bluuebunny/crossref_metadata_2025 huggingface dataset:
Early Goal‐directed Therapy, Corticosteroid, and Recombinant Human Activated Protein C for the Treatment of Severe Sepsis and Septic Shock in the Emergency Department
Authors: Nguyen H. Bryant , Corbett Stephen W. , Menes Kevin , Cho Thomas , Daugharthy Jennifer , Klein Walter , Wittlake William A.
Published: December 2005

Objectives: To describe our experience with early goal‐directed therapy (EGDT), corticosteroid administration, and recombinant human activated protein C (rhAPC) administration in patients with severe sepsis or septic shock and an Acute Physiology and Chronic Health Evaluation (APACHE) II score ≥25 in the emergency department (ED).

Methods: This was a retrospective case series of a prospectively maintained ED sepsis registry. Data are presented as median (25th, 75th percentile). The setting was an academic tertiary ED with approximately 60,000 annual patient visits. Patients with severe sepsis or septic shock and an APACHE II score ≥25 entered in an ED sepsis registry over a four‐month period were included. Patients who received rhAPC in the intensive care unit were excluded. Central venous catheterization for central venous pressure and central venous oxygen saturation monitoring, antibiotics, fluid resuscitation, mechanical ventilation, vasopressors, inotropes, corticosteroids, and rhAPC were initiated by the emergency physicians and continued in the intensive care unit by intensivists.

Results: Twenty‐four patients were enrolled. Patient characteristics were as follows: age, 79.5 (68.0, 83.5) years; APACHE II score, 31.5 (29.8, 36.0); ED length of stay, 6.5 (4.0, 10.5) hours; predicted mortality, 76.7% (71.9, 86.4); and in‐hospital mortality, 45.8%. All patients received broad‐spectrum antibiotics, 54.2% completed EGDT, 33.3% received corticosteroids, and 33.3% received rhAPC. Time of antibiotic administration was 1.5 (1.0, 2.0) hours, time of central venous pressure/central venous oxygen saturation monitoring was 1.0 (0.5, 2.5) hour, and time of rhAPC administration was 9.5 (6.8, 10.5) hours after patients met criteria for severe sepsis or septic shock. In‐hospital mortality of patients who received rhAPC in addition to other therapies was 25.0%.

Conclusions: EGDT, corticosteroid administration, and rhAPC administration are feasible in the ED setting. While these evidence‐based therapies individually have been shown to improve outcomes for patients with severe sepsis or septic shock, further studies are needed to examine their combined effectiveness during the early stages of this disease.
Propofol for Emergency Department Procedural Sedation and Analgesia: A Tale of Three Centers
Authors: Burton John H. , Miner James R. , Shipley Eric R. , Strout Tania D. , Becker Chris , Thode Henry C.
Published: December 2005

Objectives:To characterize propofol procedural sedation and analgesia (PSA) encounters for a large patient population at multiple emergency department (ED) sites. The authors sought to assess the frequency of respiratory and cardiovascular events during propofol PSA within these settings.

Methods:This study was a prospective, descriptive series of a consecutive sample of ED patients receiving propofol for PSA at three study sites. Patients were monitored for PSA‐related events, including predefined clinically relevant cardiovascular and respiratory events. Data collection was performed during PSA with a standardized data collection sheet unique to each site.

Results:Propofol was administered during PSA to 792 patients during the respective reporting period at each center. Indications for sedation included dislocation reduction (38%), cardioversion (10%), fracture reduction (35%), abscess incision and drainage (8%), computed tomography imaging (2%), and tube thoracostomy (1%). The cumulative rate of oxygen desaturation events for all study sites was 7.7% with a brief period of assisted ventilation with bag‐valve mask in 3.9%. The cumulative rate of PSA‐related hypotensive events was 3.5%. Increasing patient age and specific clinical procedure were clinical variables most associated with any propofol‐related respiratory event. All PSA‐related events resolved with supportive interventions during the PSA encounter. No patients required endotracheal intubation, prolonged observation, or admission for PSA‐related complications.

Conclusions:Propofol typically confers a deep sedation experience for ED PSA. The most common PSA events associated with propofol are respiratory related and appear consistent across these three practice settings. All propofol‐related PSA events resolved with brief supportive interventions in the ED with no adverse sequelae.
Dealing With a Deluge of Data: An Assessment of Adverse Event Data on North Central Cancer Treatment Group Trials
Authors: Mahoney Michelle R. , Sargent Daniel J. , O'Connell Michael J. , Goldberg Richard M. , Schaefer Paul , Buckner Jan C.
Published: December 2005

Purpose

Adverse events (AEs) are monitored in clinical trials for patient safety, to satisfy reporting requirements, and develop safety profiles. Recently, much attention has been placed on the reporting of serious AEs (SAEs) that are either life threatening or lethal in clinical trials. However, SAEs comprise a small subset of all AE data collected for trials; the majority of AE data collected are routine AEs (RAEs) regarding non–life-threatening events. We assessed the utility of the RAE data collected, relative to the volume.

Patients and Methods

We surveyed the RAE data from 26 North Central Cancer Treatment Group coordinated trials.

Results

A total of 8,318 (11%) of 75,598 of RAEs required queries. Of these, 86% were protocol-required RAEs, 83% of RAEs required per protocol were within normal limits (eg, platelets) or not present, and 61% of extra AEs were mild. One fifth of RAEs were considered unlikely to be related or unrelated to treatment. Overall, 3% of events were severe, life threatening, or caused death. Only 1% of RAE data reported required expedited reporting (eg, via Adverse Event Expedited Reporting System). Results indicate that 72% of RAEs would be eliminated if only the maximum severity per patient and type were required. These results were validated in a large phase III trial.

Conclusion

The majority of RAEs identified, transcribed, and entered are not clinically important. Our data suggest that reducing the number of AEs monitored will affect substantially neither overall patient safety nor compromise evaluation of regimens undergoing testing. We present several considerations for such a reduction in data collection, as well as a policy that we have used to address the deluge of RAE data.
Phase I Clinical and Pharmacokinetic Study of Flavopiridol in Children With Refractory Solid Tumors: A Children's Oncology Group Study
Authors: Whitlock James A. , Krailo Mark , Reid Joel M. , Ruben Stacie L. , Ames Matthew M. , Owen William , Reaman Gregory
Published: December 2005

Purpose

To determine the dose-limiting toxicities, maximum-tolerated dose, and pharmacokinetics of the cyclin-dependent kinase inhibitor flavopiridol (NSC 649890) when administered as a 1-hour infusion over 3 consecutive days to children with recurrent or refractory solid tumors.

Patients and Methods

Flavopiridol was administered as a 1-hour intravenous infusion daily for 3 consecutive days every 21 days, or when hematologic toxicity or any grade 2 or greater nonhematologic toxicity resolved. The starting dose was 37.5 mg/m2/d. Dose escalation was in cohorts of three patients in a standard fashion until dose-limiting toxicity and the maximum-tolerated dose were determined. Flavopiridol levels were measured on days 1, 2, and 3.

Results

Twenty-five children received flavopiridol at doses of 37.5 to 80 mg/m2/day over 3 consecutive days. The maximum-tolerated dose was 62.5 mg/m2/d. The primary dose-limiting toxicities were neutropenia and diarrhea. No antitumor effect was observed in this population. Mean peak plasma concentrations of 3.71 and 9.11 μmol/L were achieved at the end of the 1-hour infusion, following dose escalation from 37.5 mg/m2 to 80 mg/m2, respectively. The median flavopiridol plasma clearance was 8.0 L/h/m2 (range, 2.6 to 17.1 L/h/m2).

Conclusion

The maximum-tolerated dose of flavopiridol in children, and the recommended phase II dose for pediatric studies, was 62.5 mg/m2/day when administered as a 1-hour infusion for 3 consecutive days. Dose-limiting toxicities of neutropenia and diarrhea were similar to those in adult studies.
Phase III Trial of Paclitaxel Plus Carboplatin With or Without Tirapazamine in Advanced Non–Small-Cell Lung Cancer: Southwest Oncology Group Trial S0003
Authors: Williamson Stephen K. , Crowley John J. , Lara Primo N. , McCoy Jason , Lau Derick H.M. , Tucker Robert W. , Mills Glenn M. , Gandara David R.
Published: December 2005

Purpose

Tumor hypoxia confers chemotherapy resistance. Tirapazamine is a cytotoxin that selectively targets hypoxic cells. We conducted a phase III clinical trial to determine whether the addition of tirapazamine to paclitaxel and carboplatin offered a survival advantage when used in the treatment of patients with advanced non–small-cell lung cancer (NSCLC).

Patients and Methods

Of 396 patients registered, 367 eligible patients were randomly assigned to either arm 1 (n = 181), which consisted of treatment every 21 days with paclitaxel 225 mg/m2/3 h, carboplatin (area under the curve = 6), and tirapazamine 260 mg/m2 in cycle 1 (which was escalated, if tolerable, to 330 mg/m2 in cycle 2), or arm 2 (n = 186), which consisted of paclitaxel and carboplatin as in arm 1 with no tirapazamine.

Results

Patient characteristics were similar between the two arms. There were no statistically significant differences in response rates, progression-free survival, or overall survival. Patients on arm 1 had significantly (P < .05) more abdominal cramps, fatigue, transient hearing loss, febrile neutropenia, hypotension, myalgias, and skin rash and were removed from treatment more often as a result of toxicity than patients in arm 2 (26% v 13%, respectively; P = .003). More than 40% of patients did not have the tirapazamine dose escalated, primarily because of toxicity. The trial was closed early after an interim analysis demonstrated that the projected 37.5% improvement in survival (8 v 11 months median survival) in arm 1 was unachievable (P = .003).

Conclusion

The addition of tirapazamine to paclitaxel and carboplatin does not result in improved survival in advanced NSCLC compared with paclitaxel and carboplatin alone but substantially increases toxicity.
Targeting the Cell Cycle: A New Approach to Cancer Therapy
Authors: Schwartz Gary K. , Shah Manish A.
Published: December 2005

The cell cycle represents a series of tightly integrated events that allow the cell to grow and proliferate. Critical parts of the cell cycle machinery are the cyclin-dependent kinases (CDKs), which, when activated, provide a means for the cell to move from one phase of the cell cycle to the next. The CDKs are regulated positively by cyclins and regulated negatively by naturally occurring CDK inhibitors (CDKIs). Cancer represents a dysregulation of the cell cycle such that cells that overexpress cyclins or do not express the CDKIs continue to undergo unregulated cell growth. The cell cycle also serves to protect the cell from DNA damage. Thus, cell cycle arrest, in fact, represents a survival mechanism that provides the tumor cell the opportunity to repair its own damaged DNA. Thus, abrogation of cell cycle checkpoints, before DNA repair is complete, can activate the apoptotic cascade, leading to cell death. Now in clinical trials are a series of targeted agents that directly inhibit the CDKs, inhibit unrestricted cell growth, and induce growth arrest. Recent attention has also focused on these drugs as inhibitors of transcription. In addition, there are now agents that abrogate the cell cycle checkpoints at critical time points that make the tumor cell susceptible to apoptosis. An understanding of the cell cycle is critical to understanding how best to clinically develop these agents, both as single agents and in combination with chemotherapy.
Health Insurance Coverage in Survivors of Childhood Cancer: The Childhood Cancer Survivor Study
Authors: Park Elyse R. , Li Frederick P. , Liu Yan , Emmons Karen M. , Ablin Arthur , Robison Leslie L. , Mertens Ann C.
Published: December 2005

Purpose

To examine the prevalence and predictors of health insurance coverage and the difficulties obtaining coverage in a large cohort of childhood cancer survivors.

Patients and Methods

This study included 12,358 5-year survivors of childhood cancer and 3,553 sibling controls participating in the Childhood Cancer Survivor Study. Data were collected by surveys distributed in 1994 (baseline) and 2000 (follow-up).

Results

At baseline, 83.9% of adult survivors, compared with 88.3% of siblings, had health insurance coverage (P < .01); 6 years later, small but significant survivor-sibling differences remained (88% v 91%; P < .01). Twenty-nine percent of survivors reported having had difficulties obtaining coverage, compared with only 3% of siblings (P < .01). In multivariate analysis of survivors 18 years of age or older, factors associated with being uninsured included younger age at diagnosis (diagnosis age of 0 to 4 years; odds ratio [OR] = 1.7; 95% CI, 1.3 to 2.2), male sex (OR = 1.3; 95% CI, 1.2 to 1.5), age at baseline survey (age 22 to 24 years; OR = 1.6; 95% CI, 1.2 to 2.1), lower level of attained education (less than high school, OR = 2.6, 95% CI, 2.1 to 3.3; high school graduate, OR = 2.1, 95% CI, 1.8 to 2.5), income less than $20,000 (OR = 5.6, 95% CI, 4.5 to 7.1), marital status (widowed/divorced/separated; OR = 1.3; 95% CI, 1.1 to 1.6), smoking status (current smoker, OR = 2.0, 95% CI, 1.7 to 2.3; former smoker, OR = 1.4, 95% CI, 1.2 to 1.8), and treatment that included cranial radiation (OR = 1.3, 95% CI, 1.0 to 1.6).

Conclusion

Compared with siblings, adult survivors of childhood cancer had significantly lower rates of health insurance coverage and more difficulties obtaining coverage. Since lack of coverage likely has serious health and financial implications for this at-risk population, any disparity in availability and quality of coverage is of great concern.
Efficacy and Safety Analysis of Epoetin Alfa in Patients With Small-Cell Lung Cancer: A Randomized, Double-Blind, Placebo-Controlled Trial
Authors: Grote Thomas , Yeilding Allen L. , Castillo Rene , Butler Dean , Fishkin Ellioth , Henry David H. , DeLeo Michael , Fink Kenneth , Sullivan Daniel J.
Published: December 2005

Purpose

This randomized, double-blind, placebo-controlled trial (N93-004) evaluated the effects of epoetin alfa on tumor response to chemotherapy and survival in patients with small-cell lung cancer (SCLC).

Patients and Methods

Adult patients with hemoglobin ≤ 14.5 g/dL starting chemotherapy received epoetin alfa 150 U/kg or placebo subcutaneously 3 times weekly until 3 weeks after completion of chemotherapy. Survival was assessed for 3 years. The primary end point was the proportion of patients with complete or partial response after three chemotherapy cycles.

Results

The trial was terminated prematurely after 224 of a projected 400 patients were accrued. Baseline characteristics were similar between groups. Epoetin alfa and placebo patients (n = 109 and n = 115, respectively) had mean baseline hemoglobin of 12.8 g/dL and 13.0 g/dL, respectively. Overall tumor response was similar between the epoetin alfa and placebo groups after three chemotherapy cycles (72% and 67%, respectively; 95% CI of difference, −6% to 18%) and after completion of chemotherapy (60% and 56%, respectively; 95% CI of difference, −9% to 17%). Epoetin alfa and placebo groups had similar median overall survival (10.5 and 10.4 months, respectively) and overall mortality (91.7% and 87.8%, respectively; hazard ratio, 1.172; 95% CI, 0.887 to 1.549; P = .264). Hemoglobin was maintained in the prechemotherapy range in epoetin alfa patients, but decreased substantially in placebo patients. Fewer epoetin alfa patients than placebo patients required transfusion.

Conclusion

These results suggest that in newly diagnosed patients with SCLC epoetin alfa does not affect tumor response to chemotherapy or survival. However, the early trial closure makes these conclusions preliminary.
Dietary Patterns and Survival After Breast Cancer Diagnosis
Authors: Kroenke Candyce H. , Fung Teresa T. , Hu Frank B. , Holmes Michelle D.
Published: December 2005

Purpose

There is little prior study of major dietary patterns and breast cancer survival.

Methods

Patients included 2,619 Nurses' Health Study participants who were diagnosed with invasive breast cancer between 1982 and 1998 and completed a dietary questionnaire more than 1 year after diagnosis. Participants were followed through 2002 (median = 9 years). During follow-up, 414 patients died of any cause, 242 patients died of breast cancer, and 172 patients died from causes other than breast cancer. Women with in situ or metastatic disease at diagnosis were excluded. We used Cox proportional hazards models to evaluate prospective associations of prudent and Western dietary patterns assessed both before and after diagnosis with time to event after diagnosis.

Results

In multivariate-adjusted analyses assessed after diagnosis, the Western and prudent dietary patterns were unrelated to all-cause or breast cancer mortality. However, compared with women with the lowest intake of the prudent dietary pattern, the relative risks (and 95% CIs) of death from causes other than breast cancer were 0.85 (95% CI, 0.53 to 1.35), 0.74 (95% CI, 0.45 to 1.21), 0.70 (95% CI, 0.42 to 1.17), and 0.54 (95% CI, 0.31 to 0.95; P = .03, from lowest to highest quintile of intake). In contrast, the Western dietary pattern was positively associated with this outcome (P = .04). Results for the assessment of dietary patterns before diagnosis were similar, except the prudent dietary pattern was unrelated to mortality.

Conclusion

A higher intake of the prudent pattern and a lower intake of the Western pattern may protect against mortality from causes unrelated to breast cancer.
Role of Imaging in Pretreatment Evaluation of Early Invasive Cervical Cancer: Results of the Intergroup Study American College of Radiology Imaging Network 6651–Gynecologic Oncology Group 183
Authors: Hricak Hedvig , Gatsonis Constantine , Chi Dennis S. , Amendola Marco A. , Brandt Kathy , Schwartz Lawrence H. , Koelliker Susan , Siegelman Evan S. , Brown Jeffrey J. , McGhee Robert B. , Iyer Revathy , Vitellas Kenneth M. , Snyder Bradley , Long Harry J. , Fiorica James V. , Mitchell Donald G.
Published: December 2005

Purpose

To compare magnetic resonance imaging (MRI) and computed tomography (CT) with each other and to International Federation of Gynecology and Obstetrics (FIGO) clinical staging in the pretreatment evaluation of early invasive cervical cancer, using surgicopathologic findings as the reference standard.

Patients and Methods

This prospective multicenter clinical study was conducted by the American College of Radiology Imaging Network and the Gynecologic Oncology Group from March 2000 to November 2002; 25 United States health centers enrolled 208 consecutive patients with biopsy-confirmed cervical cancer of FIGO stage ≥ IB who were scheduled for surgery based on clinical assessment. Patients underwent FIGO clinical staging, helical CT, and MRI. Surgicopathologic findings constituted the reference standard for statistical analysis.

Results

Complete data were available for 172 patients; surgicopathologic findings were consistent with FIGO stages IA to IIA in 76% and stage ≥ IIB in 21%. For the detection of advanced stage (≥ IIB), sensitivity was poor for FIGO clinical staging (29%), CT (42%), and MRI (53%); specificity was 99% for FIGO clinical staging, 82% for CT, and 74% for MRI; and negative predictive value was 84% for FIGO clinical staging, 84% for CT, and 85% for MRI. MRI (area under the receiver operating characteristic curve [AUC], 0.88) was significantly better than CT (AUC, 0.73) for detecting cervical tumors (P = .014). For 85% of patients, FIGO clinical staging forms were submitted after MRI and/or CT was performed.

Conclusion

CT and MRI performed similarly; both had lower staging accuracy than in prior single-institution studies. Accuracy of FIGO clinical staging was higher than previously reported. The temporal data suggest that FIGO clinical staging was influenced by CT and MRI findings.
Docetaxel Plus Gemcitabine or Docetaxel Plus Cisplatin in Advanced Pancreatic Carcinoma: Randomized Phase II Study 40984 of the European Organisation for Research and Treatment of Cancer Gastrointestinal Group
Authors: Lutz Manfred P. , Cutsem Eric Van , Wagener Theo , Van Laethem Jean-Luc , Vanhoefer Udo , Wils Jacques A. , Gamelin Eric , Koehne Claus H. , Arnaud Jean P. , Mitry Emmanuel , Husseini Faress , Reichardt Peter , El-Serafi Mustafa , Etienne Pierre-Luc , Lingenfelser Thomas , Praet Michel , Genicot Bruno , Debois Muriel , Nordlinger Bernard , Ducreux Michel P.
Published: December 2005

Purpose

To define the efficacy and toxicity of docetaxel plus gemcitabine or docetaxel plus cisplatin for advanced pancreatic carcinoma.

Patients and Methods

Chemotherapy-naive patients with measurable disease and WHO performance status less than 2 were randomly assigned to receive 21-day cycles of gemcitabine 800 mg/m2 on days 1 and 8 plus docetaxel 85 mg/m2 on day 8 (arm A) or docetaxel 75 mg/m2 on day 1 plus cisplatin 75 mg/m2 on day 1 (arm B). Primary end points were tumor response and rate of febrile neutropenia grade.

Results

Of 96 randomly assigned patients (49 patients in arm A and 47 patients in arm B), 70 patients were analyzed for response (36 in arm A and 34 in arm B) and 89 patients were analyzed for safety (45 in arm A and 44 in arm B). Confirmed responses were observed in 19.4% (95% CI, 8.2% to 36.0%) of patients in arm A and 23.5% (95% CI, 10.7% to 41.2%) in arm B. In arm A, the median progression-free survival (PFS) was 3.9 months (95% CI, 3.0 to 4.7 months), median survival was 7.4 months (95% CI, 5.6 to 11.0 months), and 1-year survival was 30%. In arm B, the median PFS was 2.8 months (95% CI, 2.6 to 4.6 months), median survival was 7.1 months (95% CI, 4.8 to 8.7 months), and 1-year survival was 16%. Febrile neutropenia occurred in 9% and 16% of patients in arms A and B, respectively.

Conclusion

Both regimens are well tolerated and show activity in advanced pancreatic carcinoma. The safety profile and survival analyses favor docetaxel plus gemcitabine for further evaluation.
Risk of Epithelial Ovarian Cancer Recurrence in Patients With Rising Serum CA-125 Levels Within the Normal Range
Authors: Santillan Antonio , Garg Ruchi , Zahurak Marianna L. , Gardner Ginger J. , Giuntoli Robert L. , Armstrong Deborah K. , Bristow Robert E.
Published: December 2005

Purpose

To evaluate the risk of epithelial ovarian cancer (EOC) recurrence in patients with rising serum cancer antigen 125 (CA-125) levels that remain below the upper limit of normal (< 35 U/mL).

Patients and Methods

All patients treated for EOC between September 1997 and March 2003 were identified and screened retrospectively for the following: (1) elevated serum CA-125 at time of diagnosis, (2) complete clinical and radiographic response (CR) to initial treatment with normalization of serum CA-125, (3) at least three serial serum CA-125 determinations that remained within the normal range, and (4) clinical and/or radiographic determination of disease status at the time of last follow-up or recurrence. For statistical analyses, univariate regression models were used to compare absolute and relative changes in CA-125 levels among patients with recurrent disease and those without EOC recurrence.

Results

A total of 39 patients satisfied study inclusion criteria; 22 patients manifested EOC recurrence at a median interval from complete response of 11 months. The median follow-up time from complete response to last contact was 32 months for the 17 patients in the no recurrence group. A relative increase in CA-125 of 100% (odds ratio [OR] = 23.7; 95% CI, 2.9 to 192.5; P = .003) was significantly predictive of recurrence. From baseline CA-125 nadir levels, an absolute increase in CA-125 of 5 U/mL (OR = 8.4; 95% CI, 2.2 to 32.6; P = .002) and 10 U/mL (OR = 71.2; 95% CI, 4.8 to > 999.9; P = .002) were also significantly associated with the likelihood of concurrent disease recurrence.

Conclusion

Among patients with EOC in complete clinical remission, a progressive low-level increase in serum CA-125 levels is strongly predictive of disease recurrence.
Targeted Induction of Apoptosis in Cancer Management: The Emerging Role of Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand Receptor Activating Agents
Authors: Rowinsky Eric K.
Published: December 2005

Targeted induction of programmed cell death or apoptosis via the extrinsic apoptotic pathway represents an unexploited therapeutic strategy to destroy cancer cells. The activation of cell surface receptors by the tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) results in direct stimulation of apoptotic signaling pathways (extrinsic stimulation). Molecules that directly activate these receptors, such as agonistic monoclonal antibodies to the TRAIL receptors and recombinant TRAIL, are being developed as monotherapies and as part of combination therapies with existing chemotherapeutic drugs and other therapeutic modalities. This article examines the TRAIL receptors as potential targets for activating the TRAIL-mediated apoptosis pathway and presents the current status of novel therapeutics that exploit this pathway, particularly focusing on agonistic monoclonal antibodies to the TRAIL receptors. The preclinical activity, the status of ongoing evaluations, and the potential clinical impact of these novel agents are reviewed.
14-3-3σ Methylation in Pretreatment Serum Circulating DNA of Cisplatin-Plus-Gemcitabine-Treated Advanced Non–Small-Cell Lung Cancer Patients Predicts Survival: The Spanish Lung Cancer Group
Authors: Ramirez José Luis , Rosell Rafael , Taron Miquel , Sanchez-Ronco Maria , Alberola Vicente , de las Peñas Ramon , Sanchez José Miguel , Moran Teresa , Camps Carlos , Massuti Bartomeu , Sanchez José Javier , Salazar Fernanda , Catot Silvia
Published: December 2005

Purpose

Survival in patients with advanced non–small-cell lung cancer (NSCLC) who are treated with platinum-based chemotherapy is rather variable. Methylation-dependent transcriptional silencing of 14-3-3σ, a major G2-M checkpoint control gene, could be a predictor of longer survival.

Patients and Methods

A sensitive methylation-specific polymerase chain reaction assay was used to evaluate 14-3-3σ methylation status in pretreatment serum DNA obtained from 115 cisplatin-plus-gemcitabine–treated advanced NSCLC patients.

Results

14-3-3σ methylation was observed in all histologic types of 39 patients (34%). After a median follow-up of 9.8 months, median survival was significantly longer in the methylation-positive group (15.1 v 9.8 months; P = .004). Median time to progression was 8 months in the methylation-positive group and 6.3 months in the methylation-negative group (log-rank test, P = .027). A multivariate Cox regression model identified only 14-3-3σ methylation status and Eastern Cooperative Oncology Group performance status as independent prognostic factors for survival. In an exploratory analysis, median survival for 22 methylation-positive responders has not been reached, whereas survival was 11.3 months for 29 methylation-negative responders (P = .001).

Conclusion

Methylation of 14-3-3σ is a new independent prognostic factor for survival in NSCLC patients receiving platinum-based chemotherapy. It can be reliably and conveniently detected in the serum, thus obviating the need for tumor tissue analysis.
Outcome After Pathologic Complete Eradication of Cytologically Proven Breast Cancer Axillary Node Metastases Following Primary Chemotherapy
Authors: Hennessy Bryan T. , Hortobagyi Gabriel N. , Rouzier Roman , Kuerer Henry , Sneige Nour , Buzdar Aman U. , Kau Shu Wan , Fornage Bruno , Sahin Aysegul , Broglio Kristine , Singletary S. Eva , Valero Vicente
Published: December 2005

Purpose

Pathologic complete remission (pCR) of primary breast tumors after primary chemotherapy (PCT) is associated with higher relapse-free survival (RFS) and overall survival (OS) rates. The purpose of this study was to determine long-term outcome in patients achieving pCR of cytologically proven axillary lymph node (ALN) metastases.

Methods

Patients with cytologically documented ALN metastases were treated in five prospective PCT trials. After surgery, patients were subdivided into those with and without residual ALN carcinoma. Survival was calculated by the Kaplan-Meier method.

Results

Of 925 patients treated, 403 patients had cytologically confirmed ALN metastases. Eighty-nine patients (22%) achieved ALN pCR after PCT. Compared with the group without ALN pCR, 5-year OS and RFS were improved in patients achieving ALN pCR (93% [95% CI, 87.5 to 98.5] and 87% [95% CI, 79.7 to 94.3] v 72% [95% CI, 66.5 to 77.5] and 60% [95% CI, 54.1 to 65.9], respectively; P < .0001). Residual primary tumor did not affect outcome of those with ALN pCR. Combination anthracycline/taxane-based PCT resulted in significantly more ALN pCRs, although outcome after ALN pCR was not improved by taxanes. We constructed a nomogram demonstrating that patients who do not benefit from neoadjuvant anthracyclines are unlikely to benefit from subsequent taxanes.

Conclusion

ALN pCR is associated with an excellent prognosis, even with a residual primary tumor, pointing to biologic differences between primary and metastatic cells. ALN pCR represents an early surrogate marker of long-term outcome. Response to initial PCT has important potential as a guide to subsequent therapy.
Evaluation of Factors Affecting Awareness of and Willingness to Participate in Cancer Clinical Trials
Authors: Lara Primo N. , Paterniti Debora A. , Chiechi Christine , Turrell Corinne , Morain Claudia , Horan Nora , Montell Lisa , Gonzalez Jose , Davis Sharon , Umutyan Ari , Martel Cynthia L. , Gandara David R. , Wun Ted , Beckett Laurel A. , Chen Moon S.
Published: December 2005

Purpose

Annually, only 3% of patients participate in cancer clinical trials (CCTs). Barriers to accrual include lack of CCT awareness and uncertain third-party payer coverage. In January 2002, a California law (Senate Bill 37 [SB37]) required all third-party payers to reimburse patient care costs related to CCTs. We evaluated the level of awareness of patients and/or their family members/friends regarding CCTs and SB37.

Methods

We used both a written survey for patients and/or their family members and friends seen in oncology clinics, and a verbal telephone version for Cancer Information Service callers. We tested for correlations between CCT awareness and SB37 knowledge, and willingness to participate in CCTs.

Results

Of 1,188 respondents, 59% were aware of CCTs, 19% knew of SB37, and 36% were very likely to consider a CCT. There were significant positive correlations between CCT awareness and willingness to participate (P < .001, Spearman), and between SB37 knowledge and willingness to participate (P = .001, Pearson χ2). Reduced awareness was seen in respondents who were either black or African American (odds ratio [OR], 0.44; P = .004), Hispanic (OR, 0.56; P = .03), had an annual income less than $25,000 (OR, 0.38; P < .001), or had less than a college degree (OR, 0.12 to 0.53; P < .001 to .013). Reduced willingness to participate in CCTs was seen in black or African American participants (OR, 0.38; P < .001), Asians (OR, 0.44; P < .006), or respondents aged 18 to 24 years (OR, 0.35; P = .002).

Conclusion

These results support the hypothesis that improving CCT awareness and SB37 knowledge especially among lower income, less educated, and minority patients, may potentially overcome barriers to participation and subsequently increase accrual in California.
Risk Factors and Therapy for Isolated Central Nervous System Relapse of Pediatric Acute Myeloid Leukemia
Authors: Johnston Donna L. , Alonzo Todd A. , Gerbing Robert B. , Lange Beverly J. , Woods William G.
Published: December 2005

Purpose

CNS relapse of pediatric acute myeloid leukemia (AML) is an infrequent occurrence. This review examines the risk factors and therapy used for patients with an isolated CNS relapse.

Patients and Methods

Records of 886 patients with de novo AML were reviewed, and patients who entered remission at the end of one course of therapy and developed an isolated CNS relapse as their first event were analyzed (n = 690).

Results

Thirty-three patients developed an isolated CNS relapse. Factors at diagnosis significantly associated with an isolated CNS relapse, compared with no CNS relapse, included age 0 to 2 years (70% v 27%, respectively; P < .001), enlarged liver (79% v 39%, respectively; P < .001) or spleen (79% v 39%, respectively; P < .001) at diagnosis, CNS disease at diagnosis (33% v 9%, respectively; P < .001), median WBC count (79.2 v 19.3 × 103 μL, respectively; P < .001), French-American-British M5 morphology (45% v 15%, respectively; P < .001), and chromosome 11 abnormalities (44% v 18%, respectively; P = .022). Treatment of the isolated CNS relapse varied from local therapy with intrathecal chemotherapy and/or radiation therapy to systemic therapy with chemotherapy with or without bone marrow transplantation. Survival rate in the patients treated with local therapy was only 31.5% compared with 21.4% in patients treated with systemic therapy. The 8-year overall survival for patients after an isolated CNS relapse was similar to patients after a bone marrow relapse (26% ± 16% v 21% ± 5%, respectively).

Conclusion

Significant predictors for isolated CNS relapse were identified. This study demonstrated that there may be no benefit to systemic therapy versus CNS-directed therapy in outcome. The data support CNS-directed therapy to treat isolated CNS relapse.
Low Rectal Cancer: A Call for a Change of Approach in Abdominoperineal Resection
Authors: Nagtegaal Iris D. , van de Velde Cornelius J.H. , Marijnen Corrie A.M. , van Krieken Jan H.J.M. , Quirke Philip
Published: December 2005

Purpose

Despite the major improvements that have been made due to total mesorectal excision (TME), low rectal cancer still remains a challenge.

Methods

By investigating a prospective randomized rectal cancer trial in which surgeons had undergone training in TME the factors responsible for the poor outcome were determined and a new method for assessing the quality of surgery was tested.

Results

Survival differed greatly between abdominoperineal resection (APR) and anterior resection (AR; 38.5% v 57.6%, P = .008). Low rectal carcinomas have a higher frequency of circumferential margin involvement (26.5% v 12.6%, P < .001). More positive margins were present in the patients operated with APR (30.4%) compared to AR (10.7%, P = .002). Furthermore, more perforations were present in these specimens (13.7% v 2.5%, P < .001). The plane of resection lies within the sphincteric muscle, the submucosa or lumen in more than 1/3 of the APR cases, and in the remainder lay on the sphincteric muscles.

Conclusion

We systematically described and investigated the pathologic properties of low rectal cancer in general, and APR in particular, in a prospective randomized trial including surgeons who had been trained in TME. The poor prognosis of the patients with an APR is ascribed to the resection plane of the operation leading to a high frequency of margin involvement by tumor and perforation with this current surgical technique. The clinical results of this operation could be greatly improved by adopting different surgical techniques and possibly greater use of radiochemotherapy.
Predictive Utility of Circulating Methylated DNA in Serum of Melanoma Patients Receiving Biochemotherapy
Authors: Mori Takuji , O’Day Steven J. , Umetani Naoyuki , Martinez Steve R. , Kitago Minoru , Koyanagi Kazuo , Kuo Christine , Takeshima Teh-Ling , Milford Robert , Wang He-Jing , Vu Vu D. , Nguyen Sandy L. , Hoon Dave S.B.
Published: December 2005

Purpose

Currently, no validated blood-based assays accurately predict treatment response or outcome in melanoma patients. We hypothesized that methylation of tumor-related genes detected in serum DNA could predict disease outcome and therapeutic response in patients receiving concurrent biochemotherapy (BC) for metastatic melanoma.

Patients and Methods

American Joint Committee on Cancer stage IV melanoma patients (N = 50) had blood drawn before administration of BC. Patients (n = 47) were classified as BC responders or nonresponders. Responders (n = 23) demonstrated a complete or partial response following BC; nonresponders (n = 24) demonstrated progressive disease. Hypermethylation of Ras association domain family 1 (RASSF1A), retinoic acid receptor-β2 (RAR-β2), and O6-methylguanine DNA methyltransferase (MGMT) genes were assessed by methylation-specific polymerase chain reaction.

Results

Circulating methylated RASSF1A was significantly less frequent for responders (three of 23 patients; 13%) than nonresponders (10 of 24 patients; 42%; P = .028). Patients with RASSF1A, RAR-β2, or at least one serum methylated gene had significantly worse overall survival than patients with no methylated genes (log-rank, P = .013, .021, and .01, respectively). Methylated RASSF1A was the only factor that significantly correlated with overall survival and BC response (risk ratio, 2.38; 95% CI, 1.16 to 4.86; P = .018; odds ratio = 0.21; 95% CI, 0.05 to 0.90; P = .036).

Conclusion

Detection of circulating methylated DNA in serum can predict response to BC and disease outcome.
Phase III Clinical Trial of Thalidomide Plus Dexamethasone Compared With Dexamethasone Alone in Newly Diagnosed Multiple Myeloma: A Clinical Trial Coordinated by the Eastern Cooperative Oncology Group
Authors: Rajkumar S. Vincent , Blood Emily , Vesole David , Fonseca Rafael , Greipp Philip R.
Published: December 2005

Purpose

To determine if thalidomide plus dexamethasone yields superior response rates compared with dexamethasone alone as induction therapy for newly diagnosed multiple myeloma.

Patients and Methods

Patients were randomly assigned to receive thalidomide plus dexamethasone or dexamethasone alone. Patients in arm A received thalidomide 200 mg orally for 4 weeks; dexamethasone was administered at a dose of 40 mg orally on days 1 to 4, 9 to 12, and 17 to 20. Cycles were repeated every 4 weeks. Patients in arm B received dexamethasone alone at the same schedule as in arm A.

Results

Two hundred seven patients were enrolled: 103 were randomly assigned to thalidomide plus dexamethasone and 104 were randomly assigned to dexamethasone alone; eight patients were ineligible. The response rate with thalidomide plus dexamethasone was significantly higher than with dexamethasone alone (63% v 41%, respectively; P = .0017). The response rate allowing for use of serum monoclonal protein levels when a measurable urine monoclonal protein was unavailable at follow-up was 72% v 50%, respectively. The incidence rates of grade 3 or higher deep vein thrombosis (DVT), rash, bradycardia, neuropathy, and any grade 4 to 5 toxicity in the first 4 months were significantly higher with thalidomide plus dexamethasone compared with dexamethasone alone (45% v 21%, respectively; P < .001). DVT was more frequent in arm A than in arm B (17% v 3%); grade 3 or higher peripheral neuropathy was also more frequent (7% v 4%, respectively).

Conclusion

Thalidomide plus dexamethasone demonstrates significantly superior response rates in newly diagnosed myeloma compared with dexamethasone alone. However, this must be balanced against the greater toxicity seen with the combination.
Randomized Phase II Trial of the Clinical and Biological Effects of Two Dose Levels of Gefitinib in Patients With Recurrent Colorectal Adenocarcinoma
Authors: Rothenberg Mace L. , LaFleur Bonnie , Levy Donna E. , Washington Mary Kay , Morgan-Meadows Sherry L. , Ramanathan Ramesh K. , Berlin Jordan D. , Benson Al B. , Coffey Robert J.
Published: December 2005

Purpose

The clinical objective of this trial was to evaluate gefitinib in patients with metastatic colorectal cancer that had progressed despite prior treatment. Serial tumor biopsies were performed when possible and analyzed for activation of the epidermal growth factor receptor (EGFR) signaling pathway. Serial serum samples were measured for amphiregulin and transforming growth factor–alpha (TGFα).

Patients and Methods

One hundred fifteen patients were randomly assigned to receive gefitinib 250 or 500 mg orally once a day. One hundred ten patients were assessable for clinical efficacy. Biologic evaluation was performed on paired tumor samples from 28 patients and correlated with clinical outcome.

Results

Median progression-free survival was 1.9 months (95% CI, 1.8 to 2.1 months) and 4-month progression-free survival rate was 13% ± 5%. One patient achieved a radiographic partial response (RR = 1%; 95% CI, 0.01% to 5%). Median survival was 6.3 months (95% CI, 5.1 to 8.2 months). The most common adverse events were skin rash, diarrhea, and fatigue. In the biopsy cohort, expression of total or activated EGFR, activated Akt, activated MAP-kinase, or Ki67 did not decrease following 1 week of gefitinib. However, a trend toward decreased post-treatment levels of activated Akt and Ki67 was observed in patients with a PFS higher than the median, although these did not reach the .05 level of significance.

Conclusion

Gefitinib is inactive as a single agent in patients with previously treated colorectal cancer. In tumor samples, gefitinib did not inhibit activation of its proximal target, EGFR. Trends were observed for inhibition of downstream regulators of cellular survival and proliferation in patients achieving longer progression-free survival.
Phase II Study of Imatinib Mesylate Plus Hydroxyurea in Adults With Recurrent Glioblastoma Multiforme
Authors: Reardon David A. , Egorin Merrill J. , Quinn Jennifer A. , Rich Jeremy N. , Gururangan Idharan , Vredenburgh James J. , Desjardins Annick , Sathornsumetee Sith , Provenzale James M. , Herndon James E. , Dowell Jeannette M. , Badruddoja Michael A. , McLendon Roger E. , Lagattuta Theodore F. , Kicielinski Kimberly P. , Dresemann Gregor , Sampson John H. , Friedman Allan H. , Salvado August J. , Friedman Henry S.
Published: December 2005

Purpose

We performed a phase II study to evaluate the combination of imatinib mesylate, an adenosine triphosphate mimetic, tyrosine kinase inhibitor, plus hydroxyurea, a ribonucleotide reductase inhibitor, in patients with recurrent glioblastoma multiforme (GBM).

Patients and Methods

Patients with GBM at any recurrence received imatinib mesylate plus hydroxyurea (500 mg twice a day) orally on a continuous, daily schedule. The imatinib mesylate dose was 500 mg twice a day for patients on enzyme-inducing antiepileptic drugs (EIAEDs) and 400 mg once a day for those not on EIAEDs. Assessments were performed every 28 days. The primary end point was 6-month progression-free survival (PFS).

Results

Thirty-three patients enrolled with progressive disease after prior radiotherapy and at least temozolomide-based chemotherapy. With a median follow-up of 58 weeks, 27% of patients were progression-free at 6 months, and the median PFS was 14.4 weeks. Three patients (9%) achieved radiographic response, and 14 (42%) achieved stable disease. Cox regression analysis identified concurrent EIAED use and no more than one prior progression as independent positive prognostic factors of PFS. The most common toxicities included grade 3 neutropenia (16%), thrombocytopenia (6%), and edema (6%). There were no grade 4 or 5 events. Concurrent EIAED use lowered imatinib mesylate exposure. Imatinib mesylate clearance was decreased at day 28 compared with day 1 in all patients, suggesting an effect of hydroxyurea.

Conclusion

Imatinib mesylate plus hydroxyurea is well tolerated and associated with durable antitumor activity in some patients with recurrent GBM.
Pharmacogenetics of Tamoxifen Biotransformation Is Associated With Clinical Outcomes of Efficacy and Hot Flashes
Authors: Goetz Matthew P. , Rae James M. , Suman Vera J. , Safgren Stephanie L. , Ames Matthew M. , Visscher Daniel W. , Reynolds Carol , Couch Fergus J. , Lingle Wilma L. , Flockhart David A. , Desta Zeruesenay , Perez Edith A. , Ingle James N.
Published: December 2005

Purpose

Polymorphisms in tamoxifen metabolizing genes affect the plasma concentration of tamoxifen metabolites, but their effect on clinical outcome is unknown.

Methods

We determined cytochrome P450 (CYP)2D6 (*4 and *6) and CYP3A5 (*3) genotype from paraffin-embedded tumor samples and buccal cells (living patients) in tamoxifen-treated women enrolled onto a North Central Cancer Treatment Group adjuvant breast cancer trial. The relationship between genotype and disease outcome was determined using the log-rank test and Cox proportional hazards modeling.

Results

Paraffin blocks were obtained from 223 of 256 eligible patients, and buccal cells were obtained from 17 living women. CYP2D6 (*4 and *6) and CYP3A5 (*3) genotypes were determined from 190, 194, and 205 patient samples and in 17 living women. The concordance rate between buccal and tumor genotype was 100%. Women with the CYP2D6 *4/*4 genotype had worse relapse-free time (RF-time; P = .023) and disease-free survival (DFS; P = .012), but not overall survival (P = .169) and did not experience moderate to severe hot flashes relative to women heterozygous or homozygous for the wild-type allele. In the multivariate analysis, women with the CYP2D6 *4/*4 genotype still tended to have worse RFS (hazard ratio [HR], 1.85; P = .176) and DFS (HR, 1.86; P = .089). The CYP3A5*3 variant was not associated with any of these clinical outcomes.

Conclusion

In tamoxifen-treated patients, women with the CYP2D6 *4/*4 genotype tend to have a higher risk of disease relapse and a lower incidence of hot flashes, which is consistent with our previous observation that CYP2D6 is responsible for the metabolic activation of tamoxifen to endoxifen.
Women With Synchronous Primary Cancers of the Endometrium and Ovary: Do They Have Lynch Syndrome?
Authors: Soliman Pamela T. , Broaddus Russell R. , Schmeler Kathleen M. , Daniels Molly S. , Gonzalez Delia , Slomovitz Brian M. , Gershenson David M. , Lu Karen H.
Published: December 2005

Purpose

Lynch syndrome (hereditary nonpolyposis colorectal cancer; HNPCC) is an autosomal-dominant cancer predisposition syndrome that increases risk for multiple cancers, including colon, endometrial, and ovarian cancer. Revised Bethesda Criteria recommend that patients with two HNPCC-associated cancers undergo molecular evaluation to determine whether they have a mismatch repair (MMR) defect associated with HNPCC. The purpose of our study was to determine the likelihood of MMR defects (MSH2, MSH6, MLH1) in women with synchronous endometrial and ovarian cancer.

Patients and Methods

Between 1989 and 2004, 102 women with synchronous endometrial and ovarian cancers were identified; 59 patients had tumor blocks available for analysis. Patients were divided into risk groups based on family history: high (met Amsterdam criteria), medium (personal history or first-degree relative with an HNPCC-associated cancer), and low (all others). Protein expression for MSH2, MSH6, and MLH1 was evaluated by immunohistochemistry. Microsatellite instability and MLH1 promoter methylation analyses were performed on a subset of cases.

Results

Median age was 50 years. Two patients met Amsterdam criteria for HNPCC. Five additional patients, all medium-risk, had molecular findings consistent with a germline mutation of either MSH2 or MLH1. None of the low-risk patients had molecular results consistent with a germline mutation.

Conclusion

Overall, 7% of women in our cohort met either clinical or molecular criteria for Lynch syndrome. All of these women had a prior history or a first-degree relative with an HNPCC-associated cancer. Limiting genetic evaluation to women with synchronous endometrial and ovarian cancer who have a family history suggestive of HNPCC may appropriately identify women with Lynch syndrome.