Elizabeth Lyden

Prognostic Factors and Clinical Outcomes in Children and Adolescents With Metastatic Rhabdomyosarcoma--A Report From the Intergroup Rhabdomyosarcoma Study IV

PURPOSE To identify risk factors associated with outcomes in children with metastatic rhabdomyosarcoma (RMS) treated on the fourth Intergroup Rhabdomyosarcoma Study (IRS-IV). PATIENTS AND METHODS Patients with metastatic RMS were treated with one of two regimens that incorporated a window of either ifosfamide and etoposide (IE) with vincristine, dactinomycin, and cyclophosphamide (VAC) or vincristine, melphalan (VM) and VAC. Study end points were failure-free survival (FFS) and overall survival (OS). Clinical factors including age, histology, sites of primary and metastatic disease, and number of sites of metastatic disease were correlated with those end points. RESULTS One hundred twenty-seven patients were eligible for analysis. The estimated 3-year OS and FFS for all patients were 39% and 25%, respectively. By univariate analysis, 3-year OS was significantly influenced by histology (47% for embryonal v 34% for all others, P =.026) and increasing number of metastatic sites (P =.028). By multivariate analysis, the presence of two or fewer metastatic sites was the only significant predictor (P =.007 and.006, respectively). The combination of embryonal histology with two or fewer metastatic sites identified a subgroup with 3-year FFS of 40% and OS of 47%. CONCLUSION Children with group IV RMS treated on the IRS-IV study had improved OS and FFS if they had two or fewer metastatic sites and embryonal histology. This favorable subset of patients has outcomes approaching those observed in selected patients with localized, nonmetastatic disease. Thus, these patients might not be appropriate candidates for regimens that include experimental agents with substantial toxicities or unproven antitumor activity.

Influence of margins on overall survival after hepatic resection for colorectal metastasis: A meta-analysis

Objective: The aim of our study was to conduct a meta-analysis of reports published on hepatic resection for colorectal liver metastasis (CRLM) and determine whether a negative margin of 1 cm or more confers a survival advantage over subcentimeter negative margins. Background: Surgical margin is an important prognostic factor in patients undergoing hepatic resection for CRLM. Although there is a consensus that positive margins portend a worse outcome than negative margins, the extent of negative margins remains controversial. Methods: A PubMed search was conducted to identify articles on hepatic resection for CRLM. The 357 initially located articles were screened to identify 90 articles of interest. The texts of these 90 articles were completely reviewed to finalize 18 articles for inclusion in the study on the basis of absolute and relative inclusion criteria. Patients with positive margins were excluded from the meta-analysis. Meta-analysis was performed using STATA 9.2 statistical software. Results: A total of 4821 patients with negative margins from the 18 studies were included in the meta-analysis. The overall 5-year survival for all patients was 41% [95% confidence interval (CI), 40%-43%]. The overall 5-year survival for the ≥1 cm negative margin subgroup was 46% (95% CI, 44%-48%) when compared with 38% (95% CI, 36%-40%) for less than 1 cm negative margin subgroup. The odds ratio for 1-cm or more negative margins was found to be 0.773 (95% CI, 0.638-0.938; P = 0.009) when compared with less than 1 cm negative margins. Conclusions: The results of this meta-analysis demonstrate that in patients undergoing hepatic resection for CRLM, a negative margin of 1 cm or more confers a survival advantage when compared with subcentimeter negative margins.

Valganciclovir for Cytomegalovirus Prevention in Solid Organ Transplant Patients: An Evidence-Based Reassessment of Safety and Efficacy

Background Several anti-viral drugs have demonstrated efficacy in preventing Cytomegalovirus (CMV) infections in solid organ transplant (SOT) patients. The recently approved valganciclovir is the most commonly used and most expensive drug for CMV prevention. The safety and efficacy data have been drawn from a single trial. We hypothesized that valganciclovir may not be as safe as nor more effective than other therapies for CMV prevention. Methods All experimental and analytical studies that compared valganciclovir with other therapies for prevention of CMV infection after SOT were selected. Based on meta-analytic and multivariate regression methodologies we critically analyzed all available evidence. Findings Nine studies were included (N = 1,831). In trials comparing valganciclovir with ganciclovir, the risk for CMV disease is 0.98 (95% Confidence Interval (95%CI) 0.67 to 1.43; P = 0.92; I2 = 0%). Valganciclovir was significantly associated with the risk of absolute neutropenia (<1,500/mm3) compared with all therapies (Odds Ratio (OR) 3.63 95%CI 1.75 to 7.53; P = 0.001; I2 = 0%); with ganciclovir only (OR 2.88, 95%CI 1.27 to 6.53; P = 0.01; I2 = 0%); or with non-ganciclovir therapies (OR 8.30, 95%CI 1.51 to 45.58; P = 0.01; I2 = 10%). For a neutropenia cut-off of <1,000/mm3, the risk remained elevated (OR 1.97, 95%CI 1.03 to 3.67; P = 0.04; I2 = 0%). For every 24 patients who receive valganciclovir prophylaxis, one more will develop neutropenia compared to other therapies. The risk of late-onset CMV disease with valganciclovir was similar to ganciclovir and higher than those with non-ganciclovir therapies (OR 8.95, 95%CI 1.07 to 74.83; P = 0.04; I2 = 0%]. One more patient will develop late-onset CMV disease for every 25 who receive valganciclovir compared to treatment with non-ganciclovir therapies. The risk of CMV tissue-invasive disease in liver recipients receiving valganciclovir was 4.5 times the risk seen with ganciclovir [95%CI 1.00 to 20.14] (p = 0.04). All results remained consistent across different study designs, valganciclovir doses, and CMV serostatus. Conclusions Valganciclovir shows no superior efficacy and significantly higher risk of absolute neutropenia, CMV late-onset disease, and CMV tissue-invasive disease compared to other standard therapies. Due to the availability of efficacious, safer, and lower cost drugs (high-dose acyclovir, valacyclovir, ganciclovir), our results do not favor the use of valganciclovir as a first-line agent for CMV preemptive or universal prophylaxis in SOT patients.

Prognostic Significance and Tumor Biology of Regional Lymph Node Disease in Patients With Rhabdomyosarcoma: A Report From the Children's Oncology Group

PURPOSE Regional lymph node disease (RLND) is a component of the risk-based treatment stratification in rhabdomyosarcoma (RMS). The purpose of this study was to determine the contribution of RLND to prognosis for patients with RMS. PATIENTS AND METHODS Patient characteristics and survival outcomes for patients enrolled onto Intergroup Rhabdomyosarcoma Study IV (N = 898, 1991 to 1997) were evaluated among the following three patient groups: nonmetastatic patients with clinical or pathologic negative nodes (N0, 696 patients); patients with clinical or pathologic positive nodes (N1, 125 patients); and patients with a single site of metastatic disease (77 patients). RESULTS Outcomes for patients with nonmetastatic alveolar N0 RMS were significantly better than for patients with N1 RMS (5-year failure-free survival [FFS], 73% v 43%, respectively; 5-year overall survival [OS], 80% v 46%, respectively; P < .001). Patients with a single site of alveolar metastasis had even worse FFS and OS (23% FFS and OS, P = .01) when compared with patients with N1 RMS; however, the differences was not as large as the differences between patients with N0 RMS and N1 RMS. For embryonal RMS, there was no statistically significant difference in FFS or OS (P = .41 and P = .77, respectively) for patients with N1 versus N0 RMS. Gene array analysis of primary tumor specimens identified that genes associated with the immune system and antigen presentation were significantly increased in N1 versus N0 alveolar RMS. CONCLUSION RLND alters prognosis for alveolar but not embryonal RMS. For patients with N1 disease and alveolar histology, outcomes were more similar to distant metastatic disease rather than local disease. Current data suggest that more aggressive therapy for patients with alveolar N1 RMS may be warranted.

Intensive Multiagent Therapy, Including Dose-Compressed Cycles of Ifosfamide/Etoposide and Vincristine/Doxorubicin/Cyclophosphamide, Irinotecan, and Radiation, in Patients With High-Risk Rhabdomyosarcoma: A Report From the Children's Oncology Group

PURPOSE Patients with metastatic rhabdomyosarcoma (RMS), except those younger than 10 years with embryonal RMS, have an estimated long-term event-free survival (EFS) of less than 20%. The main goal of this study was to improve outcome of patients with metastatic RMS by dose intensification with interval compression, use of the most active agents determined in phase II window studies, and use of irinotecan as a radiation sensitizer. PATIENTS AND METHODS Patients with metastatic RMS received 54 weeks of therapy: blocks of therapy with vincristine/irinotecan (weeks 1 to 6, 20 to 25, and 47 to 52), interval compression with vincristine/doxorubicin/cyclophosphamide alternating with etoposide/ifosfamide (weeks 7 to 19 and 26 to 34), and vincristine/dactinomycin/cyclophosphamide (weeks 38 to 46). Radiation therapy occurred at weeks 20 to 25 (primary) but was also permitted at weeks 1 to 6 (for intracranial or paraspinal extension) and weeks 47 to 52 (for extensive metastatic sites). RESULTS One hundred nine eligible patients were enrolled, with a median follow-up of surviving patients of 3.8 years (3-year EFS for all patients, 38% [95% CI, 29% to 48%]; survival, 56% [95% CI, 46% to 66%]). Patients with one or no Oberlin risk factor (age > 10 years or < 1 year, unfavorable primary site of disease, ≥ three metastatic sites, and bone or bone marrow involvement) had a 3-year EFS of 69% (95% CI, 52% to 82%); high-risk patients with two or more risk factors had a 3-year EFS of 20% (95% CI, 11% to 30%). Toxicity was similar to that on prior RMS studies. CONCLUSION Patients with metastatic RMS with one or no Oberlin risk factor had an improved 3-year EFS of 69% on ARST0431 compared with an historical cohort from pooled European and US studies; those with two or more risk factors have a dismal prognosis, and new approaches are needed for this very-high-risk group.

Lack of utility of intestinal fatty acid binding protein levels in predicting intestinal allograft rejection.

Introduction. The enterocyte-specific protein, intestinal fatty acid binding protein (I-FABP), is detectable in serum only after intestinal injury. Previous studies in animals suggest that I-FABP might be a useful marker of intestinal allograft rejection. Materials and Methods. I-FABP was repetitively measured in nine intestinal transplant recipients and correlated with findings of surveillance endoscopy. Results. Average interval between I-FABP determination and biopsy was 3.4 days (SD=4.2 days). Average number of rejection episodes per patient totalled 1.6±1.2. General linear modeling demonstrated no tendency for increases in serum FABP to precede histologic graft rejection (P =0.263). Restriction of the analysis to I-FABP determinations 1 day before or on the day of biopsy failed to affect these results. Minor increases in I-FABP were often associated with histologically normal grafts, whereas rejection often occurred when I-FABP was not detectable. Discussion. Serum I-FABP levels do not predict clinical intestinal allograft rejection.

Delayed primary excision with subsequent modification of radiotherapy dose for intermediate-risk rhabdomyosarcoma: a report from the Children's Oncology Group Soft Tissue Sarcoma Committee.

The majority of intermediate‐risk rhabdomyosarcoma (RMS) patients have gross residual disease (Group III) after their first operative procedure. It is currently not known if local control rates can be maintained when, following induction chemotherapy, the radiation therapy (RT) dose is decreased after a delayed primary excision (DPE). To answer this question we evaluated patients enrolled on COG D9803 (1999–2005) who had Group III tumors of the bladder dome, extremity or trunk (thorax, abdomen and pelvis) were candidates for DPE at Week 12 if the primary tumor appeared resectable. RT dose was then adjusted by the completeness of DPE: no evidence of disease 36 Gy, microscopic residual 41.4 Gy and gross residual disease (GRD) 50.4 Gy. A total of 161 Group III patients were evaluated (24 bladder dome, 63 extremity and 74 trunk). Seventy‐three patients (45%) underwent DPE which achieved removal of all gross disease in 61 (84%) who were then eligible for reduced RT dose (43/73 received 36 Gy, 19/73 received 41.4 Gy). The local 5‐year failure rate (0% for bladder dome, 7% for extremity and 20% for trunk) was similar to IRS‐IV, which did not encourage DPE and did not allow for DPE adapted RT dose reduction. In conclusion, DPE was performed in 45% of Group III RMS patients with tumors at select anatomic sites (bladder dome, extremity and trunk) and 84% of those who had DPE were eligible for RT dose reduction. Local control outcomes were similar to historic results with RT alone.

Local Control for Intermediate-Risk Rhabdomyosarcoma: Results From D9803 According to Histology, Group, Site, and Size: A Report From the Children's Oncology Group

PURPOSE To determine local control according to clinical variables for patients with intermediate-risk rhabdomyosarcoma (RMS) treated on Childrens Oncology Group protocol D9803. PATIENTS AND METHODS Of 702 patients enrolled, we analyzed 423 patients with central pathology-confirmed group III embryonal (n=280) or alveolar (group III, n=102; group I-II, n=41) RMS. Median age was 5 years. Patients received 42 weeks of VAC (vincristine, dactinomycin, cyclophosphamide) or VAC alternating with VTC (T = topotecan). Local therapy with 50.4 Gy radiation therapy with or without delayed primary excision began at week 12 for group III patients. Patients with group I/II alveolar RMS received 36-41.4 Gy. Local failure (LF) was defined as local progression as a first event with or without concurrent regional or distant failure. RESULTS At a median follow-up of 6.6 years, patients with clinical group I/II alveolar RMS had a 5-year event-free survival rate of 69% and LF of 10%. Among patients with group III RMS, 5-year event-free survival and LF rates were 70% and 19%, respectively. Local failure rates did not differ by histology, nodal status, or primary site, though there was a trend for increased LF for retroperitoneal (RP) tumors (P=.12). Tumors ≥5 cm were more likely to fail locally than tumors <5 cm (25% vs 10%, P=.0004). Almost all (98%) RP tumors were ≥5 cm, with no difference in LF by site when the analysis was restricted to tumors ≥5 cm (P=.86). CONCLUSION Local control was excellent for clinical group I/II alveolar RMS. Local failure constituted 63% of initial events in clinical group III patients and did not vary by histology or nodal status. The trend for higher LF in RP tumors was related to tumor size. There has been no clear change in local control over RMS studies, including IRS-III and IRS-IV. Novel approaches are warranted for larger tumors (≥5 cm).

The Relationship between Dietary Fiber Intake and Lung Function in the National Health and Nutrition Examination Surveys.

RATIONALE Extensive research supports a protective effect of a high-fiber diet in certain disease states; however, little is known about its relationship to lung health. The National Health and Nutrition Examination Surveys (NHANES) contain spirometry measures and dietary intake information, allowing us to assess this relationship. OBJECTIVE Determine the association between fiber intake and measures of lung function in a representative sample of U.S. adults. METHODS Participants included 1,921 adults who had spirometry measurements and fiber intake available. The primary outcomes were lung function measurements, including FEV1, FVC, and percent predicted FEV1 and FVC. We also conducted a categorical analysis of fiber intake and airflow restriction and obstruction based on Global Initiative for Chronic Obstructive Lung Disease and Spirometry Grade (SG) classifications. Multivariable regression models were used to look at the association of lung function measurements with dietary fiber intake after adjustment for relevant confounders. All analyses accounted for the weighted data and complex design of the NHANES sample. MEASUREMENTS AND MAIN RESULTS Subjects in the highest quartile intake of fiber had mean FEV1 and FVC measurements that were 82 ml and 129 ml higher than the lowest quartile of intake (P = 0.05 and 0.01, respectively), and mean percent predicted FEV1 and FVC values that were 2.4 and 2.8 percentage points higher (P = 0.07 and 0.02, respectively). In the categorical analysis, higher fiber intake was associated with a higher percentage of those with normal lung function (P = 0.001) and a significant decline in the proportion of participants with airflow restriction (P = 0.001). CONCLUSION Low fiber intake was associated with reduced measures of lung function. A diet rich in fiber-containing foods may play a role in improving lung health.

Faculty attitudes about interprofessional education.

Background Interprofessional education (IPE) is an important component to training health care professionals. Research is limited in exploring the attitudes that faculty hold regarding IPE and what barriers they perceive to participating in IPE. The purpose of this study was to identify faculty attitudes about IPE and to identify barriers to participating in campus-wide IPE activities. Methods A locally used questionnaire called the Nebraska Interprofessional Education Attitudes Scale (NIPEAS) was used to assess attitudes related to interprofessional collaboration. Questions regarding perceived barriers were included at the end of the questionnaire. Descriptive and non-parametric statistics were used to analyze the results in aggregate as well as by college. In addition, open-ended questions were analyzed using an immersion/crystallization framework to identify themes. Results The results showed that faculty had positive attitudes of IPE, indicating that is not a barrier to participating in IPE activities. Most common barriers to participation were scheduling conflicts ( =19.17, p=0.001), lack of department support ( 4,285=10.09, p=0.039), and lack of awareness of events (=26.38, p=0.000). Narrative comments corroborated that scheduling conflicts are an issue because of other priorities. Those who commented also added to the list of barriers, including relevance of the activities, location, and prior negative experiences. Discussion With faculty attitudes being positive, the exploration of facultys perceived barriers to IPE was considered even more important. Identifying these barriers will allow us to modify our IPE activities from large, campus-wide events to smaller activities that are longitudinal in nature, embedded within current curriculum and involving more authentic experiences.Background Interprofessional education (IPE) is an important component to training health care professionals. Research is limited in exploring the attitudes that faculty hold regarding IPE and what barriers they perceive to participating in IPE. The purpose of this study was to identify faculty attitudes about IPE and to identify barriers to participating in campus-wide IPE activities. Methods A locally used questionnaire called the Nebraska Interprofessional Education Attitudes Scale (NIPEAS) was used to assess attitudes related to interprofessional collaboration. Questions regarding perceived barriers were included at the end of the questionnaire. Descriptive and non-parametric statistics were used to analyze the results in aggregate as well as by college. In addition, open-ended questions were analyzed using an immersion/crystallization framework to identify themes. Results The results showed that faculty had positive attitudes of IPE, indicating that is not a barrier to participating in IPE activities. Most common barriers to participation were scheduling conflicts ([Formula: see text] =19.17, p=0.001), lack of department support ([Formula: see text] 4,285=10.09, p=0.039), and lack of awareness of events ([Formula: see text]=26.38, p=0.000). Narrative comments corroborated that scheduling conflicts are an issue because of other priorities. Those who commented also added to the list of barriers, including relevance of the activities, location, and prior negative experiences. Discussion With faculty attitudes being positive, the exploration of facultys perceived barriers to IPE was considered even more important. Identifying these barriers will allow us to modify our IPE activities from large, campus-wide events to smaller activities that are longitudinal in nature, embedded within current curriculum and involving more authentic experiences.