Normal Tissues Of Patients Research Articles

Glutathione content of colonic mucosa: evidence for oxidative damage in active ulcerative colitis.

Oxidative stress appears to play a role in the tissue damage of active ulcerative colitis, and it has been suggested that a defect in mucosal antioxidant defenses is a etiological factor in the disease. This study was undertaken to investigate the mucosal content and oxidation state of glutathione in ulcerative colitis in the active and inactive states and to examine the relationship between glutathione content and disease activity in this patient population. Endoscopic biopsies of colon mucosa were collected from normal subjects, from macroscopically normal tissue of patients with inactive and active ulcerative colitis, and from inflamed tissue of patients with active ulcerative colitis. The mucosal contents of GSH and GSSG were determined by liquid chromatography. We found no significant differences in tissue contents of reduced glutathione among the four groups. The median tissue level of oxidized glutathione in inflamed mucosa from patients with active ulcerative colitis was increased 1.7-fold (P = 0.017) over that of patients with inactive disease. The oxidized glutathione content of the mucosa also showed significant positive correlations with clinical and histological indices of disease severity among ulcerative colitis patients. In conclusion, a change in the redox status of mucosal glutathione is associated with inflammation and disease activity in ulcerative colitis. This change appears to be a consequence of inflammation rather than a pathogenic factor for the disease.

Clinical pharmacology of taxanes as radiosensitizers and the thiol-based radioprotectant amifostine

Although many anticancer agents have been evaluated as radiosensitizing agents in cancer patients, none has demonstrated unequivocal clinical efficacy. Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) has been shown to enhance tumor cell response to ionizing radiation in cell culture studies. The pharmacokinetics and pharmacodynamics of paclitaxel in cancer patients receiving other highly metabolized drugs have not been well described and will be a key consideration in the development of the drug as a radiosensitizing agent. In addition, drug interaction studies demonstrate that administration sequence of paclitaxel with other chemotherapeutic agents, including cisplatin, doxorubicin, and cyclophosphamide, likely will affect its radiosensitizing efficacy. Other drugs that may affect paclitaxel radiosensitizing efficacy include corticosteroids and anticonvulsants; these interactions are particularly important in patients with central nervous system tumors, as is the question of whether paclitaxel can penetrate the blood-brain barrier. Overall, paclitaxel pharmacokinetics appear to favor radiosensitization, and results from an ongoing series of randomized trials should help define the drug's role in this setting. In contrast, amifostine, a sulfhydryl-containing agent, is currently being evaluated as a radioprotectant for normal tissues in patients who are receiving radiation therapy. Recent clinical trials have focused on amifostine's ability to reduce platinum-induced nephrotoxicity, although the drug was originally developed as a radioprotectant. Phase I clinical trials suggest that amifostine may be administered in much lower doses for radioprotectaon than those required for protection from platinuminduced nephrotoxicity. Amifostine pharmacokinetics support this finding; elimination of the drug may be dose dependent with clearance saturated at high doses, leading to increased risk of toxicity with no added radioprotectant benefit. Large randomized trials evaluating both paclitaxel as a radiosensitizer and amifostine as a radioprotectant are needed to make any firm conclusions regarding efficacy of either drug in modulating cancer therapy.

Codon 201Arg/Gly polymorphism of DCC (deleted in colorectal carcinoma) gene in flat- and polypoid-type colorectal tumors.

Recent studies have identified the distinct existence of flat-type colorectal tumors. The low incidence of ras gene mutations in these tumors suggests that their genetic pathways of tumor progression may be different from those of the polypoid type. To elucidate further genetic alterations in flat-type colorectal tumors, codon 201Arg/Gly polymorphism in the DCC (deleted in colorectal carcinoma) gene was analyzed in normal tissue (normal colonic mucosa or peripheral lymphocytes) and in tumor tissue from 191 patients with colorectal tumors (36 patients with flat-type colorectal tumors, 81 patients with polypoid-type colorectal tumors, and 74 patients with advanced carcinomas). For normal controls, 30 samples obtained from patients who had neither colorectal tumors (confirmed by total colonoscopy) nor a family history of colorectal carcinoma were analyzed. DCC gene codon 201Arg/Gly polymorphism was investigated by polymerase chain reaction-based restriction fragment length polymorphism analysis, fluorescence-based dideoxy sequencing, or both. For the flat type, the frequency of codon 201Gly of the DCC gene was 64% and 54% in the normal tissue of patients with adenoma with high-grade dysplasia and submucosal carcinoma, respectively. It was 49%, 52%, and 49% in the normal tissue of patients with polypoid-type adenoma with high-grade dysplasia, submucosal carcinoma, and advanced carcinoma, respectively. In the normal tissue, codon 201Gly of the DCC gene was more frequently observed in patients with flat-type adenoma with low-grade dysplasia (67%) than in those with polypoid-type adenoma with low-grade dysplasia (18%) or in normal controls (17%, P < 0.05, chi2 test). Codon 201Arg/Gly polymorphism in tumor tissues did not differ from that in the corresponding normal tissues, except for 10 cases of carcinoma with loss of heterozygosity (LOH). In carcinomas with LOH, preferential loss of the codon 201Arg allele was noted (9/10 cases). These results suggest that codon 201Gly of the DCC gene is not only associated with flat-type colorectal tumors, but that it may serve as a useful genetic marker for identifying groups at higher risk for colorectal cancer.

Growth Factor Expression in Normal Peritoneum of Patients with Gynecologic Carcinoma

Both epidermal growth factor receptor (EGFR) and HER-2/neu (neu) have been found to be of prognostic importance in epithelial ovarian and endometrial carcinoma, but alterations in proto-oncogene expression of normal tissues of patients with gynecologic malignancies are unknown. Patients (118) undergoing laparotomy for gynecologic indications (78 ovarian cancer, 11 endometrial cancer, 19 benign gynecologic disease, 10 other cancers) had biopsies of normal peritoneum for quantitative assessment of neu and EGFR concentrations. Patients undergoing exploration for gynecologic malignancy were found to have significantly higher median neu expression in the peritoneal biopsies than patients with benign gynecologic disease (P = 0.002). Most patients in this study were found to have ovarian cancer, and median peritoneal neu expression was found to be significantly higher in patients with ovarian cancer versus benign ovarian masses (P = 0.0008) or any benign gynecologic disease (P = 0.004). No significant alteration of unbound EGFR was found in peritoneal biopsies of any of the groups of patients. No associations were found for a history of breast cancer, presence of ascites, or menopausal status with alteration of neu or EGFR expression in normal peritoneum. These findings of altered expression of neu in normal tissues of patients with ovarian cancer are suggestive of the presence of proto-oncogene alterations in loco-regional tissues of the peritoneum, such as might be seen if a paracrine influence existed between tumor and peritoneal cells. Alternatively, the alterations may represent subtle alterations of proto-oncogene expression of germ-line tissues.

Stereotactic radiotherapy: a technique for dose optimization and escalation for intracranial tumors.

Stereotactic radiosurgery offers the ability to treat relatively small volume intracranial lesions with single fraction, high dose radiotherapy while sparing surrounding tissue due to rapid fall off of dose outside of the treatment volume. Conventional radiotherapy takes advantage of the sparing effects of dose fractionation, but includes relatively large amounts of normal brain in the treatment volume the tolerance of which is dose-limiting. For some intracranial lesions it may not be optimal to treat with large single fractions due to tumor location or size. Conventional fractionated radiotherapy may not be optimum in all cases due to the necessary inclusion of normal structures. Through the development of relocatable head frames, the precision of stereotactic techniques and the biologic advantages of fractionation may be combined in stereotactic radiotherapy (SRT). We report on the treatment of 68 patients with intracranial lesions using a dedicated stereotactic linear accelerator to deliver SRT between June 1992 and June 1993. SRT was used either in order to optimize dose distribution and spare normal tissues in patients with excellent prognosis or in order to increase the dose to tumor while keeping doses to normal tissues below tolerance levels in patients with poorer prognosis (dose escalation). Histologies treated included meningioma, low grade astrocytoma, pituitary adenoma and acoustic neuroma. The most common treatment sites were the parasellar region and cavernous sinuses. Most patients (79%) had surgical debulking prior to SRT. 10-12 patients were treated daily. Patient positioning using relocatable stereotactic frames was highly precise. Acute and subacute side effects were minimal and radiographic responses have been similar to those expected with conventional radiotherapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Segmental Transcatheter Hepatic Artery Chemoembolization with Iodized Oil for Hepatocellular Carcinoma: Antitumor Effect and Influence on Normal Tissue

Segmental transcatheter arterial embolization (TAE) with use of iodized oil mixed with an anticancer drug, followed by injection of gelatin sponge particles, was undertaken to evaluate its antitumor effect and its influence on normal tissue in patients with hepatocellular carcinoma (HCC). Histologic findings in 12 patients who underwent hepatectomy after segmental TAE were compared with findings on plain radiographs and computed tomographic (CT) scans. Visualization of the portal veins contiguous to the tumor on radiographs and the pattern of iodized oil accumulation in the tumor and vicinity on CT scans after TAE were assessed. Complete necrosis of the tumor was achieved in 10 cases (83%), while complete necrosis of daughter nodules and capsular invasion was observed histologically in eight of these 10 patients (80%). The degree of tumor necrosis correlated with the pattern of iodized oil accumulation in and near the tumor. Partial necrosis of normal tissue near the tumor correlated with accumulation of iodized oil. Segmental TAE may be an excellent therapeutic method for treatment of HCC that is localized in one or a few segmental or subsegmental regions.

The time factor and repopulation in tumors and normal tissues

The tolerance of most normal tissues and the radioresistance of some and maybe most tumors increases as overall treatment time increases. In most cases this increase appears to be proportional to time. The time factor is measured by the additional dose that has to be delivered for a given additional time period to achieve the same effect, and is quantitated as Gy/d. Typical values for the time factor in human tumors, particularly squamous cell carcinomas, are between 0.4 and 1 Gy/d, but with great heterogeneity among different tumor types and among different patients suffering from similar tumors. In acutely responding normal tissues of patients, particularly in skin and oral mucosa, the time factor depends more on time after the start of radiotherapy and on dose intensity than on the proliferative characteristics of the tissue. It may vary, in the same tissue, between 0 and 2 Gy/d. Typical values for the time factor for chronically responding normal tissues in patients are between 0.1 and 0.4 Gy/d. The mechanisms underlying the time factor are different for the three types of response. In tumors the main cause of the time factor is accelerated repopulation of tumor “stem” cells. In acutely responding normal tissues, the main cause of the time factor is accelerated repopulation of the entire population of stem and transit cells. In chronically responding normal tissues the cause is unlikely to be related to repopulation of any target cell population, but no convincing mechanism has emerged. The most detailed studies on repopulation have been performed on acutely responding normal tissues. Acceleration occurs after a delay that depends both on the proliferation kinetics of the tissue and on the dose intensity of irradiation. The main features are a shift from asymmetrical to symmetrical stem cell division and an expansion of the transit compartment. Accelerated repopulation in acutely responding normal tissues is a well regulated process. The mechanism and timing of acceleration of repopulation in tumors is not yet well understood. However, some similarities may exist in the patterns of response to radiotherapy of tumors and the respective normal tissue from which they arose.

Interleukin-1 type I receptor messenger ribonucleic acid expression in human endometrium throughout the menstrual cycle

To investigate the messenger ribonucleic acid (mRNA) expression of interleukin-1 (IL-1) type I receptor in the endometrial tissue of normal patients during the menstrual cycle. Prospective longitudinal study. Department of Obstetrics and Gynecology, Stanford University Medical Center, Stanford, California. Twenty fertile women between 19 and 41 years of age underwent hysterectomy for benign reasons (n = 9) and laparoscopy for tubal ligation (n = 11). In all cases, endometriosis was not visualized. Endometrial biopsy using the Novak curette was obtained at the time of surgery. Total RNA extracted from unfractioned endometrial tissue was analyzed on Northern blots by using specific complementary deoxyribonucleic acid probes. We found IL-1 type I receptor mRNA expression in endometrial tissue throughout the entire menstrual cycle. However, IL-1 type I receptor mRNA levels were significantly higher during both early and late luteal phases than follicular and midluteal phases. Our results demonstrate the presence of the IL-1 system in the human endometrium and that the receptor is regulated throughout the menstrual cycle with a 4.1-fold increased expression of the IL-1 receptor gene in the early luteal phase compared with preovulatory endometrium.

Sex steroid hormone receptors, epidermal growth factor receptor, and polyamines in human colorectal cancer.

We assayed the estrogen and progesterone cytosolic receptors by using the enzyme immunoassay method, the epidermal growth factor (EGF) cell surface receptors by using 125I-labeled hormone, and the levels of polyamines (putrescine, spermine, and spermidine) by using a high-pressure liquid chromatography (HPLC) procedure in neoplastic and surrounding normal tissues of patients with colorectal cancer. Our findings show that mean polyamine levels in neoplastic tissue were approximately two-fold greater than the levels in normal colonic mucosa. Estrogen and progesterone receptorial content in normal mucosa were twofold greater than those in neoplastic tissue. No significant differences in EGF receptors were found between colonic cancer tissue and the surrounding normal tissues. The correlations we found between 1) estrogen and polyamine levels and 2) estrogen and EGF binding suggest the existence of a modulation of the estrogens on colonic mucosa cell proliferation. Furthermore, there was no significant dependency of polyamine and receptor concentrations from the tumor site, the histologic differentiation, or the age and sex of patients.

Preliminary study on the differences in the transmembrane resting potential of normal and neoplastic transformed tissue

The cell membrane acts as the interface between the intracellular environment and the external milieu. The transmembrane resting potential of a single cell can be correlated directly with the state of the membrane and the metabolic processes that influence the movements of molecules across the membrane and the inherent membrane permeability [l]. It is known that the neoplastic transformation of cells is correlated with alterations of the electrical membrane properties [2,3]. In this study, cancerous and normal tissue of tumor patients and tissue of patients with non-malignant diseases (as control) were measured and compared to each other. The aim was to investigate if histologically normal tissue of patients with carcinomas in a progressive state already show pretransformal electrophysiological changes.

Effects of Lithotripter-Generated High Energy Shock Waves on Mammalian Cells in Vitro

The effects of high energy shock waves on an established human prostatic carcinoma cell line (PC-3) were investigated. HESW were administered to PC-3 cell suspensions using an electrohydraulic lithotripter (Dornier HM3). Experimental variables included the number of shocks to which the cells were exposed, spark generator potential, and the position of the cell sample in the acoustic field. Two types of cellular damage were observed: immediate cell destruction (lysis) as measured by electronic particle counting and the loss of reproductive capacity (viability) among the remaining cells as determined by colony formation assay. Over the range of the experimental variables studied, cell lysis was dependent to a greater extent on the number of shocks administered than the generator potential. Viability was affected less but was also dependent on both the generator potential and shock number. Cell lysis was strongly dependent on the position of the sample in the acoustic field with the extent of damage increasing as the sample was moved along the central axis of the shock wave from the f2 focus towards the electrodes. Possible mechanisms of damage and the relationship of the in vitro effects to the damage observed in normal tissues of patients undergoing extracorporeal lithotripsy for kidney stone disease are discussed.

Ornithine decarboxylase activity and polyamine content in adenocarcinomas of human stomach and large intestine

Ornithine decarboxylase (ODC) activity and differential polyamine composition have been studied in macroscopically normal mucosa, adjacent mucosa, and neoplastic tissue of 95 patients with adenocarcinomas of stomach and large intestine. In tumors, we found increased ODC activity and polyamine content as compared with surrounding mucosa. ODC activity in macroscopically normal tissue of patients with tumors of stomach and large intestine increased as the disease progressed. An inverse relationship was observed between ODC activity in adenocarcinomas and differentiation.

Recruitment, follow-up and analysis times in clinical trials of cancer treatment: a case study

A study has been made of the way in which the number of events available for analysis in a clinical trial was dependent on the recruitment period, the maximum follow-up time on individual patients and the length of time between the start of the trial and its analysis. The events considered were deaths, local recurrences and late radiation effects on normal tissue in patients treated for cancer of the laryngo-pharynx by two different fractionation regimes. The relationship is demonstrated between the number of events and the 95% confidence intervals that can be placed on differences between results in the two arms of the trial. It was found, in this particular trial, that no significant improvement in precision was gained by following up patients beyond 5 years or carrying out the analysis later than 2 years after the end of recruitment. The results are discussed in the context of the initial design of clinical trials, particularly those in which the aim is to test therapeutic equivalence.

Ring chromosome in a patient with MEN IIA S

Three patients with MEN IIA S belonging to the same family, which has five affected subjects in two generations, have been studied. Constitutional karyotype examination identified an extra ring chromosome in 3% of the cells in one of the affected subjects. The number of rings for each cell varied, and different evolutionary aspects of the ring, such as doubling and interlocking, were present. Furthermore, asynchronous DNA replication of doubling rings was observed. This nonhomogeneous, nonrandom chromosome abnormality found in normal tissue of patients with MEN IIA S could be indicative of sensitivity to structural alteration of some chromosome regions.

Human Papillomavirus in Clinically and Histologically Normal Tissue of Patients With Genital Cancer

Abstract To study the association of human papillomavirus (HPV) and herpes simplex virus (HSV) with genital cancer, we collected specimens of cervical, vulvar, endometrial, and vaginal tumors at the time of operation in patients with cancer. In some patients, matched internalcontrol (histologically normal) tissue was also collected. DNA extracted from the tissue was probed with Radio-labeled HPV type 16 DNA, HPV type 18 DNA, and cloned fragments of HSV type 2 DNA. Hybridization to the HindIIIa clone of HSV-2 was detected in only 1 cervical tumor and 1 vulvar tumor (9 percent) among the 22 tumors tested. However, DNA sequences hybridizing to HPV-16 were detected in 21 of 25 tumors (84 percent) and in 8 of 11 (73 percent) of the DNA samples from clinically and histologically normal, paired, internal-control tissues from the patients with cancer. HPV-16 DNA was found in one of nine normal cervixes (11 percent) of women without genital neoplastic disease or abnormal cytology. HPV-18 DNA was detected in only 2...

Human papillomavirus in clinically and histologically normal tissue of patients with genital cancer.

To study the association of human papillomavirus (HPV) and herpes simplex virus (HSV) with genital cancer, we collected specimens of cervical, vulvar, endometrial, and vaginal tumors at the time of operation in patients with cancer. In some patients, matched internal-control (histologically normal) tissue was also collected. DNA extracted from the tissue was probed with radiolabeled HPV type 16 DNA, HPV type 18 DNA, and cloned fragments of HSV type 2 DNA. Hybridization to the HindIIIa clone of HSV-2 was detected in only 1 cervical tumor and 1 vulvar tumor (9 percent) among the 22 tumors tested. However, DNA sequences hybridizing to HPV-16 were detected in 21 of 25 tumors (84 percent) and in 8 of 11 (73 percent) of the DNA samples from clinically and histologically normal, paired, internal-control tissues from the patients with cancer. HPV-16 DNA was found in one of nine normal cervixes (11 percent) of women without genital neoplastic disease or abnormal cytology. HPV-18 DNA was detected in only 2 of 24 tumors (8 percent), 1 cervical and 1 vulvar. Our results show a strong association between the presence of HPV-16 genomes and genital tumors and between HPV-16 genomes and histologically normal tissue within 2 to 5 cm of the tumors. The implications of these findings remain to be explored.

Specific chromosome anomalies and predisposition to human breast, renal cell, and colorectal carcinoma

Specific chromosome abnormalities in three human solid tumors of adulthood—renal cell carcinoma, breast tumor, and colon carcinoma—are described. Two of the neoplasms are associated with a reciprocal translocation involving chromosome #3 (breakpoint at band p13–14 with 6, 8, 11, and 16) in renal cell carcinomas and chromosome #1 (breakpoint at band q21 with chromosomes #3, #5, #10, #11, and #12) in breast carcinomas. Most of these chromosomal rearrangements have been seen as tumor-specific acquired changes in tumor cells, as well as some constitutionally present in normal tissues of patients. In a limited number of colorectal carcinoma samples a deletion in the short arm of a chromosome #12 is implicated as a specific abnormality. The expression of fragile sites in these specific chromosomal regions in the normal peripheral blood cultures might identify an individual predisposed to develop a particular type of neoplasm.

CLINICAL EXPERIENCE OF CHEMOTHERAPY. A STUDY OF 100 CASES OF ADVANCED HEAD AND NECK CANCER.

THE PROGNOSIS for a patient with cancer of the head and neck is little better today than it was 25 years ago. Modern radiotherapy is undoubtedly less damaging to the patient's normal tissues and radical surgery a safer procedure, but except in the very early cases only one third can expect to be alive five years after the initial diagnosis of their disease! The success of systemic chemotherapy against bacterial infections stimulated research into the possibilities of attacking the cancer cell with cytotoxic agents. During the last few years vast numbers of such drugs have been synthesized and tested against animal and human tumors. None have had the dramatic success experienced by their predecessors against invading bacteria, yet it is possible that the wise and discriminative application of selective cytotoxic agents could alleviate the suffering of patients with advanced cancer, and might in favorable circumstances prolong life by many years.

Quantitative measurements of oxygen tension in normal tissues and in the tumours of patients before and after radiotherapy.

Quantitative measurements of oxygen tension in tumors and normal tissues of patients were made by the oxygen cathode technique before and after radiotherapy. Statistical analysis showed that log oxygen tension has a normal distribution. The ratio (tissue oxygen tension when breathing oxygen/tissue oxygen tension when breathing air) = K, a constant of mean value 2.1 to 2.3 for muscle, subcutaneous tissue, tissues near tumor, and tumor before treatment. Afier radiotherapy, K is sigrificantly higher for tumor, but for no other tissue. The effect of the radiosensitizer Synkavit on the oxygen tension is described. Warming by diathermy reduced tumor oxygen tension and the response to breathing oxygen. The findings encourage use of oxygen inhaled at atmospheric pressure as a radiosensitizer, but patients require 7 to 8 l/min for 30 min, to obtain maximum tumor oxygen tension. (auth)