Role of cyclooxygenase-2 inhibitors in combination with radiation therapy in lung cancer

Cyclooxygenase-2 (COX-2) is an enzyme involved in prostaglandin production in pathologic states such as inflammatory disorders and cancer. The enzyme is often overexpressed in premalignant lesions and cancer of the lung. Overexpression of COX-2 in lung cancer is associated with more aggressive biological tumor behavior and adverse patient outcome. In preclinical studies, inhibition of this enzyme with selective COX-2 inhibitors enhances tumor response to radiation and chemotherapeutic agents. These findings have been rapidly advanced to clinical oncology. Clinical trials of the combination of selective COX-2 inhibitors with radiation therapy, chemotherapy, or both in patients with lung cancer have been initiated and some preliminary results are available. In this review, we describe the relationship between overexpression of COX-2 and lung cancer, the antitumor effect of selective COX-2 inhibitors, discuss the rationale for using selective COX-2 inhibitors combined with radiation therapy and chemotherapy, and summarize current clinical protocols and initial findings.     

Loss of heterozygosity of DPC4 tumor suppressor gene in human sporadic colon cancer

We investigated the prevalence of DPC4 loss of heterozygosity in sporadic colorectal cancer. Thirty-six cases of human sporadic colon carcinoma and corresponding normal tissue samples were examined to evaluate loss of heterozygosity at the DPC4 tumor suppressor locus using variable nucleotide tandem repeat (VNTR) analysis and three polymorphic markers. From 36 analyzed samples 35 (97%) were heterozygous or informative. Loss of heterozygosity at the DPC4 locus was detected in 18 (51%) of informative tumor DNAs. The DPC4 LOH was more frequent in smaller tumors (<5 cm) than in larger ones. There was no correlation between DPC4 LOH and age or sex of patients. There was a negative correlation between DPC4 LOH and histological grade or Dukes' stage of tumors, but without statistic significance. Observed results are in agreement with the view that malignant progression is consequence of many genetic changes. It can be concluded that inactivation of the DPC4 gene plays a role in a multistep process of outgrowth and progression of colon cancer.     

Chemoradiotherapy: emerging treatment improvement strategies

BACKGROUND: The use of chemotherapeutic drugs in combination with radiotherapy has become a common strategy for the treatment of advanced cancer. Solid evidence exists showing that chemotherapy administered during the course of radiotherapy (concurrent chemoradiotherapy) increases both local tumor control and patient survival in a number of cancer sites, including head and neck cancer. These therapy improvements, however, have been achieved at the expense of considerable toxicity, which underscores the need for further improvements. METHODS: The current status of chemoradiotherapy clinical trials for head and neck cancer and research on the emerging treatment improvements were reviewed. A review of potential treatment improvement strategies focused on preclinical investigations on newer chemotherapeutic agents, notably taxanes and nucleoside analogues, as well as on molecular targets such as epidermal growth factor receptor (EGFR) or cyclooxygenase-2 (COX-2) enzyme. RESULTS: Concurrent, but not induction (drugs given before radiotherapy), chemoradiotherapy improves locoregional tumor control and survival benefit in head and neck carcinoma relative to radiotherapy alone. In comparison, both concurrent and induction chemoradiotherapy showed therapeutic advantage over radiotherapy alone in the treatment of lung cancer. These therapeutic improvements were achieved with standard chemotherapeutic drugs, most commonly cisplatin-based chemotherapy. Biologically, chemotherapy interacts with radiation through a number of mechanisms, including inhibition of cellular repair, cell cycle effects, and inhibition of tumor cell regeneration. Potential avenues emerged to further improve chemoradiotherapy. One of these involves the newer chemotherapeutic agents, taxanes and nucleoside analogues, which in preclinical studies exhibited strong tumor radiosensitization and therapeutic gain. The clinical benefit of these agents is currently under testing. Another approach for improvement of chemoradiotherapy consists of inhibiting molecules selectively or preferentially expressed on tumor cells, such as EGFR and COX-2, both shown to render cellular resistance to drugs or radiation. Agents that selectively inhibit these molecules are becoming available at a rapid rate, and many of them have been shown in preclinical testing to be highly effective in improving tumor radioresponse or chemoresponse without affecting normal tissues. CONCLUSIONS: Concurrent chemoradiotherapy, using standard chemotherapeutic agents, has emerged as an effective treatment for advanced cancer, but unfortunately at the expense of considerable increase in normal tissue toxicity. There are a number of potential emerging treatment strategies to further improve chemoradiotherapy. One consists of using newer chemotherapeutic drugs, which in preclinical studies are potent enhancers of tumor radioresponse. Another approach consists of targeting EGFR or COX-2 with selective inhibitors of these molecules.     

Effectiveness of accelerated radiotherapy for patients with inoperable non-small cell lung cancer (NSCLC) and borderline prognostic factors without distant metastasis: a retrospective review

Purpose: The standard treatment for patients with unresectable or medically inoperable non-small cell lung cancer (NSCLC) and good prognostic factors (e.g., weight loss [WL] ≤5% and Karnofsky performance status [KPS] ≥70) is induction chemotherapy followed by definitive radiotherapy to the primary site at 1.8–2.0 Gy per fraction with a total dose of 60–63 Gy to the target volume. Patients with poor prognostic factors usually receive radiotherapy alone, but the fractionation schedule and total dose have not been standardized. To attempt to optimize irradiation doses and schedule, we compared the effectiveness of accelerated radiotherapy (ACRT) alone to 45 Gy at 3 Gy per fraction with standard radiation therapy (STRT) of 60–66 Gy at 2 Gy per fraction in regard to tumor response, local control, distant metastasis, toxicity, and survival.

Methods and Materials: Fifty-five patients treated with radiation for NSCLC at The University of Texas M. D. Anderson Cancer Center between 1990 and 1994 were identified. All 55 patients had node-positive, and no distant metastasis (N+, M0) of NSCLC. Two cohorts were identified. One cohort (26 patients) had borderline poor prognostic factors (KPS less than 70 but higher than 50, and/or WL of more than 5%) and was treated with radiotherapy alone to 45 Gy over 3 weeks at 3 Gy/fraction (ACRT). The second cohort (29 patients) had significantly better prognostic factors (KPS ≥70 and WL ≤5%) and was treated to 60–66 Gy over 6 to 6 weeks at 2 Gy per fraction (STRT) during the same period.

Results: In the first cohort treated by ACRT, the distribution of patients by AJCC stage was IIB 8%, IIIA 19%, and IIIB 73%. Sixty-two percent had KPS <70, and 76% had a WL of >5%. The maximum response rate as determined by chest X-ray was 60% among 45 of 55 patients who were evaluable for response: combined complete responses (20%) and partial responses (40%). Overall survival in these patients was 13% at 2 and 5 years, with a locoregional control rate of 42% and a freedom from distant metastasis rate of 54%. The ACRT cohort treated with 3 Gy per fraction had significantly lower KPS scores (p = 0.003) and greater WL (p = 0.063) than the cohort STRT treated with 2 Gy per fraction. However, treatment results and toxicity were not significantly different between the two cohorts in spite of significantly better prognostic factors in the STRT cohort.

Conclusions: Despite having worse prognostic factors, the cohort treated with radiotherapy alone to 45 Gy at 3 Gy per fraction over 3 weeks (ACRT) had response rates, locoregional control, and overall survival comparable to those in the cohort treated by a total dose of 60–66 Gy at 2 Gy per fraction over 6 to 6 weeks (STRT). Given that accelerated treatment schedules decrease treatment time and cost less, these may, in the current health care environment, be important factors for health care providers to consider in treating patients who have locally advanced NSCLC and borderline poor prognostic factors.     

Infection of central nervous system after kidney transplantation

Central nervous system (CNS) infection remains an important problem among transplant recipients. The recent review by Singh and Husain and this letter from Yugoslavia underline the following: a subacute‐chronic presentation is typical of fungal and bacterial CNS infections; early diagnosis is the key to effective therapy; the indication for a CNS evaluation is an unexplained headache, particularly in conjunction with a change in the level of consciousness (classical meningeal findings may not be present in a timely fashion); and the minimum CNS evaluation is a cranial computerized tomographic (CT) scan and a lumbar puncture. Robert H. Rubin, MD     

Tick-borne encephalitis – lipid peroxidation and its consequences

Background: The purpose of this study was to assess the processes of lipid peroxidation with prostaglandin derivatives and reactive aldehydes being its major indicators in cerebrospinal fluid (CSF), plasma and urine of patients with tick-borne encephalitis (TBE). Materials and methods: This study included 60 patients with TBE and 56 healthy subjects. Lipid peroxidation was estimated by the measurement of 4-hydroxynonenal (4-HNE), 4-hydroxyhexenal (4-HHE), malondialdehyde (MDA), acrolein, crotonaldehyde, and 4-oxononenal (4-ONE), determined by GC-MS, F₂-isoprostanes and neuroprostanes (NPs) level determined by LC-MS. The level of 4-HNE-protein adducts was determined by ELISA. Phospholipase A₂ (PLA₂), platelet-activating factor acetylhydrolase (PAF-AH) and glutathione peroxidase (GSH-Px) activities and vitamin E level were determined spectrophotometrically and by HPLC, respectively. In parallel, the plasma levels of phospholipid acids such as arachidonic acid (AA), linoleic acid (LA) and docosahexaenoic acid (DHA) were monitored. Results: A significant decrease in AA, LA, DHA level and GSH-Px activity (by about 20, 69, 11 and 18%, respectively) was observed. The consequence of enhanced phospholipid peroxidation was almost 7 times higher plasma level of F₂-isoprostanes and 3-fold increase in NPs level in CSF of TBE patients. Additionally a 3.5-fold increase in the CSF level of MDA, 5-fold increase in the plasma level of 4-HNE and urine level of 4-HHE in TBE patients was observed. Decreased plasma activity of PLA₂ with an increase in the PAF-AH activity was observed. Conclusion: Lipid peroxidation occurring during TBE development indicates its relevance in pathophysiology of this disease. Moreover lipid peroxidation products might be useful for the diagnosis of TBE.     

Genotoxicity of marine sediments in the fish hepatoma cell line PLHC-1 as assessed by the Comet assay

The main goal of this study was to test the usefulness of the Comet assay in the PLHC-1 hepatoma fish cell line as a tool for detecting the presence of genotoxic compounds in contaminated marine sediments. The system has been tested using both model chemicals (benzo[a]pyrene (B[a]P) and ethyl methanesulfonate (EMS)) and extracts of sediment samples obtained with solvent dichloromethane/methanol. For all of the analysed sediment extracts as well as for the model chemicals a concentration dependent genotoxic effect was observed. The sediment with the highest observed genotoxic potential was additionally extracted using various solvents in order to test which class of compounds, according to their polarity, is most responsible for the observed genotoxic effect. Non-polar solvents (cyclohexane and dichloromethane) yielded stronger genotoxic effect but the highest level of DNA damage was determined after exposure to sediment extract obtained with the solvent mixture dichloromethane/methanol which extracts a wide range of contaminants. Our results indicate that the PLHC-1 cell line is a suitable in vitro model in sediment genotoxicity assessment and encourage the use of fish cell lines as versatile tools in ecogenotoxicology.