Aryl hydrocarbon receptor activation by diesel exhaust particles mediates epithelium-derived cytokines expression in severe allergic asthma.

BACKGROUND: Exposure to environmental pollutants promotes Th2 cell responses. Aryl hydrocarbon receptor (AhR) activation aggravates allergic responses. Epithelium-derived thymic stromal lymphopoietin (TSLP), interleukin (IL)-25, and IL-33 are implicated in the dysregulation of Th2 immune responses in severe allergic asthma. METHODS: Bronchial biopsies of 28 allergic severe asthma and 6 mild asthma subjects from highly polluted areas were analyzed for AhR nuclear translocation (NT), cytokine expression, and gene activation. Cultured primary epithelial cells were stimulated with diesel exhausted particles (DEP) to determine AhR-mediated IL-33, Il-25, and TSLP synthesis and release. RESULTS: Primary bronchial epithelial cells exposed to DEP showed upregulation of IL-33, IL-25, and TSLP. These effects were abolished by knockdown of AhR by siRNA. Increased AhR/ARNT binding to promoters of IL-33, IL-25, and TSLP was found using chromatin immunoprecipitation (ChIP) assay. Allergic severe asthma with high AhR NT had higher bronchial gene and protein expression of IL-33, IL-25, and TSLP. These patients derived clinical benefit from anti-IgE treatment. CONCLUSION: Aryl hydrocarbon receptor activation by DEP mediates upregulation of IL-33, IL-25, and TSLP with Th2 activation, potentially linking environmental pollution and allergic severe asthma.

Radiotherapy in the management of solitary extramedullary plasmacytoma.

BACKGROUND: Solitary extramedullary plasmacytoma (SEP) is a rare tumour for which the standard treatment remains local radiotherapy (RT). We present a study of a multi-institutional experience, between 1980 and 1999, in an attempt to better understand the natural history of SEP and to identify possible prognostic factors. METHODS: The records at Radiation Oncology Victoria and Peter MacCallum Cancer Centre, Melbourne, were used for the identification of patients. The inclusion criteria were as follows: (i) histological confirmation of clonal plasma cells involving a single extramedullary site with or without lymph node involvement; (ii) no histological evidence of bone marrow involvement; (iii) no evidence of distant bone lesion on radiographic skeletal survey (bone erosions adjacent to the primary thought to be due to contiguous involvement were permitted) and (iv) no anaemia, hypercalcaemia or renal impairment due to plasma cell dyscrasia. RESULTS: A total of 16 patients was identified, with a median follow up of 66 months (range 12-211 months). The head and neck region accounted for the majority of presentations (88%). Among all patients, a serum mono-clonal paraprotein was found in three patients and bone erosion was identified in seven patients. All patients received local RT, although two patients also received elective nodal irradiation (ENI). The median RT dose was 45 Gy (range 40-50.4 Gy). Local control was achieved in all patients (100%), however, regional recurrence outside the RT fields occurred in 2/16. Multiple myeloma (MM) developed in five patients, all within 5 years. The predicted 10-year myeloma free survival is 75% and 10-year overall survival is 54%. CONCLUSION: RT can achieve excellent local control of SEP. The rate of conversion to MM is 31%. Moderate dose RT of at least 40 Gy using limited radiation fields is recommended, although ENI should be considered if toxicity is not increased.

Practical issues in adjuvant therapy for rectal cancer.

INTRODUCTION: While the standard adjuvant therapy for rectal cancer includes radiation therapy (RT) and chemotherapy (CT), the optimal treatment combination and sequencing have yet to be determined. In recent years, a large number of clinical trials have been reported in this rapidly evolving field. MATERIALS AND METHODS: A review of pivotal trials in rectal cancer was undertaken with a focus on the important recent literature that has determined the current approach to adjuvant treatment. RESULTS: Multiple well-conducted, randomised studies have demonstrated that, for patients with stage II and III rectal cancer, the combination of adjuvant CT and RT reduces the risk of local recurrence (LR) and distant recurrence, improves overall survival and should form part of the standard treatment. Due to the reduced risk of LR, the absolute benefit from adjuvant RT is less if optimal oncologic surgery has been performed. Theoretical advantages and preliminary clinical results suggest that delivering part of the adjuvant therapy preoperatively will produce superior results. Ongoing randomised trials will define the relative merits of long-course RT (with CT) and short-course RT alone as preoperative therapy. Preoperative combined modality therapy might increase the rate of sphincter preservation, although definitive data supporting this is still being awaited, whereas RT alone does not facilitate sphincter preservation. CONCLUSION: Management of patients with rectal cancer is complex and requires ongoing close collaboration between the colorectal surgeon, medical oncologist and radiation therapist in order to achieve the best possible outcomes. The optimal combination of CT and RT will be defined by current clinical trials.

Primary adenocarcinoma of the anus: a retrospective analysis.

PURPOSE: To report the clinical features and outcome of patients with primary adenocarcinoma of the anus following radiotherapy with or without chemotherapy. METHODS AND MATERIALS: A retrospective analysis was performed on 15 patients referred to Peter MacCallum Cancer Institute between 1981 to 1998 with primary adenocarcinoma of the anus. The median follow-up was 7.5 years. Six patients underwent treatment with curative intent-either chemoradiation or radiotherapy alone. Surgery was mainly limited to either incisional or excisional biopsy. The remaining nine patients were treated with palliative intent because of advanced age, advanced disease, or poor medical status. The biological equivalent doses were calculated for all patients and correlated with time to progression. RESULTS: None of the curative group had relapsed after a median follow-up of 6.6 years. All except one were alive and well. No patient developed any serious long-term toxicity and all patients avoided colostomy. All patients managed with palliative intent died with persistent locoregional disease with a median survival of 0.8 year. CONCLUSION: Primary adenocarcinoma of the anus is a very rare disease that precludes a rigorous analysis. This study demonstrates that radiation and in particular chemoradiation are effective therapies consistent with other recent series and analogous to squamous cell carcinomas of the anus. It also emphasizes the poor prognosis of patients treated with palliative intent.

Radiation myelopathy following transplantation and radiotherapy for non-Hodgkin's lymphoma.

BACKGROUND: Combined modality therapy with chemotherapy and radiotherapy has become increasingly popular in the management of solid malignancies. However, unexpected toxicities may arise from their interactions. METHODS AND MATERIALS: We report the case of a young woman with a large mediastinal non-Hodgkin's lymphoma who underwent high-dose chemotherapy with autologous bone marrow transplantation and involved field radiotherapy, and who developed radiation myelopathy after a latent period of only 3 months. The spinal cord dose did not exceed 40.3 Gy in 22 fractions over 4.5 weeks, which is well within accepted tolerance limits. She had no other identifiable risk factors for radiation myelopathy, suggesting an adverse drug-radiation interaction as the most likely cause of her injury. RESULTS AND CONCLUSIONS: This represents the first report of radiation myelopathy at accepted safe radiation doses following high-dose chemotherapy with autologous bone marrow transplantation, and we recommend caution in the choice of radiotherapeutic dose in this setting.

Results of treating primary tumors of the trachea with radiotherapy.

PURPOSE: To report the efficacy of treatment and to identify prognostic factors that were predictive of survival in primary tumors of the trachea treated with radiotherapy. METHODS AND MATERIALS: The medical records of patients treated at the Peter MacCallum Cancer Institute in the period 1962 to 1995 were reviewed. Forty-two patients were eligible for the study and were treated with radiotherapy. Squamous cell carcinoma (SCC) was the commonest subtype and patients generally presented with long-standing respiratory symptoms. Eleven patients were planned for treatment with at least 50 Gy to the primary, while the rest were treated with lower doses. RESULTS: The estimated median survival for all patients was 5.7 months, with 13% surviving at 2 years. Univariate analysis revealed performance status, weight loss, and lymph node or distant metastatic involvement as significant prognostic factors. Patients planned for treatment with at least 50 Gy survived longer than patients treated with less than 50 Gy, but this was probably due to selection of patients with better prognostic factors for higher dose treatment.

Postoperative adjuvant radiotherapy and 5-fluorouracil chemotherapy for rectal carcinoma.

Postoperative combined modality therapy with radiotherapy and 5-fluorouracil (5FU) chemotherapy is an effective adjuvant approach that reduces locoregional and distant metastatic disease in patients with high-risk rectal carcinoma. However, this approach results in a treatment regimen of at least 6 months' duration. The present prospective study investigates the integration of radiotherapy and 5FU chemotherapy in a protocol designed to minimize toxicity and reduce the overall treatment time. A total of 40 patients with TNM stage II or III disease received postoperative radiotherapy at four fractions per week with weekly 5FU bolus injections delivered on the fifth non-radiotherapy day. Patients also received systemic chemotherapy with leucovorin both before and after pelvic irradiation, with the total treatment duration extending for only 18 weeks. Patients were able to complete radiotherapy in 90% of cases, while the delivery of full-dose chemotherapy was achievable in the vast majority. The incidence of haematologic and gastrointestinal toxicities requiring the cessation of treatment was acceptable. With a median follow-up of 20.9 months among surviving patients, the estimated progression-free and overall survival at 2 years were 71% and 79%, respectively.