bluuebunny/crossref_metadata_2025 huggingface dataset:
Epoetin Alfa in Patients With Advanced-Stage Hodgkin's Lymphoma: Results of the Randomized Placebo-Controlled GHSG HD15EPO Trial
Authors: Engert Andreas , Josting Andreas , Haverkamp Heinz , Villalobos Matthias , Lohri Andreas , Sökler Martin , Zijlstra Josée , Sturm Isrid , Topp Max S. , Rank Andreas , Zenz Thorsten , Vogelhuber Martin , Nogova Lucia , Borchmann Peter , Fuchs Michael , Flechtner Hans-Henning , Diehl Volker
Published: April 2010

Purpose

To determine whether epoetin alfa reduces anemia-related fatigue, improves other aspects of health-related patient-recorded outcomes (PROs), reduces the number of RBC transfusions, and has an impact on freedom from treatment failure (FFTF) and overall survival (OS) in patients with advanced-stage Hodgkin's lymphoma (HL).

Patients and Methods

The prospectively randomized HD15EPO study performed by the German Hodgkin Study Group investigated epoetin alfa administered at doses of 40,000 U weekly during and after chemotherapy (six to eight cycles of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone [BEACOPP]) in a double-blind, placebo-controlled setting. The study accrued 1,379 patients, of whom 1,328 were assessable for safety, 1,303 were assessable for clinical outcome, and 930 were assessable for PROs.

Results

PROs were not different in patients receiving placebo or epoetin alfa, both after the end of chemotherapy and 6 months thereafter. There was no difference between patients treated with epoetin alfa or placebo with respect to FFTF and OS. There were also no differences in the numbers of deaths, progressions, relapses, and thromboembolic events. The median number of RBC transfusions was reduced from four per patient in the placebo group to two per patient in the epoetin alfa group (P < .001), with 27.4% of patients needing no RBC transfusion in the placebo group compared with 36.7% of patients in the epoetin alfa group (P < .001).

Conclusion

Epoetin alfa administered at 40,000 U weekly parallel to BEACOPP chemotherapy was safe in patients with advanced-stage HL and reduced the number of RBC transfusions but had no impact on fatigue and other PRO domains.
Effect of Changing Breast Cancer Incidence Rates on the Calibration of the Gail Model
Authors: Schonfeld Sara J. , Pee David , Greenlee Robert T. , Hartge Patricia , Lacey James V. , Park Yikyung , Schatzkin Arthur , Visvanathan Kala , Pfeiffer Ruth M.
Published: April 2010

Purpose

The Gail model combines relative risks (RRs) for five breast cancer risk factors with age-specific breast cancer incidence rates and competing mortality rates from the Surveillance, Epidemiology, and End Results (SEER) program from 1983 to 1987 to predict risk of invasive breast cancer over a given time period. Motivated by changes in breast cancer incidence during the 1990s, we evaluated the model's calibration in two recent cohorts.

Methods

We included white, postmenopausal women from the National Institutes of Health (NIH) –AARP Diet and Health Study (NIH-AARP, 1995 to 2003), and the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO, 1993 to 2006). Calibration was assessed by comparing the number of breast cancers expected from the Gail model with that observed. We then evaluated calibration by using an updated model that combined Gail model RRs with 1995 to 2003 SEER invasive breast cancer incidence rates.

Results

Overall, the Gail model significantly underpredicted the number of invasive breast cancers in NIH-AARP, with an expected-to-observed ratio of 0.87 (95% CI, 0.85 to 0.89), and in PLCO, with an expected-to-observed ratio of 0.86 (95% CI, 0.82 to 0.90). The updated model was well-calibrated overall, with an expected-to-observed ratio of 1.03 (95% CI, 1.00 to 1.05) in NIH-AARP and an expected-to-observed ratio of 1.01 (95% CI: 0.97 to 1.06) in PLCO. Of women age 50 to 55 years at baseline, 13% to 14% had a projected Gail model 5-year risk lower than the recommended threshold of 1.66% for use of tamoxifen or raloxifene but ≥ 1.66% when using the updated model. The Gail model was well calibrated in PLCO when the prediction period was restricted to 2003 to 2006.

Conclusion

This study highlights that model calibration is important to ensure the usefulness of risk prediction models for clinical decision making.
Parametric Response Map As an Imaging Biomarker to Distinguish Progression From Pseudoprogression in High-Grade Glioma
Authors: Tsien Christina , Galbán Craig J. , Chenevert Thomas L. , Johnson Timothy D. , Hamstra Daniel A. , Sundgren Pia C. , Junck Larry , Meyer Charles R. , Rehemtulla Alnawaz , Lawrence Theodore , Ross Brian D.
Published: April 2010

Purpose

To assess whether a new method of quantifying therapy-associated hemodynamic alterations may help to distinguish pseudoprogression from true progression in patients with high-grade glioma.

Patients and Methods

Patients with high-grade glioma received concurrent chemoradiotherapy. Relative cerebral blood volume (rCBV) and blood flow (rCBF) maps were acquired before chemoradiotherapy and at week 3 during treatment on a prospective institutional review board–approved study. Pseudoprogression was defined as imaging changes 1 to 3 months after chemoradiotherapy that mimic tumor progression but stabilized or improved without change in treatment or for which resection revealed radiation effects only. Clinical and conventional magnetic resonance (MR) parameters, including average percent change of rCBV and CBF, were evaluated as potential predictors of pseudoprogression. Parametric response map (PRM), an innovative, voxel-by-voxel method of image analysis, was also performed.

Results

Median radiation dose was 72 Gy (range, 60 to 78 Gy). Of 27 patients, stable disease/partial response was noted in 13 patients and apparent progression was noted in 14 patients. Adjuvant temozolomide was continued in all patients. Pseudoprogression occurred in six patients. Based on PRM analysis, a significantly reduced blood volume (PRMrCBV) at week 3 was noted in patients with progressive disease as compared with those with pseudoprogression (P < .01). In contrast, change in average percent rCBV or rCBF, MR tumor volume changes, age, extent of resection, and Radiation Therapy Oncology Group recursive partitioning analysis classification did not distinguish progression from pseudoprogression.

Conclusion

PRMrCBV at week 3 during chemoradiotherapy is a potential early imaging biomarker of response that may be helpful in distinguishing pseudoprogression from true progression in patients with high-grade glioma.
Bortezomib Plus Melphalan and Prednisone Compared With Melphalan and Prednisone in Previously Untreated Multiple Myeloma: Updated Follow-Up and Impact of Subsequent Therapy in the Phase III VISTA Trial
Authors: Mateos Maria-Victoria , Richardson Paul G. , Schlag Rudolf , Khuageva Nuriet K. , Dimopoulos Meletios A. , Shpilberg Ofer , Kropff Martin , Spicka Ivan , Petrucci Maria T. , Palumbo Antonio , Samoilova Olga S. , Dmoszynska Anna , Abdulkadyrov Kudrat M. , Schots Rik , Jiang Bin , Esseltine Dixie L. , Liu Kevin , Cakana Andrew , van de Velde Helgi , San Miguel Jesús F.
Published: April 2010

Purpose

The purpose of this study was to confirm overall survival (OS) and other clinical benefits with bortezomib, melphalan, and prednisone (VMP) versus melphalan and prednisone (MP) in the phase III VISTA (Velcade as Initial Standard Therapy in Multiple Myeloma) trial after prolonged follow-up, and evaluate the impact of subsequent therapies.

Patients and Methods

Previously untreated symptomatic patients with myeloma ineligible for high-dose therapy received up to nine 6-week cycles of VMP (n = 344) or MP (n = 338).

Results

With a median follow-up of 36.7 months, there was a 35% reduced risk of death with VMP versus MP (hazard ratio, 0.653; P < .001); median OS was not reached with VMP versus 43 months with MP; 3-year OS rates were 68.5% versus 54.0%. Response rates to subsequent thalidomide- (41% v 53%) and lenalidomide-based therapies (59% v 52%) appeared similar after VMP or MP; response rates to subsequent bortezomib-based therapy were 47% versus 59%. Among patients treated with VMP (n = 178) and MP (n = 233), median survival from start of subsequent therapy was 30.2 and 21.9 months, respectively, and there was no difference in survival from salvage among patients who received subsequent bortezomib, thalidomide, or lenalidomide. Rates of adverse events were higher with VMP versus MP during cycles 1 to 4, but similar during cycles 5 to 9. With VMP, 79% of peripheral neuropathy events improved within a median of 1.9 months; 60% completely resolved within a median of 5.7 months.

Conclusion

VMP significantly prolongs OS versus MP after lengthy follow-up and extensive subsequent antimyeloma therapy. First-line bortezomib use does not induce more resistant relapse. VMP used upfront appears more beneficial than first treating with conventional agents and saving bortezomib- and other novel agent–based treatment until relapse.
Phase II Trial of Bevacizumab and Everolimus in Patients With Advanced Renal Cell Carcinoma
Authors: Hainsworth John D. , Spigel David R. , Burris Howard A. , Waterhouse David , Clark Bobby L. , Whorf Robert
Published: April 2010

Purpose

To evaluate the efficacy and toxicity of the combination of bevacizumab, an angiogenesis inhibitor, and everolimus, an mTOR inhibitor, in the treatment of patients with advanced clear cell renal carcinoma.

Patients and Methods

Two groups of patients with metastatic renal cell carcinoma were eligible for this study: those with no previous treatment with targeted agents and those with previous treatment with sunitinib and/or sorafenib. All patients received bevacizumab 10 mg/kg intravenously every 2 weeks and everolimus 10 mg orally daily. Patients were evaluated for response after 8 weeks of treatment; patients with objective response or stable disease continued treatment until disease progression or unacceptable toxicity occurred.

Results

Eighty patients (50 untreated, 30 previously treated) entered this clinical trial. The combination of bevacizumab/everolimus showed activity in both groups. Median progression-free survivals in previously untreated and previously treated patients were 9.1 and 7.1 months, respectively. Overall response rates (30% and 23%) were similar in both groups. The regimen was well tolerated by most patients, with a toxicity profile as expected based on the known toxicities of these two agents. Grade 3 to 4 proteinuria was more frequent than expected (25%) and led to treatment discontinuation in six patients.

Conclusion

Bevacizumab/everolimus is active and well tolerated in the treatment of advanced clear cell renal cancer, either as first-line treatment or after treatment with sunitinib and/or sorafenib. The benefits of this combination regimen, versus sequential use of these two agents, requires further study.
Adherence and Persistence With Oral Adjuvant Chemotherapy in Older Women With Early-Stage Breast Cancer in CALGB 49907: Adherence Companion Study 60104
Authors: Partridge Ann H. , Archer Laura , Kornblith Alice B. , Gralow Julie , Grenier Debjani , Perez Edith , Wolff Antonio C. , Wang Xiaofei , Kastrissios Helen , Berry Donald , Hudis Clifford , Winer Eric , Muss Hyman
Published: April 2010

Purpose

Patient adherence is critical in evaluating the effectiveness of an oral therapy. We sought to measure adherence among women randomly assigned to capecitabine in a preplanned substudy of a multicenter clinical trial.

Patients and Methods

Cancer and Leukemia Group B study CALGB 49907 was a randomly assigned trial comparing standard chemotherapy versus oral chemotherapy with capecitabine in patients age 65 years or older with early-stage breast cancer. We used microelectronic monitoring system (MEMS) caps on participants' capecitabine bottles to record pill bottle openings. Capecitabine was given in two divided daily doses for 14 consecutive days of a 21-day cycle for six cycles. Adherence was calculated as the number of doses taken divided by doses expected, taking into account toxicity-related dosing changes. A participant was defined as adherent if 80% or more of expected doses were recorded by MEMS.

Results

Overall, 161 patients were enrolled. Median age was 71 years (range, 65 to 89 years); 124 patients (83%) persisted with capecitabine to completion of planned protocol therapy. Adherence was 78% across all cycles, and adherence did not vary by cycle (P = .32). Twenty-five percent of participants took fewer than 80% of expected doses and were nonadherent. In a logistic regression model, participants with node-negative disease (P = .01) and mastectomy (P = .01) were more likely to be nonadherent. Adherence was not related to age, tumor stage, or hormone receptor status. Adherence was not significantly associated with relapse-free survival or grade 3 or 4 toxicity.

Conclusion

Most older women with early-stage breast cancer were adherent to short-term oral chemotherapy in a randomized clinical trial. Age was not associated with adherence.
Phase III Trial of Bevacizumab Plus Interferon Alfa Versus Interferon Alfa Monotherapy in Patients With Metastatic Renal Cell Carcinoma: Final Results of CALGB 90206
Authors: Rini Brian I. , Halabi Susan , Rosenberg Jonathan E. , Stadler Walter M. , Vaena Daniel A. , Archer Laura , Atkins James N. , Picus Joel , Czaykowski Piotr , Dutcher Janice , Small Eric J.
Published: April 2010

Purpose

Bevacizumab is an antibody that binds vascular endothelial growth factor and has activity in metastatic renal cell carcinoma (RCC). Interferon alfa (IFN-α) is the historic standard initial treatment for RCC. A prospective, randomized, phase III trial of bevacizumab plus IFN-α versus IFN-α monotherapy was conducted.

Patients and Methods

Patients with previously untreated, metastatic clear cell RCC were randomly assigned to receive either bevacizumab (10 mg/kg intravenously every 2 weeks) plus IFN-α (9 million units subcutaneously three times weekly) or the same dose and schedule of IFN-α monotherapy in a multicenter phase III trial. The primary end point was overall survival (OS). Secondary end points were progression-free survival (PFS), objective response rate, and safety.

Results

Seven hundred thirty-two patients were enrolled. The median OS time was 18.3 months (95% CI, 16.5 to 22.5 months) for bevacizumab plus IFN-α and 17.4 months (95% CI, 14.4 to 20.0 months) for IFN-α monotherapy (unstratified log-rank P = .097). Adjusting on stratification factors, the hazard ratio was 0.86 (95% CI, 0.73 to 1.01; stratified log-rank P = .069) favoring bevacizumab plus IFN-α. There was significantly more grade 3 to 4 hypertension (HTN), anorexia, fatigue, and proteinuria for bevacizumab plus IFN-α. Patients who developed HTN on bevacizumab plus IFN-α had a significantly improved PFS and OS versus patients without HTN.

Conclusion

OS favored the bevacizumab plus IFN-α arm but did not meet the predefined criteria for significance. HTN may be a biomarker of outcome with bevacizumab plus IFN-α.
Polymorphisms of LIG4, BTBD2, HMGA2, and RTEL1 Genes Involved in the Double-Strand Break Repair Pathway Predict Glioblastoma Survival
Authors: Liu Yanhong , Shete Sanjay , Etzel Carol J. , Scheurer Michael , Alexiou George , Armstrong Georgina , Tsavachidis Spyros , Liang Fu-Wen , Gilbert Mark , Aldape Ken , Armstrong Terri , Houlston Richard , Hosking Fay , Robertson Lindsay , Xiao Yuanyuan , Wiencke John , Wrensch Margaret , Andersson Ulrika , Melin Beatrice S. , Bondy Melissa
Published: April 2010

Purpose

Glioblastoma (GBM) is the most common and aggressive type of glioma and has the poorest survival. However, a small percentage of patients with GBM survive well beyond the established median. Therefore, identifying the genetic variants that influence this small number of unusually long-term survivors may provide important insight into tumor biology and treatment.

Patients and Methods

Among 590 patients with primary GBM, we evaluated associations of survival with the 100 top-ranking glioma susceptibility single nucleotide polymorphisms from our previous genome-wide association study using Cox regression models. We also compared differences in genetic variation between short-term survivors (STS; ≤ 12 months) and long-term survivors (LTS; ≥ 36 months), and explored classification and regression tree analysis for survival data. We tested results using two independent series totaling 543 GBMs.

Results

We identified LIG4 rs7325927 and BTBD2 rs11670188 as predictors of STS in GBM and CCDC26 rs10464870 and rs891835, HMGA2 rs1563834, and RTEL1 rs2297440 as predictors of LTS. Further survival tree analysis revealed that patients ≥ 50 years old with LIG4 rs7325927 (V) had the worst survival (median survival time, 1.2 years) and exhibited the highest risk of death (hazard ratio, 17.53; 95% CI, 4.27 to 71.97) compared with younger patients with combined RTEL1 rs2297440 (V) and HMGA2 rs1563834 (V) genotypes (median survival time, 7.8 years).

Conclusion

Polymorphisms in the LIG4, BTBD2, HMGA2, and RTEL1 genes, which are involved in the double-strand break repair pathway, are associated with GBM survival.
Intratumor Heterogeneity and Precision of Microarray-Based Predictors of Breast Cancer Biology and Clinical Outcome
Authors: Barry William T. , Kernagis Dawn N. , Dressman Holly K. , Griffis Ryan J. , Hunter J'Vonne D. , Olson John A. , Marks Jeff R. , Ginsburg Geoffrey S. , Marcom Paul K. , Nevins Joseph R. , Geradts Joseph , Datto Michael B.
Published: April 2010

Purpose

Identifying sources of variation in expression microarray data and the effect of variance in gene expression measurements on complex predictive and diagnostic models is essential when translating microarray-based experimental approaches into clinical assays. The technical reproducibility of microarray platforms is well established. Here, we investigate the additional impact of intratumor heterogeneity, a largely unstudied component of variance, on the performance of several microarray-based assays in breast cancer.

Patients and Methods

Genome-wide expression profiling was performed on 50 core needle biopsies from 18 breast cancer patients using Affymetrix GeneChip Human Genome U133 Plus 2.0 arrays. Global profiles of expression were characterized using unsupervised clustering methods and variance components models. Array-based measures of estrogen receptor (ER) and progesterone receptor (PR) status were compared with immunohistochemistry. The precision of genomic predictors of ER pathway status, recurrence risk, and sensitivity to chemotherapeutics was evaluated by interclass correlation.

Results

Global patterns of gene expression demonstrated that intratumor variation was substantially less than the total variation observed across the patient population. Nevertheless, a fraction of genes exhibited significant intratumor heterogeneity in expression. A high degree of reproducibility was observed in single-gene predictors of ER (intraclass correlation coefficient [ICC] = 0.94) and PR expression (ICC = 0.90), and in a multigene predictor of ER pathway activation (ICC = 0.98) with high concordance with immunohistochemistry. Substantial agreement was also observed for multigene signatures of cancer recurrence (ICC = 0.71) and chemotherapeutic sensitivity (ICC = 0.72 and 0.64).

Conclusion

Intratumor heterogeneity, although present at the level of individual gene expression, does not preclude precise microarray-based predictions of tumor behavior or clinical outcome in breast cancer patients.
Phase III Trial of Bevacizumab Plus Interferon Alfa-2a in Patients With Metastatic Renal Cell Carcinoma (AVOREN): Final Analysis of Overall Survival
Authors: Escudier Bernard , Bellmunt Joaquim , Négrier Sylvie , Bajetta Emilio , Melichar Bohuslav , Bracarda Sergio , Ravaud Alain , Golding Sophie , Jethwa Sangeeta , Sneller Vesna
Published: April 2010

Purpose

A phase III trial of bevacizumab combined with interferon alfa-2a (IFN) showed significant improvements in progression-free survival (PFS) in metastatic renal cell carcinoma (mRCC). Here, we report overall survival (OS) data.

Patients and Methods

Six hundred forty-nine patients with previously untreated mRCC were randomly assigned to receive bevacizumab (10 mg/kg every 2 weeks) plus IFN (9 MIU subcutaneously three times a week; n = 327) or IFN plus placebo (n = 322) in a multicenter, randomized, double-blind, phase III trial. The primary end point was OS. Final analysis of the secondary end point (PFS) was reported earlier.

Results

Median OS was 23.3 months with bevacizumab plus IFN and 21.3 months with IFN plus placebo (unstratified hazard ratio [HR] = 0.91; 95% CI, 0.76 to 1.10; P = .3360; stratified HR = 0.86; 95% CI, 0.72 to 1.04; P = .1291). Patients (> 55%) in both arms received at least one postprotocol antineoplastic therapy, possibly confounding the OS analysis. Patients receiving postprotocol therapy including a tyrosine kinase inhibitor had longer median OS (bevacizumab plus IFN arm: 38.6 months; IFN plus placebo arm: 33.6 months; HR = 0.80; 95% CI, 0.56 to 1.13). Tolerability was similar to that reported previously.

Conclusion

Bevacizumab plus IFN is active as first-line treatment in patients with mRCC. Most patients with mRCC receive multiple lines of therapy, so considering the overall sequence of therapy when selecting first-line therapy may optimize patient benefit.
Role of Adjuvant Therapy After Resection of Colorectal Cancer Liver Metastases
Authors: Power Derek G. , Kemeny Nancy E.
Published: April 2010

Liver resection is the goal of treatment strategies for liver-confined metastatic colorectal cancer. However, after resection the majority of patients will experience recurrence. Chemotherapy seems to improve outcomes compared with surgery alone. We reviewed the data of the role of adjuvant chemotherapy after resection of liver- confined metastatic colorectal cancer. Optimal regimens and sequencing of chemotherapies when liver resection is an option are unclear. Some suggest that resectable liver metastases, in the absence of high-risk features, should begin with surgery and consideration given to adjuvant chemotherapy after surgery. If high-risk features are present, most physicians prefer a short course of systemic preoperative chemotherapy. Perioperative therapy and regional therapy with hepatic arterial infusion (HAI) both increase disease-free survival (DFS) when compared with surgery alone. In unresectable disease, consideration should be given to systemic chemotherapy with or without a biologic agent or HAI with systemic therapy. If the disease becomes resectable, adjuvant treatment should follow surgery. Adjuvant chemotherapy is usually FOLFOX, but HAI combined with systemic chemotherapy is also an option. The role of adjuvant treatment post-liver resection should not be viewed in isolation but rather in the context of prior treatment, surgical preference, and individual patient characteristics. Perioperative therapy and regional therapy have both shown an increase in DFS. Conducting randomized trials examining the role of adjuvant chemotherapy has been difficult because of rapidly changing chemotherapies.
Impact of the Extent of Surgery and Postoperative Chemoradiotherapy on Recurrence Patterns in Gastric Cancer
Authors: Dikken Johan L. , Jansen Edwin P.M. , Cats Annemieke , Bakker Berdine , Hartgrink Henk H. , Kranenbarg Elma Meershoek-Klein , Boot Henk , Putter Hein , Peeters Koen C.M.J. , van de Velde Cornelis J.H. , Verheij Marcel
Published: April 2010

Purpose

The Intergroup 0116 trial has demonstrated that postoperative chemoradiotherapy (CRT) improves survival in gastric cancer. We retrospectively compared survival and recurrence patterns in two phase I/II studies evaluating more intensified postoperative CRT with those from the Dutch Gastric Cancer Group Trial (DGCT) that randomly assigned patients between D1 and D2 lymphadenectomy.

Patients and Methods

Survival and recurrence patterns of 91 patients with adenocarcinoma of the stomach who had received surgery followed by radiotherapy combined with fluorouracil and leucovorin (n = 5), capecitabine (n = 39), or capecitabine and cisplatin (n = 47) were analyzed and compared with survival and recurrence patterns of 694 patients from the DGCT (D1, n = 369; D2, n = 325). For both groups, the Maruyama Index of Unresected Disease (MI) was calculated and correlated with survival and recurrence patterns.

Results

With a median follow-up of 19 months in the CRT group, local recurrence rate after 2 years was significantly higher in the surgery only (DGCT) group (17% v 5%; P = .0015). Separate analysis of CRT patients who underwent a D1 dissection (n = 39) versus DGCT-D1 (n = 369) showed fewer local recurrences after chemoradiotherapy (2% v 8%; P = .001), whereas comparison of CRT-D2 (n = 25) versus DGCT-D2 (n = 325) demonstrated no significant difference. CRT significantly improved survival after a microscopically irradical (R1) resection. The MI was found to be a strong independent predictor of survival.

Conclusion

After D1 surgery, the addition of postoperative CRT had a major impact on local recurrence in resectable gastric cancer.
Primary Analysis of the Phase II Component of a Phase I/II Dose Intensification Study Using Three-Dimensional Conformal Radiation Therapy and Concurrent Chemotherapy for Patients With Inoperable Non–Small-Cell Lung Cancer: RTOG 0117
Authors: Bradley Jeffrey D. , Bae Kyounghwa , Graham Mary V. , Byhardt Roger , Govindan Ramaswamy , Fowler Jack , Purdy James A. , Michalski Jeff M. , Gore Elizabeth , Choy Hak
Published: April 2010

Purpose

Phase I of Radiation Therapy Oncology Group (RTOG) 0117 determined that 74 Gy was the maximum-tolerated dose with concurrent weekly carboplatin/paclitaxel chemotherapy for inoperable non–small-cell lung cancer (NSCLC). Phase II results are reported here.

Patients and Methods

Patients with unresectable stages I-III NSCLC were eligible. Chemotherapy consisted of weekly paclitaxel at 50 mg/m2 and carboplatin at area under the curve 2 mg/m2. The radiation dose was 74 Gy given in 37 fractions. Radiation therapy volumes included those of the gross tumor and involved nodes. The volume of lung at or exceeding 20 Gy (V20) was mandated to be ≤ 30%.

Results

Of the combined phase I/II enrollment, a total of 55 patients received 74 Gy, of whom 53 were evaluable. The median follow-up was 19.3 months (range, 0.9 to 57.9 months) for all patients and 25.4 months (range, 13.1 to 57.9 months) for those still alive. The median survival for all patients was 25.9 months. The percentage surviving at least 12 months was 75.5% (95% CI, 65.7% to 85.2%). The median overall survival (OS) and progression-free survival (PFS) times for stage III patients (n = 44) were 21.6 months and 10.8 months, respectively. OS and PFS rates at 12 months were 72.7% and 50.0%, respectively. Twelve patients experienced grade ≥ 3 lung toxicity (two patients had grade 5 lung toxicity).

Conclusion

The median survival time and OS rate at 12 months for this regimen are encouraging. These results serve as projection expectations for the high-dose radiation arms of the current RTOG 0617 phase III intergroup trial.
Multivariate Analysis of Prognostic Factors Among 2,313 Patients With Stage III Melanoma: Comparison of Nodal Micrometastases Versus Macrometastases
Authors: Balch Charles M. , Gershenwald Jeffrey E. , Soong Seng-jaw , Thompson John F. , Ding Shouluan , Byrd David R. , Cascinelli Natale , Cochran Alistair J. , Coit Daniel G. , Eggermont Alexander M. , Johnson Timothy , Kirkwood John M. , Leong Stanley P. , McMasters Kelly M. , Mihm Martin C. , Morton Donald L. , Ross Merrick I. , Sondak Vernon K.
Published: April 2010

Purpose

To determine the survival rates and independent predictors of survival using a contemporary international cohort of patients with stage III melanoma.

Patients and Methods

Complete clinicopathologic and follow-up data were available for 2,313 patients with stage III disease in an updated and expanded American Joint Committee on Cancer (AJCC) melanoma staging database. Kaplan-Meier and Cox multivariate survival analyses were performed.

Results

Among all 2,313 patients with stage III disease, 81% had micrometastases, and 19% had clinically detectable macrometastases. The 5-year overall survival was 63%; it was 67% for patients with nodal micrometastases, and it was 43% for those with nodal macrometastases (P < .001). Tremendous heterogeneity in survival was observed, particularly in the microscopically detected nodal metastasis subset (from 23% to 87% for 5-year survival). Multivariate analysis demonstrated that in patients with nodal micrometastases, number of tumor-containing lymph nodes, primary tumor thickness, patient age, ulceration, and anatomic site of the primary independently predicted survival (all P < .01). When added to the model, primary tumor mitotic rate was the second-most powerful predictor of survival after the number of tumor-containing nodes. In contrast, for patients with nodal macrometastases, the number of tumor-containing nodes, primary ulceration, and patient age independently predicted survival (P < .01).

Conclusion

In this multi-institutional analysis, we demonstrated remarkable heterogeneity of prognosis among patients with stage III melanoma, especially among those with nodal micrometastases. These results should be incorporated into the design and interpretation of future clinical trials involving patients with stage III melanoma.
IDH1 and IDH2 Gene Mutations Identify Novel Molecular Subsets Within De Novo Cytogenetically Normal Acute Myeloid Leukemia: A Cancer and Leukemia Group B Study
Authors: Marcucci Guido , Maharry Kati , Wu Yue-Zhong , Radmacher Michael D. , Mrózek Krzysztof , Margeson Dean , Holland Kelsi B. , Whitman Susan P. , Becker Heiko , Schwind Sebastian , Metzeler Klaus H. , Powell Bayard L. , Carter Thomas H. , Kolitz Jonathan E. , Wetzler Meir , Carroll Andrew J. , Baer Maria R. , Caligiuri Michael A. , Larson Richard A. , Bloomfield Clara D.
Published: April 2010

Purpose

To analyze the frequency and associations with prognostic markers and outcome of mutations in IDH genes encoding isocitrate dehydrogenases in adult de novo cytogenetically normal acute myeloid leukemia (CN-AML).

Patients and Methods

Diagnostic bone marrow or blood samples from 358 patients were analyzed for IDH1 and IDH2 mutations by DNA polymerase chain reaction amplification/sequencing. FLT3, NPM1, CEBPA, WT1, and MLL mutational analyses and gene- and microRNA-expression profiling were performed centrally.

Results

IDH mutations were found in 33% of the patients. IDH1 mutations were detected in 49 patients (14%; 47 with R132). IDH2 mutations, previously unreported in AML, were detected in 69 patients (19%; 13 with R172 and 56 with R140). R172 IDH2 mutations were mutually exclusive with all other prognostic mutations analyzed. Younger age (< 60 years), molecular low-risk (NPM1-mutated/FLT3-internal tandem duplication–negative) IDH1-mutated patients had shorter disease-free survival than molecular low-risk IDH1/IDH2-wild-type (wt) patients (P = .046). R172 IDH2-mutated patients had lower complete remission rates than IDH1/IDH2wt patients (P = .007). Distinctive microarray gene- and microRNA-expression profiles accurately predicted R172 IDH2 mutations. The highest expressed gene and microRNAs in R172 IDH2-mutated patients compared with the IDH1/IDH2wt patients were APP (previously associated with complex karyotype AML) and miR-1 and miR-133 (involved in embryonal stem-cell differentiation), respectively.

Conclusion

IDH1 and IDH2 mutations are recurrent in CN-AML and have an unfavorable impact on outcome. The R172 IDH2 mutations, previously unreported in AML, characterize a novel subset of CN-AML patients lacking other prognostic mutations and associate with unique gene- and microRNA-expression profiles that may lead to the discovery of novel, therapeutically targetable leukemogenic mechanisms.
Nomograms for Risk of Hepatocellular Carcinoma in Patients With Chronic Hepatitis B Virus Infection
Authors: Yang Hwai-I , Sherman Morris , Su Jun , Chen Pei-Jer , Liaw Yun-Fan , Iloeje Uchenna H. , Chen Chien-Jen
Published: April 2010

Purpose

Counseling patients with chronic hepatitis B virus (HBV) on their individual risk of liver disease progression is challenging. This study aimed to develop nomograms for predicting hepatocellular carcinoma risk in patients with chronic hepatitis B.

Patients and Methods

Two thirds of the Risk Evaluation of Viral Load Elevation and Associated Liver Disease/Cancer–Hepatitis B Virus (REVEAL-HBV) study cohort was allocated for model derivation (n = 2,435), and the remaining third was allocated for model validation (n = 1,218). Previously confirmed independent risk predictors included in three Cox proportional hazards regression models were sex, age, family history of hepatocellular carcinoma, alcohol consumption habit, serum ALT level, hepatitis B envelope antigen (HBeAg) serostatus, serum HBV DNA level, and HBV genotype. Regression coefficients were rounded into integer risk scores, and predicted risk over 5- and 10-year periods for each risk score was calculated and depicted in nomograms. The predictive accuracy was evaluated using the area under the receiver operating characteristic curve (AUROC) and the correlation between predicted and observed hepatocellular carcinoma risk.

Results

All selected risk predictors were statistically significant in all models. In each model, either HBeAg seropositivity or HBeAg seronegativity with high viral load (HBV DNA level ≥ 100,000 copies/mL) and genotype C infection had the highest risk scores. All AUROCs for risk prediction nomogram were ≥ 0.82 in both model derivation and validation sets. The correlation coefficients between the observed hepatocellular carcinoma risk and the nomogram-predicted risk were greater than 0.90 in all model derivation and validation sets.

Conclusion

These easy-to-use nomograms based on noninvasive clinical characteristics can accurately predict the risk of hepatocellular carcinoma in patients with chronic hepatitis B. They may facilitate risk communication between patients and clinicians.
Impact of IDH1 R132 Mutations and an IDH1 Single Nucleotide Polymorphism in Cytogenetically Normal Acute Myeloid Leukemia: SNP rs11554137 Is an Adverse Prognostic Factor
Authors: Wagner Katharina , Damm Frederik , Göhring Gudrun , Görlich Kerstin , Heuser Michael , Schäfer Irina , Ottmann Oliver , Lübbert Michael , Heit Wolfgang , Kanz Lothar , Schlimok Günter , Raghavachar Aruna A. , Fiedler Walter , Kirchner Hartmut H. , Brugger Wolfram , Zucknick Manuela , Schlegelberger Brigitte , Heil Gerhard , Ganser Arnold , Krauter Jürgen
Published: April 2010

Purpose

We assessed the prognostic impact of IDH1 R132 mutations and a known single nucleotide polymorphism (SNP) located in the same exon of the IDH1 gene in patients with cytogenetically normal acute myeloid leukemia (CN-AML) in the context of other prognostic markers.

Patients and Methods

IDH1 exon four was directly sequenced in 275 CN-AML patients from two subsequent AML multicenter treatment trials and 120 healthy volunteers. Moreover, mutations in NPM1, FLT3, CEBPA, and WT1 were analyzed, and mRNA expression of IDH1 was quantified.

Results

IDH1 R132 mutations were found in 10.9% of CN-AML patients. IDH1 SNP rs11554137 was found in 12% of CN-AML patients and 11.7% of healthy volunteers. IDH1 R132 mutations had no impact on prognosis. In contrast, IDH1 SNP rs11554137 was an adverse prognostic factor for overall survival in univariate and multivariate analysis. Other significant factors were age, NPM1/FLT3 mutational status, WT1 SNP rs16754, and platelet count. The impact of IDH1 SNP rs11554137 was most pronounced in the NPM1/FLT3 high-risk patients (either NPM1 wild-type or FLT3–internal tandem duplication positive). Patients with IDH1 SNP rs11554137 had a higher expression of IDH1 mRNA than patients with two wild-type alleles.

Conclusion

IDH1 SNP rs11554137 but not IDH1 R132 mutations are associated with an inferior outcome in CN-AML.
Serum Chemerin Levels Vary with Time of Day and Are Modified by Obesity and Tumor Necrosis Factor-α
Authors: Parlee Sebastian D. , Ernst Matthew C. , Muruganandan Shanmugam , Sinal Christopher J. , Goralski Kerry B.
Published: April 2010

Chemerin is an adipokine with important regulatory roles in adipogenesis. In humans, serum total chemerin (i.e. prochemerin plus chemerin) levels are positively associated with body mass index and metabolic syndrome. However, the mechanisms that increase serum chemerin concentration are unknown. We hypothesized that chronic low-grade inflammation that occurs in obesity promotes chemerin production by adipocytes. Consistent with this, TNFα treatment of 3T3-L1 adipocytes increased bioactive chemerin levels in the cell media as detected using a CMKLR1 cell-based bioassay. This effect was blocked by the protein synthesis inhibitor cycloheximide and protein secretion inhibitor brefeldin A, indicating that TNFα may enhance prochemerin synthesis and secretion from adipocytes. In vivo, TNFα produced a time-dependent increase in serum total chemerin and bioactive chemerin. Bioactive chemerin was produced by primary mouse adipocytes and hepatocytes. Only primary adipocyte-derived chemerin was responsive to TNFα regulation implicating adipocytes as a potential source of elevated serum chemerin after TNFα exposure in vivo. In lean mice, serum total chemerin levels oscillated with peak levels occurring during daytime and trough levels at night. Comparatively, leptin- and leptin receptor-deficient obese mice, which have elevated adipose tissue expression of TNFα, displayed elevated serum total chemerin levels with an enhanced oscillatory pattern. In summary, our novel results identified TNFα as a positive regulator of adipocyte-derived chemerin. We corroborate the finding of elevated chemerin in obese humans by identifying elevated serum levels of total chemerin in two obese mouse models with a corresponding alteration in the rhythmic pattern of serum chemerin levels.
Neuromuscular Blocker Mix-up in the Pharmacy; ISMP and Doctor's Digest Launch New iPhone Application; “UD” for “Ut Dictum”—an Ambiguous and Dangerous Abbreviation; Order by Metric Weight, Not Volume
Authors: Cohen Michael R. , Smetzer Judy L.
Published: April 2010

These medication errors have occurred in health care facilities at least once. They will happen again—perhaps where you work. Through education and alertness of personnel and procedural safeguards, they can be avoided. You should consider publishing accounts of errors in your newsletters and/or presenting them at your inservice training programs.

Your assistance is required to continue this feature. The reports described here were received through the Institute for Safe Medication Practices (ISMP) Medication Errors Reporting Program. Any reports published by ISMP will be anonymous. Comments are also invited; the writers' names will be published if desired. ISMP may be contacted at the address shown below.

Errors, close calls, or hazardous conditions may be reported directly to ISMP through the ISMP Web site ( www.ismp.org ), by calling 800-FAIL-SAFE, or via e-mail at ismpinfo@ismp.org . ISMP guarantees the confidentiality and security of the information received and respects reporters' wishes as to the level of detail included in publications.
Carbamazepine-Induced Pancreatitis; Quinolone-Induced Hypoglycemia; First Exposure Idarubicin and Cardiac Toxicity; Bupropion-Induced Sleepwalking; Nephrotic Syndrome Associated with Certolizumab Pegol; Extrapyramidal Effects and Suicidal Ideation with Fluoxetine
Authors: Shuster Joel
Published: April 2010

The purpose of this feature is to heighten awareness of specific adverse drug reactions (ADRs), discuss methods of prevention, and promote reporting of ADRs to the US Food and Drug Administration's (FDA's) MedWatch program (800-FDA-1088). If you have reported an interesting, preventable ADR to MedWatch, please consider sharing the account with our readers. Write to Dr. Shuster at ISMP, 200 Lakeside Drive, Suite 200, Horsham, PA 19044 (phone: 215-947-7797; fax: 215-914-1492; e-mail: joel.shuster@temple.edu ). Your report will be published anonymously unless otherwise requested. This feature is provided by the Institute for Safe Medication Practices (ISMP) in cooperation with the FDA's MedWatch program and Temple University School of Pharmacy. ISMP is an FDA MedWatch partner.
Ondansetron: Tardive Dyskinesia
Authors: Generali Joyce A. , Cada Dennis J.
Published: April 2010

This Hospital Pharmacy feature is extracted from Off-Label Drug Facts, a quarterly publication available from Wolters Kluwer Health. Off-Label Drug Facts is a practitioner-oriented resource for information about specific drug uses that are unapproved by the US Food and Drug Administration. This new guide to the literature enables the health care professional or clinician to quickly identify published studies on off-label uses and determine if a specific use is rational in a patient care scenario. A summary of the most relevant data is provided, including background, study design, patient population, dosage information, therapy duration, results, safety, and therapeutic considerations. References direct the reader to the full literature for more comprehensive information before patient care decisions are made. Direct questions or comments regarding Off-Label Drug Uses to jgeneral@kumc.edu .
Integrated Care of Anemia in Chronic Kidney Disease Patients: Concepts in Intravenous Iron Management: Part Two
Authors: Lew Indu , Mullarkey Tamira , Adamson Robert T. , Ashton Maria E. , Amara Shilpa
Published: April 2010

Iron deficiency anemia (IDA), as a result of chronic kidney disease (CKD), has become a worldwide public health issue with increasing prevalence in the United States. An awareness of clinical practice guidelines and safety profiles of intravenous (IV) iron products enables health care professionals to improve patient outcomes in the treatment of CKD-associated IDA. Selection of appropriate IV iron therapy in all patient care settings may encompass considerations such as product premedication and test-dose requirements, preparation and administration, monitoring parameters, safety concerns, cost of care, patient education, and patient self-administration when appropriate. More specifically, a medication use process (prescribing, preparing, dispensing, administering, monitoring, and specific outcomes) should be applied by health systems during the evaluation process to achieve optimal patient outcomes. This performance improvement process serves to promote appropriate medication therapy, improve patient safety, control costs of therapy, stimulate improvements in processes, and provide educational opportunities. This article, the second of a two-part series, describes elements of the medication use process for care of CKD patients with IDA, whereas the preceding article in this series discusses the optimization of IV iron therapy in CKD patients and compares the four parenteral iron agents available on the market.
Leadership Advice for the Front Lines: Interviews with Max Ray, Sara White, and Scott Knoer
Authors: Westanmo Anders , Geurkink Eric , Carmichael Jannet M.
Published: April 2010

Pharmacy is striving to evolve from a technical profession in which pharmacists prepare and dispense medications to one in which they take responsibility for the development and execution of each patient's pharmacotherapeutic plan. This is being guided by pharmacy leaders and professional organizations, but they are not able to make the changes necessary to achieve their vision alone. In order to effectively implement change, pharmacists need to own their vision of pharmacy practice. The authors spoke to a number of established leaders in the pharmacy profession about what the individual pharmacist could do to change the culture and environment at the local level. The leaders' advice proved remarkably consistent and could be summarized into three categories: vision, socialization (relationships and networks), and self-development. Excerpts from three of these interviews were compiled into one report to be used as a guide to help pharmacists implement changes needed to achieve the vision of pharmacy practice.
Differences in Pharmacy Interventions at a Psychiatric Hospital: Comparison of Staff Pharmacists, Pharmacy Faculty, and Student Pharmacists
Authors: Marino Jehan , Caballero Joshua , Llosent Marlene , Hinkes Roberta
Published: April 2010

Purpose

Previous evidence suggests psychiatric pharmacists have improved patient symptoms and provide valuable information. However, there are limited recent data regarding clinical pharmacists performing interventions in a psychiatric setting and its effects on costs. Additionally, there are no data that differentiate between psychiatric hospital staff pharmacists' (HSP), faculty clinical pharmacists' (FCP), and student pharmacists' (SP) interventions. Therefore, the objective of this study is to evaluate and describe interventions made by HSPs, FCPs, and SPs in a psychiatric hospital and cost savings.

Methods

A retrospective review of interventions made in a psychiatric hospital over 18 months was performed. Descriptive statistics and cost analysis were also determined through Pharmacy OneSource.

Results

A total of 2,220 interventions were made. Among HSPs (n = 4), there were 1,734 interventions including clarifications of orders (n = 592) and MAR discrepancies (n = 385). FCPs (n = 2) contributed 358 interventions consisting of dose recommendations/adjustments (n = 78), drug lab/level recommendations (n = 47), and therapeutic recommendations (n = 37). Additionally, SPs (n = 27) made 128 interventions including patient medication history (n = 31), drug information (n = 30), and counseling patients (n = 25). Annual cost savings were estimated at $125,500 with approximately 90% contributed by HSPs.

Conclusion

Pharmacy personnel contributed a considerable amount of interventions providing a cost savings to the hospital. Also, HSPs provided a greater number of interventions resulting in decreased costs. In our setting, HSPs, FCPs, and SPs contribute different clinical therapeutic interventions that may optimize patient care.
Ustekinumab
Authors: Cada Dennis J. , Levien Terri L. , Baker Danial E.
Published: April 2010

Each month, subscribers to The Formulary Monograph Service receive five to six well-documented monographs on drugs that are newly released or are in late phase 3 trials. The monographs are targeted to Pharmacy & Therapeutics Committees. Subscribers also receive monthly 1-page summary monographs on agents that are useful for agendas and pharmacy/nursing inservices. A comprehensive target drug utilization evaluation (DUE) is also provided each month. With a subscription, the monographs are sent in print and are also available online. Monographs can be customized to meet the needs of a facility. Subscribers to The Formulary Monograph Service also receive access to a pharmacy bulletin board, The Formulary Information Exchange (The F.I.X.). All topics pertinent to clinical and hospital pharmacy are discussed on The F.I.X.

Through the cooperation of The Formulary, Hospital Pharmacy publishes selected reviews in this column. For more information about The Formulary Monograph Service or The F.I.X., call The Formulary at 800-322-4349. The April 2010 monograph topics are on liraglutide, dalfampridine, collagenase clostridium histolyticum for injection, roflumilast, and belimumab. The DUE is on liraglutide.
New Drugs Approved by the FDA; New Dosage Forms and Indications Approved by the FDA; Agents Pending FDA Approval; New Drug/Biologics License Applications Filed by Manufacturer; Significant Labeling Changes or “Dear Health Professional” Letters Related to Safety
Authors: Baker Danial E.
Published: April 2010

This monthly feature will help readers keep current on new drugs, new indications, dosage forms, and safety-related changes in labeling or use. Efforts have been made to ensure the accuracy of this information; however, if there are any questions, please let us know at bakerdan@wsu.edu .