOME MEASURES Overall survival and disease-specific survival were analyzed according to tumor size and location. RESULTS Sixty percent of patients with sympathetic paragangliomas and 25% of patients with pheochromocytomas had metastatic disease. Metastasis was more commonly associated with primary tumors located in the mediastinum (69%) and the infradiaphragmatic paraaortic area, including the organ of Zuckerkandl (66%). The primary tumor was larger in patients with metastases than in patients without metastatic disease (P < 0.0001). Patients with sympathetic paragangliomas had a shorter overall survival than patients with pheochromocytomas (P < 0.0001); increased tumor size was associated with shorter overall survival (P < 0.001). Patients with sympathetic paragangliomas were twice as likely to die of disease than patients with pheochromocytomas (hazard ratio = 1.93; 95% confidence interval = 1.20-3.12; P = 0.007). As per multivariate analysis, the location of the primary tumor was a stronger predictor of metastases than was the size of the primary tumor. CONCLUSIONS The size and location of the primary tumor were significant clinical risk factors for metastasis and decreased overall survival duration. These findings delineate the follow-up and treatment for these tumors.

Revised American Joint Committee on Cancer staging criteria accurately predict sentinel lymph node positivity in clinically node-negative melanoma patients

AbstractBackground: The American Joint Committee on Cancer (AJCC) has recently modified staging criteria for primary melanoma patients and recommends sentinel lymph node (SLN) biopsy in many because microscopic nodal metastasis represents the most important factor predicting survival. The purpose of this study was to correlate the incidence of SLN metastasis with revised AJCC staging. Methods: The records of 1375 melanoma patients undergoing SLN biopsy were reviewed. Univariate and multivariate analyses were performed to identify predictors of a positive SLN. Patients were stratified by using revised AJCC criteria to determine whether such groups also predicted positive SLNs. Results: A positive SLN was found in 16.9% of patients. By multivariate analysis, tumor thickness (relative risk [RR], 3.4) and ulceration (RR, 2.2) were dominant independent predictors of SLN metastases; age ≤50 years (RR, 1.8) and axial tumor location (RR, 1.5) were also significant. When patients were stratified by AJCC staging criteria, a significant increase in SLN metastases between successive stages was demonstrated. Conclusions: Stratification of patients by using AJCC classification reveals an increasing risk of SLN metastases with successive stage groups. Given the significant association of SLN status and survival, the ability of the revised AJCC staging system to predict survival is likely due to its ability to predict the risk of occult nodal disease.

Clinical Correlates of NRAS and BRAF Mutations in Primary Human Melanoma

Purpose:NRAS and BRAF mutations are common in cutaneous melanomas, although rarely detected mutually in the same tumor. Distinct clinical correlates of these mutations have not been described, despite in vitro data suggesting enhanced oncogenic effects. This study was designed to test the hypothesis that primary human cutaneous melanomas harboring mutations in NRAS or BRAF display a more aggressive clinical phenotype than tumors wild type at both loci. Experimental Design: Microdissection of 223 primary melanomas was carried out, followed by determination of the NRAS and BRAF mutational status. Genotypic findings were correlated with features known to influence tumor behavior including age, gender, Breslow depth, Clark level, mitotic rate, the presence of ulceration, and American Joint Committee on Cancer (AJCC) staging. Results: Breslow depth and Clark level varied significantly among the genotypes, with NRAS mutants showing the deepest levels and wild-type tumors the least depth. Ulceration also differed significantly among the genotypes, with BRAF mutants demonstrating the highest rate. In addition, tumors with mutated NRAS were more likely to be located on the extremities. Patients whose tumors carried either mutation presented with more advanced AJCC stages compared with patients with wild-type tumors, and specifically, were more likely to have stage III disease at diagnosis. Overall survival did not differ among the 3 groups. Conclusions: Distinct clinical phenotypes exist for melanomas bearing NRAS and BRAF mutations, whether considered together or separately, and are associated with features known to predict aggressive tumor behavior. The impact of these mutations is most evident at earlier stages of disease progression. Clin Cancer Res; 17(2); 229–35. ©2010 AACR. Clin Cancer Res; 17(2); 229–35. ©2010 AACR.

Predictors and Natural History of In-Transit Melanoma After Sentinel Lymphadenectomy

BackgroundIn-transit recurrence is a unique and uncommon pattern of treatment failure in patients with melanoma. Little information exists concerning the incidence, predictors, and natural history of in-transit disease since the introduction of sentinel lymph node biopsy (SLNB).MethodsBetween 1991 and 2001, 1395 patients with primary melanoma underwent SLNB. Univariate and multivariate logistic regression analyses were performed to examine the association among known clinicopathologic factors, in-transit recurrence, and distant metastatic failure after the development of in-transit disease.ResultsWith a median follow-up of 3.9 years, 241 patients (17.3%) experienced disease recurrence, including 91 (6.6%) who developed in-transit recurrence. Independent predictors of in-transit recurrence included age >50 years, a lower extremity location of the primary tumor, Breslow depth, ulceration, and sentinel lymph node (SLN) status. Of the 69 patients who presented with in-transit disease as the sole site of first recurrence, 39 developed distant disease. By univariate analysis, predictors of distant failure among patients with in-transit disease included SLN status, largest metastatic focus in the SLN >2.5 mm2, subcutaneous location of in-transit disease, in-transit tumor size ≥ 2 cm, and a disease-free interval before in-transit recurrence of <12 months. In-transit tumor size remained a significant predictor of distant metastasis by multivariate analysis (odds ratio, 9.69).ConclusionsThe overall incidence of in-transit metastases in patients undergoing SLNB is low and does not seem to have increased since the introduction of the SLNB technique. In-transit recurrence, as well as subsequent distant metastatic failure, can be predicted on the basis of adverse tumor factors and SLN status.

Microscopic Tumor Burden in Sentinel Lymph Nodes Predicts Synchronous Nonsentinel Lymph Node Involvement in Patients With Melanoma

PURPOSE We and others have demonstrated that additional positive lymph nodes (LNs) are identified in only 8% to 33% of patients with melanoma who have positive sentinel LNs (SLNs) and undergo complete therapeutic LN dissection (cTLND). We sought to determine predictors of additional regional LN involvement in patients with positive SLNs. PATIENTS AND METHODS Patients with clinically node-negative melanoma who underwent SLN biopsy (1991 to 2003) and had positive SLNs were identified. Clinicopathologic factors, including extent of microscopic disease within SLNs, were evaluated as potential predictors of positive non-SLNs. RESULTS Overall, 359 (16.3%) of the 2,203 patients identified had a positive SLN. Positive non-SLNs were identified in 48 (14.0%) of the 343 patients with positive SLNs who underwent cTLND. On univariate analysis, several measures of SLN microscopic tumor burden, one versus three or more SLNs harvested, tumor thickness more than 2 mm, age older than 50 years, and Clark level higher than III were predictive of positive non-SLNs; primary tumor ulceration and number of positive SLNs had no apparent impact. On multivariable logistic regression analysis, measures of SLN microscopic tumor burden were the most significant independent predictors of positive non-SLNs; tumor thickness more than 2 mm and number of SLNs harvested also predicted additional disease. A model was developed that stratified patients according to their risk for non-SLN involvement. CONCLUSION In melanoma patients with positive SLNs, SLN tumor burden, primary tumor thickness, and number of SLNs harvested may be useful in identifying a group at low risk for positive non-SLNs and be spared the potential morbidity of a cTLND.