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Biomedical subjects

H Wagner

Publications and source records attributed to H Wagner.

At least 109 records · Page 6Linked to original sources

Anti-sickling, analgesic and anti-inflammatory properties of 3,5-dimethoxy-4-hydroxy benzoic acid and 2,3,4-trihydroxyacetophenone.

Effects of 3,5-dimethoxy-4-hydroxybenzoic acid and 2,3,4-trihydroxyacetophenone were studied on haemoglobin S (Hb S) polymerisation, analgesia and inflammation using Hb S solution, rats and mice. UV spectrophotometric procedure was used to monitor the polymerization of the Hb S. Acetic acid induced writhing in mice and egg albumin induced rat paw edema procedures were used to evaluate analgesic and anti-inflammatory activities of the compounds respectively. The results indicate that both drugs inhibit the process of polymerization significantly, possibly by direct action on the Hb S molecules. The drugs inhibited acetic acid induced pain and decreased egg albumin induced oedema. It is concluded that 3,5-dimethoxy-4-hydroxybenzoic acid and 2,3,4-trihydroxyacetophenone may have some value in the management of sickle cell disease.

Acetic Acid↗

Treatment of chemotherapy-induced leukopenia in a rat model with aqueous extract from Uncaria tomentosa.

The Uncaria tomentosa water extracts (C-Med-100) depleted of indole alkaloids (< 0.05%, w/w) have been shown to induce apoptosis and inhibit proliferation in tumor cells in vitro and to enhance DNA repair, mitogenic response and white blood cells in vivo. In this study, the effect of C-Med-100 in the treatment of chemically induced leukopenia was evaluated in a rat model. W/Fu rats were treated first with doxorubicin (DXR) 2 mg/kg x 3 (i.p. injection at 24 hour-intervals) to induce leukopenia. Twenty-four hours after the last DXR treatment, the rats were daily gavaged with C-Med-100 for 16 consecutive days. As a positive control, Neupogen, a granulocyte colony stimulator was also administered by subcutaneous injection at a dose of 5 and 10 microg/ml for 10 consecutive days. The results showed that both C-Med-100 and Neupogen treatment groups recovered significantly sooner (p < 0.05 by Duncan test) than DXR group. However, the recovery by C-Med-100 treatment was a more natural process than Neupogen because all fractions of white blood cells were proportionally increased while Neupogen mainly elevated the neutrophil cells. These results were also confirmed by microscopic examination of the blood smears. The mechanism of the C-Med-100 effect on WBC is not known but other data showing enhanced effects on DNA repair and immune cell proliferative response support a general immune enhancement.

Administration, Oral↗

Drug distribution in human skin using two different in vitro test systems: comparison with in vivo data.

PURPOSE: Two in vitro test systems used to study drug penetration into human skin--the Franz diffusion cell (FD-C) and the Saarbruecken penetration model (SB-M)--were evaluated, and the results were compared with data gained under analogous in vivo conditions. METHODS: Excised human skin was used in all in vitro experiments. Flufenamic acid dissolved in wool alcohols ointment, was chosen as a model drug, and the preparation was applied using 'infinite dose' conditions. To acquire quantitative information about the drug penetration, the skin was segmented into surface parallel sections at the end of each experiment, first by tape stripping the stratum corneum (SC), and second by cutting the deeper skin layers with a cryomicrotome. The flufenamic acid was extracted from each sample and assayed by high performance liquid chromatography (HPLC). For in vivo experiments, only the tape stripping technique was used. RESULTS: a) Drug penetration into the SC: In both in vitro test systems the total drug amounts detected in the SC were found to increase over the different incubation times. Similar conditions were obtained in vivo, but on a lower level. Using Michaelis-Menten kinetics, the m(max) value was calculated for the skin of two donors. The relations of the m(max) values for the FD-C and the SB-M closely correspond (1.26 [donor 1] and 1.29 [donor 2]). A direct linear correlation of the drug amount in the SC and the time data were found for in vivo with both in vitro test systems. b) Drug penetration into the deeper skin layers: The detected drug amounts in the deeper skin layers continuously increased with the incubation time in the SB-M, while in the FD-C, only very small drug amounts were observed after incubation times of 30 and 60 minutes. It was also noticed, that the drug amounts rose steeply at time points 3 and 6 hours. Additional studies showed a remarkable penetration of water into the skin from the basolateral acceptor compartment in the FD-C. This could explain the different drug transport into the deeper skin layers between the two in vitro test systems. CONCLUSIONS: Both in vitro models showed comparable results for the drug penetration into the SC and a robust correlation with in vitro data. Different results were obtained for the deeper skin layers. Whether a correlation between in vitro and in vivo data is also possible here has to be investigated by further experiments.

Administration, Topical↗

Poly-guanosine motifs costimulate antigen-reactive CD8 T cells while bacterial CpG-DNA affect T-cell activation via antigen-presenting cell-derived cytokines.

Pathogen-derived pattern recognition ligands like lipopolysaccharide (LPS) and bacterial cytidine-guanosine (CpG)-DNA not only activate dendritic cells and macrophages but are also mitogenic for B cells. Less clear are the claimed effects of CpG-DNA on T cells, which range from direct activation, costimulation, or indirect transient activation via antigen-presenting cell (APC)-derived interferon type I (IFN type I). Here we demonstrate that CpG-DNA sequence specifically triggers macrophages to produce IFN type I, interleukin (IL)-12, IL-6 and tumour necrosis factor (TNF), but lacks the ability to directly costimulate T cells. Strikingly, poly-guanosine (poly-G) extensions to CpG-containing oligonucleotides (ODN) abolished the macrophage stimulatory potential yet generated T-cell costimulatory activities. In fact, independently of CpG-motifs, poly-G-ODN displayed the ability to costimulate T cells. Costimulation was operative on CD8 T cells but not CD4 T cells. Poly-G-mediated costimulation resulted in IL-2-driven T-cell proliferation and induced cytolytic T cells. Overall the data imply that poly-G motifs costimulate antigen reactive CD8 T cells, while CpG-DNA motifs fail to do so but may affect T-cell activation via APC derived cytokines such as IFN type I.

Animals↗

CpG-oligodeoxynucleotides enhance T-cell receptor-triggered interferon-gamma production and up-regulation of CD69 via induction of antigen-presenting cell-derived interferon type I and interleukin-12.

Bacterial cytidine-phosphate-guanosine (CpG-DNA) activates antigen-presenting cells (APC) and drives T helper 1 (Th1)-polarized immune responses in the mouse. Claims have been made that CpG-DNA costimulates murine T cells. We examined the direct and indirect effects of CpG-oligodeoxynucleotides (CpG-ODN) on human T-cell activation. CpG-ODN failed to costimulate purified human T cells activated with alpha-CD3 or alpha-T-cell receptor (TCR)alphabeta antibodies. In contrast, CpG-ODN sequence-specifically caused increased expression of CD69 on CD4 and CD8 T cells when peripheral blood mononuclear cells (PBMC) were stimulated via alpha-CD3. CpG-ODN and alpha-CD3 stimulation synergized to induce interferon-gamma (IFN-gamma) in T cells and natural killer (NK) cells, as shown by intracellular fluorescence-activated cell sorter (FACS) staining. These effects of CpG-ODN on human T cells were caused by the release of IFN type I (IFN-I) and interleukin-12 (IL-12) from PBMC. Enhancement of CD69 expression on alpha-CD3-triggered T cells could be reproduced in a coculture transwell system of purified T cells and PBMC, was inhibited by neutralizing antibodies to IFN-I and could be mimicked by adding exogenous IFN-I. Furthermore, neutralization of either IFN-I or IL-12 diminished, and in combination abolished, IFN-gamma production. These findings show that CpG-ODN potentiate TCR-triggered activation of human T cells in an APC-dependent manner.

Adjuvants, Immunologic↗

Neural basis of alertness and cognitive performance impairments during sleepiness. I. Effects of 24 h of sleep deprivation on waking human regional brain activity.

The negative effects of sleep deprivation on alertness and cognitive performance suggest decreases in brain activity and function, primarily in the thalamus, a subcortical structure involved in alertness and attention, and in the prefrontal cortex, a region subserving alertness, attention, and higher-order cognitive processes. To test this hypothesis, 17 normal subjects were scanned for quantifiable brain activity changes during 85 h of sleep deprivation using positron emission tomography (PET) and (18)Fluorine-2-deoxyglucose ((18)FDG), a marker for regional cerebral metabolic rate for glucose (CMRglu) and neuronal synaptic activity. Subjects were scanned prior to and at 24-h intervals during the sleep deprivation period, for a total of four scans per subject. During each 30 min (18)FDG uptake, subjects performed a sleep deprivation-sensitive Serial Addition/Subtraction task. Polysomnographic monitoring confirmed that subjects were awake. Twenty-four hours of sleep deprivation, reported here, resulted in a significant decrease in global CMRglu, and significant decreases in absolute regional CMRglu in several cortical and subcortical structures. No areas of the brain evidenced a significant increase in absolute regional CMRglu. Significant decreases in relative regional CMRglu, reflecting regional brain reductions greater than the global decrease, occurred predominantly in the thalamus and prefrontal and posterior parietal cortices. Alertness and cognitive performance declined in association with these brain deactivations. This study provides evidence that short-term sleep deprivation produces global decreases in brain activity, with larger reductions in activity in the distributed cortico-thalamic network mediating attention and higher-order cognitive processes, and is complementary to studies demonstrating deactivation of these cortical regions during NREM and REM sleep.

Adult↗

Medium-term results of a modern metal-on-metal system in total hip replacement.

Since 1988, metal-on-metal articulation from cobalt-chromium-molybdenum alloy was reintroduced into hip arthroplasty as an alternative to metal-on-polyethylene or ceramic-on-polyethylene components. Modular joint surfaces were developed for the second generation metal-on-metal articulation using newly introduced and proven prosthetic implants. Since 1990, 78 patients with 78 uncemented total hip replacements were followed up in a prospective study. The mean followup was 60 months. Three patients were lost to followup. The average age of the patients at the time of surgery was 48.8 years. Thirty-three patients had been operated on previously. No early infections occurred; one late infection occurred after 3 years. Dislocation of the prosthesis occurred in one patient who was lost to followup. In two patients ectopic ossifications were removed 17 and 27 months postoperatively. At revision surgery no metallosis could be identified. At the last followup examination, the Harris hip score was 96.8 points on average. There was no evidence that the metal-on-metal articulation gave rise to new problems or complications. Metal-on-metal articulation reduced wear considerably in the authors' previous experience. It is hoped that foreign body reactions are reduced significantly so that an alternative for total hip replacement in younger and active patients will be available.

Adolescent↗

Role of interleukin-18 (IL-18) during lethal shock: decreased lipopolysaccharide sensitivity but normal superantigen reaction in IL-18-deficient mice.

Lethal shock can be associated with excessive secretion of cytokines such as tumor necrosis factor (TNF) and gamma interferon (IFN-gamma). IFN-gamma mediates macrophage activation and appears to be controlled by interleukin (IL)-12 and IL-18. To investigate the role of IL-18 in vivo, we generated IL-18-deficient mice by gene targeting. IL-18(-/-) mice showed decreased sensitivity towards lipopolysaccharide (LPS)-induced shock. LPS-induced IFN-gamma production was abrogated, yet induction of IL-12 and TNF was not affected. Both wild-type and IL-18-deficient mice succumbed to LPS-induced lethal shock after sensitization with D-galactosamine. However, in marked contrast to LPS, the bacterial superantigen Staphylococcus aureus enterotoxin B (SEB) induced comparable serum levels of IFN-gamma in IL-18(+/+) and IL-18(-/-) mice, accompanied by an upregulation of cell surface markers CD14, CD122 (IL-2Rbeta), and CD132 (IL-2Rgamma) on peritoneal macrophages. Moreover, SEB injection rendered IL-18-deficient mice sensitive for subsequent challenge with LPS. The degree of sensitization was comparable to that in wild-type controls with respect to lethality. However, LPS-induced TNF levels in serum were significantly reduced in SEB-sensitized IL-18-deficient mice. These results imply that IL-18 plays an important role in induction of IFN-gamma and lethality in response to LPS.

Animals↗

Failure of an automated blood culture system to detect nonfermentative gram-negative bacteria.

During a 1-year study we observed that both aerobic and anaerobic blood culture bottles from patients were negative by the BacT/Alert system during a 7-day incubation period. However, upon subcultivation of negative bottles, growth of Pseudomonas aeruginosa was detectable. In an attempt to explain this observation, aerobic BacT/Alert Fan bottles were seeded with a defined inoculum (0.5 McFarland standard; 1 ml) of Escherichia coli, Klebsiella pneumoniae, Serratia marcescens, P. aeruginosa, Stenotrophomonas maltophilia, or Acinetobacter baumannii. Half of the inoculated bottles were loaded into the BacT/Alert system immediately, and the remainder were preincubated for 4, 8, 16, and 24 h at 36 degrees C. With preincubation all bottles seeded with the Enterobacteriaceae signaled positive during the next 1.5 h. Organisms in bottles seeded with the nonfermentative species P. aeruginosa and A. baumannii remained undetected by the BacT/Alert system for 7 days. S. maltophilia was detected if the preincubation time was equal or less than 8 h. Without preincubation all bottles seeded with the Enterobacteriaceae or nonfermentative species signaled positive. Since nonfermentative species seem to enter a state of bacteriostasis within the preincubation period, we reasoned that an unknown factor is consumed. Accordingly, a smaller inoculum should allow the detection of nonfermentative species, even after preincubation, and serial dilutions of P. aeruginosa were detected in preincubated bottles. In this case preincubated bottles signaled positive faster than bottles without preincubation. We conclude that all bottles from clinical settings should be subcultured prior to loading to avoid false negatives. An alternative may be preincubation at room temperature.

Acinetobacter↗

Functional analysis of the env open reading frame in human endogenous retrovirus IDDMK(1,2)22 encoding superantigen activity.

Mice harbor a family of endogenous retroviruses, the mouse mammary tumor viruses (MMTV), which encode superantigens. These superantigens are responsible for the deletion of T cells expressing certain Vbeta chains of the T-cell receptor in the thymus. Human T cells are able to recognize MMTV-encoded superantigens presented by human major histocompatibility complex class II-positive cells. Owing to this and to the similarity of the human and murine immune systems, it was speculated that human endogenous retroviruses might also code for superantigens. Recently, it was reported that a proviral clone (IDDMK(1,2)22) of the human endogenous retrovirus family HTDV/HERV-K encodes a superantigen. The putative superantigen gene was located within the env region of the virus. Stimulated by these findings, we amplified by PCR and cloned into eucaryotic expression vectors open reading frames (ORFs) which were identical or very similar to IDDMK(1,2)22. When we transfected these vectors into A20 cells, a murine B-cell lymphoma, we were able to demonstrate mRNA expression and protein production. However, we did not find any evidence that the ORF stimulated human or murine T cells in a Vbeta-specific fashion, the most prominent feature of superantigens.

Animals↗

Exercise adaptation attenuates VEGF gene expression in human skeletal muscle.

Angiogenesis is a component of the multifactoral adaptation to exercise training, and vascular endothelial growth factor (VEGF) is involved in extracellular matrix changes and endothelial cell proliferation. However, there is limited evidence supporting the role of VEGF in the exercise training response. Thus we studied mRNA levels of VEGF, using quantitative Northern analysis, in untrained and trained human skeletal muscle at rest and after a single bout of exercise. Single leg knee-extension provided the acute exercise stimulus and the training modality. Four biopsies were collected from the vastus lateralis muscle at rest in the untrained and trained conditions before and after exercise. Training resulted in a 35% increase in muscle oxygen consumption and an 18% increase in number of capillaries per muscle fiber. At rest, VEGF/18S mRNA levels were similar before (0.38 +/- 0.04) and after (1.2 +/- 0.4) training. When muscle was untrained, acute exercise greatly elevated VEGF/18S mRNA levels (16.9 +/- 6.7). The VEGF/18S mRNA response to acute exercise in the trained state was markedly attenuated (5.4 +/- 1.3). These data support the concept that VEGF is involved in exercise-induced skeletal muscle angiogenesis and appears to be subject to a negative feedback mechanism as exercise adaptations occur.

Adaptation, Physiological↗

Nitric oxide synthase inhibition attenuates the skeletal muscle VEGF mRNA response to exercise.

Vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and transforming growth factor-beta(1) (TGF-beta(1)) mRNA increase in rat skeletal muscle in response to a single acute exercise bout. Nitric oxide (NO) is released locally by muscle vascular endothelium and muscle fibers during exercise, contributes to the blood flow response to exercise, and regulates mitochondrial respiration. We hypothesized that a reduction in NO production, via NO synthase inhibition, would demonstrate a link between NO and the VEGF, bFGF, and TGF-beta(1) gene responses to exercise. To investigate this hypothesis, 9-wk-old female Wistar rats were divided into eight treatment groups (n = 6 each): 1) saline + rest, 2) saline + exercise, 3) 30 mg/kg N(omega)-nitro-L-arginine methyl ester (L-NAME, a known NOS inhibitor) + rest, 4) 30 mg/kg L-NAME + exercise, 5) 300 mg/kg L-NAME + rest, 6) 300 mg/kg L-NAME + exercise, 7) 300 mg/kg N(omega)-nitro-D-arginine methyl ester (D-NAME, inactive enantiomer of L-NAME) + rest, and 8) 300 mg/kg D-NAME + exercise. Exercise consisted of 1 h of running at 20 m/min on a 10 degrees incline. VEGF, TGF-beta(1), and bFGF mRNA from left gastrocnemius were analyzed by quantitative Northern blot. Submaximal exercise for 1 h increased VEGF mRNA 4.2-fold and TGF-beta(1) mRNA 1.5-fold in untreated rats but did not increase bFGF mRNA. The exercise-induced increase in VEGF mRNA was attenuated approximately 50% by 30 and 300 mg/kg L-NAME; the TGF-beta(1) mRNA increase was unaffected by 300 mg/kg L-NAME. In addition, 300 mg/kg D-NAME had no effect on the exercise-induced increase in VEGF mRNA. Administration of 300 mg/kg L-NAME had no effect on bFGF mRNA. These findings suggest that NO is important in the regulation of the VEGF gene response to exercise through increases in VEGF transcription or by increases in the VEGF mRNA half-life.

Animals↗

Effect of captopril on skeletal muscle angiogenic growth factor responses to exercise.

Acute exercise increases vascular endothelial growth factor (VEGF), transforming growth factor-beta(1) (TGF-beta(1)), and basic fibroblast growth factor (bFGF) mRNA levels in skeletal muscle, with the greatest increase in VEGF mRNA. VEGF functions via binding to the VEGF receptors Flk-1 and Flt-1. Captopril, an angiotensin-converting enzyme inhibitor, has been suggested to reduce the microvasculature in resting and exercising skeletal muscle. However, the molecular mechanisms responsible for this reduction have not been investigated. We hypothesized that this might occur via reduced VEGF, TGF-beta(1), bFGF, Flk-1, and Flt-1 gene expression at rest and after exercise. To investigate this, 10-wk-old female Wistar rats were placed into four groups (n = 6 each): 1) saline + rest; 2) saline + exercise; 3) 100 mg/kg ip captopril + rest; and 4) 100 mg/kg ip captopril + exercise. Exercise consisted of 1 h of running at 20 m/min on a 10 degrees incline. VEGF, TGF-beta(1), bFGF, Flk-1, and Flt-1 mRNA were analyzed from the left gastrocnemius by quantitative Northern blot. Exercise increased VEGF mRNA 4.8-fold, TGF-beta(1) mRNA 1.6-fold, and Flt-1 mRNA 1.7-fold but did not alter bFGF or Flk-1 mRNA measured 1 h after exercise. Captopril did not affect the rest or exercise levels of VEGF, TGF-beta(1), bFGF, and Flt-1 mRNA. Captopril did reduce Flk-1 mRNA 30-40%, independently of exercise. This is partially consistent with the suggestion that captopril may inhibit capillary growth.

Angiotensin-Converting Enzyme Inhibitors↗

Horizontal-disparity tuning of neurons in the visual forebrain of the behaving barn owl.

Stereovision plays a major role in depth perception of animals having frontally-oriented eyes, most notably primates, cats, and owls. Neuronal mechanisms of disparity sensitivity have only been investigated in anesthetized owls so far. In the current study, responses of 160 visual Wulst neurons to static random-dot stereograms (RDS) were recorded via radiotelemetry in awake, fixating barn owls. The majority of neurons (76%) discharged significantly as a function of horizontal disparity in RDS. The distribution of preferred disparities mirrored the behaviorally relevant range of horizontal disparities that owls can exploit for depth vision. Most tuning profiles displayed periodic modulation and could well be fitted with a Gabor function as expected if disparity detectors were implemented according to the disparity energy model. Corresponding to this observation, a continuum of tuning profiles was observed rather than discrete categories. To assess a possible clustering of neurons with similar disparity-tuning properties, single units, and multi-unit activity recorded at individual recording sites were compared. Only a minority of neurons were clustered according to their disparity-tuning properties, suggesting that neurons in the visual Wulst are not organized into columns by preferred disparity. To assess whether variable vergence eye movements influenced tuning data, we correlated tuning peak positions on a trial-by-trial basis for units that were recorded simultaneously. The general lack of significant correlation between single-trial peak positions of simultaneously recorded units indicated that vergence, if at all, had only a minor influence on the data. Our study emphasizes the significance of visual Wulst neurons in analyzing stereoscopic depth information and introduces the barn owl as a second model system to study stereopsis in awake, behaving animals.

Action Potentials↗

Cisplatin, ifosfamide, oral etoposide, and concurrent accelerated hyperfractionated thoracic radiation for patients with limited small-cell lung carcinoma: results of radiation therapy oncology group trial 93-12.

PURPOSE: The combination of cisplatin, ifosfamide, and oral etoposide (PIEo) given concurrently with accelerated hyperfractionated thoracic radiation was studied in patients with limited small-cell lung cancer in a phase II trial to assess response, survival, and toxicity. PATIENTS AND METHODS: Sixty-seven patients were accrued between March 1994 and April 1996. Chemotherapy doses were cisplatin 20 mg/m(2) and ifosfamide 1,200 mg/m(2) on days 1 to 3 and etoposide 40 mg/m(2) administered orally days 1 through 14. Radiation consisted of accelerated hyperfractionated thoracic radiation (AHTRT) 1.5 Gy bid x 30 fractions (total 45 Gy) days 1 through 19, concurrent with cycle 1 of chemotherapy. Three additional cycles of chemotherapy were given every 4 weeks after completion of chemoradiation. Prophylactic cranial radiation (25 Gy in 10 fractions) was offered to patients for whom complete response (CR) after completion of chemotherapy was achieved. RESULTS: An overall objective response rate of 78% (41 CRs [67%] and seven partial responses [11%]) was seen in 61 patients whose disease response could be evaluated. Median progression-free and overall survival estimates were 12.7 and 23.7 months, respectively. Two- and 3-year survival rates were estimated at 50% and 39%, respectively. Major toxic effects included grade 4 granulocytopenia in 34 (55%), grade 4 thrombocytopenia in 16 (26%), grade 3 to 5 fever/infection in six (10%; with one death resulting from sepsis), and grade 3/4 esophagitis in 27 patients (43%). Other nonhematologic toxic greater than grade 2 occurred in 11 patients (18%). CONCLUSION: Relative to conventional etoposide/cisplatin and concurrent AHTRT, chemoradiation with PIEo produced similar median and 2-year survival rates and a higher rate of acute esophageal toxicity. However, the locoregional control rate with a minimum follow-up of 2 years is excellent at 80%. It is conceivable that longer follow-up will prove this regimen more promising. Research efforts should focus on other methods to improve disease control in all potential sites of recurrence.

Administration, Oral↗

Chemical characterization and biological activity of Macfadyena unguis-cati (Bignoniaceae).

Macfadyena unguis-cati (L.) has been widely used in folk medicine as an anti-inflammatory, antimalarial and antivenereal. The purpose of this study was to chemically characterize the main plant components, and to evaluate the biological properties of some of the fractions derived from leaves (MACb) and liana (MACa) of this plant. Chemical characterization allowed the identification of the compounds corymboside, vicenin-2, quercitrin, chlorogenic acid, isochlorogenic acid, lupeol, beta-sitosterol, beta-sitosterylglucoside, allantoin and lapachol. The biological screening of fractions and/or purified substances derived from fractions revealed antitumoral and antitrypanosomal activities in fractions MACa/lapachol and MACb/MACb21, respectively. The anti-lipoxygenase and anti-cyclooxygenase effect seen in fractions MACa and MACb showed a partial correlation with the anti-inflammatory property attributed to this plant.

Animals↗

Postoperative adjuvant therapy for patients with resected non-small cell lung cancer: still controversial after all these years.

Patients with clinical stage I and II non-small cell lung cancer (NSCLC) generally are considered candidates for surgical resection, with cure rates as high as 80% reported for some subsets. Locoregional and systemic adjuvant therapies have been evaluated in patients with lymph node involvement or pathologic T3 status, although considerable controversy regarding an appropriate standard of care continues to exist. Several trials have evaluated postoperative radiation therapy, the majority of which suggest that overall survival may be only minimally improved with this adjuvant therapy, but local failure is probably reduced. Trials evaluating the role of adjuvant chemotherapy have been few, often enrolling small numbers of patients. Several recent reviews summarizing the results of these trials suggest that, although some adjuvant chemotherapy regimens may have biological activity, results have not been consistent, and further study is warranted for regimens that include newer chemotherapy agents. CNS relapse is one of the most common sites of metastasis in NSCLC, and prophylactic cranial irradiation (PCI) has been evaluated in a number of trials to reduce the risk of local failure at this site. Data from these trials strongly suggest that a prospective trial of PCI in patients with NSCLC at high risk for isolated CNS relapse is warranted. Future clinical trials evaluating new radiographic, immunologic, and molecular technologies for early detection of second primary tumors also should be considered, particularly in patients with resected T1N0M0 lesions.

Carcinoma, Non-Small-Cell Lung↗