Chronic diuretic therapy with moderate doses of triamterene is not associated with folate deficiency

The diuretic drug triamterene has previously been shown to be a competitive inhibitor of folate absorption in the rat intestine (J Lab Clin Med 1986;108:272-6). We therefore investigated whether human subjects who are taking the drug on a long-term basis are at increased risk of folate deficiency. In each of two free-living populations, a study was performed to compare the folate status of triamterene users with those not taking the drug. The first population consisted of 272 elderly individuals not living in institutions who were participants in a nutrition status survey and who were taking a variety of antihypertensive medications; 32 of these individuals were daily users of triamterene. The hemoglobin concentration, red blood cell (RBC) count, and mean corpuscular volume (MCV) values were not significantly different between the triamterene users and nonusers. The female triamterene users had a slightly higher serum folate level than the female nonusers (p less than 0.04); a similar pattern was observed among the men, although the difference was not statistically significant. The second population consisted of 27 individuals attending a hypertension clinic; 18 subjects were taking 50 to 150 mg of triamterene per day and nine were taking antihypertensive drugs other than triamterene. The hemoglobin concentration, RBC count, MCV, serum folate values, and RBC folate values were found to not differ significantly between the triamterene users and the hypertensive controls (p greater than 0.05). These data suggest that chronic triamterene administration in individuals not living in institutions, at the doses examined in this study, is not associated with indications of folate deficiency.     

Half-body and local chest irradiation as consolidation following response to standard induction chemotherapy for disseminated small cell lung cancer: an Eastern Cooperative Oncology Group pilot report

A two-institution Phase 11 Pilot Study for the Eastern Cooperative Oncology Group (ECOG) used standard induction chemotherapy (cyclophosphamide and CCNU) followed by consolidation radiation therapy (RT) (600 rad of upper half-body irradiation plus 2000 rad in one week of localized chest irradiation) followed by maintenance chemotherapy in patients with extensive small cell bronchogenic carcinoma (SCBC). Nineteen patients were entered and 9 (47%) had partial responses (PR) after induction chemotherapy. No complete responses (CR) were seen. The 10 patients whose disease progressed were ineligible for consolidation RT and died with a short median survival time (MST) of 15 weeks. Of the 9 patients who were consolidated, 7(78%) had complete responses in the chest; five (63%) became overall complete responders. The MST of all consolidated responders was 44 weeks. At this writing, two of the 5 patients who achieved CR after RT consolidation were alive without disease for more than one year; another patient was alive with disease for almost one year. A control group consisting of patients with extensive SCBC was used for comparison; these patients were treated by the two participating institutions in an earlier ECOG protocol with the same chemotherapy regimen but without RT consolidation.     

Potentiation of tumor response to radiation or chemoradiation by selective cyclooxygenase-2 enzyme inhibitors

Cyclooxygenase-2 (COX-2) is an enzyme expressed primarily in pathologic states, such as inflammatory disorders and cancer, where it mediates prostaglandin production. Its overexpression is associated with more aggressive biologic tumor behavior and adverse patient outcome. Increasing evidence shows that agents that selectively inhibit COX-2 enhance tumor response to radiation or chemotherapeutic agents. This article gives an overview of some of this evidence. In addition, we describe new results showing that celecoxib, a selective COX-2 inhibitor, enhanced response of A431 human tumor xenografts in nude mice to radiation by an enhancement factor (EF) of 1.43 and to the chemotherapeutic agent docetaxel by an EF of 2.07. Celecoxib also enhanced tumor response when added to the combined docetaxel plus radiation treatment (EF = 2.13). Further experiments showed that selective COX-2 inhibitors enhanced tumor cell sensitivity to ionizing radiation, involving inhibition of cellular repair from radiation damage and cell cycle redistribution as mechanisms for some cell types. The results show that selective COX-2 inhibitors have the potential to improve tumor radiotherapy or radiochemotherapy, and this therapeutic strategy is currently under clinical testing.     

Exercise, training and neutrophil microbicidal activity

The concentration in human plasma of putative neutrophil-"priming" cytokines like endogenous pyrogens is known to increase significantly in response to moderate exercise (11). This is characteristic of an acute-phase response. The ability of blood neutrophils isolated from both trained and untrained human subjects (n = 11, 9) to produce microbicidal reactive oxygen species was determined using luminol-enhanced chemiluminescence both before and after one hour of aerobic exercise at 60% VO2max. Irrespective of training and stimulus concentration, exercise nearly always caused significant "priming" of the capacity of neutrophils to produce H2O2 and HOCl upon stimulation with opsonized zymosan (P less than 0.01); however, compared to their untrained counterparts, the activity of cells isolated from trained individuals was depressed about 50% at unit stimulus concentration, both before and after exercise (P less than 0.075), whilst remaining unaltered at saturating concentrations. Although neutrophil oxygenation activity is only one parameter that contributes to immunological status, regular episodes of moderate exercise may increase resistance to infection by priming the "killing capacity" of neutrophils. In contrast, prolonged periods of intensive training may lead to increased susceptibility to common infections by diminishing this activity.     

C225 antiepidermal growth factor receptor antibody enhances the efficacy of docetaxel chemoradiotherapy

PURPOSE: C225 anti-EGFR (epidermal growth factor receptor) antibody has been shown to enhance tumor response to radiation and a number of chemotherapeutic agents. Because of increased use of concurrent chemoradiotherapy in cancer treatment, it is important to determine whether C225 enhances also the antitumor efficacy of radiation when combined with chemotherapy. This study assessed the effect of C225 on tumor response when combined with docetaxel plus single or fractionated radiation. METHODS AND MATERIALS: MDA468 human adenocarcinoma and A431 human epidermoid carcinoma cells growing as xenografts in the right hind leg of nude mice were used. Mice bearing 8-mm tumors were treated with C225 antibody at a dose of 1 mg given i.p. once, twice, or three times 3 days apart, 10 or 30 mg/kg docetaxel given i.v., and/or local tumor irradiation of 8 or 10 Gy single dose or fractionated irradiation consisting of 2 Gy daily for 5 days. When all three agents were combined, C225 was given 6 h before or 18 h after docetaxel, and radiation was given 24 h after docetaxel. The treatment end point was tumor growth delay. RESULTS: C225 enhanced the antitumor efficacy of docetaxel, local tumor irradiation, and docetaxel combined with radiation. The response of both MDA468 and A431 carcinomas was enhanced. The enhancement factors ranged from 1.19 to 8.52, the degree of the enhancement depending on experimental conditions such as administration of multiple vs. single dose C225 or single or fractionated irradiation. C225 given twice or 3 times was more effective than when administered as a single dose. The effect of C225 was more pronounced when combined with single than fractionated irradiation with or without docetaxel. The triple-agent therapy was more effective than a single agent or double combination therapies, expressed by both increased tumor growth delay and the rate of tumor cure. CONCLUSIONS: Our results show that C225 anti-EGFR antibody is a potent enhancer of tumor response to docetaxel or radiation as single agents, and to docetaxel when combined with radiation. Thus, these findings provide strong preclinical evidence in support of combination of anti-EGFR blockade with chemoradiotherapy.     

Epidermal growth factor receptor as a target to improve treatment of lung cancer

Despite considerable efforts to reduce tobacco use, lung cancer remains the most common cancer in both men and women. Recent advances in radiation therapy and chemotherapy for lung cancer have yielded encouraging results, but survival in patients with locally advanced non-small-cell lung cancer (NSCLC) remains poor. As more and more molecular changes and their importance in malignant tissues continue to be characterized, approaches to target those aberrant pathways are being actively explored. The epidermal growth factor receptor (EGFR) is commonly overexpressed in NSCLC, particularly squamous cell carcinoma, and has been implicated in the development and progression of this disease, although a clear correlation with prognosis has not been established. Several different strategies have been developed to target and block the EGFR and its downstream effects, and some of them have been intensively studied in preclinical and clinical studies as a single-agent approach or in combination with radiation therapy or chemotherapy. In this article, we review the role of EGFR in lung cancer, as well as preclinical and clinical data on strategies to interfere with EGFR signaling alone or in combination with chemotherapy, radiation, or both.     

The value of immunocytochemical methods in the differential diagnosis of anaplastic thyroid tumours

The practical usefulness of a panel of monoclonal antibodies recognising epithelial and lymphoid antigens has been evaluated on a series of 10 routinely processed thyroid tumours of uncertain origin. All 6 small cell tumours were shown to be of lymphoid origin whereas of the 4 large cell tumours two were lymphomas and two carcinomas. Two of the tumours, one large cell and one small cell, were undiagnosable due to technical reasons (crush artefact or small size of biopsy) and emphasized the value of immunohistology in this context. Clinical follow-up of all 10 cases indicated that these distinctions are of both prognostic and therapeutic value. It is concluded that immunocytochemistry using a carefully selected panel of monoclonal antibodies is a valuable and convenient means of making an objective distinction between anaplastic thyroid tumours of epithelial or lymphoid origin.     

Changes in cyclic adenosine 3':5'-monophosphate-dependent protein kinases during the progression of urethan-induced mouse lung tumors

The cyclic adenosine 3':5'-monophosphate (cAMP)-dependent protein kinases in lung adenomas are functionally different from those of normal lung. The relevance of this change to neoplastic conversion was examined by comparing tumor kinases with those obtained from the normal cell of origin and by studying the kinases at different stages of tumor growth. Lung tumors were collected from A strain mice at different times after a single injection of urethan. These tumors are predominantly of alveolar type two cell origin, and cAMP-binding proteins in extracts from isolated type two cells and from lung adenomas at various stages of tumor progression were compared. Both the incorporation of the cAMP photoaffinity analogue, cyclic 8-azidoadenosine 3':5'-[32P]monophosphate (8-N3-[32P]cAMP), into the regulatory subunits of the type I (RI) and type II (RII) cAMP-dependent protein kinases and the autophosphorylation of RII were similar in extracts from whole normal lung and from type two cells. Altered protein kinases are thus not characteristic of normal type two cells. Lung tumors showed a decrease in photodetectable RII which correlated in degree with tumor size and extent of anaplasticity. This decreased RII photolabeling during tumor growth was associated with increased RII autophosphorylation. In contrast, decreased RII photolabeling in extracts from neonatal lung is accompanied by a substantial decrease in RII autophosphorylation. The characteristics of RII during normal development thus clearly differ from those during neoplastic development. An increase in the amount of an Mr 37,000 proteolytic fragment derived from R-subunits was also noted as a function of tumor progression. DEAE-cellulose chromatography of tumor cytosol showed that the increase in the amount of Mr 37,000 protein was accompanied by increased subunit dissociation of the type I isozyme. The dissociated RI subunit has been shown to be more sensitive to cleavage by a Ca2+-dependent neutral protease than when RI was in the holoenzyme form. This protease is present in both normal lung and lung adenomas, and its activity increases during the later stages of tumor progression. A comparison of cAMP binding and the light-induced covalent incorporation of 8-N3-[32P]cAMP showed that, for both RI and RII, photoincorporation was about 75% as efficient as noncovalent binding. In contrast, although the Mr 37,000 fragment can be photolabeled with low concentrations of 8-N3-[32P]cAMP, noncovalent cAMP binding to the endogenous Mr 37,000 fragment could not be demonstrated with a standard filtration assay. Such altered cAMP binding characteristics following Ca2+-dependent proteolysis of R-subunits would all     

The role of arthroscopy in the problem total knee replacement

Fourteen patients were retrospectively reviewed to examine the role of arthroscopy in the diagnosis and treatment of the problem total knee arthroplasty (TKA), and to define parameters for indications, techniques, and results. All patients had undergone a previous TKA, and postoperatively had problems with pain and/or range of motion. Routine evaluation failed to reveal sepsis or aseptic loosening. Arthroscopy was used to evaluate and treat certain specific conditions. The arthroscope was successful in removing loose bodies, correcting patella subluxation with an arthroscopic lateral release, excising a symptomatic pseudomeniscus, and releasing intraarticular adhesions to improve motion and relieve pain. The postoperative knee score improved 73%. Arthroscopy is a valuable tool to evaluate a painful TKA, and can be used to treat certain conditions that would otherwise require an arthrotomy. The rehabilitation time is easier on the patient and much quicker. Arthroscopy of a TKA does not compromise any future procedures. However, it remains a technically demanding procedure whose indications and expectations are still being defined.     

Responsiveness of cells in the cat's superior colliculus to textured visual stimuli

Summary Responses to texture motion (visual noise) were investigated in the superior colliculus of paralysed cats, lightly anaesthetized with N₂O/O₂ supplemented with pentobarbitone or Althesin. Within the superficial layers two classes of texture-sensitive neurones were found: Type I units with weak responses to noise, often related to specific elements in the texture and Type II units which were driven independently of the texture structure, and tended to be recorded deep to the Type I units. Type III units recorded from the deep collicular layers were insensitive to texture. Anatomical bases for this differential sensitivity and the notion of two collicular subsystems are discussed.