The important role of radiation therapy in early-stage diffuse large B-cell lymphoma: time to review the evidence once again

Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin's lymphoma in the USA, and approximately one-third of patients present with early stage, localized disease. While significant controversy still exists regarding the appropriate management of these patients, the overwhelming evidence from a wide range of studies over the last 40 years points to the superior efficacy of combined-modality therapy for this disease. The current standard of care for the vast majority of early-stage DLBCL cases now involves a combination of chemotherapy, immunotherapy and consolidation radiotherapy. Using this multimodality approach, very high rates of local control can be achieved, which will translate into significant survival benefits for patients with localized disease. The use of intensive immunochemotherapy without radiation therapy requires formal testing and validation in a randomized clinical trial before it can be used as an alternative treatment regimen for early-stage DLBCL. In this article, we discuss the results of the key randomized trials, critical retrospective studies and recent clinical trials, which collectively address the important role of radiotherapy in the treatment of early-stage DLBCL.     

Aggressive fibromatosis of the head and neck: a new classification based on a literature review over 40 years (1968–2008)

Background

Fibromatosis is an aggressive fibrous tumor of unknown etiology that is, in some cases, lethal. Until now, there has been no particular classification for the head and neck. Therefore, the aim of the present study was to review the current literature in order to propose a new classification for future studies.

Methods

An evidence-based literature review was conducted from the last 40 years regarding aggressive fibromatosis in the head and neck. Studies that summarized patients’ data without including individual data were excluded.

Results

Between 1968 and 2008, 179 cases with aggressive fibromatosis of the head and neck were published. The male to female ratio was 91 to 82 with a mean age of 16.87 years, and 57.32% of the described cases that involved the head and neck were found in patients under 11 years. The most common localization was the mandible, followed by the neck. All together, 143 patients were followed up, and in 43 (30.07%), a recurrence was seen.

Conclusion

No clear prognostic factors for recurrence (age, sex, or localization) were observed. A new classification with regard to hormone receptors and bone involvement could improve the understanding of risk factors and thereby assist in future studies.     

Expression of cyclooxygenase-2 (COX-2) in an advanced metastasized hypopharyngeal carcinoma and cultured tumor cells

Purpose

The inducible enzyme cyclooxygenase-2 (COX-2) catalyzes PGE₂ production and plays an important role in the progression of many solid cancers. However, the role of COX-2 expression in cervical lymph node metastases of head and neck cancer has not been clarified yet.

Patient and methods

We comment on a male patient aged 53 who was admitted to an ENT-department with acute bleeding from an advanced hypopharyngeal carcinoma and a frontotemporal mass. Prior to palliative intended radiotherapy, the metastasis was resected. During the procedure, a small amount of tumor tissue was harvested for primary tumor cell culture.

Results

COX-2 overexpression was demonstrated in the primary tumor tissue, the metastasis, in the cultured tumor cells by standard immunohistochemistry, as well as cytochemistry.

Conclusions

A simultaneous expression of COX-2 in head and neck carcinoma was presented for the first time. Besides the prognostic impact in oral carcinogenesis, this COX-2 role of biomarker for aggressive head and neck squamous cell carcinomas should be further evaluated. Additionally, treatment of hypopharyngeal carcinomas with selective COX-2 inhibitors could be beneficial when administered in combination with radiochemotherapy.     

Impact of moderate renal insufficiency on restenosis and adverse clinical events after sirolimus-eluting and bare metal stent implantation (from the SIRIUS trials)

Whether drug-eluting stents are effective and safe in patients with moderate renal insufficiency (RI) is unknown. We performed a pooled analysis of data from 3 blinded randomized trials of sirolimus-eluting stents (SESs) versus bare metal stents (BMSs; SIRIUS, C-SIRIUS, E-SIRIUS) that included 1,510 patients. Clinical and angiographic outcomes were stratified by the presence of RI defined by creatinine clearance calculated by the Cockcroft-Gault formula (normal ≥ 90, mild 60 to 89, moderate < 60 ml/min). Patients with baseline creatinine > 3.0 mg/dl were excluded from these trials. Baseline mild RI was present in 517 patients (34.7%, mean creatinine clearance 75.7 ml/min) and moderate RI in 228 patients (15.3%, mean creatinine clearance 47.2 ml/min). Treatment with SESs resulted in lower rates of 8-month angiographic restenosis rates in patients with RI (mild RI 6.7% vs 42.6%, p < 0.001; moderate RI 9.7% vs 39.7%, p < 0.001) and without baseline RI (7.7% vs 37.2%, p < 0.001). One-year target vessel revascularization rates were similarly decreased with SESs in patients with (mild RI 4.7% vs 24.2%, p < 0.001; moderate RI 5.5% vs 26.9%, p < 0.001) and without (8.1% vs 22.4%, p < 0.001) RI, and this benefit was maintained at 5 years. Compared to patients with normal or mild RI, patients with moderate RI had higher rates of overall mortality and cardiac death at 1 year and 5 years (death 2.6% vs 0.6%, p <0.01, and 17.5% vs 6.3%, p < 0.01, at 1 year and 5 years, respectively; cardiac death 1.3% vs 0.2%, p = 0.05, and 6.6% vs 3.4%, p = 0.04, at 1 year and 5 years, respectively). However, there was no differential effect of SESs versus BMSs on any safety end point. In conclusion, patients with moderate RI have a nearly threefold increase in 5-year mortality after percutaneous coronary intervention compared to patients without RI. The effectiveness of SESs in decreasing restenosis compared to BMSs in patients with moderate RI was preserved and rates of death and myocardial infarction were not adversely affected.     

A population pharmacokinetic model for pegylated-asparaginase in children

We analysed 1221 serum activity measurements in 168 children from the Berlin-Frankfürt-Münster acute lymphoblastic leukaemia studies, ALL-BFM (Berlin-Frankfürt-Münster) 95 and ALL-BFM REZ, in order to develop a pharmacokinetic model describing the activity-time course of pegylated (PEG)-asparaginase for all dose levels. Patients received 500, 750, 1000 or 2500 U/m² PEG-asparaginase on up to nine occasions. Serum samples were analysed for asparaginase activity and data analysis was done using nonlinear mixed effects modelling (NONMEM Vers. VI, Globomax, Hanouet, MD, USA). Different linear and nonlinear models were tested. The best model applicable to all dosing groups was a one-compartmental model with clearance (Cl) increasing with time according to the formula: Cl=Cl_i * e ^{(0·0793 * t )} where Cl_i = initial clearance and t  = time after dose. The parameters found were: volume of distribution ( V ) 1·02 ± 26% l/m², Cl_i 59·9 ± 59% ml/d per m² (mean ± interindividual variability). Interoccasion variability was substantial with 0·183 l/m² for V and 44·7 ml/d per m² for Cl, respectively. A subgroup of the patients showed a high clearance, probably due to the development of inactivating antibodies. This is the first model able to predict the activity-time course of PEG-asparaginase at different dosing levels and can therefore be used for developing new dosing regimens.     

Secular Changes in Mortality Disparities in New York City: A Reexamination

Previously published analyses showed that inequalities in mortality rates between residents of poor and wealthy neighborhoods in New York City (NYC) narrowed between 1990 and 2000, but these trends may have been influenced by population in-migration and gentrification. The NYC public housing population has been less subject to these population shifts than those in other NYC neighborhoods. We compared changes in mortality rates (MRs) from 1989–1991 to 1999–2001 among residents of NYC census blocks consisting entirely of public housing residences with residents of nonpublic housing low-income and higher-income blocks. Public housing and nonpublic housing low-income blocks were those in census block groups with ≥50% of residents living at <1.5 times the federal poverty level (FPL); nonpublic housing higher-income blocks were those in census block groups with <50% of residents living at <1.5 times the FPL. Information on deaths was obtained from NYC’s vital registry, and US Census data were used for denominators. Age-standardized all-cause MRs in public housing, low-income, and higher-income residents decreased between the decades by 16%, 28%, and 22%, respectively. While mortality rate ratios between low-income and higher-income residents narrowed by 8%, the relative disparity between public housing and low-income residents widened by 21%. Diseases amenable to prevention including malignancies, diabetes, and chronic lung disease contributed to the increased overall mortality disparity between public housing and lower-income residents. These findings temper previous findings that inequalities in the health of poor and wealthier NYC neighborhood residents have narrowed. NYC public housing residents should be a high-priority population for efforts to reduce health disparities.

Cytotoxic and genotoxic effects of matrices for cartilage tissue engineering

Customizing auricles with biodegradable polyurethane colonized with autologous chondrocytes as an approach for tissue engineering cartilage transplants has been suggested for the reconstruction of the external ear to repair auricular deformities. Dextrose, triethanolamine and poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol) (PEG-PPG-PEG) are matrices of an open-pored polyurethane three-dimensional scaffold. After release from the polymer, these compounds can be absorbed into the human organism. Therefore, cytotoxic effects on human chondrocytes and lymphocytes and genotoxic effects on human lymphocytes were determined. Propidium iodide and fluoresceine diacetate staining as well as quantitative proliferations testing with EZ4U served to detect cytotoxic effects on chondrocytes. In lymphocytes cytotoxicity was checked by trypan blue staining and the alkaline single cell microgel electrophoresis (Comet) assay was used to study genotoxic effects. Dose-dependent cytotoxicity and genotoxicity of the matrices could be shown. Concentrations up to 4.25 mg/ml for dextrose, 0.15 mg/ml for PEG-PPG-PEG and 0.9 mg/ml for triethanolamine did not show cytotoxic effects in chondrocytes or genotoxic effects in lymphocytes. These data suggest that dextrose, triethanolamine and PEG-PPG-PEG could be safely used if scaffolds made of open-pored polyurethane do not release these compounds at a rate giving higher concentrations at the site of implantation or in body fluids, respectively.