BACKGROUND The aim of this study was to compare imaging modalities for staging the neck in a prospective cohort of patients evaluated by CT, ultrasound with fine-needle aspiration cytology (FNAC), and [(18) F]fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET)/CT with the histologic evaluation of the neck dissection as the standard of reference. METHODS: In all, 76 consecutive patients were prospectively enrolled. RESULTS: Ultrasound-guided FNAC showed the highest level of agreement with histology for exact N classification. Ultrasound-guided FNAC showed the smallest percentage of overstaged patients, 7%, versus 16% with PET/CT, 13% with CT, and 13% with ultrasound. The rate of understaged patients was comparable between the imaging modalities. With regard to the endpoint N0 versus N+ there were no statistically significant differences to be found. CONCLUSIONS: Ultrasound-guided FNAC seems to correlate best with histologic staging compared with PET/CT and CT. None of the modality is reliable enough to replace elective neck treatment in cN0 necks.

To evaluate the prevalence of thyroid FDG-PET/CT incidentalomas and the risk of malignancy in focal findings. A retrospective study of 3,062 PET scans was performed between 05/2006 and 09/2009. Prevalence of thyroid incidentalomas, risk of malignancy and correlation between standard uptake value (SUV) and cancer risk were analysed. The overall prevalence of thyroid incidentalomas was 2.4%. 71% showed a focal and 29% a diffuse uptake. In the focal uptake group, the diagnosis was clarified in 79% with cytology/histology. In 23.8% of the patients with a focal uptake, a malignant lesion was found. Diffuse uptake was predominantly associated with autoimmune thyroiditis. There was no statistically significant difference in the SUVmax between benign and malignant focal lesions (p = 0.0982). Patients with incidental focal uptake in the thyroid during FDG-PET/CT bear a considerable risk of malignancy and should undergo cytologic clarification of the diagnosis.

Aims: Extracts from pine tree bark containing a variety of flavonoids have been used in traditional medicine. Pycnogenol is a proprietary bark extract of the French maritime pine tree (Pinus pinaster ssp. atlantica) that exerts antioxidative, anti-inflammatory, and anti-platelet effects. However, the effects of Pycnogenol on endothelial dysfunction, a precursor of atherosclerosis and cardiovascular events, remain still elusive. Methods and results: Twenty-three patients with coronary artery disease (CAD) completed this randomized, double-blind, placebo-controlled cross-over study. Patients received Pycnogenol (200 mg/day) for 8 weeks followed by placebo or vice versa on top of standard cardiovascular therapy. Between the two treatment periods, a 2-week washout period was scheduled. At baseline and after each treatment period, endothelial function, non-invasively assessed by flow-mediated dilatation (FMD) of the brachial artery using high-resolution ultrasound, biomarkers of oxidative stress and inflammation, platelet adhesion, and 24 h blood pressure monitoring were evaluated. In CAD patients, Pycnogenol treatment was associated with an improvement of FMD from 5.3 +/- 2.6 to 7.0 +/- 3.1 (P < 0.0001), while no change was observed with placebo (5.4 +/- 2.4 to 4.7 +/- 2.0; P = 0.051). This difference between study groups was significant [estimated treatment effect 2.75; 95% confidence interval (CI): 1.75, 3.75, P < 0.0001]. 15-F2t-Isoprostane, an index of oxidative stress, significantly decreased from 0.71 +/- 0.09 to 0.66 +/- 0.13 after Pycnogenol treatment, while no change was observed in the placebo group (mean difference 0.06 pg/mL with an associated 95% CI (0.01, 0.11), P = 0.012]. Inflammation markers, platelet adhesion, and blood pressure did not change after treatment with Pycnogenol or placebo. Conclusion: This study provides the first evidence that the antioxidant Pycnogenol improves endothelial function in patients with CAD by reducing oxidative stress. Clinical Trial Registration: ClinicalTrials.gov identifier: NCT00641758

Objective: Up to 9% of all burn injuries in western countries are been reported to have been caused by self-immolation with suicidal intent and usually involve extensive injuries. We sought to identify differences between suicide burn victims as opposed to those who sustained their injuries accidentally, with regards to injury severity and mortality and determine the possible impact of suicide as a prognostic variable in the context of a scoring system such as the Abbreviated Burns Severity Index (ABSI). Patients and Methods: The data of all burns patients treated at the Specialist Burns Intensive Care Unit, University Hospital Zurich, between 1968 and 2008 were analysed retrospectively. Results: Of the 2813 patients included in the study, 191 were identified as attempted suicides, most commonly involving the use of accelerants. 30% of all suicide victims had pre-existing psychiatric diagnoses. Suicide victims presented with significantly more extensive burns (53.7%, +/- 0.98 SEM versus 21.4%, +/- 0.36 SEM, p <0.0001), had higher total ABSI scores (8.4, +/-0.23 SEM versus 6.6, +/- 0.05 SEM, p< 0.0001) and higher mortality rates (42.9% (83/191) versus 16.3% (426/2622)) than accident victims. Furthermore logistic regression revealed suicide to be as significant a predictor of mortality as inhalation injury (OR 2.2, 95% CI 1.4-3.5, p< 0.0003 and OR 2.4, 95% CI 1.4-4.0, p<0.0009, respectively). Conclusions: The odds of dying from an attempted suicide are twice as high compared to those of accident patients in the same ABSI category, making suicide a powerful predictor of mortality. We therefore suggest including it as a fixed variable in scoring systems for estimating a patient's mortality after burn injuries, such as the widely used ABSI.

Questions under study: We investigated the effect of individualised proton pump inhibitors (PPI) prescription on upper gastrointestinal adverse events in a cohort of patients who received combination antiplatelet therapy (aspirin and clopidogrel) after percutaneous coronary intervention (PCI). Methods: Upper gastrointestinal risk factors and other parameters were extracted from a dedicated electronic database. Patients were contacted with a standardised questionnaire. A structured phone interview was performed in all patients with upper gastrointestinal adverse events. Results: A cohort of 718 patients on combination therapy yielded 87 (12.1%) patients with prophylactic PPI treatment. Upper gastrointestinal adverse events occurred in 18.4% patients with and in 11.1% patients without prophylactic PPI (OR 1.80, P=0.054). Co-treatment with corticosteroids was the main identifiable risk factor for upper gastrointestinal adverse events (adjusted OR 5.45, P=0.014). Conclusion: Individualised prescription of PPI-prophylaxis after PCI in patients on combined antiplatelet therapy based on risk assessment for upper gastrointestinal-bleeding seems to represent an effective measure to minimise upper gastrointestinal adverse events after PCI.

Background and Objectives: The potential of avoiding a secondary surgery for therapeutic neck dissection (TND) by sentinel node (SN) positivity makes the intraoperative evaluation of SNs an attractive option. The aim of this study was to analyze accuracy of intraoperative frozen section (FS) for detection of occult metastases in a large single institutional patient cohort undergoing SN-biopsy. Methods: Between 2000 and 2010, 92 consecutive patients with early stage oropharyngeal squamous cell carcinoma (OSCC) (cT1/cT2/cN0) were prospectively enrolled. Detection rate of occult metastases by monoslice FS was compared with the definitive histopathologic work up by step serial sectioning (SSS) and immunohistochemistry (IHC). In case of SN-positivity on FS TND was performed in the same narcosis. Results: 15/92 patients revealed positive SNs by FS compared to 34/92 after SSS and IHC. Sensitivity, NPV and FNR for the detection of all sizes of metastases by FS was 47, 77, and 52%, for isolated tumor cells (ITC) 8, 86, 92%, for micrometastases 43, 90, 57%, and for macro- metastases 93, 98, 7%. Conclusion: Sensitivity of FS by the monoslice depends on the metastases size and allows a single-stage procedure in half of the SN-positive patients. To improve sensitivity for small tumor deposits either a multislice-technique or molecular methods are needed.

In light of changes in patient demographics together with constant developments in burn care, the predictive accuracy of the Abbreviated Burns Severity Index (ABSI) - first described in 1982 - for estimating the mortality of present day burns patients, may be questionable. We reviewed the records of 2813 burns patients treated between January 1968 and December 2008 in the intensive care unit at our institution, aiming to identify emerging discrepancies between the estimated and calculated outcome, based on each of the ABSI variables and the total burn score. The predictive value of each of the defined ABSI variables was confirmed to be highly significant. Univariable and multivariable analysis revealed an exponential increase in odds ratio (OR) for mortality for patients older than 60 years and more than 30% TBSA burned and showed OR values over 10 times higher than other significant variables like inhalation injury. Nevertheless, the ABSI for the estimation of mortality in our entire patient collective was highly accurate and could not be optimised by adapting the point distribution to the increase in OR. Our data indicates that despite significant changes in patient demographics and medical advances over the past 30 years, the ABSI scoring system is still an accurate and valuable tool in the prediction of burn patient mortality.

Function of the skin lymphatics as well as blood perfusion of a meshed transplant is crucial for the healing. The lymphatic regeneration and arterial perfusion of skin transplants after severe burns of the extremities had been studied in eight patients by microlymphography, laser doppler perfusion imaging and transcutaneous oxygen pressure measurements 1, 6 and 18 months after transplantation. One month after transplantation, only fragmented as well as many giant lymphatic skin vessels were present in the transplant. After 6 months a normal lymphatic network had developed in all grafts. The extension of the dye in the lymphatics decreased from 4.5 (0-16) at 1 month to 3.0 (1-6) mm after 18 months, indicating improved lymph drainage capacity. The permeability of the lymphatics in the graft was normal. After 1 month, median laser flux in the transplant was 155.6% (105-246%) of the normal skin but it normalised within 18 months. By contrast, transcutaneous oxygen measurement (TcPO(2)) increased from 44 (21-47) to 55 (50-76) mmHg. In meshed transplants used to cover severely burned skin morphological and functional normal lymphatics develop within 6 months and the initially increased laser flux due to inflammatory reaction normalises. Our results provide important insights into the healing process of skin transplants after burn.

Background. Sentinel node biopsy (SNB) has been proposed for staging of the cN0 neck in early oral/oropharyngeal squamous cell carcinomas (SCC). As SNB is a minimally invasive procedure, it is thought to be associated with less morbidity than elective neck dissection. Methods. Sixty-two consecutive patients were included from 2000 to 2009. Two groups were analyzed consisting of 33 patients after SNB and 29 after elective neck dissection. Subjective impairment and functional shoulder status were assessed with the Neck Dissection Impairment Index (NDII) questionnaire and the modified individual relative Constant Score. Postoperative complications were retrieved from the clinical charts. Results. The investigated scores were significantly better in the SNB group. All postoperative complications occurred in the elective neck dissection group. Conclusion. SNB is associated with significantly less postoperative morbidity and better shoulder function than elective neck dissection. This supports our opinion that patients with nodal negative early SCC of the oral cavity should be offered SNB.

Background: Sugar-sweetened beverages (SSBs) have unfavorable effects on glucose and lipid metabolism if consumed in high quantities by obese subjects, but the effect of lower doses in normal-weight subjects is less clear. Objective: The aim was to investigate the effects of SSBs consumed in small to moderate quantities for 3 wk on LDL particle distribution and on other parameters of glucose and lipid metabolism as well as on inflammatory markers in healthy young men. Design: Twenty-nine subjects were studied in a prospective, randomized, controlled crossover trial. Six 3-wk interventions were assigned in random order as follows: 600 mL SSBs containing 1)40 g fructose/d [medium fructose (MF)], 2) 80 g fructose/d [high fructose (HF)], 3) 40 g glucose/d [medium glucose (MG)], 4) 80 g glucose/d [high glucose (HG)], 5) 80 g sucrose/d [high sucrose (HS)], or 6) dietary advice to consume low amounts of fructose. Outcome parameters were measured at baseline and after each intervention. Results: LDL particle size was reduced after HF by -0.51 nm (95% CI: -0.19, -0.82 nm) and after HS by -0.43 nm (95% CI: -0.12, -0.74; P < 0.05 for both). Similarly, a more atherogenic LDL subclass distribution was seen when fructose-containing SSBs were consumed (MF, HF, and HS: P < 0.05). Fasting glucose and high-sensitivity C-reactive protein (hs-CRP) increased significantly after all interventions (by 4-9% and 60-109%, respectively; P < 0.05); leptin increased during interventions with SSBs containing glucose only (MG and HG: P < 0.05). Conclusion: The present data show potentially harmful effects of low to moderate consumption of SSBs on markers of cardiovascular risk such as LDL particles, fasting glucose, and hs-CRP within just 3 wk in healthy young men, which is of particular significance for young consumers. This trial was registered at clinicaltrials.gov as NCT01021969.

PRINCIPLES: High-dose chemotherapy with subsequent autologous stem cell transplantation (ASCT) is an important treatment option in younger patients with multiple myeloma (MM). We analysed the outcome of patients treated at our institution outside the clinical trials framework and tried to identify risk factors prognostic for survival. METHODS: Medical histories of the patients were screened for response, event-free survival (EFS) and overall survival (OS). Pre-transplant variables were analysed to identify possible prognostic risk factors. RESULTS: Overall, 182 ASCT were performed in 120 patients with MM from 2002 to 2007. Treatment-related mortality (TRM) was 0.5%. Median EFS was 23.1 months (95% confidence interval [CI]: 19.4 - 28.4) and median OS was 49.8 months (95%CI: 43.7 - not reached) in the whole patient population. The median OS in patients who received one ASCT was 46.4 months (95%CI: 35.2 - not reached), and 63.7 months (95%CI: 48.9 - not reached) in patients who underwent double ASCT. Patients who already achieved a complete remission (CR) before ASCT had a longer EFS (p = 0.016) than patients without CR. Additionally, patients who achieved a CR after ASCT had a longer EFS (p = 0.0061) and OS (p = 0.0024) than patients without CR. ISS stage <III at first diagnosis strongly correlated with improved EFS (p = 0.0006) and OS (p <0.0001). CONCLUSIONS: ASCT is a safe and effective treatment mode in eligible patients with MM. TRM was below average at our institution. Achievement of CR after transplantation was the most valuable predictor for improved overall survival.

OBJECTIVE: Long-term results of sentinel node biopsy (SNB) in early (T1/T2) oral and oropharyngeal squamous cell carcinoma (OSCC) in a single-institution experience. METHODS: Prospective consecutive cohort analysis of 79 patients (67% male, median age 60 years, age range 34-87 years) included between 2000 and 2006. Lymphatic mapping consisted of preoperative lymphoscintigraphy, single photon emission computed tomography (SPECT/CT), and intraoperative use of a handheld gamma probe. Endpoints of the study were neck control rate, overall (OS), disease-specific (DSS), and disease-free survival (DFS). RESULTS: Twenty-nine of 79 patients (37%) had positive sentinel nodes (SN). Six of 29 (21%) patients showed isolated tumor cells, 14/29 (48%) micrometastases, and 9/29 (31%) macrometastases. OS, DFS, and DSS at 5 years for the entire cohort were 80, 85, and 87%, for SN-negative patients were 88, 96, and 96%, and for SN-positive patients were 74, 73, and 77%, respectively. Only the difference in DSS achieved statistical significance. The neck control rate after 5 years was 96% in SN-negative and 74% in SN-positive patients. This difference was statistically significant. CONCLUSIONS: SNB is a safe and accurate staging modality to select patients with clinically stage I/II OSCC with occult lymph node disease for elective neck dissection (END). The promising reported short-term results have been sustained by long-term follow-up. Patients with negative SN and no END achieve an excellent neck control rate which compares favorably with reports on primary END. The neck control rate in SN-negative patients is superior to that in SN-positive patients, which is reflected in superior DSS.

Rationale: HIV protease inhibitors (HIV-PI: Ritonavir, Lopinavir, Saquinavir, Nelfinavir, Amprenavir, Indinavir, Atazanavir, Tipranavir and Darunavir) are oral drugs for HIV treatment. Although designed to inhibit the HIV protease, HIV-PI may also target the proteasome implicating therapeutic potential especially in hematologic malignancies. Objective: We compared the effects of HIV-PI on proteasome activity, cytotoxicity, ER-stress induction and AKT-phosphorylation in myeloma and AML cells. Results: Lopinavir, Nelfinavir, Ritonavir and Saquinavir showed biological and molecular activity at concentrations within or near therapeutic drug levels (10-20 μM). In this dose range, they triggered ER stress-induced apoptosis, inhibited AKT-phosphorylation and showed synergistic cytotoxicity with Bortezomib. Nelfinavir stood out as the only HIV-PI with proteasome-inhibiting activity at near-therapeutic drug levels. Nelfinavir inhibited not only the Bortezomib-sensitive proteasome β1/β5 subunits, but to a similar extent also the Bortezomib-insensitive β2 subunits. It induced significant additional proteasome inhibition and synergistic cytotoxicity in Bortezomib-pretreated cells and Bortezomib-resistant primary myeloma cells. Significant inhibition of the proteasomal β1, β2 and β5 active subunits was observed in PBMCs from patients treated with Nelfinavir. Conclusions: Nelfinavir inhibits proteasome activity in vitro and in vivo in a pattern distinct from that of Bortezomib. Nelfinavir acts synergistically with Bortezomib, warranting clinical testing in hematologic malignancies.

To reduce the duration of neutropenia after conditioning chemotherapy and autologous peripheral blood stem cell transplantation (APBSCT), granulocyte-colony stimulating factors (G-CSF) are commonly administered. We retrospectively evaluated the impact of pegfilgrastim compared to filgrastim on neutrophil engraftment, hospital stay, and supportive measures in patients with multiple myeloma after conditioning with Melphalan 200 (Mel200) followed by APBSCT. Ninety-two APBSCT after Mel200 treatment were performed in 72 patients between January 2006 and December 2009 at our institution. Patients received either single-dose pegfilgrastim (n=46; 50%), or daily filgrastim (n=46; 50%) after APBSCT (median duration of filgrastim use, 9 days; range, 3-14 days). Duration of neutropenia grade IV was shorter with pegfilgrastim compared with filgrastim (median, 5 days (range, 3-14 days) versus 6 days (range, 3-9 days), p=0.0079). The length of hospitalization differed significantly (pegfilgrastim (median, 14.5 days; range, 11-47 days) versus filgrastim (median, 15.5 days; range, 12-64 days), p=0.024). Pegfilgrastim-treated patients had less red blood cell transfusions (median, 0 transfusions (range, 0-10) versus 0.5 transfusions (range, 0-9), p=0.00065). Pegfilgrastim was associated with reduced cost of the treatment procedure compared with filgrastim (p=0.031). Pegfilgrastim appears to be at least equivalent to filgrastim without additional expenditure in myeloma patients treated with Mel200 and APBSCT.

BACKGROUND: An outcome assessment was performed of patients with unresectable colorectal liver metastases (CRLM) treated in second or third line with floxuridine (FUDR)-based hepatic artery infusion (HAI). METHODS: Twenty-three patients who were pretreated with systemic (immuno)chemotherapy received FUDR-HAI alone or combined with systemic chemotherapy. We reviewed patient charts and our prospective patient database for survival and associated risk factors. RESULTS: Patients received FUDR-HAI for unresectable CRLM from January 2000 to September 2010. Twelve patients (52%) received concurrent systemic chemotherapy. Median overall survival (OS), progression-free survival (PFS), and hepatic PFS were 15.6 months (range, 2.5-55.7 months), 3.9 months (range, 0.7-55.7 months), and 5.5 months (range, 1.6-55.7 months), respectively. The liver resection rate after HAI was 35%. PFS was better in patients undergoing secondary resection than in patients without resection (hazard ratio [HR] 0.21; 95 interval [95% CI] 0.07-0.66; P = 0.0034), while OS showed a trend toward improvement (HR 0.4; 95% CI 0.13-1.2; P = 0.09). No differences were observed in OS (P = 0.69) or PFS (P = 0.086) in patients who received FUDR-HAI alone compared with patients treated with combined regional and systemic chemotherapy. No statistically significant differences were seen in patients previously treated with one chemotherapy line compared with patients treated with two lines. Presence of extrahepatic disease was a negative risk factor for PFS (liver-only disease: HR 0.03; 95% CI 0.0032-0.28; P < 0.0001). Toxicities were manageable with dose modifications and supportive measures. CONCLUSIONS: FUDR-HAI improves PFS and results in a trend toward improved OS in selected patients able to undergo liver resection after tumor is downsized.

Background: The purpose of this study was to evaluate the impact of 2-[fluorine-18]fluoro-2-deoxy-D-glucose–positron emission tomography/computed tomography (FDG-PET/CT) during follow-up of patients with diffuse large B-cell lymphoma (DLBCL) being in complete remission or unconfirmed complete remission after first-line therapy. Patients and methods: DLBCL patients receiving FDG-PET/CT during follow-up were analyzed retrospectively. Confirmatory biopsy was mandatory in cases of suspected disease recurrence. Results: Seventy-five patients were analyzed and 23 (30%) had disease recurrence. The positive predictive value (PPV) of FDG-PET/CT was 0.85. Patients >60 years [P = 0.036, hazard ratio (HR) = 3.82, 95% confidence interval (CI) 1.02-7.77] and patients with symptoms indicative of a relapse (P = 0.015; HR = 4.1; 95% CI 1.20-14.03) had a significantly higher risk for relapse. A risk score on the basis of signs of relapse, age >60 years, or a combination of these factors identified patients at high risk for recurrence (P = 0.041). Conclusions: FDG-PET/CT detects recurrent DLBCL after first-line therapy with high PPV. However, it should not be used routinely and if only in selected high-risk patients to reduce radiation burden and costs. On the basis of our retrospective data, FDG-PET/CT during follow-up is indicated for patients <60 years with clinical signs of relapse and in patients >60 years with and without clinical signs of relapse.

Preclinical data indicated a detrimental effect of statins on the anti-lymphoma activity of rituximab. We evaluated the impact of concomitant statin medication on the response and survival of patients with diffuse large B cell lymphoma (DLBCL) receiving rituximab-cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP) as first-line therapy. Medical histories of patients with DLBCL who were treated with R-CHOP as first-line therapy were assessed for concomitant statin use, response after completion of chemotherapy, event-free survival (EFS), and overall survival (OS). Furthermore, 2-[(18)F]fluor-2-deoxyglucose (FDG)-PET/CT results after completion of first-line therapy were compared between the groups. Overall, 145 patients with DLBCL treated with R-CHOP from January 2001 to December 2009 were analyzed. Twenty-one (15 was 67.3 receiving statins during R-CHOP (HR, 0.47; 95 p = 0.2). Five-year OS was 81.4 with 93.3 p = 0.6). There were no statistically significant differences in the rates of complete remissions between the two groups (75 non-statin group versus 86 toward a lower rate of complete metabolic responses in FDG-PET/CT after chemotherapy was seen in patients without statin medication compared with the patients taking statins (84 Concomitant statin use had no adverse impact on response to chemotherapy, EFS, and OS in patients treated with R-CHOP for DLBCL.

Intravenous immunoglobulin (IVIG) is used for many indications beyond the original substitution in primary antibody deficiency. Whereas many reports mention adverse reactions, no comparative data exist concerning the incidence of side-effects among the different brands of IVIG. We describe here our experience with the use of different IVIG formulations and their tolerability in a select cohort of 40 patients. The IVIG dose ranged from 0.4 to 3 g/kg/day and was given for 1–2742 days. Fourteen patients (35%) experienced mild to severe adverse reactions during or within 48 h of administration of standard IVIG preparation, which did not recur after switching to an alternative preparation. Adverse reactions included headache, fever, chills, nausea, emesis, hypotension and muscle cramps. One patient experienced a severe adverse reaction; he had a 3-day headache following IVIG infusion. Among the 16 patients who received alternative preparation initially, none experienced adverse reactions. In conclusion, this study shows that IVIG preparations are not all equally well tolerated in patients. The data suggest that, perhaps to a comparable extent to the preparation itself, the infusion rate has a major effect. If a reduction in the infusion rate does not minimize sideeffects, one should consider switching the IVIG formulation.

Keywords: intravenous immunoglobulin; adverse drug reaction; prevention; toxic epidermal necrolysis; hypogammaglobulinaemia; lung transplantation.

Objective: To evaluate the impact of pegfilgrastim on engraftment, hospital stay and resources in patients with Hodgkin’s and non-Hodgkin’s lymphoma after conditioning with high-dose BEAM followed by autologous peripheral blood stem cell transplantation (APBSCT) compared with filgrastim. Methods: We reviewed patient charts and our prospective transplantation database for clinical data from the post-transplant period. An integrated cost analysis, including the use of blood products and length of hospital stay, was also performed. Results: Fourteen (26%) patients with Hodgkin’s lymphoma and 40 (74%) patients with non-Hodgkin’s lymphoma were analyzed. Thirty-four (68%) patients received single-dose pegfilgrastim (6 mg), and 20 (32%) patients received daily filgrastim (5 μg/kg) after APBSCT. No differences were observed regarding duration of neutropenia grade 4 (pegfilgrastim median 7 days/filgrastim median 8 days; p = 0.13), thrombocytopenia grade 4 (7/9.5 days, respectively; p = 0.21), fever (4.5/2 days; p = 0.057), intravenous antibiotic treatment (11/10 days; p = 0.75) or length of hospital stay (16.5/16 days; p = 0.27) between the groups. The use of pegfilgrastim resulted in 12% higher treatment-related costs when compared to filgrastim, without reaching statistical significance (p = 0.38). Conclusion: Pegfilgrastim appears to be equivalent to filgrastim after high-dose BEAM followed by APBSCT in the treatment of lymphoma patients.

Background: Since traditional non-steroidal anti-inflammatory drugs are associated with increased risk for acute cardiovascular events, current guidelines recommend acetaminophen as the first-line analgesic of choice on the assumption of its greater cardiovascular safety. Data from randomized clinical trials prospectively addressing cardiovascular safety of acetaminophen, however, are still lacking, in particular in patients at increased cardiovascular risk. Hence, it was the aim of this study to evaluate the safety of acetaminophen in patients with coronary artery disease. Methods and Results: 33 patients with coronary artery disease were included in this randomized, double-blind, placebo-controlled, crossover study and received acetaminophen (1g TID) on top of standard cardiovascular therapy for 2 weeks. Ambulatory blood pressure, heart rate, endothelium-dependent and -independent vasodilatation, platelet function, endothelial progenitor cells, markers of the renin-angiotensin-system, inflammation and oxidative-stress were determined at baseline and after each treatment period. Treatment with acetaminophen resulted in a significant increase of mean systolic (from 122.4±11.9 to 125.3±12.0 mmHg, p=0.007 vs placebo) and diastolic (from 73.2±6.9 to 75.4±7.9 mmHg, p=0.015 vs. BL, p=0.008 vs. placebo) ambulatory blood pressure. On the other hand, heart rate, endothelial function, early endothelial progenitor cells and platelet function did not change. Conclusions: As this study for the first time demonstrates that acetaminophen induces a significant increase in ambulatory blood pressure in patients with coronary artery disease, the use of acetaminophen should be as rigorously evaluated as traditional NSAIDs and COX-2 inhibitors, in patients at increased cardiovascular risk in particular. Trial Registration: ClinicalTrials.gov Identifier: NCT00534651

While nonparametric methods have been well established for inference on competing risks data, parametric methods for such data have not been developed as much. Because the cumulative incidence functions are improper by their nature, flexible distribution families accommodating improperness are needed for modeling competing data more accurately. Additionally, different types of events present in a competing risks setting may be correlated, yet current inference methods do not permit inferring such data taking into account the correlation between failure time distributions. This work first presents two new distributions which are well-suited for modeling competing risks data. In existing inference procedures for competing risks data, it appears that the correlation between failure time distributions of competing events are fixed as a constant. In the second part of this dissertation, a novel approach is proposed which allows researchers to model competing risks data by taking the correlation into account by estimating it. The methods are illustrated by analyzing survival data from a breast cancer trial of the National Surgical Adjuvant Breast and Bowel Project. Simulation studies are also presented for each of the proposed new distributions. Public Health Significance: Competing risks occur often in many clinical studies, and must be accounted for whenever researchers are interested in only one type of event. For example, researchers may be interested in investigating only local recurrences of breast cancer, but must also take into account all other possible types of events as competing. Parametric methods are not currently as well established as other methods for competing risks data. Development of flexible parametric inference procedures suitable for modeling competing risks data would provide more accurate information, which will serve to improve patient care in clinical settings.

Background: NSABP B-32, a phase III randomized trial of SN resection vs SN resection followed by AD (SNAD) in early stage breast cancer, provided a unique opportunity to compare patient-reported outcomes (PROs) arm function, symptoms, and quality of life (QOL). We report the final treatment (TX) comparison of PROs. Methods: Women with operable invasive breast cancer were eligible for B-32; those whose SNs were negative were eligible for the PRO questionnaire sub-study. Symptoms, arm-related disabilities, and QOL were assessed at baseline, 1 week after surgery (post-op), 2-3 weeks post-op, and 6, 12, 18, 24, 30, 36 months (mos). The primary endpoint, a multi- item ipsilateral surgery symptom scale, was compared between TX at 6 and 12 mos using two-sided, two-sample t-tests, with Bonferroni correction. An anticipated accrual of 819 patients (pts) was calculated to yield 87 the primary comparisons. We compared each PRO item by TX with repeated measures analysis. We analyzed separately pts who received lumpectomy vs mastectomy, and accounted for breast reconstruction and dominant hand. Results: 749 pts enrolled in the PRO sub-study before B-32 completed accrual (358 SNAD, 391 SN). Arm symptoms were greater for SNAD pts (effect size 0.4, p<0.0001 at 6 mos; effect size 0.25, p=0.006 at 12 mos). Over the complete time on study, SNAD pts had more difficulty pushing large objects, lifting objects, reaching, and conducting social and work activity (p<0.001). They were more likely to avoid arm use and to experience symptoms (p=0.002 breast tenderness; p<0.001 all other items). The treatment difference persisted over time for avoidance of arm use; arm or breast tenderness or swelling; and breast pain, numbness, skin sensitivity, or tightness. Overall QOL was better among SN pts (p<0.001) and improved over time (p<0.001). In both groups, treatment was well tolerated by 6 mos: only 10 restriction of social/recreational activity, and overall QOL averaged 8 (scale 0-10). Conclusions: SN pts experienced significantly fewer symptoms and activity limitations. However, long-term levels of symptoms and limitations were low, and QOL was high, for both groups.

PURPOSE: This report describes interventions undertaken by the National Surgical Adjuvant Breast and Bowel Project (NSABP) to improve compliance with patient-reported outcome (PRO) assessments in the setting of multicenter cancer clinical trials. We describe the effectiveness of several interventions and of observational factors. METHODS: PRO submission rates were analyzed for the following three NSABP protocols: the Study of Raloxifene and Tamoxifen (STAR), B-32, and B-35. Institutions participating in protocol B-35 were randomly assigned to receive automated reminders of upcoming assessments or not. Compliance was analyzed with a logistic repeated measures mixed modeling. RESULTS: Compliance was high in the three protocols, with rates greater than 80% for nearly all time points. Institutions were a significant source of variability (P < .01). The largest institutions had the highest compliance in STAR (odds ratio [OR] = 0.68 for < 50 participants enrolled and OR = 0.82 for 50 to 99 participants enrolled v larger institutions; P < .001). Midsized institutions had highest compliance in B-32 (OR = 4.63 for 31 to 50 patients enrolled and OR = 3.12 for > 50 patients enrolled v small institutions; P = .007). Compliance increased with participant age in STAR (OR = 0.57, 0.89, and 1.01 for ages < 50, 50 to 60, and 60 to 70 years, respectively, v > 70 years; P < .001). Race was significant in B-32 (OR = 2.63 for white v nonwhite; P < .001) and in STAR (OR = 1.41 for white v nonwhite; P < .001). Treatment group was significant in B-32 (OR = 0.74; P = .006). The B-35 prospective reminder did not improve compliance significantly (P = .30), but in B-32, delinquency sanctions were significant (OR = 1.56; P = .007). CONCLUSION: Compliance in NSABP PRO studies is higher now than a decade ago. Results for compliance initiatives were mixed. Age and race are important factors, but institutional variation remains significant and largely unexplained.

BACKGROUND: We sought to identify the risk of axillary node involvement in patients with ductal carcinoma in situ (DCIS) and to determine whether axillary node assessment is necessary in these patients. Sentinel node biopsy (SNB) is replacing standard axillary lymph node dissection (ALND) for surgical staging of invasive breast cancer. Its use in patients with DCIS versus local excision (LE), observation, and/or breast irradiation remains in question. METHODS: We examined the records of 813 patients with localized DCIS and disease-negative margins after LE who were randomly assigned to no further therapy or to breast irradiation in National Surgical Adjuvant Breast and Bowel Project (NSABP) trial B-17 and 1799 patients randomized to receive placebo or tamoxifen after LE + radiotherapy in NSABP trial B-24. An ALND was performed in 253 patients in NSABP B-17 and in 162 in NSABP B-24. RESULTS: We found that in NSABP trial B-17, seven patients developed ipsilateral nodal recurrence (INR). Overall INR rate was 0.83/1000 patient-years. In NSABP B-24, overall INR rate was 0.36/1000 patient-years. INR can be considered a surrogate for axillary involvement at the time of DCIS diagnosis. CONCLUSIONS: INR in patients with DCIS treated conservatively is extremely rare. Our findings do not support the routine use of SNB in patients with conservatively treated, localized DCIS.

Background: The 3-year results of NSABP protocol C-03 published in 1993 (Wolmark, et al J Clin Oncol 11:1879-87, 1993) indicated significant improvement in DFS and OS for patients (pts) with stage II or III colon cancer treated with postoperative FL compared to pts treated with lomustine (MeCCNU), vincristine, and 5-FU (MOF). The present analysis reports long-term results. Methods: Pts with stage II or III (Dukes' B or C) colon cancer who had undergone a potentially curative surgical resection were randomized postoperatively to receive adjuvant chemotherapy with either MOF or FL (given on the “Roswell Park schedule”) for approximately 1 year. Results: 1081 pts (1044 eligible-96.6 pts 986 (94.4 and 1022 (97.9 estimates, relative risks from a stratified Cox model, and stratified logrank p values (stratified for gender, # positive nodes [0, 1-4, 5+], and tumor location [right colon, non-right], as specified in the protocol) for DFS and OS are shown below. Tests for interactions of the stratification variables (gender, # positive nodes, and tumor location) with treatment were not significant (p>0.16). Conclusions: The 10-year results of NSABP C-03 confirm and extend the previously published analysis, and indicate a highly significant and clinically relevant improvement in DFS and OS for pts with stage II or III colon cancer treated with FL compared to MOF. These data serve as a standard for evaluation of new adjuvant regimens.